Conditions: Locally Advanced or Metastatic Urothelial Carcinoma
Keywords: Cancer Bladder Urethra Ureter metastatic or locally advanced
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 82
Healthy volunteers: no

Brief summary:
Phase II, multicenter, non-randomized, single-arm, open-label trial of atezolizumab in combination of split-doses of gemcitabine plus cisplatin in patients with locally advanced or metastatic urothelial carcinoma.

The Aurea trial aims to evaluate the preliminary efficacy of atezolizumab plus split-dose gemcitabine and cisplatin (GC) for the first-line setting, in patients with histologically confirmed advanced (locally advanced and metastatic) urothelial cancer in terms of overall response rate (ORR) assessed by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Secondary objectives include: efficacy (clinical benefit rate, duration of response, time to response, overall survival and progression-free survival); safety (frequency and severity of adverse events assessed by NCI CTCAE v5.0) and exploratory endpoints ( correlation of prognostic biomarkers/factors with efficacy and relationship between the expression of PD-L1 and microbiome with ORR and PFS).

At least 66 patients will be included.

The treatment schedule is as follows:

Atezolizumab at a fixed dose of 1200 mg/m2 by intravenous (IV) infusion on D1 of each 21-day cycle up to disease progression, unacceptable toxicity or absence of clinical benefit.

Gemcitabine 1000 mg/m2 IV on D1 and 1000 mg/m2 IV on D8 of each 21-day cycle plus Cisplatin 70 mg/m2 by IV on split-dose schedule of 35 mg/m2 on day 1 (D1) and 35 mg/m2 on day 8 (D8) for up to 6 cycles.

Detailed description:
The results of trials combining checkpoint inhibitors or platinum-based chemotherapy plus PD-1/PD-L1 inhibitors are eagerly awaited. The combination of split cisplatin with atezolizumab is a feasible treatment that may provide better outcomes than carboplatin/based combinations.

In the IMvigor130, 52% of patients considered cisplatin eligible at the entry of the study were treated with carboplatin. Subanalysis presented at European Society of Medical Oncology (ESMO) 2019 (Grande E, et al. 2019) has also shown a longer median OS are achieved with cisplatin-based chemotherapy combined with atezolizumab (21.7 months) when compared to the carboplatin-based chemotherapy plus atezolizumab (14.2 months), with similar findings when it comes to PFS 8.8 months with cisplatin/gemcitabine/atezolizumab vs 7.1 months carboplatin/gemcitabine/atezolizumab.

A reasonable strategy may be the use of split cisplatin with atezolizumab to increase the number of patients receiving cisplatin.

The AUREA study is a multicenter, open labelled, single arm, multicohort Phase II clinical trial of of atezolizumab in combination of split-dose cisplatin plus gemcitabine in patients with locally advanced or metastatic urothelial carcinoma (additional details on the eligibility criteria of the study are found in section 6 of this protocol).

The design includes screening phase, combined treatment initial phase, monotherapy treatment phase, follow-up phase and translational research with biopsies, blood samples and faecal samples.

The dose scheme includes the initial dose of atezolizumab (1200 mg) intravenously administered every 21 days (one cycle) up to disease progression, unacceptable toxicity or absence of clinical benefit. Dose adjustment or dose reductions of atezolizumab are not expected. AUREA is an Investigator Initiated Study, the Sponsor will supply Atezolizumab for up to 24 months of treatment for each patient. For those patients in which the PI considers that the best option for the patient is continuing atezolizumab for more than 24 months, available commercial Site supplies should be used, after managed local administrative regulation. Gemcitabine 1000 mg/m2 IV on D1 and 1000 mg/m2 IV on D8 of each 21-day cycle plus Cisplatin 70 mg/m2 by IV on split-dose schedule of 35 mg/m2 on day 1 (D1) and 35 mg/m2 on day 8 (D8) for up to 6 cycles.

Study treatment will begin as soon as possible after signing the informed consent. Before each treatment administration chemotherapy/atezolizumab administration laboratory, medical consulting and other determinations will be performed to ensure that treatment can be safely administered.

A CT Scan or MRI will be performed at baseline, on week 9, week 18 and then every 12 weeks (q12w) ± 1w until objective disease progression as per PI's criteria or death (whichever comes first). Blood samples for biomarkers studies should be collected before administration of cycle 4 and at the time of Progression Disease (PD) (end of treatment if applicable).

For patients with progression reported as per RECIST criteria at week 9, continuity of treatment with atezolizumab should be evaluated by the PI of each site as per clinical benefit criteria.

Arms:
arm 1: Atezolizumab (1200 mg) intravenously administered every 21 days (one cycle) up to disease progression, unacceptable toxicity or absence of clinical benefit.

Gemcitabine 1000 mg/m2 IV on D1 and 1000 mg/m2 IV on D8 of each 21-day cycle plus Cisplatin 70 mg/m2 by IV on split-dose schedule of 35 mg/m2 on day 1 (D1) and 35 mg/m2 on day 8 (D8) for up to 6 cycles.

Interventions: intervention 1: Atezolizumab 1200 mg/m2 intervention 2: Gemcitabine 1000 mg/m2 intervention 3: Cisplatin 70 mg/m2
Intervention descriptions: intervention 1: Fixed dose of 1200 mg/m2 by intravenous (IV) infusion on D1 of each cycle up to disease progression, unacceptable toxicity or absence of clinical benefit. intervention 2: Gemcitabine 1000 mg/m2 IV on D1 and 1000 mg/m2 IV on D8 of each 21-day cycle for up to 6 cycles. intervention 3: Cisplatin 70 mg/m2 by IV on split-dose schedule of 35 mg/m2 on day 1 (D1) and 35 mg/m2 on day 8 (D8) for up to 6 cycles.

Protocol document:
Prot_000.pdf: 
‭Clinical Trial Protocol‬
‭Protocol Number:‬
‭SOGUG-2020-IEC(VEJ)-1‬
‭Title:‬
‭Phase‬ ‭II,‬ ‭multicenter,‬ ‭non-randomized,‬ ‭single-arm,‬ ‭open-label‬ ‭trial‬ ‭of‬
‭atezolizumab‬‭in‬‭combination‬‭of‬‭split-doses‬‭of‬‭gemcitabine‬‭plus‬‭cisplatin‬‭in‬
‭patients with locally advanced or metastatic urothelial carcinoma‬
‭Short title:‬
‭Study‬‭of‬‭atezolizumab‬‭combined‬‭with‬‭split-dose‬‭gemcitabine‬‭plus‬‭cisplatin‬
‭in urothelial carcinoma‬
‭Acronym:‬
‭AUREA‬
‭Nº EudraCT:‬
‭2020-001326-65‬
‭Sponsor:‬
‭Spanish Oncology Genitourinary Group (SOGUG)‬
‭Velázquez, 7, 3a. planta, 28001‬
‭Madrid, Spain‬
‭Coordinating:‬
‭Investigator:‬
‭Guillermo de Velasco, M.D., PhD.‬
‭Medical Oncology Department‬
‭Hospital Universitario 12 de Octubre,‬
‭Av Córdoba s/n 28041,‬
‭Madrid, Spain‬
‭VERSION 3.0 - 22AUG2023‬
‭Confidentiality Statement‬
‭The‬ ‭information‬ ‭contained‬ ‭in‬‭this‬‭document‬‭is‬‭the‬‭property‬‭of‬‭the‬‭sponsor‬‭and‬‭therefore‬‭is‬
‭provided‬‭confidentially‬‭for‬‭review‬‭by‬‭you,‬‭your‬‭investigative‬‭team,‬‭the‬‭Investigational‬‭Ethics‬
‭Committee,‬‭and‬‭the‬‭competent‬‭authorities.‬‭This‬‭information‬‭must‬‭not‬‭be‬‭revealed‬‭to‬‭any‬‭other‬
‭party‬‭without‬‭previous‬‭authorization‬‭in‬‭writing‬‭by‬‭the‬‭sponsor,‬‭except‬‭as‬‭needed‬‭to‬‭obtain‬‭the‬
‭informed consent of the subjects who may be given the medicinal product.‬


‭SPONSOR’S PROTOCOL SIGNATURE PAGE‬
‭I‬‭approve‬‭the‬‭design‬‭of‬‭the‬‭clinical‬‭trial‬‭and‬‭I‬‭understand‬‭and‬‭will‬‭conduct‬‭the‬‭trial‬‭according‬
‭to‬‭the‬‭clinical‬‭trial‬‭protocol,‬‭any‬‭approved‬‭protocol‬‭amendments,‬‭International‬‭Conference‬‭on‬
‭Harmonization‬‭Good‬‭Clinical‬‭Practice,‬‭and‬‭all‬‭applicable‬‭Health‬‭Authority‬‭requirements‬‭and‬
‭national laws.‬
‭Dra. Aránzazu González del Alba‬
‭SOGUG Chairman‬
‭Signature‬
‭Signature date‬
‭(DD-mm-YYYY)‬
‭Dr. Guillermo de Velasco‬
‭Coordinating Investigator‬
‭Signature‬
‭Signature date‬
‭(DD-mm-YYYY)‬
‭AUREA -  SOGUG-2020-IEC(VEJ)-1 - Protocol version 3.0 22AUG2023‬
‭Page‬‭2‬‭of‬‭315‬


‭PRINCIPAL INVESTIGATOR’S PROTOCOL SIGNATURE PAGE‬
‭I have read this protocol and agree to conduct this clinical trial in accordance with all the‬
‭provisions of the Protocol, any approved protocol amendments, International Conference on‬
‭Harmonization‬ ‭Good‬ ‭Clinical‬ ‭Practice,‬ ‭Helsinki‬ ‭Declaration‬ ‭and‬ ‭all‬ ‭applicable‬ ‭Health‬
‭Authority  requirements and national laws‬
‭Site‬‭: _______________________________________________‬
‭Name:‬‭__________________________________________‬
‭Date:‬‭_________________________________________‬
‭Principal Investigator Signature:‬‭__________________________________‬
‭AUREA -  SOGUG-2020-IEC(VEJ)-1 - Protocol version 3.0 22AUG2023‬
‭Page‬‭3‬‭of‬‭315‬


‭SPONSOR’S PROTOCOL SIGNATURE PAGE‬
‭1‬
‭PRINCIPAL INVESTIGATOR’S PROTOCOL SIGNATURE PAGE‬
‭3‬
‭1. SUMMARY‬
‭9‬
‭1.1. Type of application‬
‭9‬
‭1.2. Study Title‬
‭9‬
‭1.3. Protocol Number and Version‬
‭9‬
‭1.4. Nº EudraCT‬
‭9‬
‭1.5. Sponsor Data‬
‭9‬
‭1.6. Coordinating Investigator‬
‭9‬
‭1.7. Principal Investigators‬
‭9‬
‭1.8. Study Sites‬
‭9‬
‭1.9. Monitoring Organization‬
‭9‬
‭1.10. Disease under study‬
‭9‬
‭1.11. Study Phase‬
‭9‬
‭1.12. Study Treatments‬
‭9‬
‭1.13. Objectives‬
‭10‬
‭1.14. Endpoints‬
‭11‬
‭1.15. Sample Size‬
‭11‬
‭1.16. Eligibility and withdrawal criteria‬
‭11‬
‭1.17. Planned trial period‬
‭15‬
‭2. GENERAL INFORMATION‬
‭19‬
‭2.1. Study Identification‬
‭19‬
‭2.2. Monitoring Organization‬
‭19‬
‭2.3. Sponsor information‬
‭19‬
‭2.4. Coordinating investigator‬
‭19‬
‭2.5. Investigators and study centres‬
‭19‬
‭3. INVESTIGATIONAL MEDICINAL PRODUCT (IMP) DESCRIPTION‬
‭20‬
‭3.1. Study medication‬
‭20‬
‭4. RATIONALE AND OBJECTIVES‬
‭21‬
‭4.1. Rationale‬
‭21‬
‭4.1.1. Current state of the art‬
‭21‬
‭4.1.2. Split-Dose Cisplatin‬
‭21‬
‭4.1.3. PD-L1 and the role of atezolizumab in mUC‬
‭21‬
‭4.2. Hypothesis‬
‭23‬
‭4.3. Rationale for dose selection‬
‭23‬
‭4.4. Study Objectives‬
‭23‬
‭4.4.1. Primary Objectives‬
‭23‬
‭4.4.2. Secondary Objectives‬
‭24‬
‭4.4.3. Exploratory objectives‬
‭24‬
‭5. STUDY DESIGN‬
‭25‬
‭5.1. Study design‬
‭25‬
‭5.2. Patient selection‬
‭26‬
‭5.3. Screening period and screening failure‬
‭26‬
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‭Page‬‭4‬‭of‬‭315‬


‭5.4. Patient registration/enrollment‬
‭27‬
‭5.5. Treatment description, doses and schedules‬
‭27‬
‭5.6. Duration of study, recruitment, treatment and follow-up‬
‭28‬
‭5.7. Determinations during the study‬
‭28‬
‭5.7.1. Screening phase‬
‭28‬
‭5.7.2. Treatment phase‬
‭29‬
‭5.7.3. Safety visit (after the end of treatment by any reason)‬
‭29‬
‭5.7.4. Follow up until progression‬
‭29‬
‭5.7.5. Follow up after progression‬
‭29‬
‭5.8. End of study (EoS)‬
‭29‬
‭5.9. Outcome assessments‬
‭29‬
‭5.9.1. Response evaluation according RECIST 1.1‬
‭29‬
‭5.9.2. Safety assessments‬
‭30‬
‭6. STUDY POPULATION‬
‭31‬
‭6.1. Inclusion criteria‬
‭31‬
‭6.2. Exclusion criteria‬
‭32‬
‭6.3. Criteria for withdrawal from the treatment and study‬
‭34‬
‭6.3.1. Permanent Interruption of study treatments‬
‭34‬
‭6.3.2. Withdrawal from the study‬
‭35‬
‭7. TREATMENT DESCRIPTION‬
‭37‬
‭7.1. Study medication‬
‭37‬
‭7.1.1. Atezolizumab‬
‭37‬
‭7.1.2.   Gemcitabine and Cisplatin‬
‭37‬
‭7.2. Treatment accountability and compliance‬
‭37‬
‭7.2.1. Atezolizumab accountability and compliance‬
‭37‬
‭7.2.2. Gemcitabine and Cisplatin accountability and compliance‬
‭38‬
‭7.3. Preparation and Dispensing‬
‭38‬
‭7.3.1. Atezolizumab preparation and dispensing‬
‭38‬
‭7.3.2. Gemcitabine plus cisplatin preparation and dispensing‬
‭38‬
‭7.4. Investigational Medical Products Administration‬
‭38‬
‭7.4.1. Atezolizumab administration‬
‭38‬
‭7.4.1.1. Intrapatient Atezolizumab Dose Reduction‬
‭39‬
‭7.4.2. Gemcitabine and cisplatin administration‬
‭39‬
‭7.4.2.1. Gemcitabine administration‬
‭39‬
‭7.4.2.2. Cisplatin administration‬
‭40‬
‭7.4.2.3. Intrapatient Gemcitabine and Cisplatin Dose Reduction‬
‭40‬
‭7.5. Special Precautions for Investigational Medical Products‬
‭41‬
‭7.5.1. Special Precautions for Atezolizumab‬
‭41‬
‭7.5.1.1. Hepatic impairment‬
‭42‬
‭7.5.1.2. Renal impairment‬
‭42‬
‭7.5.1.3. Reproductive and Developmental Toxicity‬
‭42‬
‭7.5.1.4. Immune-mediated adverse reactions‬
‭42‬
‭7.5.2. Special Precautions for Gemcitabine‬
‭48‬
‭7.5.3. Special Precautions for Cisplatin‬
‭48‬
‭AUREA -  SOGUG-2020-IEC(VEJ)-1 - Protocol version 3.0 22AUG2023‬
‭Page‬‭5‬‭of‬‭315‬


‭7.6. Investigational Product Storage‬
‭48‬
‭7.6.1. Atezolizumab storage‬
‭49‬
‭7.6.2. Gemcitabine and cisplatin storage‬
‭49‬
‭7.7. Investigational Product Accountability‬
‭49‬
‭7.8. Destruction of Investigational Product Supplies‬
‭49‬
‭7.9. Concomitant Treatments‬
‭50‬
‭7.9.1. Inhibitors and Inducers of CYP Enzymes‬
‭50‬
‭7.9.2. Concomitant Surgery‬
‭50‬
‭7.9.3. Concomitant Radiotherapy‬
‭50‬
‭7.9.4. Other Prohibited Concomitant Medications and Therapies‬
‭51‬
‭7.10. Rescue Medications and Supportive Care‬
‭51‬
‭7.10.1. Supportive Care Guidelines‬
‭51‬
‭8. STUDY PROCEDURES AND EVALUATIONS‬
‭53‬
‭8.1. Definition of efficacy variables‬
‭53‬
‭8.2. Safety and tolerability‬
‭54‬
‭8.3. Study determinations‬
‭54‬
‭8.4. Determinations in the selection phase (screening and baseline determinations)‬
‭57‬
‭8.5. Determinations and procedures during the treatment period (up to cycle 6)‬
‭58‬
‭8.5.1. Day 1 (considering 3 week cycles)‬
‭58‬
‭8.5.2. Day 8 (considering 3 week cycles)‬
‭58‬
‭8.5.3. Other determinations during treatment‬
‭58‬
‭8.5.4. Determinations and procedures on day 1 of cycle 7 (D1-C7) and subsequent‬
‭cycles (D1-Cn)‬
‭59‬
‭8.6. Determinations at safety visit‬
‭60‬
‭8.7. Follow-up determinations‬
‭60‬
‭8.7.1. Follow up after end of treatment (prior PD)‬
‭60‬
‭8.7.2. Follow up after end of treatment (after PD)‬
‭60‬
‭9. SAFETY EVALUATION‬
‭61‬
‭9.1. Definitions‬
‭61‬
‭9.1.1. Adverse event (AE)‬
‭61‬
‭9.1.2. Atezolizumab Adverse Event of Special Interest‬
‭62‬
‭9.1.3. Laboratory Abnormalities‬
‭62‬
‭9.1.4. Medication errors‬
‭63‬
‭9.1.4.1. Atezolizumab overdose‬
‭63‬
‭9.1.4.2. Gemcitabine overdose‬
‭63‬
‭9.1.4.3. Cisplatin overdose‬
‭63‬
‭An acute overdose of cisplatin may result in renal failure, liver failure, deafness,‬
‭ocular toxicity (including detachment of the retina), significant myelosuppression,‬
‭untreatable nausea and vomiting and/or neuritis. An overdose may be fatal.‬
‭63‬
‭9.1.5. Adverse reaction (AR)‬
‭64‬
‭9.1.6. Serious Adverse Event (SAE)‬
‭64‬
‭9.1.7. Protocol-Specified Serious Adverse Events‬
‭65‬
‭9.1.8. Life Threatening Event‬
‭65‬
‭9.1.9. Hospitalization / Prolongation of Hospitalization‬
‭65‬
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‭Page‬‭6‬‭of‬‭315‬


‭9.1.10. Unexpected adverse event (not listed)‬
‭65‬
‭9.1.11. Adverse Event Associated With the Use of the Drug (Adverse Reaction)‬
‭65‬
‭9.1.12. Attribution Definitions‬
‭66‬
‭9.1.3. Intensity (Severity) Criteria‬
‭66‬
‭9.1.14. Exposure during Pregnancy‬
‭67‬
‭9.1.15. Occupational Exposure‬
‭68‬
‭9.1.16. Expedited reporting‬
‭68‬
‭9.2. Collection and reporting of Adverse Events information‬
‭68‬
‭10. STATISTICAL CONSIDERATIONS‬
‭70‬
‭10.1. Sample size calculation‬
‭70‬
‭10.2. Study endpoints‬
‭70‬
‭10.2.1. Primary endpoint‬
‭70‬
‭10.2.2. Secondary endpoints‬
‭70‬
‭10.3. Efficacy assessment‬
‭71‬
‭10.3.1. Efficacy variables‬
‭71‬
‭10.4. Safety assessment‬
‭72‬
‭10.5. Definition of study populations‬
‭72‬
‭10.6. Data quality control‬
‭72‬
‭10.7. Statistical analysis‬
‭73‬
‭11. LEGAL AND ETHICS CONSIDERATION‬
‭74‬
‭11.1. Ethical conduct of the study‬
‭74‬
‭11.2. Independent Ethical Committee (IEC) Review‬
‭74‬
‭11.3. Authorities‬
‭74‬
‭11.4. Informed consent‬
‭74‬
‭11.5. Confidentiality‬
‭75‬
‭11.6. Insurance Policy‬
‭75‬
‭11.7. End of study definition‬
‭75‬
‭11.8. Early study termination‬
‭75‬
‭12. STUDY PROCEDURES‬
‭76‬
‭12.1. Responsibilities according to Good Clinical Practice‬
‭76‬
‭12.2. Instructions for e-CRF completion‬
‭76‬
‭12.3. Drug supply‬
‭76‬
‭12.3.1. Packaging and labelling‬
‭77‬
‭12.4. Final report and Publications‬
‭77‬
‭12.5. Monitoring‬
‭77‬
‭12.6. Clinical Study Report‬
‭78‬
‭12.7. Protocol Amendments‬
‭78‬
‭12.8. Data Handling‬
‭78‬
‭12.9. Documentation‬
‭79‬
‭12.10. Audits and inspections‬
‭79‬
‭13. TRANSLATIONAL SUBSTUDIES‬
‭79‬
‭13.1. Archived Tumor Biospecimens‬
‭80‬
‭13.2. Peripheral Blood‬
‭80‬
‭13.3. Fecal samples‬
‭81‬
‭AUREA -  SOGUG-2020-IEC(VEJ)-1 - Protocol version 3.0 22AUG2023‬
‭Page‬‭7‬‭of‬‭315‬


‭14. REFERENCES‬
‭82‬
‭APPENDICES‬
‭85‬
‭Appendix 1. Management of Atezolizumab-specific Adverse Events‬
‭85‬
‭A) Management Guidelines for Pulmonary Events, Including Pneumonitis‬
‭85‬
‭B) Management Guidelines for Pulmonary Events, Including Pneumonitis table‬
‭86‬
‭C) Management Guidelines for Hepatic Events‬
‭88‬
‭D) Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis)‬
‭90‬
‭E) Management Guidelines for Endocrine Events‬
‭91‬
‭F) Management Guidelines for Ocular Events‬
‭94‬
‭G) Management Guidelines for Immune-Mediated Cardiac Events‬
‭95‬
‭H) Management Guidelines for Infusion-Related Reactions and Cytokine-Release‬
‭Syndrome‬
‭96‬
‭I) Management Guidelines for Pancreatic Events, Including Pancreatitis‬
‭99‬
‭J) Management Guidelines for Dermatologic Events‬
‭100‬
‭K) Management Guidelines for Neurologic Disorders‬
‭101‬
‭L) Management Guidelines for Immune-Mediated Meningoencephalitis‬
‭103‬
‭M) Management Guidelines for Renal Events‬
‭103‬
‭N) Management Guidelines for Immune-Mediated Myositis‬
‭105‬
‭O) Management Guidelines for Hemophagocytic Lymphohistiocytosis and‬
‭Macrophage Activation Syndrome‬
‭107‬
‭P) Management Guidelines for Immune-Mediated Myelitis‬
‭108‬
‭AUREA -  SOGUG-2020-IEC(VEJ)-1 - Protocol version 3.0 22AUG2023‬
‭Page‬‭8‬‭of‬‭315‬


‭1.‬
‭SUMMARY‬
‭1.1.‬
‭Type of application‬
‭Clinical trial with approved medications with a potential better regimen.‬
‭1.2.‬
‭Study Title‬
‭Phase‬ ‭II,‬ ‭multicenter,‬ ‭non-randomized,‬ ‭single-arm,‬ ‭open-label‬ ‭trial‬ ‭of‬ ‭atezolizumab‬ ‭in‬
‭combination‬‭of‬‭split-doses‬‭of‬‭gemcitabine‬‭plus‬‭cisplatin‬‭in‬‭patients‬‭with‬‭locally‬‭advanced‬‭or‬
‭metastatic urothelial carcinoma‬
‭1.3.‬
‭Protocol Number and Version‬
‭SOGUG-2020-IEC(VEJ)-1 -  VERSION 3.0 22AUG2023‬
‭1.4.‬
‭Nº EudraCT‬
‭2020-001326-65‬
‭1.5.‬
‭Sponsor Data‬
‭Spanish Oncology Genitourinary Group (SOGUG)‬
‭C/ Velazquez 7, 3a. planta‬
‭28001, Madrid, Spain‬
‭secretaria@sogug.es‬
‭1.6.‬
‭Coordinating Investigator‬
‭Guillermo de Velasco, M.D., PhD.‬
‭Medical Oncology Department‬
‭Hospital Universitario 12 de Octubre‬
‭1.7.‬
‭Principal Investigators‬
‭The‬ ‭list‬ ‭of‬ ‭sites‬ ‭and‬ ‭the‬ ‭corresponding‬ ‭Principal‬ ‭Investigators‬ ‭is‬ ‭provided‬ ‭in‬ ‭the‬ ‭attached‬
‭document.‬
‭1.8.‬
‭Study Sites‬
‭It is expected the participation of 12 Sites in Spain.‬
‭1.9.‬
‭Monitoring Organization‬
‭MFAR Clinical Research‬
‭C/ Sinfonía 28, 2-1, 28001, Madrid, Spain‬
‭investigacion@mfar.net‬
‭1.10.‬ ‭Disease under study‬
‭Locally advanced and metastatic urothelial carcinoma (mUC)‬
‭1.11.‬
‭Study Phase‬
‭Phase II clinical trial; Investigator Initiated Study (IIS)‬
‭1.12.‬ ‭Study Treatments‬
‭All‬‭study‬‭treatments‬‭are‬‭intended‬‭for‬‭administration‬‭as‬‭described‬‭below‬‭(regarding‬‭maximum‬
‭treatment‬‭duration‬‭as‬‭per‬‭protocol),‬‭until‬‭PD,‬‭unacceptable‬‭toxicity,‬‭investigator’s‬‭decision‬‭or‬
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‭patient’s consent withdrawal (whichever occurs first).‬
‭●‬ ‭Atezolizumab‬‭at‬‭a‬‭fixed‬‭dose‬‭of‬‭1200‬‭mg/m‬‭2‬‭by‬‭intravenous‬‭(IV)‬‭infusion‬‭on‬‭D1‬‭of‬
‭each‬ ‭cycle‬ ‭up‬ ‭to‬ ‭disease‬ ‭progression,‬ ‭unacceptable‬ ‭toxicity‬ ‭or‬ ‭absence‬ ‭of‬ ‭clinical‬
‭benefit.‬ ‭AUREA‬ ‭is‬ ‭an‬ ‭Investigator‬ ‭Initiated‬ ‭Study,‬ ‭the‬ ‭Sponsor‬ ‭will‬ ‭supply‬
‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬‭months‬‭of‬‭treatment‬‭for‬‭each‬‭patient.‬‭For‬‭those‬‭patients‬‭in‬
‭which‬‭the‬‭PI‬‭considers‬‭that‬‭the‬‭best‬‭option‬‭for‬‭the‬‭patient‬‭is‬‭continuing‬‭atezolizumab‬
‭for‬ ‭more‬ ‭than‬ ‭24‬ ‭months,‬ ‭available‬‭commercial‬‭Site‬‭supplies‬‭should‬‭be‬‭used,‬‭after‬
‭managed‬‭local‬‭administrative‬‭regulation.‬‭In‬‭case‬‭that‬‭the‬‭site‬‭cannot‬‭provide‬‭the‬‭drug‬
‭for‬‭regulatory‬‭reasons‬‭(for‬‭example,‬‭the‬‭indication‬‭is‬‭not‬‭financed)‬‭and‬‭always‬‭with‬
‭prior‬‭approval‬‭by‬‭the‬‭study‬‭sponsor‬‭(SOGUG)‬‭and‬‭by‬‭Roche,‬‭and‬‭if‬‭it‬‭is‬‭thus‬‭indicated‬
‭in‬ ‭the‬ ‭contract‬ ‭between‬ ‭the‬ ‭Sponsor‬ ‭and‬ ‭the‬ ‭Site,‬ ‭the‬ ‭patient‬ ‭could‬ ‭continue‬ ‭in‬
‭treatment‬ ‭with‬ ‭Atezollizumab‬ ‭participating‬ ‭in‬ ‭a‬ ‭Post-Trial‬ ‭Access‬ ‭(PTA)‬ ‭Program,‬
‭previously approved by Roche. The maximum duration of the PTA will be 1 year.‬
‭●‬ ‭Gemcitabine‬‭1000‬‭mg/m‬‭2‬ ‭IV‬‭on‬‭D1‬‭and‬‭1000‬‭mg/m‬‭2‬ ‭IV‬‭on‬‭D8‬‭of‬‭each‬‭21-day‬‭cycle‬
‭plus‬‭Cisplatin‬‭70‬‭mg/m‬‭2‬ ‭by‬‭IV‬‭on‬‭split-dose‬‭schedule‬‭of‬‭35‬‭mg/m‬‭2‬‭on‬‭day‬‭1‬‭(D1)‬‭and‬
‭35 mg/m‬‭2‬‭on day 8 (D8)‬‭for up to 6 cycles.‬
‭1.13.‬ ‭Objectives‬
‭Primary Objective:‬
‭To‬‭evaluate‬‭the‬‭preliminary‬‭efficacy‬‭of‬‭atezolizumab‬‭plus‬‭split-dose‬‭gemcitabine‬‭and‬‭cisplatin‬
‭(GC)‬ ‭for‬ ‭the‬ ‭first-line‬ ‭setting,‬ ‭in‬ ‭patients‬ ‭with‬ ‭histologically‬ ‭confirmed‬ ‭advanced‬ ‭(locally‬
‭advanced‬‭and‬‭metastatic)‬‭urothelial‬‭cancer‬‭in‬‭terms‬‭of‬‭overall‬‭response‬‭rate‬‭(ORR)‬‭assessed‬‭by‬
‭the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.‬
‭Secondary Objectives‬
‭Efficacy:‬
‭●‬ ‭To‬ ‭evaluate‬ ‭the‬ ‭duration‬ ‭of‬ ‭response‬ ‭(DoR)‬ ‭associated‬ ‭with‬ ‭the‬ ‭study‬ ‭treatment,‬
‭understood‬‭as‬‭the‬‭time‬‭from‬‭first‬‭confirmed‬‭response‬‭(CR‬‭or‬‭PR)‬‭to‬‭the‬‭date‬‭of‬‭the‬
‭documented‬‭progressive‬‭disease‬‭as‬‭determined‬‭using‬‭RECIST‬‭1.1‬‭criteria‬‭or‬‭death‬‭due‬
‭to any cause, whichever occurs first.‬
‭●‬ ‭To‬ ‭determine‬ ‭the‬ ‭overall‬ ‭survival‬ ‭(OS)‬ ‭of‬ ‭patients‬ ‭with‬ ‭locally-advanced‬ ‭or‬ ‭mUC‬
‭treated‬‭with‬‭the‬‭intended‬‭treatment‬‭regimen,‬‭understood‬‭as‬‭the‬‭time‬‭from‬‭first‬‭dosing‬
‭date‬‭to‬‭the‬‭date‬‭of‬‭death.‬‭A‬‭subject‬‭who‬‭has‬‭not‬‭died‬‭will‬‭be‬‭censored‬‭at‬‭last‬‭known‬
‭date alive.‬
‭●‬ ‭To‬‭evaluate‬‭the‬‭time‬‭to‬‭response‬‭(TtR)‬‭associated‬‭with‬‭the‬‭study‬‭treatment,‬‭understood‬
‭as‬‭the‬‭time‬‭from‬‭the‬‭first‬‭dose‬‭of‬‭the‬‭study‬‭treatment‬‭and‬‭confirmed‬‭response‬‭(CR‬‭or‬
‭PR) based on RECIST 1.1 criteria.‬
‭●‬ ‭To evaluate the‬‭clinical benefit rate (CBR)‬‭, defined‬‭as the percentage of patients who‬
‭have achieved complete response, partial response and stable disease. Stable disease‬
‭should be maintained for at least 6 months to be considered as CBR event.‬
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‭●‬ ‭To‬‭determine‬‭the‬‭progression-free‬‭survival‬‭(PFS)‬‭of‬‭patients‬‭with‬‭locally-advanced‬‭or‬
‭mUC‬ ‭treated‬ ‭with‬ ‭the‬ ‭intended‬ ‭treatment‬ ‭regimen,‬ ‭defined‬ ‭as‬ ‭the‬ ‭time‬ ‭from‬ ‭first‬
‭dosing‬‭date‬‭until‬‭disease‬‭progression‬‭or‬‭death‬‭from‬‭any‬‭cause.‬‭Patients‬‭who‬‭have‬‭not‬
‭progressed and start a new line of treatment will be censored.‬
‭Safety:‬
‭●‬ ‭To‬ ‭evaluate‬ ‭safety‬ ‭of‬ ‭the‬ ‭intended‬ ‭treatment‬ ‭regimen‬ ‭based‬ ‭on‬ ‭the‬ ‭frequency‬ ‭and‬
‭severity of adverse events assessed by NCI CTCAE v5.0.‬
‭Exploratory objectives‬
‭●‬ ‭To‬ ‭explore‬ ‭potential‬ ‭correlation‬ ‭of‬ ‭efficacy‬ ‭with‬ ‭relevant‬ ‭potential‬ ‭prognostic‬
‭factors/stratification factors‬
‭●‬ ‭To‬‭evaluate‬‭the‬‭relationship‬‭between‬‭the‬‭expression‬‭of‬‭PD-L1‬‭and‬‭microbiome‬‭with‬
‭ORR and PFS during experimental treatment.‬
‭1.14.‬ ‭Endpoints‬
‭Primary endpoint:‬
‭●‬ ‭Overall Response Rate (ORR)‬
‭Secondary endpoints‬
‭●‬ ‭Duration of response‬‭(DoR)‬
‭●‬ ‭Overall Survival‬‭(OS)‬
‭●‬ ‭Time to response‬‭(TtR)‬
‭●‬ ‭Clinical benefit‬‭(CB)‬
‭●‬ ‭Progression-Free Survival‬‭(PFS)‬
‭Safety endpoints‬
‭●‬ ‭Adverse events‬‭(AE)‬
‭●‬ ‭Treatment-related AEs‬‭(TRAEs)‬
‭Exploratory endpoints‬
‭●‬ ‭Biomarkers expression‬
‭1.15.‬ ‭Sample Size‬
‭A minimum of 66 patients will be included in the trial.‬
‭1.16.‬ ‭Eligibility and withdrawal criteria‬
‭Inclusion criteria‬
‭1.‬ ‭Male or female subjects ≥ 18 years old.‬
‭2.‬ ‭Written‬‭informed‬‭consent‬‭approved‬‭by‬‭the‬‭Independent‬‭Ethics‬‭Committee‬‭(IEC),‬‭prior‬
‭to the performance of any trial activities.‬
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‭3.‬ ‭Patients‬ ‭with‬ ‭histologically‬ ‭documented,‬ ‭locally‬ ‭advanced‬ ‭(T4B,‬ ‭any‬ ‭N;‬ ‭or‬ ‭any‬‭T,‬
‭N2-3) or metastatic urothelial carcinoma (M1, Stage IV)*.‬
‭*Also‬‭termed‬‭transitional‬‭cell‬‭carcinoma‬‭(TCC)‬‭or‬‭urothelial‬‭cell‬‭carcinoma‬‭[UCC]‬‭of‬
‭the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra).‬
‭4.‬ ‭Patients‬‭should‬‭not‬‭be‬‭eligible‬‭(unfit)‬‭for‬‭full‬‭dose‬‭of‬‭cisplatin,‬‭in‬‭the‬‭investigator’s‬
‭judgement, based on:‬
‭a.‬ ‭Age older than 70 years.‬
‭b.‬ ‭ECOG‬ ‭Performance‬ ‭status‬ ‭(PS)‬ ‭2‬ ‭or‬ ‭Karnofsky‬ ‭PS‬ ‭of‬ ‭60‬ ‭-‬ ‭70%‬ ‭(only‬‭15‬
‭patients will be included with ECOG 2).‬
‭c.‬ ‭Measured‬ ‭creatinine‬ ‭clearance‬ ‭(ClCr)‬ ‭>‬ ‭30‬ ‭and‬ ‭<‬ ‭60‬ ‭mL/min‬ ‭by‬ ‭the‬
‭Cockcroft-Gault‬ ‭formula‬ ‭(Cockcroft‬ ‭and‬ ‭Gault‬ ‭1976)‬ ‭or‬ ‭by‬ ‭24-hour‬ ‭urine‬
‭collection for the determination of creatinine clearance:‬
‭Males:‬
‭Creatinine CL (mL/min)  =‬
‭Weight (kg) × (140 – Age)‬
‭72 x serum creatinine (mg/dL)‬
‭Females:‬
‭Creatinine CL (mL/min)  =‬
‭Weight (kg) × (140 – Age)‬‭×0.85‬
‭72 x serum creatinine (mg/dL)‬
‭d.‬ ‭Any‬‭other‬‭reason‬‭the‬‭physician‬‭considers‬‭but‬‭should‬‭specify‬‭in‬‭the‬‭CRF‬‭and‬
‭discussed with the PI.‬
‭5.‬ ‭At‬ ‭least‬ ‭one‬ ‭measurable‬ ‭lesion‬ ‭through‬ ‭radiographic‬‭tumor‬‭evaluation‬‭(CT‬‭scan‬‭or‬
‭magnetic‬ ‭resonance‬ ‭imaging/MRI)‬ ‭as‬ ‭defined‬‭by‬‭RECIST‬‭version‬‭1.1,‬‭that‬‭has‬‭not‬
‭been previously irradiated within 4 weeks prior to the study enrolment.‬
‭6.‬ ‭Patients‬ ‭with‬ ‭an‬ ‭archival‬ ‭or‬ ‭de‬ ‭novo‬ ‭tumor‬ ‭biopsy‬ ‭(representative‬ ‭formalin-fixed‬
‭paraffin-embedded/FFPE‬ ‭paraffin‬ ‭block‬ ‭obtained‬ ‭as‬‭close‬‭as‬‭possible‬‭to‬‭the‬‭patient‬
‭inclusion)‬‭with‬‭an‬‭associated‬‭pathology‬‭report,‬‭for‬‭testing‬‭of‬‭PD-L1‬‭expression,‬‭prior‬
‭to‬ ‭study‬ ‭enrollment.‬ ‭Samples‬ ‭in‬ ‭unstained‬ ‭slides‬ ‭could‬ ‭be‬ ‭acceptable‬ ‭(at‬ ‭least‬ ‭15‬
‭slides).‬
‭7.‬ ‭Patients with adequate normal organ and marrow function as defined below:‬
‭a.‬ ‭Haemoglobin ≥ 9.0 g/dL.‬
‭b.‬ ‭Absolute neutrophil count (ANC)‬‭>‬‭1500 per mm‬‭3‬‭.‬
‭c.‬ ‭Platelet count ≥ 100,000 per mm‬‭3‬‭.‬
‭d.‬ ‭Serum‬‭bilirubin‬‭≤‬‭1.5‬‭X‬‭institutional‬‭upper‬‭limit‬‭of‬‭normal‬‭(ULN)‬‭unless‬‭liver‬
‭metastases‬ ‭are‬ ‭present,‬ ‭in‬ ‭which‬ ‭case‬ ‭it‬‭must‬‭be‬‭≤‬‭2X‬‭ULN.‬‭This‬‭will‬‭not‬
‭apply‬‭to‬‭patients‬‭with‬‭confirmed‬‭Gilbert’s‬‭syndrome‬‭(persistent‬‭or‬‭recurrent‬
‭hyperbilirubinemia‬ ‭that‬ ‭is‬ ‭predominantly‬ ‭unconjugated‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬
‭haemolysis‬ ‭or‬ ‭hepatic‬ ‭pathology);‬ ‭however,‬ ‭they‬ ‭will‬ ‭be‬ ‭allowed‬ ‭only‬ ‭in‬
‭consultation with their physician.‬
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‭e.‬ ‭Serum‬‭transaminases‬‭(ALT,‬‭AST‬‭and‬‭GGT)‬‭≤‬‭2.5X‬‭institutional‬‭upper‬‭limit‬‭of‬
‭normal‬ ‭unless‬ ‭liver‬ ‭metastases‬ ‭are‬ ‭present,‬ ‭in‬ ‭which‬ ‭case‬‭it‬‭must‬‭be‬‭≤‬‭3X‬
‭ULN.‬
‭8.‬ ‭No major active bleeding.‬
‭9.‬ ‭Female‬ ‭subjects‬ ‭of‬ ‭childbearing‬ ‭potential‬ ‭(not‬ ‭surgically‬ ‭sterile‬ ‭or‬ ‭at‬ ‭least‬‭2‬‭years‬
‭postmenopausal)‬‭must‬‭provide‬‭a‬‭negative‬‭urine‬‭pregnancy‬‭test‬‭at‬‭screening,‬‭and‬‭use‬‭a‬
‭medically‬ ‭accepted‬ ‭double‬ ‭barrier‬ ‭method‬ ‭of‬ ‭contraception‬ ‭(i.e.‬ ‭condom‬ ‭with‬
‭spermicide‬‭+‬‭IUD‬‭or‬‭cervical‬‭caps).‬‭In‬‭addition,‬‭they‬‭must‬‭agree‬‭to‬‭continue‬‭the‬‭use‬‭of‬
‭this‬ ‭double‬ ‭barrier‬ ‭method‬ ‭for‬ ‭the‬ ‭duration‬ ‭of‬ ‭the‬ ‭study‬ ‭and‬ ‭for‬ ‭6‬ ‭months‬ ‭after‬
‭participation in the study.‬
‭10.‬‭Males‬‭should‬‭agree‬‭to‬‭abstain‬‭from‬‭sexual‬‭intercourse‬‭with‬‭a‬‭female‬‭partner‬‭or‬‭agree‬
‭to‬ ‭use‬ ‭a‬ ‭double‬ ‭barrier‬ ‭method‬ ‭of‬ ‭contraception‬ ‭(i.e.‬ ‭condom‬ ‭with‬ ‭spermicide,‬ ‭in‬
‭addition‬‭to‬‭having‬‭their‬‭female‬‭partner‬‭use‬‭some‬‭contraceptive‬‭measures‬‭such‬‭as‬‭oral‬
‭contraceptive‬ ‭drugs,‬ ‭intrauterine‬ ‭device‬ ‭(IUD)‬ ‭hormonal‬ ‭contraception,‬ ‭or‬ ‭cervical‬
‭caps), for the duration of the study and for 6 months after participation in the study‬
‭11.‬ ‭Willingness‬‭and‬‭ability‬‭of‬‭patients‬‭to‬‭comply‬‭with‬‭the‬‭protocol‬‭for‬‭the‬‭duration‬‭of‬‭the‬
‭study‬‭including‬‭undergoing‬‭treatment‬‭as‬‭well‬‭as‬‭availability‬‭for‬‭scheduled‬‭visits‬‭and‬
‭examinations including follow up.‬
‭Exclusion criteria‬
‭1.‬ ‭Prior‬‭treatment‬‭with‬‭any‬‭immune‬‭checkpoint‬‭inhibitor‬‭therapy‬‭(e.g.,‬‭CTLA4,‬‭PD-1,‬‭or‬
‭PD-L1 targeting agent).*‬
‭*‬‭Note‬‭:‬ ‭Prior‬ ‭adjuvant‬ ‭or‬ ‭neoadjuvant‬ ‭treatment‬ ‭with‬ ‭targeted‬ ‭therapy/checkpoint‬
‭inhibitors‬‭is‬‭allowed,‬‭as‬‭long‬‭as‬‭the‬‭last‬‭dose‬‭was‬‭administered‬‭at‬‭least‬‭12‬‭months‬‭prior‬
‭to the patient inclusion in this trial.‬
‭2.‬ ‭Presence‬‭of‬‭active‬‭second‬‭malignancy‬‭and/or‬‭prior‬‭malignancy‬‭in‬‭the‬‭last‬‭2‬‭years‬‭is‬
‭allowed except for the following:‬
‭a.‬ ‭adequately treated basal cell or squamous cell skin cancer,‬
‭b.‬ ‭adequately‬‭treated‬‭Stage‬‭I‬‭or‬‭II‬‭cancer‬‭from‬‭which‬‭the‬‭patient‬‭is‬‭currently‬‭in‬
‭complete remission per investigators' clinical judgment.‬
‭3.‬ ‭Patient receiving radiation therapy within 4 weeks before inclusion.‬
‭4.‬ ‭Active‬ ‭or‬ ‭prior‬ ‭documented‬ ‭autoimmune‬ ‭disease‬ ‭within‬ ‭the‬ ‭past‬ ‭2‬ ‭years‬ ‭NOTE:‬
‭Subjects‬‭with‬‭vitiligo,‬‭Grave's‬‭disease,‬‭or‬‭psoriasis‬‭not‬‭requiring‬‭systemic‬‭treatment‬
‭(within the past 2 years) are not excluded.‬
‭5.‬ ‭Active‬ ‭or‬ ‭prior‬‭documented‬‭inflammatory‬‭bowel‬‭disease‬‭(e.g..,‬‭Crohn's‬‭disease‬‭and‬
‭ulcerative colitis).‬
‭6.‬ ‭History of allogeneic organ transplant.‬
‭7.‬ ‭Subjects‬ ‭having‬ ‭a‬ ‭diagnosis‬ ‭of‬‭immunodeficiency‬‭or‬‭are‬‭receiving‬‭systemic‬‭steroid‬
‭therapy‬‭or‬‭any‬‭other‬‭form‬‭of‬‭immunosuppressive‬‭therapy‬‭within‬‭28‬‭days‬‭prior‬‭to‬‭the‬
‭first dose of trial treatment.‬
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‭8.‬ ‭Current‬ ‭or‬ ‭prior‬ ‭use‬ ‭of‬ ‭immunosuppressive‬ ‭medication‬ ‭within‬ ‭7‬ ‭days‬ ‭prior‬ ‭to‬
‭enrolment, except the following:‬
‭a.‬ ‭Intranasal,‬ ‭inhaled,‬ ‭topical‬ ‭steroids,‬ ‭or‬ ‭local‬ ‭steroid‬ ‭injections‬ ‭(eg,‬
‭intra-articular injection);‬
‭i.‬
‭Systemic‬ ‭corticosteroids‬ ‭at‬ ‭physiologic‬ ‭doses‬ ‭≤10‬ ‭mg/day‬ ‭of‬
‭prednisone or equivalent;‬
‭ii.‬
‭Steroids‬‭as‬‭premedication‬‭for‬‭hypersensitivity‬‭reactions‬‭(eg,‬‭CT‬‭scan‬
‭premedication).‬
‭9.‬ ‭The‬‭subject‬‭has‬‭uncontrolled,‬‭significant‬‭intercurrent‬‭or‬‭recent‬‭illness‬‭(within‬‭6‬‭months‬
‭prior to inclusion) including, but not limited to, the following conditions:‬
‭a.‬ ‭Cardiovascular disorders:‬
‭i.‬
‭Class‬‭3‬‭or‬‭4‬‭congestive‬‭heart‬‭failure‬‭as‬‭defined‬‭by‬‭the‬‭New‬‭York‬‭Heart‬
‭Association,‬
‭unstable‬
‭angina‬
‭pectoris,‬
‭and‬
‭serious‬
‭cardiac‬
‭arrhythmias.‬
‭ii.‬
‭Uncontrolled‬‭hypertension‬‭defined‬‭as‬‭sustained‬‭blood‬‭press‬‭>‬‭150‬‭mm‬
‭hg‬‭systolic‬‭or‬‭>‬‭100‬‭mm‬‭hg‬‭diastolic‬‭despite‬‭optimal‬‭antihypertensive‬
‭treatment.‬
‭iii.‬
‭Stroke‬ ‭(including‬ ‭transient‬ ‭ischemic‬ ‭attack‬ ‭[TIA]),‬ ‭myocardial‬
‭infarction,‬‭other‬‭ischemic‬‭event,‬‭or‬‭thromboembolic‬‭event‬‭(e.g.,‬‭deep‬
‭venous‬‭thrombosis‬‭[DVT]‬‭and‬‭pulmonary‬‭embolism)‬‭within‬‭6‬‭months‬
‭before‬‭inclusion.‬‭Subjects‬‭with‬‭a‬‭more‬‭recent‬‭diagnosis‬‭of‬‭DVT‬‭are‬
‭allowed‬‭if‬‭stable,‬‭asymptomatic,‬‭and‬‭treated‬‭with‬‭LMWH‬‭for‬‭at‬‭least‬
‭6 weeks before study treatment.‬
‭b.‬ ‭Gastrointestinal‬ ‭disorders‬ ‭(e.g.,‬ ‭malabsorption‬ ‭syndrome‬ ‭or‬ ‭gastric‬ ‭outlet‬
‭obstruction)‬ ‭including‬ ‭those‬ ‭associated‬ ‭with‬ ‭a‬ ‭high‬ ‭risk‬ ‭of‬ ‭perforation‬ ‭or‬
‭fistula formulation:‬
‭i.‬
‭Tumours‬ ‭invading‬ ‭the‬ ‭GI‬ ‭tract,‬ ‭active‬ ‭peptic‬ ‭ulcer‬ ‭disease,‬
‭inflammatory‬
‭bowel‬
‭disease,‬
‭ulcerative‬
‭colitis,‬ ‭diverticulitis,‬
‭cholecystitis,‬
‭symptomatic‬
‭cholangitis‬
‭or‬
‭appendicitis,‬
‭acute‬
‭pancreatitis‬‭or‬‭acute‬‭obstruction‬‭of‬‭the‬‭pancreatic‬‭or‬‭biliary‬‭duct,‬‭or‬
‭gastric outlet obstruction.‬
‭ii.‬
‭Abdominal‬
‭fistula,‬
‭GI‬
‭perforation,‬
‭bowel‬
‭obstruction,‬
‭or‬
‭intra-abdominal‬ ‭abscess‬ ‭within‬ ‭6‬ ‭months‬ ‭before‬ ‭inclusion.‬ ‭Note:‬
‭complete‬ ‭healing‬ ‭of‬ ‭an‬ ‭intra-abdominal‬ ‭abscess‬ ‭must‬‭be‬‭confirmed‬
‭prior to start of the treatment.‬
‭c.‬ ‭Clinically‬‭significant‬‭hematemesis‬‭or‬‭hemoptysis‬‭of‬‭>‬‭0.5‬‭teaspoon‬‭(>‬‭2.5‬‭ml)‬
‭of‬‭red‬‭blood‬‭or‬‭history‬‭of‬‭other‬‭significant‬‭bleeding‬‭within‬‭3‬‭months‬‭before‬
‭treatment.‬
‭d.‬ ‭Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.‬
‭e.‬ ‭Lesions invading major pulmonary blood vessels.‬
‭f.‬
‭Other clinically significant disorders such as:‬
‭i.‬
‭Active‬ ‭infection‬‭requiring‬‭systemic‬‭treatment,‬‭infection‬‭with‬‭human‬
‭immunodeficiency‬
‭virus‬
‭or‬
‭acquired‬
‭immunodeficiency‬
‭syndrome-related illness, or chronic hepatitis B or C infection.‬
‭ii.‬
‭Serious non-healing wound/ulcer/bone fracture.‬
‭iii.‬
‭Malabsorption syndrome.‬
‭iv.‬
‭Moderate to severe hepatic impairment (child-pugh B or C).‬
‭v.‬
‭Requirement for hemodialysis or peritoneal dialysis.‬
‭vi.‬
‭Uncontrolled diabetes mellitus.‬
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‭10.‬‭Major‬‭surgery‬‭(e.g.,‬‭GI‬‭surgery‬‭and‬‭removal‬‭or‬‭biopsy‬‭of‬‭brain‬‭metastasis)‬‭within‬‭8‬
‭weeks‬ ‭before‬ ‭inclusion.‬ ‭Complete‬ ‭wound‬ ‭healing‬ ‭from‬ ‭major‬ ‭surgery‬ ‭must‬ ‭have‬
‭occurred‬ ‭4‬ ‭weeks‬ ‭before‬ ‭study‬ ‭treatment‬ ‭and‬ ‭from‬ ‭minor‬ ‭surgery‬ ‭(e.g.,‬ ‭simple‬
‭excision,‬ ‭tooth‬ ‭extraction)‬ ‭at‬ ‭least‬ ‭10‬ ‭days‬ ‭before‬ ‭study‬ ‭treatment.‬ ‭Subjects‬ ‭with‬
‭clinically relevant ongoing complications from prior surgery are not eligible.‬
‭11.‬ ‭Known‬ ‭human‬ ‭immunodeficiency‬ ‭virus‬ ‭(HIV)‬ ‭or‬ ‭acquired‬ ‭immunodeficiency‬
‭syndrome (AIDS)-related illness.‬
‭12.‬‭Any‬‭test‬‭for‬‭hepatitis‬‭B‬‭virus‬‭(HBV)‬‭or‬‭hepatitis‬‭C‬‭virus‬‭(HCV)‬‭indicating‬‭acute‬‭or‬
‭chronic infection.‬
‭13.‬‭Women who are pregnant or are breastfeeding.‬
‭14.‬‭Male‬‭patients‬‭must‬‭be‬‭surgically‬‭sterile‬‭or‬‭must‬‭agree‬‭to‬‭use‬‭effective‬‭contraception‬
‭during the period of therapy.‬
‭15.‬‭Any‬ ‭of‬ ‭the‬ ‭following‬ ‭within‬ ‭6‬ ‭months‬ ‭prior‬ ‭to‬ ‭study‬‭entry:‬‭myocardial‬‭infarction,‬
‭uncontrolled‬ ‭angina,‬ ‭uncontrolled‬ ‭hypertension,‬ ‭coronary/peripheral‬ ‭artery‬ ‭bypass‬
‭graft,‬ ‭symptomatic‬ ‭congestive‬ ‭heart‬ ‭failure,‬ ‭cerebrovascular‬ ‭accident‬ ‭or‬ ‭transient‬
‭ischemic attack.‬
‭16.‬‭Previously‬‭identified‬‭allergy‬‭or‬‭hypersensitivity‬‭to‬‭components‬‭of‬‭the‬‭study‬‭treatment‬
‭formulations.‬
‭1.17.‬ ‭Planned trial period‬
‭●‬ ‭Enrolment/recruitment period: 12 months‬
‭●‬ ‭First patient first visit (FPFV): 8ENE2021‬
‭●‬ ‭Last patient last visit (LPLV): January 2024 (expected)‬
‭●‬ ‭Treatment period: Up to 24 months of LPFV‬
‭●‬ ‭Follow-up period: 24 months‬
‭●‬ ‭Planned end of study date: First quarter 2024 (expected)‬
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‭GLOSSARY OF ABBREVIATIONS‬
‭Abbreviation or‬
‭Specialist Term‬
‭Explanation‬
‭ADR‬
‭Adverse drug reaction‬
‭AE‬
‭Adverse event‬
‭aUC‬
‭Advanced urothelial cancer‬
‭BMI‬
‭Body Mass Index‬
‭BP‬
‭Blood Pressure‬
‭CIs‬
‭Confidence intervals‬
‭CK‬
‭Creatine‬ ‭kinase‬ ‭(CK),‬ ‭also‬ ‭known‬ ‭as‬ ‭creatine‬ ‭phosphokinase‬ ‭(CPK)‬ ‭or‬
‭phosphocreatine kinase‬
‭CB‬
‭Clinical benefit‬
‭CR‬
‭Complete Response‬
‭CRA‬
‭Clinical Research Associate‬
‭CTCAE‬
‭Common Terminology Criteria for Adverse Events‬
‭CT Scan‬
‭Computed Tomography Scan‬
‭DMP‬
‭Data Management Plan‬
‭CYP‬
‭Cytochromes P450 enzymes‬
‭DoR‬
‭Duration of response‬
‭DVP‬
‭Data Validation Plan‬
‭ECHO‬
‭Echocardiogram‬
‭ECG‬
‭Electrocardiogram‬
‭ECOG‬
‭Eastern Cooperative Oncology Group‬
‭eCRF‬
‭Electronic Case Report Form‬
‭EDC‬
‭Electronic Data Capture‬
‭ECG‬
‭Electrocardiogram‬
‭EMA‬
‭European Medicines Agency‬
‭ESMO‬
‭European Society of Medical Oncology‬
‭FBE‬
‭Full blood examination‬
‭FDA‬
‭US Food and Drug Administration‬
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‭FFPE‬
‭Formalin-fixed paraffin-embedded‬
‭FPFV‬
‭First patient first visit‬
‭FU‬
‭Follow-up‬
‭GC‬
‭Gemcitabine plus cisplatin‬
‭GCP‬
‭Good Clinical Practice‬
‭G-CSF‬
‭Granulocyte colony-stimulating factor‬
‭GH‬
‭Growth hormone‬
‭Hb‬
‭Haemoglobin‬
‭IB‬
‭Investigator Brochure‬
‭ICF‬
‭Informed Consent Form‬
‭ICH‬
‭International Conference on Harmonization‬
‭ICI‬
‭Immune Checkpoint Inhibitors‬
‭IEC‬
‭Independent Ethics Committee‬
‭IgG1‬
‭Immunoglobulin G1‬
‭IIS‬
‭Investigator Initiated Study‬
‭IMP‬
‭Investigational Medicinal Product‬
‭ISF‬
‭Investigator Site File‬
‭ITT‬
‭Intention To Treat‬
‭IUD‬
‭Intrauterine device‬
‭LPLV‬
‭Last visit Last patient‬
‭MedDRA‬
‭Medical Dictionary for Regulatory Activities‬
‭MRI‬
‭Magnetic Resonance Imaging‬
‭mUC‬
‭Metastatic urothelial cancer‬
‭MUGA‬
‭Multigated Acquisition Scan‬
‭MVAC‬
‭Dose-dense methotrexate, vinblastine, doxorubicin and cisplatin‬
‭NCI‬
‭National Cancer Institute (USA)‬
‭ORR‬
‭Overall response rate‬
‭OS‬
‭Overall Survival‬
‭PD‬
‭Progression disease‬
‭PE‬
‭Physical Examination‬
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‭PFS‬
‭Progression Free Survival‬
‭PI‬
‭Principal Investigator‬
‭PP‬
‭Per Protocol‬
‭PR‬
‭Partial Response‬
‭PS‬
‭Performance Status‬
‭QD‬
‭Quaque die, every day “once daily”‬
‭QxW‬
‭Every X weeks‬
‭RECIST‬
‭Response Evaluation Criteria In Solid Tumours‬
‭REEC‬
‭Registro Español de Estudios Clínicos (Spanish Registry of Clinical Studies)‬
‭Rx‬
‭Radiography‬
‭SAE‬
‭Serious adverse event‬
‭SAP‬
‭Statistical Analysis Plan‬
‭SAR‬
‭Serious adverse reaction‬
‭SC‬
‭Subcutaneous‬
‭SD‬
‭Stable disease‬
‭SDV‬
‭Source Data Verification‬
‭SmPC‬
‭Summary of Product Characteristics‬
‭SP‬
‭Safety Population‬
‭SUSAR‬
‭Suspected unexpected serious adverse reaction‬
‭PD-1‬
‭Programmed death-1‬
‭PD-L1‬
‭Programmed death ligand-1‬
‭TR‬
‭Translational Research‬
‭UC‬
‭Urothelial cancer‬
‭ULN‬
‭Upper Limit of Normality‬
‭VS‬
‭Vital Signs‬
‭WBC‬
‭White Blood Count‬
‭wGC‬
‭weekly Gemcitabine plus cisplatin‬
‭WHO‬
‭World Health Organization‬
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‭2.‬
‭GENERAL INFORMATION‬
‭2.1.‬
‭Study Identification‬
‭Short‬ ‭title‬‭:‬ ‭Study‬ ‭of‬ ‭atezolizumab‬ ‭and‬ ‭split-dose‬ ‭cisplatin/gemcitabine‬ ‭and‬ ‭in‬ ‭urothelial‬
‭carcinoma‬
‭Protocol number:‬‭SOGUG-2020-IEC (VEJ-1)‬
‭EudraCT No.‬‭: 2020-001326-65‬
‭2.2.‬
‭Monitoring Organization‬
‭MFAR Clinical Research‬
‭C/ Sinfonía 28, 2-1, 28001, Madrid, Spain‬
‭investigacion@mfar.net‬
‭2.3.‬
‭Sponsor information‬
‭Spanish Oncology Genitourinary Group (SOGUG)‬
‭C/ Velazquez 7, 3a planta,‬
‭28001, Madrid, Spain‬
‭secretaria@sogug.es‬
‭2.4.‬
‭Coordinating investigator‬
‭Guillermo de Velasco M.D., PhD.‬
‭Hospital Universitario 12 de Octubre‬
‭Av Córdoba s/n‬
‭28041, Madrid, Spain.‬
‭2.5.‬
‭Investigators and study centres‬
‭It‬‭is‬‭expected‬‭the‬‭participation‬‭of‬‭12‬‭Sites‬‭in‬‭Spain.‬‭The‬‭list‬‭of‬‭Sites‬‭and‬‭the‬‭corresponding‬
‭Principal Investigators is provided in a separated document.‬
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‭3.‬
‭INVESTIGATIONAL MEDICINAL PRODUCT (IMP) DESCRIPTION‬
‭3.1.‬
‭Study medication‬
‭Atezolizumab:‬
‭Pharmacotherapeutic‬ ‭group:‬ ‭Antineoplastic‬ ‭agents,‬ ‭monoclonal‬ ‭antibodies.‬ ‭ATC‬ ‭code:‬
‭L01XC‬
‭Presentation:‬‭60‬‭mg/mL‬‭glass‬‭vials‬‭of‬‭20-mL,‬‭nominal‬‭atezolizumab‬‭amount‬‭per‬‭vial,‬‭1200‬
‭mg. Commercial medication labeled for clinical trial.‬
‭Pharmaceutical‬ ‭form:‬ ‭Concentrate‬ ‭for‬ ‭solution‬ ‭for‬ ‭infusion.‬ ‭Clear,‬ ‭colourless‬ ‭to‬ ‭slightly‬
‭yellowish liquid.‬
‭Supply:‬‭Roche‬‭Pharma‬‭will‬‭supply‬‭atezolizumab‬‭to‬‭the‬‭Sponsor‬‭that‬‭will‬‭supply‬‭this‬‭product‬
‭to the sites pharmacy.‬
‭Gemcitabine‬
‭Pharmacotherapeutic‬‭group:‬‭Antineoplastic‬‭agents‬‭-‬‭Alkylating‬‭agents‬‭-‬‭Antimetabolites‬‭-‬
‭Pyrimidine analogues, ATC code: L01BC05‬
‭Presentation:‬‭;‬ ‭Glass‬ ‭vial:‬ ‭*200‬ ‭mg/5.3‬ ‭mL‬ ‭or‬ ‭200‬ ‭mg/2‬ ‭mL;‬ ‭1000‬ ‭mg/10‬ ‭mL‬ ‭or‬ ‭1000‬
‭mg/26.3mL;‬ ‭1500‬ ‭mg/15‬ ‭mL‬ ‭and‬ ‭*2000‬ ‭mg/52.6‬ ‭mL‬ ‭or‬ ‭2000‬ ‭mg/20‬ ‭mL.‬ ‭Commercial‬
‭medication not-labeled for clinical trial.‬
‭Pharmaceutical‬‭form:‬ ‭*‬‭Concentrate‬ ‭for‬ ‭solution‬ ‭for‬ ‭infusion‬ ‭according‬ ‭to‬ ‭different‬
‭commercial presentations authorized in Spain.‬
‭Supply:‬‭By participating sites under standard treatment‬‭criteria‬
‭Cisplatin‬
‭Pharmacotherapeutic‬‭group:‬‭Antineoplastic‬‭agents‬‭-‬‭Other‬‭antineoplastic‬‭agents,‬‭ATC‬‭code:‬
‭L01XA01‬
‭Presentation:‬‭1‬‭mg/mL‬‭glass‬‭vials‬‭of‬‭10-mL,‬‭50-mL‬‭and‬‭100-mL.‬‭Commercial‬‭medication‬
‭not-labeled for clinical trial.‬
‭Pharmaceutical form:‬‭Concentrate for solution for‬‭infusion.‬
‭Supply:‬‭By participating sites under standard treatment‬‭criteria.‬
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‭4.‬
‭RATIONALE AND OBJECTIVES‬
‭4.1.‬
‭Rationale‬
‭4.1.1.‬ ‭Current state of the art‬
‭Cisplatin-based‬‭chemotherapy‬‭(70 mg/m‬‭2‬‭)‬‭has‬‭been‬‭the‬‭standard‬‭of‬‭care‬‭for‬‭first-line‬‭treatment‬
‭for‬‭surgically‬‭unresectable‬‭and‬‭metastatic‬‭patients‬‭fit‬‭enough‬‭to‬‭tolerate‬‭cisplatin‬‭for‬‭more‬‭than‬
‭30‬ ‭years‬ ‭(‬‭Saxman‬ ‭SB,‬ ‭et‬ ‭al.‬ ‭1997;‬ ‭Von‬ ‭der‬ ‭Maase,‬ ‭et‬ ‭al.‬ ‭2000;‬ ‭Bellmunt‬ ‭J,‬‭et‬‭al.‬‭2016‬‭).‬
‭However,‬‭a‬‭standard‬‭dose‬‭schedule‬‭is‬‭not‬‭feasible‬‭for‬‭a‬‭significant‬‭number‬‭of‬‭patients‬‭(about‬
‭50%).‬‭Age-related‬‭physiological‬‭changes‬‭and‬‭comorbidities‬‭are‬‭common‬‭in‬‭the‬‭uro-oncology‬
‭field‬ ‭and,‬ ‭as‬ ‭expected,‬ ‭affect‬ ‭treatment‬ ‭choices‬ ‭and‬ ‭outcomes.‬‭Renal‬‭function‬‭impairment,‬
‭cardiovascular‬ ‭disease,‬ ‭neuropathy,‬ ‭hearing‬ ‭loss‬ ‭are‬ ‭commonly‬ ‭reported‬ ‭in‬ ‭patients‬ ‭with‬
‭bladder‬‭cancer‬‭(‬‭Bellmunt‬‭J,‬‭et‬‭al.‬‭2016‬‭;‬‭Katz‬‭H,‬‭et‬‭al.‬‭2017‬‭);‬‭but‬‭its‬‭toxicity‬‭(‬‭van‬‭Leenders‬
‭GJLH, 2019‬‭).‬
‭According‬‭to‬‭the‬‭most‬‭recent‬‭update‬‭on‬‭cumulative‬‭evidence‬‭and‬‭as‬‭summarized‬‭in‬‭the‬‭most‬
‭recent‬‭ESMO‬‭Bladder‬‭Cancer‬‭Treatment‬‭Recommendations‬‭published‬‭on‬‭16‬‭December‬‭2019,‬
‭a‬‭number‬‭of‬‭cisplatin-containing‬‭regimens‬‭are‬‭acceptable‬‭although‬‭gemcitabine‬‭and‬‭cisplatin‬
‭[I,‬‭A]‬‭is‬‭the‬‭most‬‭widely‬ ‭accepted‬‭(‬‭Von‬‭der‬‭Maase,‬‭et‬‭al.‬‭2000‬‭).‬ ‭Dose-dense‬‭methotrexate,‬
‭vinblastine,‬ ‭doxorubicin‬ ‭and‬ ‭cisplatin‬ ‭(MVAC)‬ ‭[I,‬ ‭B],‬ ‭MVAC‬ ‭with‬ ‭granulocyte‬
‭colony-stimulating‬‭factor‬‭(G-CSF)‬‭[I,‬‭B],‬‭and‬‭gemcitabine,‬‭cisplatin‬‭and‬‭paclitaxel‬‭[I,‬‭C]‬‭are‬
‭alternatives‬‭which‬‭have‬‭established‬‭themselves‬‭as‬‭options‬‭over‬‭time‬‭(‬‭Loehrer‬‭PJ,‬‭et‬‭al.‬‭1992;‬
‭Sternberg‬ ‭CN,‬‭et‬‭al‬‭2006;‬‭Bellmunt‬‭J,‬‭et‬‭al.‬‭2012;‬‭Grande‬‭E,‬‭et‬‭al.‬‭2019‬‭).‬‭Although‬‭these‬
‭specific‬‭regimens‬‭may‬‭lack‬‭proven‬‭advantage‬‭or‬‭non-inferiority‬‭compared‬‭with‬‭gemcitabine‬
‭and cisplatin, they can be considered as options in selected patients.‬
‭4.1.2.‬ ‭Split-Dose Cisplatin‬
‭For‬‭those‬‭patients‬‭with‬‭mUC‬‭cisplatin-ineligible‬‭or‬‭who‬‭have‬‭progressed‬‭on‬‭a‬‭platinum-based‬
‭regimen‬‭treatment‬‭options‬‭are‬‭limited‬‭(‬‭Koshkin‬‭VS,‬‭et‬‭al.‬‭2018‬‭)‬‭and‬‭are‬‭usually‬‭palliated‬‭with‬
‭carboplatin-based‬ ‭regimen,‬ ‭single-agent‬‭taxane‬‭or‬‭gemcitabine,‬‭or‬‭split-dose‬‭cisplatin-based‬
‭regimens‬‭may‬‭be‬‭employed.‬‭In‬‭fact,‬‭some‬‭studies‬‭have‬‭presented‬‭data‬‭on‬‭up‬‭to‬‭50%‬‭of‬‭patients‬
‭eligible‬‭for‬‭cisplatin‬‭might‬‭be‬‭treated‬‭with‬‭carboplatin-based‬‭chemotherapy‬‭based‬‭on‬‭physician‬
‭criteria (ie. IMvigor 130;‬‭Grande E, et al. 2019‬‭).‬
‭The‬ ‭difficult-to-treat‬ ‭concept‬ ‭of‬ ‭this‬ ‭disease‬ ‭entails‬ ‭the‬ ‭undoubtedly‬ ‭high‬ ‭age‬ ‭of‬ ‭most‬ ‭of‬
‭around 80% of patients with UC (‬‭Gore JL, et al. 2010‬‭).‬
‭Administration‬‭of‬‭cisplatin‬‭35 mg/m2‬‭on‬‭day‬‭1 + 8‬‭or‬‭1 + 2‬‭(i.e.,‬‭split‬‭schedule)‬‭is‬‭a‬‭commonly‬
‭used‬ ‭alternative.‬ ‭Several‬ ‭studies‬‭have‬‭reported‬‭that‬‭split‬‭dose‬‭GC‬‭has‬‭comparable‬‭response‬
‭rates‬‭in‬‭metastatic‬‭disease‬‭to‬‭other‬‭platinum‬‭containing‬‭regimens‬‭(‬‭Morales-Barrera‬‭R,‬‭et‬‭al.‬
‭2012‬‭),‬ ‭but‬ ‭has‬ ‭a‬ ‭favourable‬ ‭toxicity‬‭profile‬‭and‬‭considerably‬‭less‬‭time‬‭burden‬‭on‬‭day‬‭care‬
‭facilities‬ ‭(‬‭Sellers‬‭LE,‬‭et‬‭al.‬‭2016‬‭).‬‭These‬‭led‬‭us‬‭to‬‭consider‬‭that‬‭split‬‭dose‬‭GC‬‭should‬‭be‬‭a‬
‭feasible alternative to the longer more toxic regimens, particularly in metastatic disease.‬
‭4.1.3.‬ ‭PD-L1 and the role of atezolizumab in mUC‬
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‭Expression‬‭of‬‭programmed‬‭death‬‭ligand-1‬‭(PD-L1)‬‭is‬‭prevalent‬‭among‬‭many‬‭human‬‭tumors‬
‭(‬‭Dong‬‭et‬‭al.‬‭2002‬‭),‬‭and‬‭its‬‭overexpression‬‭is‬‭associated‬‭with‬‭poor‬‭prognosis‬‭for‬‭patients‬‭with‬
‭certain‬‭cancers‬‭(‬‭Thompson‬‭et‬‭al.‬‭2006;‬‭Hamanishi‬‭et‬‭al.‬‭2007;‬‭Okazaki‬‭T‬‭and‬‭Honjo‬‭T,‬‭2007;‬
‭Hino‬ ‭et‬ ‭al.‬ ‭2010,‬ ‭Mu‬ ‭et‬ ‭al.‬ ‭2011‬‭).‬ ‭Therefore,‬ ‭interruption‬ ‭of‬ ‭the‬ ‭PD-L1/PD‬ ‭1‬ ‭pathway‬
‭represents an attractive strategy to reinvigorate tumor-specific T cell immunity.‬
‭Since‬ ‭May‬ ‭2016,‬ ‭five‬ ‭different‬ ‭agents‬ ‭targeting‬ ‭the‬ ‭PD-1/PD-L1‬ ‭pathway‬ ‭(atezolizumab,‬
‭pembrolizumab,‬ ‭nivolumab,‬ ‭avelumab,‬ ‭durvalumab)‬ ‭have‬ ‭received‬ ‭FDA‬ ‭approval‬ ‭for‬ ‭the‬
‭treatment‬‭of‬‭aUC‬‭in‬‭the‬‭platinum-refractory‬‭setting,‬‭while‬‭pembrolizumab‬‭and‬‭atezolizumab‬
‭are‬‭FDA-approved‬‭for‬‭cisplatin-ineligible‬‭patients‬‭in‬‭the‬‭first-line‬‭setting‬‭(‬‭Koshkin‬‭VS‬‭2018‬‭).‬
‭For‬ ‭platinum‬ ‭or‬ ‭chemotherapy-ineligible‬ ‭patients‬‭with‬‭mUC,‬‭immune‬‭checkpoint‬‭inhibitors‬
‭(ICI)‬‭such‬‭as‬‭inhibitors‬‭of‬‭programmed‬‭death-1/programmed‬‭death-ligand‬‭1‬‭(PD-1/PD-L1)‬‭are‬
‭approved‬ ‭regardless‬ ‭of‬ ‭PD-L1‬ ‭expression,‬ ‭including‬ ‭pembrolizumab‬ ‭and‬ ‭atezolizumab‬
‭(‬‭Einstein and Sonpavde, 2019‬‭).‬
‭Atezolizumab‬‭is‬‭a‬‭humanized‬‭immunoglobulin‬‭(IgG1)‬‭monoclonal‬‭antibody‬‭that‬‭is‬‭produced‬
‭in‬ ‭Chinese‬ ‭hamster‬ ‭ovary‬ ‭(CHO)‬ ‭cells.‬ ‭Atezolizumab‬ ‭targets‬ ‭programmed‬ ‭death-ligand‬ ‭1‬
‭(PD-L1)‬‭on‬‭tumor-infiltrating‬‭immune‬‭cells‬‭(ICs)‬‭or‬‭tumor‬‭cells‬‭(TCs)‬‭and‬‭prevents‬‭interaction‬
‭with‬‭the‬‭programmed‬‭death-1‬‭(PD-1)‬‭receptor‬‭and‬‭B7.1‬‭(CD80),‬‭both‬‭of‬‭which‬‭function‬‭as‬
‭inhibitory‬‭receptors‬‭expressed‬‭on‬‭T‬‭cells‬‭and‬‭other‬‭immune‬‭cells.‬‭The‬‭PD-1‬‭and‬‭PD-L1:B7.1‬
‭interactions‬ ‭may‬ ‭enhance‬ ‭the‬ ‭magnitude‬ ‭and‬ ‭quality‬ ‭of‬ ‭the‬ ‭tumor-specific‬ ‭T‬‭cell‬‭response‬
‭through‬ ‭increased‬ ‭T‬ ‭cell‬ ‭priming,‬ ‭expansion,‬ ‭and/or‬ ‭effector‬ ‭function.‬ ‭Atezolizumab‬ ‭was‬
‭engineered‬‭to‬‭eliminate‬‭Fc-effector‬‭function‬‭via‬‭a‬‭single‬‭amino‬‭acid‬‭substitution‬‭at‬‭position‬
‭298‬‭on‬‭the‬‭heavy‬‭chain,‬‭which‬‭results‬‭in‬‭a‬‭non-glycosylated‬‭antibody‬‭that‬‭has‬‭minimal‬‭binding‬
‭to‬‭Fc‬‭receptors‬‭and,‬‭consequently,‬‭eliminates‬‭detectable‬‭Fc‬‭effector‬‭function.‬‭By‬‭eliminating‬
‭Fc-effector‬ ‭function‬ ‭and‬ ‭antibody-dependent‬ ‭cell-mediated‬ ‭cytotoxicity,‬ ‭antibody-mediated‬
‭clearance of activated effector T cells is also eliminated.‬
‭Atezolizumab‬‭has‬‭demonstrated‬‭efficacy‬‭and‬‭a‬‭tolerable‬‭safety‬‭profile‬‭in‬‭a‬‭range‬‭of‬‭cancers,‬
‭including‬ ‭locally‬ ‭advanced‬ ‭or‬ ‭mUC‬ ‭(‬‭Herbst‬ ‭RS,‬ ‭et‬ ‭al.‬ ‭2014;‬ ‭Powles‬ ‭T,‬ ‭et‬ ‭al.‬ ‭2014,‬
‭Fehrenbacher‬ ‭L‬ ‭et‬ ‭al.‬ ‭2016;‬ ‭McDermott‬ ‭DF,‬ ‭et‬ ‭al.‬ ‭2016;‬ ‭Rosenberg‬ ‭JE,‬ ‭et‬ ‭al.‬ ‭2016‬‭).‬
‭Cumulative‬ ‭data‬ ‭on‬ ‭efficacy‬ ‭at‬ ‭the‬ ‭time‬ ‭of‬ ‭this‬ ‭study‬ ‭design‬ ‭(March‬ ‭2020)‬ ‭suggest‬ ‭that‬
‭atezolizumab‬‭as‬‭a‬‭single-agent‬‭for‬‭first-line‬‭in‬‭patients‬‭with‬‭mUC‬‭entails‬‭clinical‬‭benefit‬‭in‬
‭terms of objective responses, durable responses, and OS.‬
‭Clinical‬‭data‬‭from‬‭the‬‭first-line‬‭cisplatin-ineligible‬‭IMvigor210‬‭cohort—the‬‭first‬‭report‬‭of‬‭an‬
‭anti–PD-L1/PD-1‬ ‭checkpoint‬ ‭inhibitor‬ ‭in‬ ‭this‬ ‭setting—‬ ‭atezolizumab‬ ‭conferred‬ ‭significant‬
‭clinical‬‭benefit‬‭(‬‭Rosenberg‬‭JE,‬‭et‬‭al.‬‭2016‬‭),‬‭leading‬‭to‬‭accelerated‬‭regulatory‬‭approval,‬‭and‬
‭several‬ ‭biomarkers‬ ‭associated‬ ‭with‬ ‭response‬ ‭were‬ ‭identified.‬ ‭Furthermore,‬ ‭encouraging‬
‭durable‬ ‭response‬ ‭rates,‬ ‭survival‬ ‭and‬ ‭tolerability‬ ‭(‬‭Balar‬ ‭AV,‬ ‭et‬ ‭al.‬ ‭2017‬‭)‬ ‭have‬ ‭been‬ ‭also‬
‭reported.‬
‭Interim‬‭results‬‭(2018)‬‭from‬‭the‬‭ongoing‬‭IMvigor‬‭130‬‭trial‬‭(atezolizumab‬‭vs‬‭atezolizumab‬‭plus‬
‭platinum-based‬‭chemotherapy‬‭in‬‭locally‬‭advanced/mUC‬‭not‬‭previously‬‭treated)‬‭has‬‭shown‬‭a‬
‭reduction‬ ‭on‬ ‭survival‬‭for‬‭those‬‭patients‬‭treated‬‭with‬‭atezolizumab‬‭alone‬‭when‬‭compared‬‭to‬
‭those‬‭who‬‭received‬‭platinum-based‬‭chemotherapy‬‭(carbo-‬‭or‬‭cis-‬‭at‬‭physician‬‭discretion),‬‭not‬
‭previously‬‭treated‬‭and‬‭with‬‭tumors‬‭showing‬‭a‬‭low-PD-L1‬‭expression‬‭(<5%‬‭of‬‭immune‬‭cells‬
‭with positive staining) (‬‭EMA Tecentriq Assessment‬‭Report‬‭).‬
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‭4.2.‬
‭Hypothesis‬
‭The‬ ‭results‬ ‭of‬ ‭trials‬ ‭combining‬ ‭checkpoint‬ ‭inhibitors‬‭or‬‭platinum-based‬‭chemotherapy‬‭plus‬
‭PD-1/PD-L1‬ ‭inhibitors‬ ‭are‬ ‭eagerly‬ ‭awaited.‬ ‭The‬ ‭combination‬ ‭of‬ ‭split‬ ‭cisplatin‬ ‭with‬
‭atezolizumab‬‭is‬‭a‬‭feasible‬‭treatment‬‭that‬‭may‬‭provide‬‭better‬‭outcomes‬‭than‬‭carboplatin/based‬
‭combinations.‬
‭In‬‭the‬‭IMvigor130,‬‭52%‬‭of‬‭patients‬‭considered‬‭cisplatin‬‭eligible‬‭at‬‭the‬‭entry‬‭of‬‭the‬‭study‬‭were‬
‭treated‬‭with‬‭carboplatin.‬‭Subanalysis‬‭presented‬‭at‬‭ESMO‬‭2019‬‭(‬‭Grande‬‭E,‬‭et‬‭al.‬‭2019‬‭)‬‭has‬
‭also‬ ‭shown‬ ‭a‬ ‭longer‬‭median‬‭OS‬‭are‬‭achieved‬‭with‬‭cisplatin-based‬‭chemotherapy‬‭combined‬
‭with‬‭atezolizumab‬‭(21.7‬‭months)‬‭when‬‭compared‬‭to‬‭the‬‭carboplatin-based‬‭chemotherapy‬‭plus‬
‭atezolizumab‬ ‭(14.2‬ ‭months),‬ ‭with‬ ‭similar‬ ‭findings‬ ‭when‬ ‭it‬ ‭comes‬‭to‬‭PFS‬‭8.8‬‭months‬‭with‬
‭cisplatin/gemcitabine/atezolizumab vs 7.1 months carboplatin/gemcitabine/atezolizumab.‬
‭A‬ ‭reasonable‬ ‭strategy‬ ‭may‬ ‭be‬ ‭the‬ ‭use‬ ‭of‬ ‭split‬ ‭cisplatin‬ ‭with‬ ‭atezolizumab‬ ‭to‬ ‭increase‬ ‭the‬
‭number of patients receiving cisplatin.‬
‭4.3.‬
‭Rationale for dose selection‬
‭As‬‭per‬‭Atezolizumab‬‭Investigator’s‬‭Brochure‬‭(IB)‬‭at‬‭the‬‭time‬‭of‬‭this‬‭study‬‭design‬‭(‬‭version‬‭15,‬
‭July‬‭2019‬‭),‬‭the‬‭standard‬‭fixed‬‭dose‬‭of‬‭1200,‬‭equivalent‬‭to‬‭15mg/kg‬‭in‬‭a‬‭typical‬‭patient.‬‭No‬
‭dose-limiting‬ ‭toxicities‬ ‭were‬ ‭observed‬ ‭at‬ ‭the‬ ‭20‬ ‭mg/kg‬ ‭dose‬ ‭level‬ ‭and‬ ‭the‬ ‭incidence‬ ‭and‬
‭intensity‬‭of‬‭AEs‬‭reported‬‭have‬‭not‬‭been‬‭shown‬‭to‬‭be‬‭dependent‬‭on‬‭dose.‬‭A‬‭maximum‬‭tolerated‬
‭dose‬‭has‬‭not‬‭been‬‭established.‬‭Atezolizumab‬‭is‬‭supplied‬‭in‬‭vials‬‭containing‬‭the‬‭fixed‬‭1200‬‭mg‬
‭dose‬‭of‬‭drug‬‭substance,‬‭which‬‭minimizes‬‭the‬‭chance‬‭of‬‭overdose.‬‭Because‬‭the‬‭dose‬‭per‬‭patient‬
‭is‬‭not‬‭based‬‭on‬‭weight‬‭or‬‭body‬‭surface‬‭area,‬‭and‬‭no‬‭dose‬‭calculation‬‭is‬‭required,‬‭the‬‭risk‬‭of‬
‭overdose‬ ‭due‬ ‭to‬ ‭medication‬ ‭errors‬ ‭is‬ ‭minimal.‬ ‭The‬ ‭data‬ ‭available‬ ‭to‬ ‭date‬ ‭suggest‬‭that‬‭the‬
‭potential for harm from overdose is very low.‬
‭Weekly‬ ‭gemcitabine‬ ‭with‬ ‭GC‬ ‭every‬ ‭3-4‬ ‭weeks‬ ‭is‬ ‭considered‬ ‭conventional‬ ‭first-line‬
‭chemotherapy‬‭for‬‭aUC.‬‭Weekly‬‭split-dose‬‭cisplatin‬‭with‬‭wGC‬‭might‬‭be‬‭less‬‭toxic‬‭and‬‭have‬
‭similar‬ ‭activity.‬ ‭Considering‬ ‭the‬ ‭probable‬ ‭lower‬ ‭nephrotoxicity‬ ‭of‬ ‭fractionated‬ ‭cisplatin,‬
‭prospective‬ ‭evaluation‬ ‭of‬ ‭wGC‬ ‭might‬ ‭be‬ ‭warranted‬‭across‬‭cisplatin-eligible‬‭and‬‭-ineligible‬
‭patients‬‭to‬‭develop‬‭a‬‭single‬‭chemotherapy‬‭template‬‭for‬‭the‬‭development‬‭of‬‭combinations‬‭with‬
‭biological agents in a broad population of patients (‬‭Maughan BL, et al. 2013‬‭).‬
‭In‬‭conclusion,‬‭the‬‭proposed‬‭scientific‬‭rationale‬‭and‬‭the‬‭preliminary‬‭benefit-risk‬‭profile‬‭of‬‭the‬
‭study‬ ‭treatments‬ ‭observed‬ ‭in‬ ‭previous‬ ‭trials‬ ‭support‬ ‭the‬ ‭further‬ ‭investigation‬ ‭of‬ ‭the‬
‭combination in the patient population and dosification regimen chosen for this study.‬
‭4.4.‬
‭Study Objectives‬
‭4.4.1. Primary Objectives‬
‭To‬‭evaluate‬‭the‬‭preliminary‬‭efficacy‬‭of‬‭atezolizumab‬‭plus‬‭split-dose‬‭gemcitabine‬‭and‬‭cisplatin‬
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‭(GC)‬ ‭for‬ ‭the‬ ‭first-line‬ ‭setting,‬ ‭in‬ ‭patients‬ ‭with‬ ‭histologically‬ ‭confirmed‬ ‭advanced‬ ‭(locally‬
‭advanced‬‭and‬‭metastatic)‬‭urothelial‬‭cancer‬‭in‬‭terms‬‭of‬‭overall‬‭response‬‭rate‬‭(ORR)‬‭assessed‬‭by‬
‭the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.‬
‭4.4.2. Secondary Objectives‬
‭Efficacy:‬
‭●‬ ‭To‬ ‭evaluate‬ ‭the‬ ‭duration‬ ‭of‬ ‭response‬ ‭(DoR)‬ ‭associated‬ ‭with‬ ‭the‬ ‭study‬ ‭treatment,‬
‭understood‬‭as‬‭the‬‭time‬‭from‬‭first‬‭confirmed‬‭response‬‭(CR‬‭or‬‭PR)‬‭to‬‭the‬‭date‬‭of‬‭the‬
‭documented‬‭progressive‬‭disease‬‭as‬‭determined‬‭using‬‭RECIST‬‭1.1‬‭criteria‬‭or‬‭death‬‭due‬
‭to any cause, whichever occurs first.‬
‭●‬ ‭To‬ ‭determine‬ ‭the‬ ‭overall‬ ‭survival‬ ‭(OS)‬ ‭of‬ ‭patients‬ ‭with‬ ‭locally-advanced‬ ‭or‬ ‭mUC‬
‭treated‬‭with‬‭the‬‭intended‬‭treatment‬‭regimen,‬‭understood‬‭as‬‭the‬‭time‬‭from‬‭first‬‭dosing‬
‭date‬‭to‬‭the‬‭date‬‭of‬‭death.‬‭A‬‭subject‬‭who‬‭has‬‭not‬‭died‬‭will‬‭be‬‭censored‬‭at‬‭the‬‭last‬‭known‬
‭date alive.‬
‭●‬ ‭To‬‭evaluate‬‭the‬‭time‬‭to‬‭response‬‭(TtR)‬‭associated‬‭with‬‭the‬‭study‬‭treatment,‬‭understood‬
‭as‬‭the‬‭time‬‭from‬‭the‬‭first‬‭dose‬‭of‬‭the‬‭study‬‭treatment‬‭and‬‭confirmed‬‭response‬‭(CR‬‭or‬
‭PR) based on RECIST 1.1 criteria.‬
‭●‬ ‭To evaluate the‬‭clinical benefit rate (CBR)‬‭, defined‬‭as the percentage of patients who‬
‭have achieved complete response, partial response and stable disease. Stable disease‬
‭should be maintained for at least 6 months to be considered as a CBR event.‬
‭●‬ ‭To‬‭determine‬‭the‬‭progression-free‬‭survival‬‭(PFS)‬‭of‬‭patients‬‭with‬‭locally-advanced‬‭or‬
‭mUC‬ ‭treated‬ ‭with‬ ‭the‬ ‭intended‬ ‭treatment‬ ‭regimen,‬ ‭defined‬ ‭as‬ ‭the‬ ‭time‬ ‭from‬ ‭first‬
‭dosing‬‭date‬‭until‬‭disease‬‭progression‬‭or‬‭death‬‭from‬‭any‬‭cause.‬‭Patients‬‭who‬‭have‬‭not‬
‭progressed and start a new line of treatment will be censored.‬
‭Safety:‬
‭●‬ ‭To‬ ‭evaluate‬ ‭safety‬ ‭of‬ ‭the‬ ‭intended‬ ‭treatment‬ ‭regimen‬ ‭based‬ ‭on‬ ‭the‬ ‭frequency‬ ‭and‬
‭severity of adverse events assessed by NCI CTCAE v5.0.‬
‭4.‬‭4‬‭.3.‬ ‭Exploratory‬‭objectives‬
‭●‬ ‭To‬ ‭explore‬ ‭potential‬ ‭correlation‬ ‭of‬ ‭efficacy‬ ‭with‬ ‭relevant‬ ‭potential‬ ‭prognostic‬
‭factors/stratification factors‬
‭●‬ ‭To‬ ‭evaluate‬ ‭the‬ ‭relationship‬‭between‬‭the‬‭expression‬‭of‬‭PD-L1and‬‭microbiome‬‭with‬
‭ORR and PFS during experimental treatment.‬
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‭5.‬ ‭STUDY DESIGN‬
‭5.1.‬
‭Study design‬
‭The‬ ‭AUREA‬ ‭study‬ ‭is‬ ‭a‬ ‭multicenter,‬ ‭open‬ ‭labelled,‬‭single‬‭arm,‬‭Phase‬‭II‬‭clinical‬‭trial‬‭of‬‭of‬
‭atezolizumab‬‭in‬‭combination‬‭of‬‭split-dose‬‭cisplatin‬‭plus‬‭gemcitabine‬‭in‬‭patients‬‭with‬‭locally‬
‭advanced‬‭or‬‭metastatic‬‭urothelial‬‭carcinoma‬‭(additional‬‭details‬‭on‬‭the‬‭eligibility‬‭criteria‬‭of‬‭the‬
‭study are found in section 6 of this protocol).‬
‭The‬‭design‬‭includes‬‭screening‬‭phase,‬‭combined‬‭treatment‬‭initial‬‭phase,‬‭monotherapy‬‭treatment‬
‭phase,‬ ‭follow-up‬ ‭phase‬ ‭and‬ ‭translational‬ ‭research‬ ‭with‬ ‭biopsies,‬ ‭blood‬ ‭samples‬ ‭and‬ ‭faecal‬
‭samples.‬
‭The‬ ‭dose‬ ‭scheme‬ ‭includes‬ ‭the‬ ‭initial‬ ‭dose‬ ‭of‬ ‭atezolizumab‬ ‭(1200‬ ‭mg)‬ ‭intravenously‬
‭administered‬ ‭every‬ ‭21‬ ‭days‬ ‭(one‬ ‭cycle)‬‭up‬‭to‬‭disease‬‭progression,‬‭unacceptable‬‭toxicity‬‭or‬
‭absence‬ ‭of‬ ‭clinical‬ ‭benefit.‬ ‭Dose‬ ‭adjustment‬ ‭or‬ ‭dose‬ ‭reductions‬ ‭of‬ ‭atezolizumab‬ ‭are‬ ‭not‬
‭expected.‬‭Additional‬‭information‬‭on‬‭the‬‭treatment,‬‭modifications,‬‭and‬‭dose‬‭delays‬‭is‬‭available‬
‭in‬ ‭section‬ ‭7‬ ‭of‬ ‭this‬ ‭protocol.‬ ‭AUREA‬ ‭is‬ ‭an‬ ‭Investigator‬ ‭Initiated‬ ‭Study,‬ ‭the‬ ‭Sponsor‬ ‭will‬
‭supply‬‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬‭months‬‭of‬‭treatment‬‭for‬‭each‬‭patient.‬‭For‬‭those‬‭patients‬‭in‬
‭which‬‭the‬‭PI‬‭considers‬‭that‬‭the‬‭best‬‭option‬‭for‬‭the‬‭patient‬‭is‬‭continuing‬‭atezolizumab‬‭for‬‭more‬
‭than‬ ‭24‬ ‭months,‬ ‭available‬ ‭commercial‬ ‭Site‬ ‭supplies‬ ‭should‬ ‭be‬ ‭used,‬ ‭after‬ ‭managed‬ ‭local‬
‭administrative‬‭regulation.‬‭In‬‭case‬‭that‬‭the‬‭site‬‭cannot‬‭provide‬‭the‬‭drug‬‭for‬‭regulatory‬‭reasons‬
‭(for‬ ‭example,‬ ‭the‬ ‭indication‬ ‭is‬ ‭not‬ ‭financed)‬ ‭and‬ ‭always‬ ‭with‬ ‭prior‬ ‭approval‬‭by‬‭the‬‭study‬
‭sponsor‬ ‭(SOGUG)‬ ‭and‬ ‭by‬ ‭Roche,‬ ‭and‬ ‭if‬ ‭it‬ ‭is‬ ‭thus‬ ‭indicated‬ ‭in‬ ‭the‬ ‭contract‬ ‭between‬ ‭the‬
‭Sponsor‬‭and‬‭the‬‭Site,‬‭the‬‭patient‬‭could‬‭continue‬‭in‬‭treatment‬‭with‬‭Atezollizumab‬‭participating‬
‭in‬‭a‬‭Post-Trial‬‭Access‬‭(PTA)‬‭Program,‬‭previously‬‭approved‬‭by‬‭Roche.‬‭The‬‭maximum‬‭duration‬
‭of the PTA will be 1 year.‬
‭Study‬ ‭treatment‬ ‭will‬ ‭begin‬ ‭as‬ ‭soon‬ ‭as‬ ‭possible‬ ‭after‬ ‭signing‬ ‭the‬ ‭informed‬‭consent‬‭(as‬‭per‬
‭section 5.2‬‭of this protocol) and inclusion will be‬‭completed as per‬‭section 5.3‬‭of this protocol.‬
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‭Figure 1. Study design‬
‭5.2.‬
‭Patient selection‬
‭Once‬‭all‬‭regulatory‬‭and‬‭sponsor‬‭requirements‬‭are‬‭completed‬‭confirming‬‭that‬‭the‬‭study‬‭is‬‭fully‬
‭active‬‭in‬‭the‬‭corresponding‬‭site,‬‭informed‬‭consents‬‭can‬‭be‬‭offered‬‭to‬‭potential‬‭patients,‬‭and‬
‭patient selection can start in this site.‬
‭5.3.‬
‭Screening period and screening failure‬
‭Informed‬ ‭consent‬ ‭will‬ ‭be‬ ‭obtained‬ ‭prior‬ ‭to‬ ‭the‬ ‭start‬ ‭of‬ ‭the‬ ‭specified‬ ‭screening‬ ‭window.‬
‭Procedures‬‭conducted‬‭as‬‭part‬‭of‬‭the‬‭subject’s‬‭routine‬‭clinical‬‭management‬‭(e.g..,‬‭blood‬‭count‬
‭determinations‬‭and‬‭imaging‬‭studies)‬‭prior‬‭to‬‭signing‬‭of‬‭ICF‬‭may‬‭be‬‭used‬‭for‬‭screening‬‭or‬‭for‬
‭defining baseline data, provided these procedures are conducted as specified in the protocol.‬
‭Other‬‭procedures‬‭(such‬‭as‬‭the‬‭faecal‬‭sample‬‭collection)‬‭must‬‭be‬‭developed‬‭once‬‭the‬‭patient‬‭has‬
‭provided the signed consent for participation.‬
‭Once‬ ‭ICFs‬ ‭are‬ ‭signed,‬ ‭a‬ ‭trial‬ ‭screening‬ ‭number‬ ‭will‬ ‭be‬ ‭assigned‬ ‭to‬ ‭each‬ ‭patient‬ ‭after‬
‭registering‬ ‭at‬ ‭Electronic‬‭Data‬‭Capture‬‭(EDC)‬‭platform.‬‭Each‬‭site‬‭will‬‭receive‬‭access‬‭to‬‭the‬
‭EDC‬‭platform‬‭to‬‭register‬‭each‬‭screened‬‭case‬‭because‬‭as‬‭per‬‭GCP‬‭guidelines,‬‭it‬‭is‬‭mandatory‬‭to‬
‭register every patient who signs a consent form.‬
‭Furthermore,‬ ‭within‬ ‭the‬ ‭Investigator‬ ‭Site‬ ‭File‬ ‭(ISF),‬ ‭a‬ ‭Patient‬ ‭Identification‬ ‭List‬ ‭will‬ ‭be‬
‭included‬‭in‬‭order‬‭to‬‭identify‬‭patients‬‭according‬‭to‬‭local‬‭normal‬‭practice.‬‭This‬‭document‬‭will‬
‭allow‬ ‭for‬ ‭immediate‬ ‭and‬ ‭unequivocal‬ ‭identification‬ ‭of‬‭patients‬‭participating‬‭in‬‭this‬‭clinical‬
‭trial.‬
‭This‬‭document‬‭will‬‭always‬‭be‬‭stored‬‭under‬‭Investigator‬‭staff‬‭custody‬‭at‬‭the‬‭site.‬‭The‬‭screening‬
‭number‬ ‭will‬ ‭identify‬ ‭patients‬ ‭throughout‬ ‭the‬ ‭screening‬ ‭period‬ ‭while‬ ‭procedures‬ ‭needed‬ ‭to‬
‭confirm‬‭the‬‭subjects’‬‭suitability‬‭for‬‭the‬‭trial‬‭protocol,‬‭such‬‭as‬‭clinical‬‭laboratory‬‭tests,‬‭imaging,‬
‭and others are performed.‬
‭Screening‬‭determinations‬‭should‬‭be‬‭performed‬‭as‬‭per‬‭indications‬‭specified‬‭in‬‭Table‬‭4‬‭include‬
‭ICF‬‭signature,‬‭eligibility‬‭assessments,‬‭tumour‬‭characteristics,‬‭ECG,‬‭clinical‬‭evaluation‬‭(AE,‬
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‭PE,‬‭ECOG,‬‭VS,‬‭BMI,‬‭and‬‭symptom‬‭control),‬‭laboratory‬‭determinations‬‭(FBE,‬‭Biochemistry,‬
‭electrolytes,‬ ‭liver‬ ‭panel‬ ‭TF),‬ ‭Pancreatic‬ ‭enzymes,‬ ‭serology,‬ ‭urinalysis,‬ ‭pregnancy‬ ‭test,‬
‭concomitant‬ ‭medication,‬ ‭biological‬ ‭samples‬ ‭(tumour‬ ‭sample,‬‭biomarkers),‬‭CT‬‭Scan‬‭/‬‭MRI.‬
‭Availability‬ ‭of‬ ‭archival‬ ‭tumor‬ ‭blocks‬ ‭should‬ ‭be‬ ‭verified.‬ ‭Additional‬ ‭information‬ ‭about‬
‭screening procedures can be found in‬‭Section 8.4‬‭of‬‭this protocol.‬
‭5.4.‬
‭Patient registration/enrollment‬
‭After‬ ‭confirming‬ ‭that‬ ‭a‬ ‭patient‬ ‭fulfils‬ ‭all‬ ‭eligibility‬ ‭criteria‬ ‭of‬ ‭the‬ ‭study‬ ‭(‬‭Section‬ ‭6‬‭,‬‭study‬
‭population‬‭),‬ ‭site‬ ‭staff‬ ‭will‬ ‭initiate‬ ‭the‬ ‭electronic‬ ‭case‬ ‭report‬ ‭form‬ ‭(eCRF)‬ ‭registration‬
‭procedure.‬ ‭Once‬ ‭registration‬ ‭has‬ ‭been‬ ‭completed,‬ ‭the‬ ‭site‬ ‭staff‬ ‭will‬ ‭receive‬‭the‬‭“Inclusion‬
‭confirmation‬‭communication”,‬‭and‬‭study‬‭treatment‬‭can‬‭be‬‭initiated‬‭as‬‭per‬‭Section‬‭7‬‭(treatment‬
‭description‬‭).‬
‭5.5.‬
‭Treatment description, doses and schedules‬
‭During‬ ‭treatment,‬ ‭patients‬ ‭should‬ ‭be‬ ‭visited‬ ‭at‬ ‭baseline‬ ‭for‬ ‭administration‬ ‭of‬ ‭the‬ ‭study‬
‭treatment‬‭(Day‬‭1‬‭of‬‭each‬‭cycle)‬‭as‬‭follows:‬‭Atezolizumab‬‭1200‬‭mg,‬‭gemcitabine‬‭1000‬‭mg/m‬‭2‬
‭and‬ ‭cisplatin‬ ‭35‬ ‭mg/m‬‭2‬‭.‬ ‭A‬ ‭second‬ ‭visit‬ ‭on‬ ‭day‬ ‭8‬ ‭(D8)‬ ‭should‬ ‭be‬ ‭compiled‬ ‭in‬ ‭order‬ ‭to‬
‭administer the second dose of gemcitabine 1000 mg/m‬‭2‬‭and cisplatin 35 mg/m‬‭2‬‭cisplatin.‬
‭Atezolizumab‬ ‭will‬ ‭be‬ ‭administered‬ ‭first‬ ‭as‬ ‭a‬ ‭IV‬ ‭infusion‬ ‭according‬ ‭to‬ ‭what‬ ‭is‬ ‭detailed‬‭in‬
‭section‬ ‭7.4‬ ‭of‬ ‭this‬ ‭protocol,‬ ‭followed‬ ‭by‬ ‭the‬ ‭cisplatin‬ ‭infusion‬ ‭and‬ ‭then‬ ‭the‬ ‭gemcitabine‬
‭infusion.‬‭The‬‭GC‬‭infusion‬‭will‬‭start‬‭at‬‭least‬‭30‬‭minutes‬‭after‬‭completion‬‭of‬‭the‬‭atezolizumab‬
‭infusion.‬ ‭At‬ ‭the‬ ‭investigator’s‬ ‭discretion,‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭administered‬‭over‬‭a‬‭longer‬
‭infusion time (60 minutes) if the participant developed a prior infusion reaction.‬
‭This‬‭regimen‬‭will‬‭be‬‭repeated‬‭every‬‭three‬‭weeks‬‭(q3w)‬‭for‬‭up‬‭to‬‭6‬‭cycles.‬‭Once‬‭cycle‬‭6‬‭is‬
‭done,‬ ‭Atezolizumab‬ ‭1200‬ ‭mg/m‬‭2‬ ‭will‬‭be‬‭administered‬‭as‬‭monotherapy‬‭every‬‭3‬‭weeks‬‭until‬
‭disease‬ ‭progression,‬ ‭discontinuation‬ ‭due‬ ‭to‬ ‭unacceptable‬‭toxicity,‬‭withdrawal‬‭of‬‭consent‬‭or‬
‭absence‬‭of‬‭clinical‬‭benefit.‬‭AUREA‬‭is‬‭an‬‭Investigator‬‭Initiated‬‭Study,‬‭the‬‭Sponsor‬‭will‬‭supply‬
‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬‭months‬‭of‬‭treatment‬‭for‬‭each‬‭patient.‬‭For‬‭those‬‭patients‬‭in‬‭which‬
‭the‬‭PI‬‭considers‬‭that‬‭the‬‭best‬‭option‬‭for‬‭the‬‭patient‬‭is‬‭continuing‬‭atezolizumab‬‭for‬‭more‬‭than‬‭24‬
‭months,‬‭available‬‭commercial‬‭Site‬‭supplies‬‭should‬‭be‬‭used,‬‭after‬‭managed‬‭local‬‭administrative‬
‭regulation.‬‭In‬‭case‬‭that‬‭the‬‭site‬‭cannot‬‭provide‬‭the‬‭drug‬‭for‬‭regulatory‬‭reasons‬‭(for‬‭example,‬
‭the‬‭indication‬‭is‬‭not‬‭financed)‬‭and‬‭always‬‭with‬‭prior‬‭approval‬‭by‬‭the‬‭study‬‭sponsor‬‭(SOGUG)‬
‭and‬‭by‬‭Roche,‬‭and‬‭if‬‭it‬‭is‬‭thus‬‭indicated‬‭in‬‭the‬‭contract‬‭between‬‭the‬‭Sponsor‬‭and‬‭the‬‭Site,‬‭the‬
‭patient‬ ‭could‬ ‭continue‬‭in‬‭treatment‬‭with‬‭Atezollizumab‬‭participating‬‭in‬‭a‬‭Post-Trial‬‭Access‬
‭(PTA)‬‭Program,‬‭previously‬‭approved‬‭by‬‭Roche.‬ ‭The‬‭maximum‬‭duration‬‭of‬‭the‬‭PTA‬‭will‬‭be‬‭1‬
‭year.‬
‭All‬ ‭chemotherapy‬ ‭agents’‬ ‭preparation,‬ ‭premedication,‬ ‭administration,‬ ‭monitoring,‬ ‭and‬
‭management‬‭of‬‭complications‬‭are‬‭to‬‭follow‬‭local‬‭prescription‬‭guidelines‬‭and‬‭regulations.‬‭The‬
‭dose of chemotherapy may be capped per local standards.‬
‭All‬ ‭participants‬ ‭will‬ ‭be‬ ‭monitored‬ ‭continuously‬ ‭for‬ ‭adverse‬ ‭events‬ ‭(AEs)‬ ‭while‬ ‭on‬ ‭study‬
‭treatment.‬‭Treatment‬‭modifications‬‭(eg,‬‭dose‬‭delay,‬‭reduction,‬‭retreatment,‬‭or‬‭discontinuation)‬
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‭will‬‭be‬‭based‬‭on‬‭specific‬‭laboratory‬‭and‬‭adverse‬‭event‬‭criteria,‬‭as‬‭described‬‭in‬‭Section‬‭5.2‬‭and‬
‭Section 5.3‬‭.‬
‭Table 1. AUREA’s trial treatment schedule‬
‭Drug‬
‭Drug‬
‭Frequency‬
‭Administration‬
‭Treatment period‬
‭Use‬
‭Atezolizumab‬
‭1200 mg‬
‭Q3W‬
‭IV infusion‬
‭Day 1 of each cycle‬
‭Experimental‬
‭Gemcitabine‬
‭1000‬
‭mg/m‬‭2‬‭/day‬
‭Q3W‬
‭IV infusion‬
‭Day 1 and Day 8 of‬
‭each cycle up to 6‬
‭cycles‬
‭Experimental‬
‭Cisplatin‬
‭35 mg/m‬‭2‬‭/day‬
‭Q3W‬
‭IV infusion‬
‭Day 1 and Day 8 of‬
‭each cycle up to 6‬
‭cycles‬
‭Experimental‬
‭5.6.‬
‭Duration of study, recruitment, treatment and follow-up‬
‭●‬ ‭Enrolment/recruitment period: 12 months‬
‭●‬ ‭First patient first visit (FPFV): 8ENE2021‬
‭●‬ ‭Last patient last visit (LPLV): January 2024 (expected)‬
‭●‬ ‭Treatment period: Up to 24 months from LPFV‬
‭●‬ ‭Follow-up period: 24 months‬
‭●‬ ‭Planned end of study date: First quarter 2024 (expected)‬
‭5.7.‬
‭Determinations during the study‬
‭Determination‬ ‭during‬ ‭the‬ ‭study‬ ‭will‬ ‭be‬ ‭performed‬ ‭as‬ ‭per‬ ‭Table‬ ‭4‬ ‭and‬ ‭Section‬ ‭8.3‬ ‭of‬‭this‬
‭protocol.‬
‭5.7.1.‬ ‭Screening phase‬
‭The‬ ‭baseline‬ ‭assessments‬ ‭and‬ ‭procedures‬ ‭should‬ ‭be‬ ‭performed‬ ‭within‬ ‭28‬ ‭days‬ ‭before‬
‭inclusion, and when applicable, as close as possible to the start of study treatment.‬
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‭5.7.2.‬ ‭Treatment phase‬
‭Before‬ ‭each‬ ‭treatment‬ ‭administration‬ ‭chemotherapy/atezolizumab‬‭administration‬‭laboratory,‬
‭medical‬ ‭consulting‬ ‭and‬ ‭other‬ ‭determinations‬ ‭will‬ ‭be‬ ‭performed‬ ‭according‬ ‭to‬ ‭Table‬ ‭4‬ ‭and‬
‭Section 8.5‬‭to ensure that treatment can be safely‬‭administered.‬
‭A‬ ‭CT‬ ‭Scan‬ ‭or‬‭MRI‬‭will‬‭be‬‭performed‬‭at‬‭baseline,‬‭on‬‭week‬‭9,‬‭week‬‭18‬‭and‬‭then‬‭every‬‭12‬
‭weeks‬‭(q12w)‬‭±‬‭1w‬‭until‬‭objective‬‭disease‬‭progression‬‭as‬‭per‬‭PI’s‬‭criteria‬‭or‬‭death‬‭(whichever‬
‭comes‬‭first).‬‭Blood‬‭samples‬‭for‬‭biomarkers‬‭studies‬‭should‬‭be‬‭collected‬‭before‬‭administration‬
‭of cycle 4 and at the time of PD (end of treatment if applicable).‬
‭For‬ ‭patients‬ ‭with‬ ‭progression‬ ‭reported‬ ‭as‬ ‭per‬ ‭RECIST‬ ‭criteria‬ ‭at‬ ‭week‬ ‭9,‬ ‭continuity‬ ‭of‬
‭treatment‬‭with‬‭atezolizumab‬‭should‬‭be‬‭evaluated‬‭by‬‭the‬‭PI‬‭of‬‭each‬‭site‬‭as‬‭per‬‭clinical‬‭benefit‬
‭criteria.‬
‭5.7.3.‬ ‭Safety visit (after the end of treatment by any reason)‬
‭Safety‬‭follow-up‬‭visits‬‭will‬‭be‬‭scheduled‬‭up‬‭to‬‭30‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭study‬‭treatment‬
‭(end of treatment).‬
‭5.7.4.‬ ‭Follow up until progression‬
‭After‬‭the‬‭end‬‭of‬‭the‬‭combined‬‭treatment‬‭with‬‭atezolizumab‬‭and‬‭split‬‭dose‬‭of‬‭gemcitabine‬‭and‬
‭cisplatin,‬‭if‬‭the‬‭patient‬‭has‬‭finished‬‭treatment‬‭without‬‭progression‬‭and‬‭does‬‭not‬‭start‬‭a‬‭new‬
‭treatment‬‭line,‬‭will‬‭be‬‭visited‬‭every‬‭12‬‭weeks.‬‭At‬‭the‬‭time‬‭of‬‭progression‬‭blood‬‭samples‬‭should‬
‭be collected for biomarkers studies.‬
‭5.7.5.‬ ‭Follow up after progression‬
‭Overall,‬‭after‬‭progression,‬‭patients‬‭will‬‭continue‬‭the‬‭long-term‬‭follow‬‭up‬‭every‬‭6‬‭months‬‭until‬
‭death‬‭or‬‭end‬‭of‬‭study.‬‭Sponsor‬‭will‬‭ask‬‭the‬‭survival‬‭status‬‭of‬‭all‬‭patients‬‭at‬‭the‬‭final‬‭clinical‬
‭trial‬ ‭database‬ ‭closing,‬ ‭in‬ ‭order‬ ‭to‬ ‭maximise‬ ‭the‬ ‭median‬ ‭follow‬ ‭up‬ ‭of‬ ‭patients‬ ‭for‬ ‭overall‬
‭survival data.‬
‭In‬‭cases‬‭where‬‭atezolizumab‬‭treatment‬‭has‬‭been‬‭maintained‬‭because‬‭of‬‭clinical‬‭benefit,‬‭follow‬
‭up‬‭will‬‭comply‬‭with‬‭the‬‭“Follow‬‭up‬‭until‬‭progression”‬‭conditions,‬‭with‬‭visits‬‭every‬‭12‬‭weeks‬
‭along with radiological evaluation/assessment of the disease.‬
‭5.8.‬
‭End of study (EoS)‬
‭The‬‭end‬‭of‬‭study‬‭is‬‭defined‬‭as‬‭the‬‭Last‬‭Patient‬‭Last‬‭Visit‬‭(LPLV)‬‭and‬‭will‬‭be‬‭considered‬‭at‬‭24‬
‭months‬‭after‬‭last‬‭patient‬‭first‬‭visit‬‭(LPFV),‬‭Sponsor‬‭will‬‭ask‬‭survival‬‭status‬‭of‬‭all‬‭patients‬‭at‬
‭the‬‭final‬‭clinical‬‭trial‬‭database‬‭closing,‬‭in‬‭order‬‭to‬‭maximise‬‭the‬‭median‬‭follow‬‭up‬‭of‬‭patients‬
‭for overall survival data.‬
‭5.9.‬
‭Outcome assessments‬
‭5.9.1. Response evaluation according RECIST 1.1‬
‭All‬‭patients‬‭will‬‭have‬‭their‬‭best‬‭response‬‭according‬‭to‬‭RECIST‬‭criteria‬‭1.1‬‭from‬‭the‬‭start‬‭of‬
‭study treatment until the end of treatment classified as outlined below:‬
‭●‬ ‭Complete‬‭or‬‭partial‬‭responses‬‭may‬‭be‬‭claimed‬‭only‬‭if‬‭the‬‭criteria‬‭for‬‭each‬‭are‬‭met‬‭at‬‭a‬
‭subsequent time point at least 4 weeks later.‬
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‭●‬ ‭Complete‬ ‭Response‬ ‭(CR):‬ ‭disappearance‬ ‭of‬ ‭all‬ ‭target‬ ‭and‬ ‭non-target‬ ‭lesions‬ ‭and‬
‭normalization‬ ‭of‬ ‭tumour‬ ‭markers.‬ ‭Pathological‬ ‭lymph‬ ‭nodes‬ ‭must‬ ‭have‬ ‭short‬ ‭axis‬
‭measures‬ ‭<‬ ‭10‬ ‭mm‬ ‭(‬‭Note‬‭:‬ ‭continue‬ ‭to‬ ‭record‬ ‭the‬ ‭measurement‬‭even‬‭if‬‭<‬‭10‬‭mm‬‭and‬
‭considered‬ ‭CR).‬ ‭Tumour‬ ‭markers‬ ‭must‬ ‭have‬ ‭normalized.‬ ‭Residual‬ ‭lesions‬ ‭(other‬ ‭than‬
‭nodes‬‭<‬‭10‬‭mm)‬‭thought‬‭to‬‭be‬‭non-malignant‬‭should‬‭be‬‭further‬‭investigated‬‭(by‬‭cytology‬
‭or PET scans) before CR can be accepted.‬
‭●‬ ‭Partial‬‭Response‬‭(PR):‬‭at‬‭least‬‭a‬‭30%‬‭decrease‬‭in‬‭the‬‭sum‬‭of‬‭measures‬‭(longest‬‭diameter‬
‭for‬‭tumour‬‭lesions‬‭and‬‭short‬‭axis‬‭measure‬‭for‬‭nodes)‬‭of‬‭target‬‭lesions,‬‭taking‬‭as‬‭reference‬
‭the baseline sum of diameters. Non target lesions must be non-PD.‬
‭●‬ ‭Stable‬‭Disease‬‭(SD):‬‭Neither‬‭sufficient‬‭shrinkage‬‭to‬‭qualify‬‭for‬‭PR‬‭nor‬‭sufficient‬‭increase‬
‭to qualify for PD taking as reference the smallest sum of diameters on study.‬
‭●‬ ‭Progressive‬‭Disease‬‭(PD):‬‭at‬‭least‬‭a‬‭20%‬‭increase‬‭in‬‭the‬‭sum‬‭of‬‭diameters‬‭of‬‭measured‬
‭lesions‬‭taking‬‭as‬‭references‬‭the‬‭smallest‬‭sum‬‭of‬‭diameters‬‭recorded‬‭on‬‭study‬‭(including‬
‭baseline)‬ ‭AND‬ ‭an‬ ‭absolute‬ ‭increase‬ ‭of‬ ‭≥‬ ‭5‬ ‭mm.‬‭Appearance‬‭of‬‭new‬‭lesions‬‭will‬‭also‬
‭constitute‬ ‭PD‬ ‭(including‬ ‭lesions‬ ‭in‬ ‭previously‬ ‭unassessed‬ ‭areas).‬ ‭In‬ ‭exceptional‬
‭circumstances,‬ ‭unequivocal‬ ‭progression‬ ‭of‬ ‭non-target‬ ‭disease‬ ‭may‬ ‭be‬ ‭accepted‬ ‭as‬
‭evidence‬ ‭of‬ ‭disease‬ ‭progression,‬ ‭where‬ ‭the‬ ‭overall‬ ‭tumour‬ ‭burden‬ ‭has‬ ‭increased‬
‭sufficiently‬‭to‬‭merit‬‭discontinuation‬‭of‬‭treatment,‬‭for‬‭example‬‭where‬‭the‬‭tumour‬‭burden‬
‭appears‬‭to‬‭have‬‭increased‬‭by‬‭at‬‭least‬‭73%‬‭in‬‭volume‬‭(which‬‭is‬‭the‬‭increase‬‭in‬‭volume‬
‭when‬‭all‬‭dimensions‬‭of‬‭a‬‭single‬‭lesion‬‭increase‬‭by‬‭20%).‬‭Modest‬‭increases‬‭in‬‭the‬‭size‬‭of‬
‭one‬ ‭or‬ ‭more‬ ‭non-target‬ ‭lesions‬ ‭are‬ ‭NOT‬ ‭considered‬ ‭unequivocal‬ ‭progression.‬ ‭If‬ ‭the‬
‭evidence‬‭of‬‭PD‬‭is‬‭equivocal‬‭(target‬‭or‬‭non-target),‬‭treatment‬‭may‬‭continue‬‭until‬‭the‬‭next‬
‭assessment, but on further documentation, the earlier date must be used.‬
‭5.9.2.‬ ‭Safety assessments‬
‭Safety‬ ‭parameters‬ ‭are‬ ‭AE,‬ ‭SAE,‬ ‭AESI,‬ ‭pregnancy,‬ ‭medication‬ ‭error,‬ ‭overdose.‬ ‭Additional‬
‭safety‬‭information‬‭could‬‭be‬‭derived‬‭from‬‭ECG,‬‭lab‬‭test,‬‭pregnancy‬‭test,‬‭or‬‭vital‬‭sign‬‭exam.‬
‭The‬‭assessment‬‭of‬‭adverse‬‭events‬‭will‬‭include‬‭the‬‭type‬‭of‬‭event‬‭(including‬‭symptoms,‬‭physical‬
‭exam‬‭findings‬‭and‬‭laboratory‬‭abnormalities),‬‭the‬‭incidence,‬‭severity,‬‭timing,‬‭seriousness,‬‭and‬
‭relatedness‬‭regarding‬‭the‬‭treatment‬‭under‬‭study.‬‭Adverse‬‭events‬‭will‬‭be‬‭recorded‬‭and‬‭reported‬
‭in‬‭the‬‭corresponding‬‭section‬‭of‬‭the‬‭case‬‭report‬‭form.‬‭The‬‭grade‬‭of‬‭adverse‬‭events‬‭will‬‭be‬‭coded‬
‭according‬ ‭to‬ ‭the‬ ‭National‬ ‭Cancer‬ ‭Institute’s‬ ‭Common‬ ‭Toxicity‬ ‭criteria‬ ‭(NCI-CTCAE‬ ‭v5.0‬
‭scoring‬ ‭system).‬ ‭The‬ ‭worst‬ ‭toxicity‬ ‭score‬ ‭will‬ ‭be‬ ‭recorded.‬ ‭In‬‭case‬‭of‬‭SAE‬‭and‬‭AESI‬‭the‬
‭investigator‬‭should‬‭immediately‬‭fill‬‭in‬‭the‬‭dedicated‬‭SAE‬‭form‬‭and‬‭send‬‭it‬‭by‬‭as‬‭detailed‬‭in‬
‭Section 9.2‬
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‭6.‬
‭STUDY POPULATION‬
‭6.1.‬
‭Inclusion criteria‬
‭1.‬ ‭Male or female subjects ≥ 18 years old.‬
‭2.‬ ‭Written‬‭informed‬‭consent‬‭approved‬‭by‬‭the‬‭Independent‬‭Ethics‬‭Committee‬‭(IEC),‬‭prior‬
‭to the performance of any trial activities.‬
‭3.‬ ‭Patients‬ ‭with‬ ‭histologically‬ ‭documented,‬ ‭locally‬ ‭advanced‬ ‭(T4B,‬ ‭any‬ ‭N;‬ ‭or‬ ‭any‬‭T,‬
‭N2-3) or metastatic urothelial carcinoma (M1, Stage IV)*.‬
‭*Also‬‭termed‬‭transitional‬‭cell‬‭carcinoma‬‭(TCC)‬‭or‬‭urothelial‬‭cell‬‭carcinoma‬‭[UCC]‬‭of‬
‭the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra).‬
‭4.‬ ‭Patients‬‭should‬‭not‬‭be‬‭eligible‬‭(unfit)‬‭for‬‭full‬‭dose‬‭of‬‭cisplatin,‬‭in‬‭the‬‭investigator’s‬
‭judgement, based on:‬
‭a.‬ ‭Age older than 70 years‬
‭a.‬ ‭ECOG‬ ‭Performance‬ ‭status‬ ‭(PS)‬ ‭2‬ ‭or‬ ‭Karnofsky‬ ‭PS‬‭of‬‭60‬‭-‬‭70%‬ ‭(only‬‭15‬
‭patients will be included with ECOG 2)‬
‭b.‬ ‭Measured‬ ‭creatinine‬ ‭clearance‬ ‭(ClCr)‬ ‭>‬ ‭30‬ ‭and‬ ‭<‬ ‭60‬ ‭mL/min‬ ‭by‬ ‭the‬
‭Cockcroft-Gault‬ ‭formula‬ ‭(Cockcroft‬ ‭and‬ ‭Gault‬ ‭1976)‬ ‭or‬ ‭by‬ ‭24-hour‬ ‭urine‬
‭collection for the determination of creatinine clearance:‬
‭Males:‬
‭Creatinine CL (mL/min)  =‬
‭Weight (kg) × (140 – Age)‬
‭72 x serum creatinine (mg/dL)‬
‭Females:‬
‭Creatinine CL (mL/min)  =‬
‭Weight (kg) × (140 – Age)‬‭×0.85‬
‭72 x serum creatinine (mg/dL)‬
‭c.‬ ‭Any‬‭other‬‭reason‬‭the‬‭physician‬‭considers‬‭but‬‭should‬‭specify‬‭in‬‭the‬‭CRF‬‭and‬
‭discussed with the PI.‬
‭5.‬ ‭At‬ ‭least‬ ‭one‬ ‭measurable‬ ‭lesion‬ ‭through‬ ‭radiographic‬‭tumor‬‭evaluation‬‭(CT‬‭scan‬‭or‬
‭magnetic‬ ‭resonance‬ ‭imaging)‬‭as‬‭defined‬‭by‬‭RECIST‬‭version‬‭1.1,‬‭that‬‭has‬‭not‬‭been‬
‭previously irradiated within 4 weeks prior to the study enrolment.‬
‭6.‬ ‭Patients‬ ‭with‬ ‭an‬ ‭archival‬ ‭or‬ ‭de‬ ‭novo‬ ‭tumor‬ ‭biopsy‬ ‭(representative‬ ‭formalin-fixed‬
‭paraffin-embedded/FFPE‬ ‭paraffin‬ ‭block‬ ‭obtained‬ ‭as‬‭close‬‭as‬‭possible‬‭to‬‭the‬‭patient‬
‭inclusion)‬‭with‬‭an‬‭associated‬‭pathology‬‭report,‬‭for‬‭testing‬‭of‬‭PD-L1‬‭expression‬‭prior‬
‭to‬ ‭study‬ ‭enrollment.‬ ‭Samples‬ ‭in‬ ‭unstained‬ ‭slides‬ ‭could‬ ‭be‬ ‭acceptable‬ ‭(at‬ ‭least‬ ‭15‬
‭slides).‬
‭7.‬ ‭Patients with adequate normal organ and marrow function as defined below:‬
‭a.‬ ‭Haemoglobin (Hb) ≥ 9.0 g/dL.‬
‭b.‬ ‭Absolute neutrophil count (ANC)‬‭>‬‭1500 per mm‬‭3‬‭.‬
‭c.‬ ‭Platelet count ≥ 100,000 per mm‬‭3‬‭.‬
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‭d.‬ ‭Serum‬‭bilirubin‬‭≤‬‭1.5‬‭X‬‭institutional‬‭upper‬‭limit‬‭of‬‭normal‬‭(ULN)‬‭unless‬‭liver‬
‭metastases‬ ‭are‬ ‭present,‬ ‭in‬ ‭which‬ ‭case‬ ‭it‬‭must‬‭be‬‭≤‬‭2X‬‭ULN.‬‭This‬‭will‬‭not‬
‭apply‬‭to‬‭patients‬‭with‬‭confirmed‬‭Gilbert’s‬‭syndrome‬‭(persistent‬‭or‬‭recurrent‬
‭hyperbilirubinemia‬ ‭that‬ ‭is‬ ‭predominantly‬ ‭unconjugated‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬
‭haemolysis‬ ‭or‬ ‭hepatic‬ ‭pathology);‬ ‭however,‬ ‭they‬ ‭will‬ ‭be‬ ‭allowed‬ ‭only‬ ‭in‬
‭consultation with their physician.‬
‭e.‬ ‭Serum‬‭transaminases‬‭(ALT,‬‭AST‬‭and‬‭GGT)‬‭≤‬‭2.5X‬‭institutional‬‭upper‬‭limit‬‭of‬
‭normal‬ ‭unless‬ ‭liver‬ ‭metastases‬ ‭are‬ ‭present,‬ ‭in‬ ‭which‬ ‭case‬‭it‬‭must‬‭be‬‭≤‬‭3X‬
‭ULN.‬
‭8.‬ ‭No major active bleeding.‬
‭9.‬ ‭Female‬ ‭subjects‬ ‭of‬ ‭childbearing‬ ‭potential‬ ‭(not‬ ‭surgically‬ ‭sterile‬ ‭or‬ ‭at‬ ‭least‬‭2‬‭years‬
‭postmenopausal)‬‭must‬‭provide‬‭a‬‭negative‬‭urine‬‭pregnancy‬‭test‬‭at‬‭screening,‬‭and‬‭use‬‭a‬
‭medically‬ ‭accepted‬ ‭double‬ ‭barrier‬ ‭method‬ ‭of‬ ‭contraception‬ ‭(i.e.‬ ‭condom‬ ‭with‬
‭spermicide‬‭+‬‭IUD‬‭or‬‭cervical‬‭caps).‬‭In‬‭addition,‬‭they‬‭must‬‭agree‬‭to‬‭continue‬‭the‬‭use‬‭of‬
‭this‬ ‭double‬ ‭barrier‬ ‭method‬ ‭for‬ ‭the‬ ‭duration‬ ‭of‬ ‭the‬ ‭study‬ ‭and‬ ‭for‬ ‭6‬ ‭months‬ ‭after‬
‭participation in the study.‬
‭10.‬‭Males‬‭should‬‭agree‬‭to‬‭abstain‬‭from‬‭sexual‬‭intercourse‬‭with‬‭a‬‭female‬‭partner‬‭or‬‭agree‬
‭to‬ ‭use‬ ‭a‬ ‭double‬ ‭barrier‬ ‭method‬ ‭of‬ ‭contraception‬ ‭(i.e.‬ ‭condom‬ ‭with‬ ‭spermicide,‬ ‭in‬
‭addition‬‭to‬‭having‬‭their‬‭female‬‭partner‬‭use‬‭some‬‭contraceptive‬‭measures‬‭such‬‭as‬‭oral‬
‭contraceptive‬ ‭drugs,‬ ‭intrauterine‬ ‭device‬ ‭(IUD)‬ ‭hormonal‬ ‭contraception,‬ ‭or‬ ‭cervical‬
‭caps), for the duration of the study and for 6 months after participation in the study‬
‭11.‬ ‭Willingness‬‭and‬‭ability‬‭of‬‭patients‬‭to‬‭comply‬‭with‬‭the‬‭protocol‬‭for‬‭the‬‭duration‬‭of‬‭the‬
‭study‬‭including‬‭undergoing‬‭treatment‬‭as‬‭well‬‭as‬‭availability‬‭for‬‭scheduled‬‭visits‬‭and‬
‭examinations including follow up.‬
‭6.2.‬
‭Exclusion criteria‬
‭1.‬ ‭Prior‬‭treatment‬‭with‬‭any‬‭immune‬‭checkpoint‬‭inhibitor‬‭therapy‬‭(e.g.,‬‭CTLA4,‬‭PD-1,‬‭or‬
‭PD-L1 targeting agent).*‬
‭*‬‭Note‬‭:‬ ‭Prior‬ ‭adjuvant‬ ‭or‬ ‭neoadjuvant‬ ‭treatment‬ ‭with‬ ‭targeted‬ ‭therapy/checkpoint‬
‭inhibitors‬‭is‬‭allowed,‬‭as‬‭long‬‭as‬‭the‬‭last‬‭dose‬‭was‬‭administered‬‭at‬‭least‬‭12‬‭months‬‭prior‬
‭to the patient inclusion in this trial.‬
‭2.‬ ‭Presence‬‭of‬‭active‬‭second‬‭malignancy‬‭and/or‬‭prior‬‭malignancy‬‭in‬‭the‬‭last‬‭2‬‭years‬‭is‬
‭allowed except for the following:‬
‭a.‬ ‭adequately treated basal cell or squamous cell skin cancer,‬
‭b.‬ ‭adequately‬‭treated‬‭Stage‬‭I‬‭or‬‭II‬‭cancer‬‭from‬‭which‬‭the‬‭patient‬‭is‬‭currently‬‭in‬
‭complete remission per investigators' clinical judgment.‬
‭3.‬ ‭Patient receiving radiation therapy within 4 weeks before inclusion.‬
‭4.‬ ‭Active‬ ‭or‬ ‭prior‬ ‭documented‬ ‭autoimmune‬ ‭disease‬ ‭within‬ ‭the‬ ‭past‬ ‭2‬ ‭years‬ ‭NOTE:‬
‭Subjects‬‭with‬‭vitiligo,‬‭Grave's‬‭disease,‬‭or‬‭psoriasis‬‭not‬‭requiring‬‭systemic‬‭treatment‬
‭(within the past 2 years) are not excluded.‬
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‭5.‬ ‭Active‬ ‭or‬ ‭prior‬ ‭documented‬ ‭inflammatory‬ ‭bowel‬ ‭disease‬‭(e.g.,‬‭Crohn's‬‭disease‬‭and‬
‭ulcerative colitis).‬
‭6.‬ ‭History of allogeneic organ transplant.‬
‭7.‬ ‭Subjects‬ ‭having‬ ‭a‬ ‭diagnosis‬ ‭of‬‭immunodeficiency‬‭or‬‭are‬‭receiving‬‭systemic‬‭steroid‬
‭therapy‬‭or‬‭any‬‭other‬‭form‬‭of‬‭immunosuppressive‬‭therapy‬‭within‬‭28‬‭days‬‭prior‬‭to‬‭the‬
‭first dose of trial treatment.‬
‭8.‬ ‭Current‬ ‭or‬ ‭prior‬ ‭use‬ ‭of‬ ‭immunosuppressive‬ ‭medication‬ ‭within‬ ‭7‬ ‭days‬ ‭prior‬ ‭to‬
‭enrolment, except the following:‬
‭a.‬ ‭Intranasal,‬ ‭inhaled,‬ ‭topical‬ ‭steroids,‬ ‭or‬ ‭local‬ ‭steroid‬ ‭injections‬ ‭(eg,‬
‭intra-articular injection);‬
‭i.‬
‭Systemic‬ ‭corticosteroids‬ ‭at‬ ‭physiologic‬ ‭doses‬ ‭≤10‬ ‭mg/day‬ ‭of‬
‭prednisone or equivalent;‬
‭ii.‬
‭Steroids‬‭as‬‭premedication‬‭for‬‭hypersensitivity‬‭reactions‬‭(eg,‬‭CT‬‭scan‬
‭premedication).‬
‭9.‬ ‭The‬‭subject‬‭has‬‭uncontrolled,‬‭significant‬‭intercurrent‬‭or‬‭recent‬‭illness‬‭(within‬‭6‬‭months‬
‭prior to inclusion) including, but not limited to, the following conditions:‬
‭a.‬ ‭Cardiovascular disorders:‬
‭i.‬
‭Class‬‭3‬‭or‬‭4‬‭congestive‬‭heart‬‭failure‬‭as‬‭defined‬‭by‬‭the‬‭New‬‭York‬‭Heart‬
‭Association,‬
‭unstable‬
‭angina‬
‭pectoris,‬
‭and‬
‭serious‬
‭cardiac‬
‭arrhythmias.‬
‭ii.‬
‭Uncontrolled‬‭hypertension‬‭defined‬‭as‬‭sustained‬‭blood‬‭press‬‭>‬‭150‬‭mm‬
‭hg‬‭systolic‬‭or‬‭>‬‭100‬‭mm‬‭hg‬‭diastolic‬‭despite‬‭optimal‬‭antihypertensive‬
‭treatment.‬
‭iii.‬
‭Stroke‬ ‭(including‬ ‭transient‬ ‭ischemic‬ ‭attack‬ ‭[TIA]),‬ ‭myocardial‬
‭infarction,‬‭other‬‭ischemic‬‭event,‬‭or‬‭thromboembolic‬‭event‬‭(e.g.,‬‭deep‬
‭venous‬‭thrombosis‬‭[DVT]‬‭and‬‭pulmonary‬‭embolism)‬‭within‬‭6‬‭months‬
‭before‬‭inclusion.‬‭Subjects‬‭with‬‭a‬‭more‬‭recent‬‭diagnosis‬‭of‬‭DVT‬‭are‬
‭allowed‬‭if‬‭stable,‬‭asymptomatic,‬‭and‬‭treated‬‭with‬‭LMWH‬‭for‬‭at‬‭least‬
‭6 weeks before study treatment.‬
‭b.‬ ‭Gastrointestinal‬ ‭disorders‬ ‭(e.g.,‬ ‭malabsorption‬ ‭syndrome‬ ‭or‬ ‭gastric‬ ‭outlet‬
‭obstruction)‬ ‭including‬ ‭those‬ ‭associated‬ ‭with‬ ‭a‬ ‭high‬ ‭risk‬ ‭of‬ ‭perforation‬ ‭or‬
‭fistula formulation:‬
‭i.‬
‭Tumours‬ ‭invading‬ ‭the‬ ‭GI‬ ‭tract,‬ ‭active‬ ‭peptic‬ ‭ulcer‬ ‭disease,‬
‭inflammatory‬
‭bowel‬
‭disease,‬
‭ulcerative‬
‭colitis,‬ ‭diverticulitis,‬
‭cholecystitis,‬
‭symptomatic‬
‭cholangitis‬
‭or‬
‭appendicitis,‬
‭acute‬
‭pancreatitis‬‭or‬‭acute‬‭obstruction‬‭of‬‭the‬‭pancreatic‬‭or‬‭biliary‬‭duct,‬‭or‬
‭gastric outlet obstruction.‬
‭ii.‬
‭Abdominal‬
‭fistula,‬
‭GI‬
‭perforation,‬
‭bowel‬
‭obstruction,‬
‭or‬
‭intra-abdominal‬ ‭abscess‬ ‭within‬ ‭6‬ ‭months‬ ‭before‬ ‭inclusion.‬ ‭Note:‬
‭complete‬ ‭healing‬ ‭of‬ ‭an‬ ‭intra-abdominal‬ ‭abscess‬ ‭must‬‭be‬‭confirmed‬
‭prior to start of the treatment.‬
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‭c.‬ ‭Clinically‬‭significant‬‭hematemesis‬‭or‬‭hemoptysis‬‭of‬‭>‬‭0.5‬‭teaspoon‬‭(>‬‭2.5‬‭ml)‬
‭of‬‭red‬‭blood‬‭or‬‭history‬‭of‬‭other‬‭significant‬‭bleeding‬‭within‬‭3‬‭months‬‭before‬
‭treatment.‬
‭d.‬ ‭Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.‬
‭e.‬ ‭Lesions invading major pulmonary blood vessels.‬
‭f.‬
‭Other clinically significant disorders such as:‬
‭i.‬
‭Active‬ ‭infection‬‭requiring‬‭systemic‬‭treatment,‬‭infection‬‭with‬‭human‬
‭immunodeficiency‬
‭virus‬
‭or‬
‭acquired‬
‭immunodeficiency‬
‭syndrome-related illness, or chronic hepatitis B or C infection.‬
‭ii.‬
‭Serious non-healing wound/ulcer/bone fracture.‬
‭iii.‬
‭Malabsorption syndrome.‬
‭iv.‬
‭Moderate to severe hepatic impairment (child-pugh B or C).‬
‭v.‬
‭Requirement for hemodialysis or peritoneal dialysis.‬
‭vi.‬
‭Uncontrolled diabetes mellitus.‬
‭10.‬‭Major‬‭surgery‬‭(e.g.,‬‭GI‬‭surgery‬‭and‬‭removal‬‭or‬‭biopsy‬‭of‬‭brain‬‭metastasis)‬‭within‬‭8‬
‭weeks‬ ‭before‬ ‭inclusion.‬ ‭Complete‬ ‭wound‬ ‭healing‬ ‭from‬ ‭major‬ ‭surgery‬ ‭must‬ ‭have‬
‭occurred‬ ‭4‬ ‭weeks‬ ‭before‬ ‭study‬ ‭treatment‬ ‭and‬ ‭from‬ ‭minor‬ ‭surgery‬ ‭(e.g.,‬ ‭simple‬
‭excision,‬ ‭tooth‬ ‭extraction)‬ ‭at‬ ‭least‬ ‭10‬ ‭days‬ ‭before‬ ‭study‬ ‭treatment.‬ ‭Subjects‬ ‭with‬
‭clinically relevant ongoing complications from prior surgery are not eligible.‬
‭11.‬ ‭Known‬ ‭human‬ ‭immunodeficiency‬ ‭virus‬ ‭(HIV)‬ ‭or‬ ‭acquired‬ ‭immunodeficiency‬
‭syndrome (AIDS)-related illness.‬
‭12.‬‭Any‬‭test‬‭for‬‭hepatitis‬‭B‬‭virus‬‭(HBV)‬‭or‬‭hepatitis‬‭C‬‭virus‬‭(HCV)‬‭indicating‬‭acute‬‭or‬
‭chronic infection.‬
‭13.‬‭Women who are pregnant or are breastfeeding.‬
‭14.‬‭Male‬‭patients‬‭must‬‭be‬‭surgically‬‭sterile‬‭or‬‭must‬‭agree‬‭to‬‭use‬‭effective‬‭contraception‬
‭during the period of therapy.‬
‭15.‬‭Any‬ ‭of‬ ‭the‬ ‭following‬ ‭within‬ ‭6‬ ‭months‬ ‭prior‬ ‭to‬ ‭study‬‭entry:‬‭myocardial‬‭infarction,‬
‭uncontrolled‬ ‭angina,‬ ‭uncontrolled‬ ‭hypertension,‬ ‭coronary/peripheral‬ ‭artery‬ ‭bypass‬
‭graft,‬ ‭symptomatic‬ ‭congestive‬ ‭heart‬ ‭failure,‬ ‭cerebrovascular‬ ‭accident‬ ‭or‬ ‭transient‬
‭ischemic attack.‬
‭16.‬‭Previously‬‭identified‬‭allergy‬‭or‬‭hypersensitivity‬‭to‬‭components‬‭of‬‭the‬‭study‬‭treatment‬
‭formulations.‬
‭6.3.‬
‭Criteria for withdrawal from the treatment and study‬
‭6.3.1. Permanent Interruption of study treatments‬
‭Any‬ ‭reason‬ ‭for‬ ‭discontinuing‬ ‭investigational‬ ‭products‬ ‭must‬ ‭be‬ ‭clearly‬ ‭recorded‬ ‭on‬ ‭the‬
‭electronic case report forms (eCRF).‬
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‭Patients‬‭will‬‭receive‬‭the‬‭product‬‭under‬‭investigation‬‭as‬‭per‬‭schedule‬‭described‬‭in‬‭section‬‭5.5‬‭of‬
‭this protocol or until any of the following occurs:‬
‭●‬ ‭Objective‬‭disease‬‭progression‬‭.‬‭However,‬‭patients‬‭with‬‭disease‬‭progression‬‭at‬
‭week‬‭9‬‭who‬‭are‬‭continuing‬‭to‬‭derive‬‭clinical‬‭benefit‬‭from‬‭the‬‭study‬‭treatment‬‭will‬‭be‬
‭eligible‬ ‭to‬ ‭continue‬ ‭with‬ ‭single-agent‬ ‭atezolizumab,‬ ‭provided‬ ‭that‬ ‭the‬ ‭treating‬
‭physician has determined that the benefit/risk for doing so is favorable;‬
‭●‬ ‭Global deterioration of health status requiring discontinuation‬‭;‬
‭●‬ ‭Unacceptable‬‭toxicity.‬‭If‬‭the‬‭unacceptable‬‭toxicity‬‭is‬‭attributed‬‭to‬‭one‬‭of‬‭the‬
‭two‬‭study‬‭treatments,‬‭the‬‭investigator‬‭(in‬‭discussion‬‭with‬‭the‬‭sponsor)‬‭may‬‭continue‬
‭treatment with the other study treatment;‬
‭●‬ ‭Investigator’s decision;‬
‭●‬ ‭Pregnancy;‬
‭●‬ ‭Protocol‬‭violation,‬‭only‬‭when‬‭non-compliance‬‭might‬‭significantly‬‭impact‬‭in‬
‭patients‬ ‭safety‬ ‭and/or‬ ‭trial‬ ‭results‬ ‭validity,‬ ‭as‬ ‭per‬ ‭case‬ ‭by‬ ‭case‬ ‭Sponsor‬
‭assessment/criteria;‬
‭●‬ ‭Lost to follow-up;‬
‭●‬ ‭Patient refused further treatment (follow-up permitted by patient);‬
‭●‬ ‭Study terminated by sponsor;‬
‭●‬ ‭Death.‬
‭For‬‭all‬‭participants,‬‭global‬‭deterioration‬‭of‬‭health‬‭status‬‭requiring‬‭discontinuation‬‭of‬
‭treatment‬‭without‬‭objective‬‭evidence‬‭of‬‭disease‬‭progression‬‭at‬‭that‬‭time‬‭should‬‭be‬‭reported‬‭as‬
‭‘symptomatic deterioration’ in the source data and in the eCRF.‬
‭A‬‭temporary‬‭interruption‬‭in‬‭study‬‭medication‬‭due‬‭to‬‭an‬‭AE‬‭is‬‭not‬‭considered‬‭to‬‭be‬‭permanent‬
‭discontinuation from investigational product.‬
‭Tumor‬‭assessments‬‭for‬‭participants,‬‭who‬‭discontinue‬‭study‬‭treatment‬‭without‬‭radiographic‬
‭progression, should continue as per protocol until radiographic progression is determined.‬
‭Chemotherapy‬ ‭dose‬ ‭reduction‬ ‭is‬ ‭allowed‬‭in‬‭study.‬‭Any‬‭participant‬‭with‬‭two‬‭prior‬‭dose‬
‭reductions‬‭to‬‭one‬‭agent‬‭who‬‭experiences‬‭a‬‭toxicity‬‭that‬‭would‬‭cause‬‭a‬‭third‬‭dose‬‭reduction‬
‭must‬ ‭be‬ ‭discontinued‬ ‭from‬ ‭that‬ ‭agent.‬ ‭A‬ ‭participant‬ ‭who‬ ‭is‬ ‭discontinued‬ ‭from‬ ‭the‬
‭chemotherapy treatment will remain on the study and receive atezolizumab.‬
‭If‬ ‭a‬ ‭participant‬ ‭meets‬ ‭criteria‬ ‭for‬ ‭discontinuation‬ ‭and‬ ‭the‬ ‭investigator‬ ‭is‬ ‭unable‬‭to‬
‭determine‬‭whether‬‭the‬‭event‬‭is‬‭related‬‭to‬‭atezolizumab‬‭or‬‭chemotherapy,‬‭the‬‭participant‬‭should‬
‭discontinue all treatments.‬
‭The‬‭assessment‬‭for‬‭discontinuation‬‭of‬‭atezolizumab‬‭should‬‭be‬‭made‬‭separately‬‭from‬
‭the‬‭assessment‬‭made‬‭for‬‭discontinuation‬‭of‬‭chemotherapy.‬‭If‬‭criteria‬‭for‬‭discontinuation‬‭for‬
‭atezolizumab‬‭are‬‭met‬‭before‬‭the‬‭first‬‭6‬‭atezolizumab‬‭+‬‭split-doses‬‭of‬‭gemcitabine‬‭and‬‭cisplatin‬
‭chemotherapy‬ ‭cycles‬ ‭have‬ ‭been‬ ‭completed,‬ ‭the‬ ‭split-dose‬ ‭GC‬ ‭chemotherapy‬‭may‬‭continue‬
‭until 6 cycles have been completed.‬
‭6.3.2. Withdrawal from the study‬
‭Subjects‬ ‭will‬ ‭be‬ ‭encouraged‬ ‭to‬ ‭complete‬ ‭the‬ ‭study;‬‭however,‬‭they‬‭may‬‭voluntarily‬
‭withdraw at any time.‬
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‭The‬ ‭investigator‬ ‭may‬ ‭also,‬ ‭at‬ ‭his/her‬ ‭discretion,‬ ‭withdraw‬ ‭the‬ ‭subject‬ ‭from‬
‭participating in this study at any time, or the sponsor may discontinue the study.‬
‭Reasons for early withdrawal from the study should be documented in the eCRF as:‬
‭●‬ ‭Study closed/terminated by sponsor;‬
‭●‬ ‭Lost to follow-up;‬
‭●‬ ‭Investigator’s decision;‬
‭●‬ ‭Subject withdrew consent (refused further follow-up);‬
‭●‬ ‭Major‬‭protocol‬‭non-compliance.‬‭Protocol‬‭violation,‬‭only‬‭when‬‭non-compliance‬‭might‬
‭significantly‬‭impact‬‭in‬‭patients‬‭safety‬‭and/or‬‭trial‬‭results‬‭validity,‬‭as‬‭per‬‭case‬‭by‬‭case‬
‭Sponsor assessment/criteria;‬
‭●‬ ‭Death.‬
‭If‬‭a‬‭patient‬‭does‬‭not‬‭return‬‭for‬‭a‬‭scheduled‬‭visit,‬‭every‬‭effort‬‭should‬‭be‬‭made‬‭to‬‭contact‬‭the‬
‭patient.‬‭All‬‭attempts‬‭to‬‭contact‬‭the‬‭patient‬‭and‬‭information‬‭received‬‭during‬‭contact‬‭attempts‬
‭must‬‭be‬‭documented‬‭in‬‭the‬‭patient’s‬‭medical‬‭record.‬‭In‬‭any‬‭circumstances,‬‭every‬‭effort‬‭should‬
‭be‬‭made‬‭to‬‭document‬‭patient‬‭outcomes,‬‭if‬‭possible.‬‭The‬‭investigator‬‭should‬‭inquire‬‭about‬‭the‬
‭reason‬ ‭for‬ ‭withdrawal,‬ ‭request‬ ‭the‬ ‭patient‬ ‭to‬ ‭return‬ ‭all‬ ‭unused‬ ‭investigational‬ ‭product(s),‬
‭request‬‭that‬‭the‬‭patient‬‭return‬‭for‬‭a‬‭final‬‭visit,‬‭if‬‭applicable,‬‭and‬‭follow‬‭up‬‭with‬‭the‬‭patient‬
‭regarding any unresolved AEs.‬
‭If‬‭the‬‭patient‬‭withdraws‬‭from‬‭the‬‭study,‬‭and‬‭also‬‭withdraws‬‭consent‬‭for‬‭disclosure‬‭of‬‭future‬
‭information,‬ ‭no‬ ‭further‬ ‭evaluations‬ ‭should‬ ‭be‬ ‭performed,‬ ‭and‬‭no‬‭additional‬‭data‬‭should‬‭be‬
‭collected.‬ ‭The‬ ‭sponsor‬ ‭may‬ ‭retain‬ ‭and‬ ‭continue‬ ‭to‬ ‭use‬ ‭any‬ ‭data‬ ‭collected‬ ‭before‬ ‭such‬
‭withdrawal of consent.‬
‭Date‬‭of‬‭withdrawal‬‭from‬‭the‬‭study,‬‭with‬‭reason‬‭for‬‭withdrawal,‬‭will‬‭be‬‭recorded‬‭on‬‭the‬‭eCRF.‬
‭In‬‭the‬‭case‬‭of‬‭death,‬‭a‬‭death‬‭certificate‬‭should‬‭be‬‭obtained‬‭if‬‭possible,‬‭with‬‭the‬‭cause‬‭of‬‭death‬
‭evaluated and documented.‬
‭Note: Patients withdrawn the trial for any reason, cannot enter again.‬
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‭7.‬
‭TREATMENT DESCRIPTION‬
‭For‬‭the‬‭purpose‬‭of‬‭this‬‭study,‬‭the‬‭investigational‬‭products‬‭as‬‭defined‬‭by‬‭(ICH‬‭E6‬‭1.33)‬‭are‬
‭atezolizumab, cisplatin and gemcitabine.‬
‭7.1.‬
‭Study medication‬
‭​‬
‭7.1.1.‬ ‭Atezolizumab‬
‭Atezolizumab‬ ‭will‬ ‭be‬ ‭supplied‬ ‭as‬ ‭60‬ ‭mg/mL‬ ‭glass‬ ‭vials‬ ‭of‬ ‭20-mL,‬ ‭nominal‬ ‭atezolizumab‬
‭amount per vial, 1200 mg.‬
‭Packaging‬ ‭and‬‭labeling‬‭will‬‭be‬‭in‬‭accordance‬‭with‬‭applicable‬‭local‬‭regulatory‬‭requirements‬
‭and applicable Good Manufacturing Practice (GMP) guidelines.‬
‭The‬ ‭information‬ ‭on‬ ‭the‬ ‭study‬ ‭treatment‬ ‭will‬ ‭be‬ ‭in‬ ‭accordance‬ ‭with‬ ‭approved‬ ‭submission‬
‭documents.‬
‭AUREA‬‭is‬‭an‬‭Investigator‬‭Initiated‬‭Study,‬‭the‬‭Sponsor‬‭will‬‭supply‬‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬
‭months‬‭of‬‭treatment‬‭for‬‭each‬‭patient.‬‭For‬‭those‬‭patients‬‭in‬‭which‬‭the‬‭PI‬‭considers‬‭that‬‭the‬‭best‬
‭option‬ ‭for‬ ‭the‬ ‭patient‬ ‭is‬ ‭continuing‬ ‭atezolizumab‬ ‭for‬ ‭more‬ ‭than‬ ‭24‬ ‭months,‬ ‭available‬
‭commercial‬ ‭Site‬ ‭supplies‬ ‭should‬ ‭be‬ ‭used,‬‭after‬‭managed‬‭local‬‭administrative‬‭regulation.‬‭In‬
‭case‬‭that‬‭the‬‭site‬‭cannot‬‭provide‬‭the‬‭drug‬‭for‬‭regulatory‬‭reasons‬‭(for‬‭example,‬‭the‬‭indication‬‭is‬
‭not‬‭financed)‬‭and‬‭always‬‭with‬‭prior‬‭approval‬‭by‬‭the‬‭study‬‭sponsor‬‭(SOGUG)‬‭and‬‭by‬‭Roche,‬
‭and‬‭if‬‭it‬‭is‬‭thus‬‭indicated‬‭in‬‭the‬‭contract‬‭between‬‭the‬‭Sponsor‬‭and‬‭the‬‭Site,‬‭the‬‭patient‬‭could‬
‭continue‬‭in‬‭treatment‬‭with‬‭Atezollizumab‬‭participating‬‭in‬‭a‬‭Post-Trial‬‭Access‬‭(PTA)‬‭Program,‬
‭previously approved by Roche.  The maximum duration of the PTA will be 1 year.‬
‭7.1.2.‬
‭Gemcitabine and Cisplatin‬
‭Gemcitabine and cisplatin will be supplied as per site clinical standards.‬
‭Packaging‬ ‭and‬‭labeling‬‭will‬‭be‬‭in‬‭accordance‬‭with‬‭applicable‬‭local‬‭regulatory‬‭requirements‬
‭and‬ ‭applicable‬ ‭Good‬ ‭Manufacturing‬ ‭Practice‬ ‭(GMP)‬ ‭guidelines,‬ ‭under‬ ‭commercial‬
‭presentation and each site availability.‬
‭The‬ ‭information‬ ‭on‬ ‭the‬ ‭study‬ ‭treatment‬ ‭will‬ ‭be‬ ‭in‬ ‭accordance‬ ‭with‬ ‭approved‬ ‭submission‬
‭documents.‬
‭7.2.‬
‭Treatment accountability and compliance‬
‭According‬ ‭to‬ ‭local‬ ‭legislation,‬ ‭the‬ ‭investigator‬ ‭will‬ ‭record‬ ‭in‬ ‭the‬ ‭medical‬ ‭history‬ ‭that‬ ‭the‬
‭patient is taking the medication as prescribed for each new cycle in the study.‬
‭7.2.1.‬ ‭Atezolizumab accountability and compliance‬
‭Atezolizumab‬ ‭will‬ ‭be‬ ‭dosed‬ ‭at‬ ‭the‬ ‭investigational‬ ‭site,‬ ‭compliance‬ ‭will‬ ‭be‬ ‭assessed‬ ‭by‬
‭reviewing‬‭the‬‭consistency‬‭of‬‭information‬‭in‬‭the‬‭IWRS,‬‭the‬‭eCRF,‬‭patient‬‭records,‬‭nurse‬‭sheets,‬
‭and in the pharmacy source documentation.‬
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‭7.2.2.‬ ‭Gemcitabine and Cisplatin accountability and compliance‬
‭Compliance‬‭of‬‭the‬‭split-dose‬‭GC‬‭chemotherapy‬‭will‬‭be‬‭assessed‬‭by‬‭reviewing‬‭the‬‭consistency‬
‭of‬ ‭information‬ ‭in‬ ‭the‬ ‭eCRF,‬ ‭patient‬ ‭records,‬ ‭nurse‬ ‭sheets,‬ ‭and‬ ‭in‬ ‭the‬ ‭pharmacy‬ ‭source‬
‭documentation.‬
‭7.3.‬
‭Preparation and Dispensing‬
‭Only‬‭qualified‬‭personnel‬‭who‬‭are‬‭familiar‬‭with‬‭procedures‬‭that‬‭minimize‬‭undue‬‭exposure‬‭to‬
‭them‬‭and‬‭to‬‭the‬‭environment‬‭should‬‭undertake‬‭the‬‭preparation,‬‭handling,‬‭and‬‭safe‬‭disposal‬‭of‬
‭chemotherapeutic agents.‬
‭Investigational‬‭products‬‭should‬‭be‬‭prepared‬‭and‬‭dispensed‬‭by‬‭an‬‭appropriately‬‭qualified‬‭and‬
‭experienced‬ ‭member‬ ‭of‬ ‭the‬ ‭study‬ ‭staff‬ ‭(e.g.,‬ ‭physician,‬ ‭nurse,‬ ‭physician’s‬ ‭assistant,‬
‭practitioner, or pharmacist) as allowed by local, state, and institutional guidance.‬
‭7.3.1.‬ ‭Atezolizumab preparation and dispensing‬
‭Atezolizumab‬‭will‬‭be‬‭dosed‬‭at‬‭the‬‭investigational‬‭site.‬‭Atezolizumab‬‭must‬‭not‬‭be‬‭used‬‭for‬‭any‬
‭purpose‬‭other‬‭than‬‭the‬‭trial.‬‭The‬‭administration‬‭of‬‭trial‬‭investigational‬‭products‬‭to‬‭patients‬‭who‬
‭have not been enrolled into the trial is not covered by the trial insurance.‬
‭7.3.2.‬ ‭Gemcitabine plus cisplatin preparation and dispensing‬
‭The‬‭GC‬‭treatment‬‭will‬‭be‬‭administered‬‭in‬‭quantities‬‭appropriate‬‭for‬‭the‬‭study‬‭visit‬‭schedule‬
‭and‬‭according‬‭to‬‭local‬‭practice.‬‭A‬‭qualified‬‭staff‬‭member‬‭will‬‭record‬‭all‬‭the‬‭study‬‭treatment‬
‭using‬ ‭the‬ ‭local‬ ‭practise.‬ ‭Procedures‬ ‭described‬ ‭in‬ ‭each‬ ‭institution’s‬ ‭pharmacy‬ ‭or‬ ‭hospital‬
‭standard operating procedure manual should be followed when handling hazardous drugs.‬
‭7.4.‬
‭Investigational Medical Products Administration‬
‭7.4.1.‬ ‭Atezolizumab administration‬
‭Atezolizumab‬‭will‬‭be‬‭administered‬‭after‬‭all‬‭procedures/assessments‬‭have‬‭been‬‭completed‬‭as‬
‭described‬‭in‬‭the‬‭Schedule‬‭of‬‭Activities‬‭(‬‭Table‬‭4‬‭),‬‭as‬‭a‬‭1-hour‬‭IV‬‭infusion‬‭once‬‭every‬‭3‬‭weeks‬
‭until‬‭disease‬‭progression,‬‭unacceptable‬‭toxicity‬‭or‬‭absence‬‭of‬‭clinical‬‭benefitt.‬‭AUREA‬‭is‬‭an‬
‭Investigator‬ ‭Initiated‬ ‭Study,‬ ‭the‬ ‭Sponsor‬ ‭will‬‭supply‬‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬‭months‬‭of‬
‭treatment‬‭for‬‭each‬‭patient.‬‭For‬‭those‬‭patients‬‭in‬‭which‬‭the‬‭PI‬‭considers‬‭that‬‭the‬‭best‬‭option‬‭for‬
‭the‬ ‭patient‬ ‭is‬ ‭continuing‬‭atezolizumab‬‭for‬‭more‬‭than‬‭24‬‭months,‬‭available‬‭commercial‬‭Site‬
‭supplies‬‭should‬‭be‬‭used,‬‭after‬‭managed‬‭local‬‭administrative‬‭regulation.‬‭In‬‭case‬‭that‬‭the‬‭site‬
‭cannot‬‭provide‬‭the‬‭drug‬‭for‬‭regulatory‬‭reasons‬‭(for‬‭example,‬‭the‬‭indication‬‭is‬‭not‬‭financed)‬‭and‬
‭always‬ ‭with‬‭prior‬‭approval‬‭by‬‭the‬‭study‬‭sponsor‬‭(SOGUG)‬‭and‬‭by‬‭Roche,‬‭and‬‭if‬‭it‬‭is‬‭thus‬
‭indicated‬ ‭in‬ ‭the‬ ‭contract‬ ‭between‬ ‭the‬ ‭Sponsor‬ ‭and‬ ‭the‬ ‭Site,‬ ‭the‬ ‭patient‬ ‭could‬ ‭continue‬ ‭in‬
‭treatment‬‭with‬‭Atezollizumab‬‭participating‬‭in‬‭a‬‭Post-Trial‬‭Access‬‭(PTA)‬‭Program,‬‭previously‬
‭approved by Roche.  The maximum duration of the PTA will be 1 year.‬
‭The‬‭infusions‬‭must‬‭not‬‭be‬‭administered‬‭as‬‭an‬‭intravenous‬‭push‬‭or‬‭bolus.‬‭The‬‭initial‬‭dose‬‭of‬
‭atezolizumab‬‭must‬‭be‬‭administered‬‭over‬‭60‬‭minutes.‬‭If‬‭the‬‭first‬‭infusion‬‭is‬‭well‬‭tolerated,‬‭all‬
‭subsequent infusions may be administered over 30 minutes.‬
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‭Atezolizumab‬ ‭will‬ ‭be‬ ‭administered‬ ‭in‬ ‭IV‬ ‭infusion‬ ‭bags‬ ‭containing‬ ‭0.9%‬ ‭sodium‬ ‭chloride‬
‭(NaCl)‬ ‭and‬ ‭infusion‬ ‭lines‬ ‭equipped‬ ‭with‬ ‭0.2‬ ‭or‬ ‭0.22‬‭m‬‭in-line‬‭filters.‬‭The‬‭IV‬‭bag‬‭may‬‭be‬
‭constructed‬‭of‬‭polyvinyl‬‭chloride,‬‭polyolefin,‬‭polyethylene,‬‭or‬‭polypropylene.‬‭The‬‭IV‬‭infusion‬
‭line‬‭may‬‭be‬‭constructed‬‭of‬‭polyvinyl‬‭chloride,‬‭polyethylene,‬‭polybutadiene,‬‭or‬‭polyurethane‬
‭and‬‭the‬‭0.2‬‭or‬‭0.22‬‭m‬‭in-line‬‭filter‬‭may‬‭be‬‭constructed‬‭of‬‭polyethersulfone‬‭or‬‭polysulfone.‬‭The‬
‭use‬‭of‬‭administration‬‭supplies‬‭composed‬‭of‬‭materials‬‭other‬‭than‬‭those‬‭listed‬‭should‬‭be‬‭avoided‬
‭if‬ ‭possible.‬ ‭Atezolizumab‬ ‭can‬ ‭be‬ ‭diluted‬ ‭to‬ ‭concentrations‬ ‭between‬ ‭3.2‬ ‭mg/mL‬ ‭and‬ ‭16.8‬
‭mg/mL‬ ‭in‬ ‭IV‬ ‭bags‬ ‭containing‬ ‭0.9%‬ ‭NaCl.‬ ‭Atezolizumab‬ ‭must‬ ‭be‬ ‭prepared/diluted‬ ‭under‬
‭appropriate aseptic conditions as it does not contain antimicrobial preservatives.‬
‭The‬‭prepared‬‭solution‬‭for‬‭infusion‬‭should‬‭be‬‭used‬‭immediately‬‭to‬‭limit‬‭microbial‬‭growth‬‭in‬
‭case‬‭of‬‭potential‬‭accidental‬‭contamination.‬‭If‬‭not‬‭used‬‭immediately,‬‭in-use‬‭storage‬‭time‬‭and‬
‭conditions‬‭prior‬‭to‬‭use‬‭are‬‭the‬‭responsibility‬‭of‬‭the‬‭user.‬‭For‬‭flat‬‭or‬‭fixed‬‭dosing‬‭(1200‬‭mg‬‭for‬
‭this‬‭clinical‬‭trial)‬‭in‬ ‭IV‬‭infusion‬‭bags,‬‭the‬‭dose‬‭solution‬‭may‬‭be‬‭stored‬‭at‬‭2°C–8°C‬‭(36°F‬‭–‬
‭46°F)‬‭for‬‭24‬‭hours‬‭or‬‭at‬‭ambient‬‭temperature‬‭≤‬‭25°C‬‭(77°F)‬‭for‬‭8‬‭hours.‬‭This‬‭time‬‭includes‬
‭storage‬ ‭and‬ ‭time‬ ‭for‬ ‭administration‬ ‭for‬ ‭infusion..‬ ‭Do‬ ‭not‬ ‭shake‬ ‭or‬ ‭freeze‬ ‭infusion‬ ‭bags‬
‭containing the dose solution.‬
‭Detailed‬‭information‬‭on‬‭infusion‬‭bags‬‭and‬‭medical‬‭devices‬‭to‬‭be‬‭used‬‭for‬‭the‬‭preparation‬‭of‬
‭the‬‭dilutions‬‭and‬‭subsequent‬‭administration‬‭will‬‭be‬‭provided‬‭in‬‭the‬‭Dosage‬‭and‬‭Administration‬
‭Instruction‬ ‭contained‬ ‭in‬ ‭the‬ ‭Summary‬ ‭of‬ ‭Product‬‭Characteristics,‬‭and‬‭when‬‭applicable,‬‭the‬
‭corresponding Pharmacy Guidelines.‬
‭Any‬‭unused‬‭portion‬‭of‬‭the‬‭solution‬‭should‬‭be‬‭discarded‬‭in‬‭biohazard‬‭waste‬‭disposal‬‭with‬‭final‬
‭disposal by accepted local and national standards of incineration.‬
‭No‬ ‭premedication‬‭is‬‭indicated‬‭for‬‭the‬‭administration‬‭of‬‭Cycle‬‭1‬‭of‬‭atezolizumab.‬‭However,‬
‭patients‬ ‭who‬ ‭experience‬ ‭an‬ ‭infusion-related‬ ‭reaction‬ ‭(IRR)‬ ‭or‬ ‭cytokine-release‬ ‭syndrome‬
‭(CRS)‬‭with‬‭atezolizumab‬‭may‬‭receive‬‭premedication‬‭with‬‭antihistamines,‬‭antipyretics,‬‭and/or‬
‭analgesics‬‭(e.g.,‬‭acetaminophen)‬‭for‬‭subsequent‬‭infusions.‬‭See‬‭more‬‭information‬‭in‬‭Appendix‬
‭1‬‭.‬
‭7.4.1.1.‬‭Intrapatient Atezolizumab Dose Reduction‬
‭The‬‭dose‬‭amount‬‭required‬‭to‬‭prepare‬‭the‬‭atezolizumab‬‭infusion‬‭solution‬‭will‬‭be‬‭based‬‭on‬‭the‬
‭corresponding‬‭flat‬‭dose‬‭of‬‭1200‬‭mg‬‭established‬‭in‬‭this‬‭protocol.‬‭Overall,‬‭Atezolizumab‬‭dose‬
‭reduction‬ ‭for‬ ‭toxicity‬ ‭management‬ ‭is‬ ‭not‬ ‭permitted.‬ ‭Toxicity‬ ‭management‬ ‭(dose‬ ‭delay‬ ‭or‬
‭discontinuation) in case of immune-mediated events is described in‬‭Appendix 1‬‭.‬
‭7.4.2.‬ ‭Gemcitabine and cisplatin administration‬
‭The‬‭infusions‬‭must‬‭not‬‭be‬‭administered‬‭as‬‭an‬‭intravenous‬‭push‬‭or‬‭bolus.‬‭The‬‭estimated‬‭total‬
‭infusion‬‭time‬‭for‬‭this‬‭treatment‬‭takes‬‭up‬‭to‬‭two‬‭hours‬‭for‬‭Day‬‭1‬‭and‬‭Day‬‭8‬‭of‬‭each‬‭21-days‬
‭cycle.‬‭Typically,‬‭IV‬‭hydration‬‭is‬‭given‬‭both‬‭before‬‭and‬‭after‬‭cisplatin‬‭and‬‭can‬‭add‬‭up‬‭to‬‭two‬
‭hours‬‭on‬‭administration‬‭days.‬‭Infusion‬‭times‬‭may‬‭vary‬‭depending‬‭on‬‭physician‬‭preference‬‭or‬
‭patient tolerability.‬
‭7.4.2.1. Gemcitabine administration‬
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‭Gemcitabine‬ ‭will‬ ‭be‬ ‭administered‬ ‭after‬ ‭all‬‭procedures/assessments‬‭have‬‭been‬‭completed‬‭as‬
‭described‬‭in‬‭the‬‭Schedule‬‭of‬‭Activities‬‭(‬‭Table‬‭4‬‭),‬‭as‬‭a‬‭30-minutes‬‭IV‬‭infusion‬‭on‬‭days‬‭1‬‭and‬‭8‬
‭once every 3 weeks for a maximum of 6 cycles.‬
‭Gemcitabine‬ ‭is‬ ‭tolerated‬ ‭well‬ ‭during‬ ‭infusion‬ ‭and‬ ‭may‬ ‭be‬ ‭administered‬ ‭ambulant.‬ ‭If‬
‭extravasation‬‭occurs,‬‭generally‬‭the‬‭infusion‬‭must‬‭be‬‭stopped‬‭immediately‬‭and‬‭started‬‭again‬‭in‬
‭another‬ ‭blood‬ ‭vessel.‬ ‭The‬ ‭patient‬ ‭should‬ ‭be‬ ‭monitored‬ ‭carefully‬ ‭after‬ ‭the‬ ‭administration.‬
‭Treatment‬‭omitted‬‭will‬‭not‬‭be‬‭reinstated‬‭within‬‭a‬‭cycle.‬‭Treatment‬‭will‬‭start‬‭on‬‭day‬‭1‬‭of‬‭the‬
‭next‬‭cycle‬‭once‬‭the‬‭absolute‬‭granulocyte‬‭count‬‭reaches‬‭at‬‭least‬‭1,500‬‭(x10‬‭6‬‭/l)‬‭and‬‭the‬‭platelet‬
‭count reaches 100,000 (x10‬‭6‬‭/l)‬‭.‬
‭7.4.2.2.‬‭Cisplatin administration‬
‭Cisplatin‬‭should‬‭be‬‭administered‬‭by‬‭intravenous‬‭infusion‬‭over‬‭a‬‭period‬‭of‬‭2‬‭hours‬‭(up‬‭to‬‭8‬
‭hours)‬‭on‬‭days‬‭1‬‭and‬‭8‬‭once‬‭every‬‭3‬‭weeks‬‭for‬‭a‬‭maximum‬‭of‬‭6‬‭cycles.‬‭Adequate‬‭hydration‬
‭must‬‭be‬‭maintained‬‭from‬‭2‬‭to‬‭12‬‭hours‬‭prior‬‭to‬‭administration‬‭until‬‭minimum‬‭6‬‭hours‬‭after‬‭the‬
‭administration‬‭of‬‭cisplatin.‬‭Hydration‬‭is‬‭necessary‬‭to‬‭cause‬‭sufficient‬‭diuresis‬‭during‬‭and‬‭after‬
‭treatment‬‭with‬‭cisplatin.‬‭It‬‭is‬‭realised‬‭by‬‭intravenous‬‭infusion‬‭of‬‭one‬‭of‬‭the‬‭following‬‭solutions‬
‭specified on the SmPC.‬
‭7.4.2.3.‬‭Intrapatient Gemcitabine and Cisplatin Dose Reduction‬
‭According‬ ‭to‬ ‭the‬ ‭current‬ ‭version‬ ‭of‬ ‭Gemcitabine‬ ‭Summary‬ ‭of‬ ‭Product‬ ‭Characteristics‬
‭(‬‭Gemcitabine‬‭SmPC‬‭)‬‭at‬‭the‬‭time‬‭of‬‭this‬‭study‬‭design‬‭(March‬‭2020),‬‭dose‬‭modifications‬‭are‬
‭considered‬‭in‬‭case‬‭of‬‭haematological‬‭toxicity‬‭as‬‭described‬‭below.‬‭For‬‭the‬‭matter‬‭of‬‭this‬‭study,‬
‭information‬‭on‬‭dose‬‭modification‬‭recommendations‬‭for‬‭gemcitabine‬‭given‬‭in‬‭monotherapy‬‭or‬
‭in combination with cisplatin for bladder cancer are described.‬
‭Dose modifications due to haematological toxicity: Initiation of a cycle‬
‭For‬‭all‬‭indications,‬‭the‬‭patient‬‭must‬‭be‬‭monitored‬‭before‬‭each‬‭dose‬‭for‬‭platelet‬‭and‬‭granulocyte‬
‭counts.‬ ‭Patients‬ ‭should‬ ‭have‬ ‭an‬ ‭absolute‬‭granulocyte‬‭count‬‭of‬‭at‬‭least‬‭1,500‬‭(x‬‭10‬‭6‬ ‭/l)‬‭and‬
‭platelet account of 100,000 (x 10‬‭6‬‭/l) prior to the‬‭initiation of a cycle.‬
‭Dose modifications due to haematological toxicity: Within a cycle‬
‭Dose modifications of gemcitabine within a cycle should be performed according to‬‭Table 2‬‭:‬
‭Table‬‭2.‬‭Dose‬‭modification‬‭of‬‭gemcitabine‬‭within‬‭a‬‭cycle‬‭for‬‭bladder‬‭cancer,‬‭NSCLC‬‭and‬
‭pancreatic cancer, given in monotherapy or in combination with cisplatin‬
‭Absolute granulocyte count‬
‭(x 10‬‭6‬‭/l)‬
‭Platelet count‬
‭(x 10‬‭6‬‭/l)‬
‭Percentage of standard dose‬
‭of Gemcitabine (%)‬
‭> 1,000 and‬
‭> 100,000‬
‭100‬
‭500 - 1,000 or‬
‭50,000-100,000‬
‭75‬
‭<500 or‬
‭< 50,000‬
‭Omit dose*‬
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‭*Treatment‬‭omitted‬‭will‬‭not‬‭be‬‭reinstated‬‭within‬‭a‬‭cycle‬‭before‬‭the‬‭absolute‬‭granulocyte‬‭count‬‭reaches‬
‭at least 500 (x106 /l) and the platelet count reaches 50,000 (x10‬‭6‬‭/l).‬
‭Dose modifications due to haematological toxicity: Subsequent cycles for all indications‬
‭The‬‭gemcitabine‬‭dose‬‭should‬‭be‬‭reduced‬‭to‬‭75%‬‭of‬‭the‬‭original‬‭cycle‬‭initiation‬‭dose,‬‭in‬‭the‬
‭case of the following hematologic toxicities (‬‭Table‬‭3‬‭):‬
‭Table 3. Dose modification of gemcitabine in subsequent cycles for all indications‬
‭Count‬
‭(x 10‬‭6‬‭/l)‬
‭Time‬
‭Percentage of standard‬
‭dose of Gemcitabine (%)‬
‭Absolute granulocyte‬
‭< 500‬
‭> 5 days‬
‭75‬
‭< 100‬
‭> 3 days‬
‭75‬
‭Platelet count‬
‭< 25,000‬
‭Not applicable‬
‭75‬
‭Febrile neutropenia‬
‭-‬
‭-‬
‭75‬
‭Cycle delay > 1 week to toxicity‬
‭-‬
‭-‬
‭75‬
‭Patients‬ ‭will‬ ‭be‬ ‭monitored‬ ‭closely‬ ‭for‬ ‭toxicity;‬ ‭Gemcitabine‬ ‭may‬ ‭be‬ ‭adjusted‬ ‭by‬ ‭dosing‬
‭interruption with or without dose reduction as indicated in‬‭Table 2‬‭and‬‭Table‬‭3.‬
‭Management‬‭of‬‭patients‬‭requiring‬‭more‬‭than‬‭2‬‭dose‬‭reductions‬‭of‬‭any‬‭of‬‭the‬‭IMPs‬‭(one‬‭dose‬
‭level decrease at a time) should be discussed with the Coordinating Investigator.‬
‭Patients‬‭who‬‭have‬‭undergone‬‭dose‬‭reduction‬‭may‬‭also‬‭undergo‬‭dose‬‭re-escalation‬‭back‬‭to‬‭the‬
‭previous‬ ‭dose‬ ‭level‬ ‭at‬ ‭the‬ ‭discretion‬ ‭of‬ ‭the‬ ‭Investigator‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬ ‭Grade‬ ‭≥2‬
‭non-hematologic treatment-related toxicity for at least 28 days.‬
‭Cisplatin‬ ‭reduction‬ ‭will‬ ‭be‬ ‭followed‬ ‭as‬ ‭indicated‬ ‭for‬ ‭Gemcitabine‬ ‭reduction‬ ‭following‬ ‭the‬
‭current version of Cisplatin Summary of Product Characteristics (Cisplatin SmPC).‬
‭No chemotherapy reduction as allowed in Cycle 1 Day 1.‬
‭7.5.‬
‭Special Precautions for Investigational Medical Products‬
‭7.5.1.‬ ‭Special Precautions for Atezolizumab‬
‭In‬‭order‬‭to‬‭improve‬‭the‬‭traceability‬‭of‬‭biological‬‭medicinal‬‭products,‬‭the‬‭trade‬‭name‬‭and‬‭the‬
‭batch‬‭number‬‭of‬‭the‬‭administered‬‭product‬‭should‬‭be‬‭clearly‬‭recorded‬‭(or‬‭stated)‬‭in‬‭the‬‭patient‬
‭file.‬
‭Pneumonitis‬ ‭secondary‬ ‭to‬ ‭PD1/PDL1‬ ‭inhibitor‬ ‭drugs‬ ‭is‬ ‭a‬ ‭rare‬ ‭but‬ ‭potentially‬ ‭serious‬ ‭side‬
‭effect,‬‭patients‬‭should‬‭be‬‭monitored‬‭for‬‭signs‬‭and‬‭symptoms‬‭of‬‭pneumonitis‬‭during‬‭physical‬
‭examination‬‭(PE),‬‭and‬‭causes‬‭other‬‭than‬‭immune-mediated‬‭pneumonitis‬‭should‬‭be‬‭ruled‬‭out‬‭in‬
‭the case of findings during PE.‬
‭For more updated information follow the IB (Investigator's Brochure)‬
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‭7.5.1.1.‬‭Hepatic impairment‬
‭No‬ ‭dedicated‬ ‭studies‬ ‭of‬ ‭atezolizumab‬ ‭have‬ ‭been‬ ‭conducted‬ ‭in‬ ‭patients‬ ‭with‬ ‭hepatic‬
‭impairment.‬ ‭In‬ ‭the‬ ‭population‬ ‭pharmacokinetic‬ ‭analysis,‬‭there‬‭were‬‭no‬‭clinically‬‭important‬
‭differences‬‭in‬‭the‬‭clearance‬‭of‬‭atezolizumab‬‭between‬‭patients‬‭with‬‭mild‬‭hepatic‬‭impairment‬
‭(bilirubin‬ ‭≤‬ ‭ULN‬ ‭and‬ ‭AST‬ ‭>‬ ‭ULN‬ ‭or‬ ‭bilirubin‬ ‭1.0‬ ‭to‬‭1.5‬‭ULN‬‭and‬‭any‬‭AST,‬‭n=71)‬‭and‬
‭normal‬‭hepatic‬‭function‬‭(bilirubin‬‭and‬‭AST‬‭≤‬‭ULN,‬‭n=401).‬‭No‬‭data‬‭are‬‭available‬‭in‬‭patients‬
‭with‬‭either‬‭moderate‬‭(bilirubin‬‭>‬‭1.5‬‭to‬‭3.0‬‭x‬‭ULN‬‭and‬‭any‬‭AST)‬‭or‬‭severe‬‭(bilirubin‬‭>‬‭3.0‬
‭ULN‬ ‭and‬ ‭any‬ ‭AST)‬ ‭hepatic‬ ‭impairment.‬ ‭Hepatic‬ ‭impairment‬ ‭was‬ ‭defined‬‭by‬‭the‬‭National‬
‭Cancer‬ ‭Institute‬ ‭criteria‬ ‭of‬ ‭hepatic‬ ‭dysfunction.‬ ‭More‬ ‭information‬ ‭available‬ ‭in‬ ‭the‬ ‭current‬
‭version of Atezolizumab Investigator’s Brochure.‬
‭7.5.1.2.‬‭Renal impairment‬
‭No‬‭dedicated‬‭studies‬‭of‬‭atezolizumab‬‭have‬‭been‬‭conducted‬‭in‬‭patients‬‭with‬‭renal‬‭impairment.‬
‭More information available in the current version of Atezolizumab Investigator’s Brochure.‬
‭7.5.1.3.‬‭Reproductive and Developmental Toxicity‬
‭Reproductive‬‭and‬‭developmental‬‭toxicity‬‭studies‬‭with‬‭atezolizumab‬‭have‬‭not‬‭been‬‭conducted.‬
‭The‬‭PD-L1/‬‭programmed‬‭death‬‭1‬‭(PD-1)‬‭signaling‬‭pathway‬‭is‬‭well‬‭established‬‭as‬‭essential‬‭in‬
‭maternal/fetal‬ ‭tolerance‬ ‭and‬ ‭embryo-fetal‬ ‭survival‬ ‭during‬ ‭gestation‬ ‭(‬‭Guleria‬ ‭et‬ ‭al.‬ ‭2005;‬
‭Habicht‬‭et‬‭al.‬‭2007;‬‭D’Addio‬‭et‬‭al.‬‭2011‬‭).‬‭Administration‬‭of‬‭atezolizumab‬‭is‬‭expected‬‭to‬‭have‬
‭an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality.‬
‭7.5.1.4.‬‭Immune-mediated adverse reactions‬
‭Most‬‭immune-mediated‬‭adverse‬‭reactions‬‭that‬‭occur‬‭during‬‭treatment‬‭with‬‭atezolizumab‬‭are‬
‭reversible‬ ‭with‬ ‭the‬ ‭interruptions‬ ‭of‬ ‭atezolizumab‬ ‭and‬ ‭initiation‬ ‭of‬ ‭corticosteroids‬ ‭and/or‬
‭supportive‬ ‭care.‬ ‭Immune-mediated‬ ‭adverse‬ ‭reactions‬ ‭affecting‬ ‭more‬ ‭than‬ ‭one‬‭body‬‭system‬
‭have been observed; these may occur after the last dose of atezolizumab.‬
‭For‬‭suspected‬‭immune-mediated‬‭adverse‬‭reactions,‬‭thorough‬‭evaluation‬‭to‬‭confirm‬‭aetiology‬
‭or‬‭exclude‬‭other‬‭causes‬‭should‬‭be‬‭performed.‬‭Based‬‭on‬‭the‬‭severity‬‭of‬‭the‬‭adverse‬‭reaction,‬
‭atezolizumab‬ ‭should‬ ‭be‬ ‭withheld‬ ‭and‬ ‭corticosteroids‬ ‭administered.‬ ‭Upon‬ ‭improvement‬ ‭to‬
‭Grade‬ ‭≤‬ ‭1,‬ ‭corticosteroid‬ ‭should‬ ‭be‬ ‭tapered‬ ‭over‬ ‭≥‬ ‭1‬ ‭month.‬ ‭Based‬ ‭on‬ ‭limited‬ ‭data‬‭from‬
‭clinical‬‭studies‬‭in‬‭patients‬‭whose‬‭immune-mediated‬‭adverse‬‭reactions‬‭could‬‭not‬‭be‬‭controlled‬
‭with‬ ‭systemic‬ ‭corticosteroid‬ ‭use,‬ ‭the‬ ‭administration‬ ‭of‬ ‭other‬‭systemic‬‭immunosuppressants‬
‭may be considered.‬
‭Atezolizumab‬‭must‬‭be‬‭permanently‬‭discontinued‬‭for‬‭any‬‭Grade‬‭3‬‭immune-mediated‬‭adverse‬
‭reaction‬ ‭that‬ ‭recurs‬ ‭and‬ ‭for‬ ‭any‬ ‭Grade‬ ‭4‬ ‭immune-mediated‬ ‭adverse‬ ‭reactions,‬ ‭except‬ ‭for‬
‭endocrinopathies‬‭that‬‭are‬‭controlled‬‭with‬‭replacement‬‭hormones.‬‭Specific‬‭guidelines‬‭for‬‭the‬
‭management of atezolizumab-specific adverse events is available in‬‭Appendix 1‬‭.‬
‭1)‬
‭Pulmonary events‬
‭Pneumonitis‬ ‭secondary‬ ‭to‬ ‭PD1/PDL1‬ ‭inhibitor‬ ‭drugs‬ ‭is‬ ‭a‬ ‭rare‬ ‭but‬ ‭potentially‬ ‭serious‬ ‭side‬
‭effect,‬‭patients‬‭should‬‭be‬‭monitored‬‭for‬‭signs‬‭and‬‭symptoms‬‭of‬‭pneumonitis‬‭during‬‭physical‬
‭examination‬‭(PE),‬‭and‬‭causes‬‭other‬‭than‬‭immune-mediated‬‭pneumonitis‬‭should‬‭be‬‭ruled‬‭out‬‭in‬
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‭the case of findings during PE.‬
‭Cases‬‭of‬‭pulmonary‬‭events,‬‭including‬‭dyspnea,‬‭cough,‬‭fatigue‬‭and‬‭pulmonary‬‭infiltrates,‬‭have‬
‭been‬‭observed‬‭in‬‭clinical‬‭trials‬‭with‬‭atezolizumab.‬‭Patients‬‭should‬‭be‬‭monitored‬‭for‬‭pulmonary‬
‭signs and symptoms.‬
‭Treatment‬ ‭with‬ ‭atezolizumab‬ ‭should‬ ‭be‬ ‭withheld‬ ‭for‬ ‭Grade‬ ‭2‬ ‭pulmonary‬ ‭event‬ ‭,‬ ‭and‬
‭corticosteroids‬ ‭equivalent‬‭1‬‭to‬‭2‬‭mg/kg/day‬‭oral‬‭prednisone‬‭should‬‭be‬‭started.‬‭If‬‭symptoms‬
‭improve‬ ‭to‬ ‭≤‬ ‭Grade‬ ‭1,‬ ‭corticosteroids‬ ‭should‬ ‭be‬ ‭tapered‬ ‭over‬ ‭≥‬ ‭1‬ ‭month.‬ ‭Treatment‬‭with‬
‭atezolizumab‬ ‭may‬ ‭be‬ ‭resumed‬ ‭if‬ ‭the‬ ‭event‬ ‭improves‬ ‭to‬ ‭≤‬ ‭Grade‬ ‭1‬ ‭within‬ ‭12‬ ‭weeks,‬ ‭and‬
‭corticosteroids‬‭have‬‭been‬‭reduced‬‭to‬‭≤‬‭10‬‭mg‬‭prednisone‬‭or‬‭equivalent‬‭per‬‭day.‬‭Treatment‬‭with‬
‭atezolizumab must be permanently discontinued for Grade 3 or 4 pulmonary events.‬
‭2)‬
‭Hepatic events‬
‭Immune-mediated‬ ‭hepatitis‬ ‭has‬ ‭been‬ ‭associated‬ ‭with‬ ‭the‬ ‭administration‬ ‭of‬ ‭atezolizumab.‬
‭Eligible‬‭patients‬‭must‬‭have‬‭adequate‬‭liver‬‭function,‬‭as‬‭manifested‬‭by‬‭measurements‬‭of‬‭total‬
‭bilirubin‬ ‭and‬ ‭hepatic‬ ‭transaminases,‬ ‭and‬ ‭liver‬ ‭function‬‭will‬‭be‬‭monitored‬‭throughout‬‭study‬
‭treatment. Management guidelines for hepatic events are provided in‬‭Appendix 1‬‭.‬
‭3)‬
‭Gastrointestinal events‬
‭Immune-mediated‬ ‭colitis‬ ‭has‬ ‭been‬ ‭associated‬ ‭with‬ ‭the‬ ‭administration‬ ‭of‬ ‭atezolizumab.‬‭All‬
‭events‬‭of‬‭diarrhea‬‭or‬‭colitis‬‭should‬‭be‬‭thoroughly‬‭evaluated‬‭for‬‭other‬‭common‬‭etiologies.‬‭For‬
‭events‬ ‭of‬ ‭significant‬ ‭duration‬ ‭or‬ ‭or‬ ‭magnitude‬ ‭or‬ ‭associated‬ ‭with‬ ‭signs‬ ‭of‬ ‭systemic‬
‭inflammation‬ ‭or‬ ‭acute-phase‬ ‭reactants‬ ‭(e.g.,‬ ‭increased‬ ‭C-reactive‬‭protein,‬‭platelet‬‭count,‬‭or‬
‭bandemia):‬‭Perform‬‭sigmoidoscopy‬‭(or‬‭colonoscopy,‬‭if‬‭appropriate)‬‭with‬‭colonic‬‭biopsy,‬‭with‬
‭three‬‭to‬‭five‬‭specimens‬‭for‬‭standard‬‭paraffin‬‭block‬‭to‬‭check‬‭for‬‭inflammation‬‭and‬‭lymphocytic‬
‭infiltrates to confirm colitis diagnosis. More information provided in‬‭Appendix 1‬‭.‬
‭4)‬
‭Endocrine events‬
‭Thyroid‬‭disorders,‬‭adrenal‬‭insufficiency,‬‭diabetes‬‭mellitus,‬‭and‬‭pituitary‬‭disorders‬‭have‬‭been‬
‭associated with the administration of atezolizumab.‬
‭Patients‬ ‭with‬ ‭unexplained‬ ‭symptoms‬ ‭such‬ ‭as‬ ‭headache,‬ ‭fatigue,‬ ‭myalgias,‬ ‭impotence,‬
‭constipation,‬ ‭or‬ ‭mental‬ ‭status‬ ‭changes‬ ‭should‬ ‭be‬ ‭investigated‬ ‭for‬ ‭the‬ ‭presence‬ ‭of‬ ‭thyroid,‬
‭pituitary,‬‭or‬‭adrenal‬‭endocrinopathies.‬‭The‬‭patient‬‭should‬‭be‬‭referred‬‭to‬‭an‬‭endocrinologist‬‭if‬
‭an endocrinopathy is suspected.‬
‭Thyroid-stimulating‬‭hormone‬‭(TSH)‬‭and‬‭free‬‭triiodothyronine‬‭(T3)‬‭and‬‭thyroxine‬‭(T4)‬‭levels‬
‭should‬‭be‬‭measured‬‭to‬‭determine‬‭whether‬‭thyroid‬‭abnormalities‬‭are‬‭present.‬‭Pituitary‬‭hormone‬
‭levels‬‭and‬‭function‬‭tests‬‭(e.g.,‬‭TSH,‬‭GH,‬‭luteinizing‬‭hormone,‬‭follicle-stimulating‬‭hormone,‬
‭testosterone,‬ ‭prolactin,‬ ‭adrenocorticotropic‬‭hormone‬‭[ACTH]‬‭levels,‬‭and‬‭ACTH‬‭stimulation‬
‭test)‬‭and‬‭magnetic‬‭resonance‬‭imaging‬‭(MRI)‬‭of‬‭the‬‭brain‬‭(with‬‭detailed‬‭pituitary‬‭sections)‬‭may‬
‭help‬‭to‬‭differentiate‬‭primary‬‭pituitary‬‭insufficiency‬‭from‬‭primary‬‭adrenal‬‭insufficiency.‬‭More‬
‭information provided in‬‭Appendix 1‬‭.‬
‭5)‬
‭Ocular events‬
‭An‬ ‭ophthalmologist‬ ‭should‬ ‭evaluate‬ ‭visual‬ ‭complaints‬ ‭(e.g.,‬ ‭uveitis,‬ ‭retinal‬ ‭events).‬ ‭More‬
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‭information provided in‬‭Appendix 1‬‭.‬
‭6)‬
‭Immune-Mediated Myocarditis‬
‭Immune-mediated‬ ‭myocarditis‬ ‭has‬ ‭been‬ ‭associated‬‭with‬‭the‬‭administration‬‭of‬‭atezolizumab‬
‭and‬ ‭should‬ ‭be‬ ‭suspected‬ ‭in‬ ‭any‬ ‭patient‬ ‭presenting‬ ‭with‬ ‭signs‬ ‭or‬ ‭symptoms‬ ‭suggestive‬ ‭of‬
‭myocarditis,‬ ‭including,‬ ‭but‬ ‭not‬ ‭limited‬ ‭to,‬ ‭laboratory‬ ‭(e.g.,‬ ‭B-type‬ ‭Natriuretic‬ ‭Peptide])‬ ‭or‬
‭cardiac‬‭imaging‬‭abnormalities,‬‭dyspnea,‬‭chest‬‭pain,‬‭palpitations,‬‭fatigue,‬‭decreased‬‭exercise‬
‭tolerance, or syncope.‬
‭Immune-mediated‬ ‭myocarditis‬ ‭needs‬ ‭to‬ ‭be‬ ‭distinguished‬ ‭from‬ ‭myocarditis‬ ‭resulting‬ ‭from‬
‭infection‬ ‭(commonly‬‭viral,‬‭e.g.,‬‭in‬‭a‬‭patient‬‭who‬‭reports‬‭a‬‭recent‬‭history‬‭of‬‭gastrointestinal‬
‭illness),‬ ‭ischemic‬ ‭events,‬ ‭underlying‬ ‭arrhythmias,‬ ‭exacerbation‬ ‭of‬ ‭pre-existing‬ ‭cardiac‬
‭conditions, or progression of malignancy.‬
‭All‬ ‭patients‬ ‭with‬ ‭possible‬ ‭myocarditis‬ ‭should‬ ‭be‬ ‭urgently‬ ‭evaluated‬‭by‬‭performing‬‭cardiac‬
‭enzyme‬ ‭assessment,‬ ‭an‬ ‭ECG,‬ ‭a‬ ‭chest‬ ‭X-ray,‬ ‭an‬ ‭echocardiogram,‬ ‭and‬ ‭a‬ ‭cardiac‬ ‭MRI‬ ‭as‬
‭appropriate‬ ‭per‬ ‭institutional‬ ‭guidelines.‬ ‭A‬ ‭cardiologist‬ ‭should‬ ‭be‬ ‭consulted.‬ ‭An‬
‭endomyocardial‬ ‭biopsy‬ ‭may‬ ‭be‬ ‭considered‬‭to‬‭enable‬‭a‬‭definitive‬‭diagnosis‬‭and‬‭appropriate‬
‭treatment,‬ ‭if‬ ‭clinically‬ ‭indicated.‬ ‭Patients‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭myocarditis,‬ ‭in‬ ‭the‬
‭absence‬ ‭of‬ ‭an‬ ‭identified‬‭alternate‬‭etiology,‬‭should‬‭be‬‭treated‬‭according‬‭to‬‭the‬‭guidelines‬‭in‬
‭Appendix 1‬‭.‬
‭7)‬
‭Infusion-Related Reactions and Cytokine-Release Syndrome‬
‭No‬ ‭premedication‬‭is‬‭indicated‬‭for‬‭the‬‭administration‬‭of‬‭Cycle‬‭1‬‭of‬‭atezolizumab.‬‭However,‬
‭patients‬ ‭who‬ ‭experience‬ ‭an‬ ‭infusion-related‬ ‭reaction‬ ‭(IRR)‬ ‭or‬ ‭cytokine-release‬ ‭syndrome‬
‭(CRS)‬‭with‬‭atezolizumab‬‭may‬‭receive‬‭premedication‬‭with‬‭antihistamines,‬ ‭antipyretics,‬‭and/or‬
‭analgesics‬‭(e.g.,‬‭acetaminophen)‬‭for‬‭subsequent‬‭infusions.‬‭Metamizole‬‭(dipyrone)‬‭is‬‭prohibited‬
‭in‬ ‭treating‬ ‭atezolizumab-associated‬ ‭infusion-related‬ ‭reactions,‬ ‭due‬ ‭to‬ ‭IRRs‬ ‭because‬ ‭of‬ ‭its‬
‭potential for causing agranulocytosis.‬
‭IRRs‬ ‭are‬ ‭known‬ ‭to‬ ‭occur‬ ‭with‬ ‭the‬‭administration‬‭of‬‭monoclonal‬‭antibodies‬‭and‬‭have‬‭been‬
‭reported‬ ‭with‬ ‭atezolizumab.‬ ‭These‬ ‭reactions,‬ ‭which‬ ‭are‬ ‭thought‬ ‭to‬ ‭be‬ ‭due‬ ‭to‬ ‭release‬ ‭of‬
‭cytokines‬ ‭and/or‬ ‭other‬ ‭chemical‬ ‭mediators,‬ ‭occur‬ ‭within‬ ‭24‬ ‭hours‬ ‭of‬ ‭atezolizumab‬
‭administration and are generally mild to moderate in severity.‬
‭CRS‬ ‭is‬ ‭defined‬ ‭as‬ ‭a‬ ‭supraphysiologic‬ ‭response‬ ‭following‬ ‭administration‬ ‭of‬ ‭any‬ ‭immune‬
‭therapy‬‭that‬‭results‬‭in‬‭activation‬‭or‬‭engagement‬‭of‬‭endogenous‬‭or‬‭infused‬‭T‬‭cells‬‭and/or‬‭other‬
‭immune‬‭effector‬‭cells.‬‭Symptoms‬‭can‬‭be‬‭progressive,‬‭always‬‭include‬‭fever‬‭at‬‭the‬‭onset,‬‭and‬
‭may‬ ‭include‬ ‭hypotension,‬ ‭capillary‬ ‭leak‬ ‭(hypoxia),‬ ‭and‬ ‭end‬ ‭-organ‬ ‭dysfunction‬‭(Lee‬‭et‬‭al.‬
‭2019).‬ ‭CRS‬ ‭has‬ ‭been‬ ‭well‬‭documented‬‭with‬‭chimeric‬‭antigen‬‭receptor‬‭T-cell‬‭therapies‬‭and‬
‭bispecific‬‭T-cell‬‭engager‬‭antibody‬‭therapies‬‭but‬‭has‬‭also‬‭been‬‭reported‬‭with‬‭immunotherapies‬
‭that‬ ‭target‬ ‭PD-1‬ ‭or‬ ‭PD-L1‬ ‭(‬‭Rotz‬ ‭et‬ ‭al.‬ ‭2017‬‭;‬ ‭Adashek‬ ‭and‬ ‭Feldman‬ ‭2019‬‭),‬ ‭including‬
‭atezolizumab.‬
‭There‬‭may‬‭be‬‭significant‬‭overlap‬‭in‬‭signs‬‭and‬‭symptoms‬‭of‬‭IRRs‬‭and‬‭CRS,‬‭and‬‭in‬‭recognition‬
‭of‬ ‭the‬ ‭challenges‬ ‭in‬ ‭clinically‬ ‭distinguishing‬ ‭between‬ ‭the‬ ‭two,‬ ‭consolidated‬ ‭guidelines‬ ‭for‬
‭medical management of IRRs during Cycle 1 and CRS are provided in‬‭Appendix 1‬‭.‬
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‭Severe‬‭COVID-19‬‭appears‬‭to‬‭be‬‭associated‬‭with‬‭a‬‭cytokine-release‬‭syndrome‬‭(CRS)‬‭involving‬
‭the‬‭inflammatory‬‭cytokines‬‭interleukin‬‭(IL)-6,‬‭IL-10,‬‭IL-2,‬‭and‬‭interferon-‬‭(Merad‬‭and‬‭Martin‬
‭2020).‬‭If‬‭a‬‭patient‬‭develops‬‭suspected‬‭CRS‬‭during‬‭the‬‭study,‬‭a‬‭differential‬‭diagnosis‬‭should‬
‭include‬ ‭COVID-19,‬ ‭which‬ ‭should‬ ‭be‬‭confirmed‬‭or‬‭refuted‬‭through‬‭assessment‬‭of‬‭exposure‬
‭history,‬‭appropriate‬‭laboratory‬‭testing,‬‭and‬‭clinical‬‭or‬‭radiologic‬‭evaluations‬‭per‬‭investigator‬
‭judgment.‬‭If‬‭a‬‭diagnosis‬‭of‬‭COVID-19‬‭is‬‭confirmed,‬‭the‬‭disease‬‭should‬‭be‬‭managed‬‭as‬‭per‬
‭local or institutional guidelines.‬
‭8)‬
‭Pancreatic events‬
‭Symptoms‬‭of‬‭abdominal‬‭pain‬‭associated‬‭with‬‭elevations‬‭of‬‭amylase‬‭and‬‭lipase,‬‭suggestive‬‭of‬
‭pancreatitis,‬ ‭have‬ ‭been‬ ‭associated‬ ‭with‬‭the‬‭administration‬‭of‬‭atezolizumab.‬‭The‬‭differential‬
‭diagnosis‬ ‭of‬ ‭acute‬ ‭abdominal‬‭pain‬‭should‬‭include‬‭pancreatitis.‬‭Appropriate‬‭work-up‬‭should‬
‭include‬ ‭an‬ ‭evaluation‬ ‭for‬ ‭ductal‬ ‭obstruction,‬ ‭as‬ ‭well‬ ‭as‬ ‭serum‬ ‭amylase‬ ‭and‬ ‭lipase‬ ‭tests.‬
‭Management‬‭guidelines‬‭for‬‭pancreatic‬‭events,‬‭including‬‭pancreatitis,‬‭are‬‭provided‬‭in‬‭Appendix‬
‭1‬‭.‬
‭9)‬
‭Dermatologic events‬
‭Treatment-emergent‬‭rash‬‭has‬‭been‬‭associated‬‭with‬‭atezolizumab.‬‭The‬‭majority‬‭of‬‭cases‬‭of‬‭rash‬
‭were‬‭mild‬‭in‬‭severity‬‭and‬‭self-limited,‬‭with‬‭or‬‭without‬‭pruritus.‬‭Although‬‭uncommon,‬‭cases‬‭of‬
‭severe‬ ‭cutaneous‬ ‭adverse‬ ‭reactions‬‭such‬‭as‬‭Stevens-Johnson‬‭syndrome‬‭and‬‭toxic‬‭epidermal‬
‭necrolysis‬‭have‬‭been‬‭reported‬‭with‬‭atezolizumab.‬‭A‬‭dermatologist‬‭should‬‭evaluate‬‭persistent‬
‭and/or‬ ‭severe‬ ‭rash‬ ‭or‬ ‭pruritus.‬ ‭A‬ ‭biopsy‬ ‭should‬ ‭be‬ ‭considered‬ ‭unless‬ ‭contraindicated.‬
‭Management guidelines for dermatologic events are provided in‬‭Appendix 1‬‭.‬
‭10)‬
‭Neurologic Disorders‬
‭Myasthenia‬ ‭gravis‬ ‭and‬ ‭Guillain-Barré‬ ‭syndrome‬ ‭have‬ ‭been‬ ‭observed‬ ‭with‬ ‭single-agent‬
‭atezolizumab.‬ ‭Patients‬ ‭may‬ ‭present‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭sensory‬ ‭and/or‬ ‭motor‬
‭neuropathy.‬ ‭Diagnostic‬ ‭work-up‬ ‭is‬‭essential‬‭for‬‭an‬‭accurate‬‭characterization‬‭to‬‭differentiate‬
‭between‬‭alternative‬‭etiologies.‬‭Management‬‭guidelines‬‭for‬‭neurologic‬‭disorders‬‭are‬‭provided‬
‭in‬‭Appendix 1‬‭.‬
‭11)‬
‭Immune-Mediated Meningoencephalitis‬
‭Immune-mediated‬‭meningoencephalitis‬‭is‬‭an‬‭identified‬‭risk‬‭associated‬‭with‬‭the‬‭administration‬
‭of‬ ‭atezolizumab.‬ ‭Immune-mediated‬‭meningoencephalitis‬‭should‬‭be‬‭suspected‬‭in‬‭any‬‭patient‬
‭presenting‬‭with‬‭signs‬‭or‬‭symptoms‬‭suggestive‬‭of‬‭meningitis‬‭or‬‭encephalitis,‬‭including,‬‭but‬‭not‬
‭limited‬‭to,‬‭headache,‬‭neck‬‭pain,‬‭confusion,‬‭seizure,‬‭motor‬‭or‬‭sensory‬‭dysfunction,‬‭and‬‭altered‬
‭or depressed level of consciousness.‬
‭Encephalopathy‬ ‭from‬ ‭metabolic‬ ‭or‬ ‭electrolyte‬ ‭imbalances‬ ‭needs‬ ‭to‬ ‭be‬ ‭distinguished‬ ‭from‬
‭potential‬ ‭meningoencephalitis‬ ‭resulting‬ ‭from‬ ‭infection‬ ‭(bacterial,‬ ‭viral,‬ ‭or‬ ‭fungal)‬ ‭or‬
‭progression‬ ‭of‬ ‭malignancy,‬ ‭or‬ ‭secondary‬ ‭to‬ ‭a‬ ‭paraneoplastic‬ ‭process.‬ ‭All‬ ‭patients‬ ‭being‬
‭considered‬‭for‬‭meningoencephalitis‬‭should‬‭be‬‭urgently‬‭evaluated‬‭with‬‭a‬‭CT‬‭scan‬‭and/or‬‭MRI‬
‭scan‬‭of‬‭the‬‭brain‬‭to‬‭evaluate‬‭for‬‭metastasis,‬‭inflammation,‬‭or‬‭edema.‬‭If‬‭deemed‬‭safe‬‭by‬‭the‬
‭treating‬ ‭physician,‬ ‭a‬ ‭lumbar‬ ‭puncture‬ ‭should‬ ‭be‬ ‭performed‬ ‭and‬ ‭a‬ ‭neurologist‬ ‭should‬ ‭be‬
‭consulted.‬
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‭Patients‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭meningoencephalitis,‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬ ‭an‬‭identified‬
‭alternate etiology, should be treated according to the guidelines in‬‭Appendix 1‬
‭12)‬
‭Renal events‬
‭Immune-mediated‬ ‭nephritis‬ ‭has‬ ‭been‬ ‭associated‬ ‭with‬ ‭the‬ ‭administration‬ ‭of‬ ‭atezolizumab.‬
‭Eligible‬‭patients‬‭must‬‭have‬‭adequate‬‭renal‬‭function,‬‭and‬‭renal.‬‭Renal‬‭function,‬‭including‬‭serum‬
‭creatinine,‬ ‭should‬ ‭be‬ ‭monitored‬ ‭throughout‬ ‭study‬ ‭treatment.‬ ‭Patients‬ ‭with‬ ‭abnormal‬ ‭renal‬
‭function‬‭should‬‭be‬‭evaluated‬‭and‬‭treated‬‭for‬‭other‬‭more‬‭common‬‭etiologies‬‭(including‬‭prerenal‬
‭and‬ ‭postrenal‬ ‭causes,‬ ‭and‬‭concomitant‬‭medications‬‭such‬‭as‬‭non-steroidal‬‭anti-inflammatory‬
‭drugs).‬ ‭Refer‬‭the‬‭patient‬‭to‬‭a‬‭renal‬‭specialist‬‭if‬‭clinically‬‭indicated.‬‭A‬‭renal‬‭biopsy‬‭may‬‭be‬
‭required to enable a definitive diagnosis and appropriate treatment.‬
‭Patients‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭nephritis,‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬ ‭an‬ ‭identified‬ ‭alternate‬
‭etiology, should be treated according to the guidelines in‬‭Appendix 1‬‭.‬
‭13)‬
‭Immune-Mediated Myositis‬
‭Immune-mediated‬ ‭myositis‬ ‭has‬ ‭been‬ ‭associated‬ ‭with‬ ‭the‬ ‭administration‬ ‭of‬ ‭atezolizumab.‬
‭Myositis‬‭or‬‭inflammatory‬‭myopathies‬‭are‬‭a‬‭group‬‭of‬‭disorders‬‭sharing‬‭the‬‭common‬‭feature‬‭of‬
‭inflammatory‬‭muscle‬‭injury;‬‭dermatomyositis‬‭and‬‭polymyositis‬‭are‬‭among‬‭the‬‭most‬‭common‬
‭disorders.‬‭Initial‬‭diagnosis‬‭is‬‭based‬‭on‬‭clinical‬‭(muscle‬‭weakness,‬‭muscle‬‭pain,‬‭skin‬‭rash‬‭in‬
‭dermatomyositis),‬
‭biochemical‬
‭(serum‬
‭creatine‬ ‭kinase/CK‬ ‭increase),‬ ‭and‬ ‭imaging‬
‭(electromyography/MRI) features, and is confirmed with a muscle biopsy.‬
‭Patients‬‭with‬‭possible‬‭myositis‬‭should‬‭be‬‭referred‬‭to‬‭a‬‭rheumatologist‬‭or‬‭neurologist.‬‭Patients‬
‭with possible myositis should be monitored for signs of myocarditis.‬
‭14)‬
‭Severe Cutaneous Adverse Reactions (SCAR)‬
‭SCARs‬ ‭are‬ ‭a‬ ‭heterogeneous‬ ‭group‬ ‭of‬ ‭immunologically‬ ‭mediated‬ ‭drug‬‭eruptions.‬‭Although‬
‭rare,‬‭these‬‭events‬‭are‬‭potentially‬‭fatal,‬‭and‬‭mainly‬‭constituted‬‭by‬‭erythema‬‭multiforme,‬‭acute‬
‭generalised‬ ‭exanthematous‬ ‭pustulosis,‬ ‭Stevens-Johnson‬ ‭syndrome‬ ‭(SJS),‬ ‭Toxic‬ ‭Epidermal‬
‭Necrolysis‬‭(TEN)‬‭and‬‭drug‬‭rash‬‭with‬‭eosinophilia‬‭and‬‭systemic‬‭symptoms‬‭(DRESS).‬‭As‬‭per‬
‭epidemiology‬ ‭data,‬ ‭the‬ ‭incidence‬‭of‬‭SJS‬‭and‬‭TEN‬‭ranges‬‭from‬‭0.8‬‭to‬‭5.3‬‭and‬‭1.2‬‭to‬‭6‬‭per‬
‭million person-years respectively.‬
‭A‬‭cumulative‬‭analysis‬‭of‬‭the‬‭company‬‭safety‬‭database‬‭across‬‭the‬‭TECENTRIQ‬‭(atezolizumab)‬
‭program‬ ‭identified‬ ‭at‬ ‭total‬ ‭of‬ ‭99‬ ‭cases‬ ‭of‬ ‭SCARs,‬ ‭of‬ ‭which‬ ‭36‬ ‭were‬ ‭confirmed‬ ‭by‬
‭histopathology‬ ‭or‬ ‭specialist‬ ‭diagnosis,‬ ‭in‬ ‭patients‬ ‭who‬ ‭have‬ ‭received‬ ‭TECENTRIQ‬
‭(atezolizumab).‬ ‭Approximately‬ ‭23,654‬ ‭clinical‬ ‭trial‬ ‭patients‬ ‭and‬ ‭106,316‬ ‭patients‬ ‭in‬
‭post-marketing‬ ‭settings‬ ‭have‬ ‭been‬ ‭exposed‬ ‭to‬ ‭TECENTRIQ‬ ‭(atezolizumab)‬ ‭as‬ ‭of‬ ‭17‬ ‭May‬
‭2020.‬ ‭The‬ ‭incidence‬ ‭rates‬ ‭of‬ ‭SCAR,‬ ‭regardless‬ ‭of‬ ‭severity,‬ ‭from‬ ‭pooled‬ ‭atezolizumab‬
‭monotherapy‬ ‭(N=3178)‬ ‭and‬ ‭combination‬ ‭therapy‬ ‭(N=4371)‬ ‭company‬ ‭sponsored‬ ‭clinical‬
‭studies‬‭were‬‭0.7%‬‭and‬‭0.6%‬‭respectively.‬‭One‬‭fatal‬‭case‬‭of‬‭TEN‬‭was‬‭reported‬‭in‬‭a‬‭77‬‭year‬‭old‬
‭female patient who received atezolizumab monotherapy.‬
‭Patients‬‭with‬‭signs‬‭and‬‭symptoms‬‭of‬‭SCAR‬‭should‬‭be‬‭treated‬‭according‬‭to‬‭the‬‭guidelines‬‭in‬
‭Appendix 1‬‭.‬
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‭15)‬
‭Pericardial disorders‬
‭Immune-Immune-mediated‬ ‭pericarditis‬ ‭should‬ ‭be‬ ‭suspected‬ ‭in‬ ‭any‬ ‭patient‬ ‭presenting‬ ‭with‬
‭chest pain and may be associated with immune-mediated myocarditis.‬
‭Immune-mediated‬ ‭pericardial‬ ‭effusion‬ ‭and‬ ‭cardiac‬ ‭tamponade‬ ‭should‬ ‭be‬ ‭suspected‬ ‭in‬ ‭any‬
‭patient presenting with chest pain associated with dyspnea or hemodynamic instability.‬
‭Patients‬ ‭should‬ ‭be‬ ‭evaluated‬ ‭for‬ ‭other‬ ‭causes‬ ‭of‬ ‭pericardial‬ ‭disorders‬ ‭such‬ ‭as‬ ‭infection‬
‭(commonly‬ ‭viral),‬ ‭cancer‬ ‭related‬ ‭(metastatic‬ ‭disease‬ ‭or‬ ‭chest‬ ‭radiotherapy),‬ ‭cardiac‬ ‭injury‬
‭related‬‭(post‬‭myocardial‬‭infarction‬‭or‬‭iatrogenic),‬‭and‬‭autoimmune‬‭disorders,‬‭and‬‭should‬‭be‬
‭managed accordingly.‬
‭All‬‭patients‬‭with‬‭suspected‬‭pericardial‬‭disorders‬‭should‬‭be‬‭urgently‬‭evaluated‬‭by‬‭performing‬
‭an‬ ‭ECG,‬ ‭chest‬ ‭X-ray,‬ ‭transthoracic‬ ‭echocardiogram,‬ ‭and‬ ‭cardiac‬ ‭MRI‬ ‭as‬ ‭appropriate‬ ‭per‬
‭institutional guidelines. A cardiologist should be consulted.‬
‭Pericardiocentesis‬ ‭should‬ ‭be‬ ‭considered‬ ‭for‬‭diagnostic‬‭or‬‭therapeutic‬‭purposes,‬‭if‬‭clinically‬
‭indicated.‬
‭Patients‬‭with‬‭signs‬‭and‬‭symptoms‬‭of‬‭pericarditis,‬‭pericardial‬‭effusion,‬‭or‬‭cardiac‬‭tamponade,‬‭in‬
‭the‬‭absence‬‭of‬‭an‬‭identified‬‭alternate‬‭etiology,‬‭should‬‭be‬‭treated‬‭according‬‭to‬‭the‬‭guidelines‬‭in‬
‭the next Table.‬
‭Event‬
‭Management‬
‭Immune-mediated‬
‭myocarditis, Grade 2,‬
‭3 or -4‬
‭Immune-mediated pericardial‬
‭disorders, Grades 2-4‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭Medical‬
‭Monitor.‬
‭●‬
‭Refer patient to cardiologist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭as‬ ‭per‬ ‭institutional‬ ‭guidelines‬‭and‬‭consider‬
‭antiarrhythmic‬‭drugs,‬‭temporary‬‭pacemaker,‬‭ECMO,‬‭or‬‭VAD,‬
‭or pericardiocentesis as appropriate.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone or equivalent upon improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭improve‬ ‭within‬ ‭48‬ ‭hours‬ ‭after‬ ‭initiating‬
‭corticosteroids, consider adding an immunosuppressive agent.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭taper‬ ‭corticosteroids‬
‭over ≥ 1 month.‬
‭ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device.‬
‭16)‬
‭Facial paresis‬
‭Immune-mediated‬ ‭facial‬ ‭paresis‬ ‭is‬ ‭considered‬ ‭a‬ ‭rare‬ ‭event‬ ‭(0.1%)‬ ‭in‬ ‭patients‬ ‭receiving‬
‭atezolizumab‬‭monotherapy.‬‭Patients‬‭should‬‭be‬‭monitored‬‭for‬‭symptoms‬‭of‬‭motor‬‭and‬‭sensory‬
‭neuropathy.‬ ‭No‬ ‭fatal‬‭events‬‭have‬‭been‬‭reported‬‭in‬‭the‬‭monotherapy‬‭population‬‭(n‬‭3178)‬‭or‬
‭observed across the atezolizumab clinical development program.‬
‭17)‬
‭Myelitis‬
‭Immune-mediated‬ ‭myelitis‬ ‭is‬ ‭considered‬ ‭a‬ ‭rare‬ ‭event‬ ‭(0.1%)‬ ‭in‬ ‭patients‬ ‭receiving‬
‭atezolizumab‬‭monotherapy.‬‭No‬‭fatal‬‭events‬‭have‬‭been‬‭reported‬‭in‬‭the‬‭monotherapy‬‭population‬
‭(n 3178) or observed across the atezolizumab clinical development program.‬
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‭7.5.2.‬ ‭Special Precautions for Gemcitabine‬
‭Prolongation‬‭of‬‭the‬‭infusion‬‭time‬‭and‬‭increased‬‭dosing‬‭frequency‬‭have‬‭been‬‭shown‬‭to‬‭increase‬
‭toxicity.‬‭Further‬‭information‬‭on‬‭particular‬‭risk‬‭for‬‭toxicity‬‭(including‬‭haematological‬‭toxicity,‬
‭hepatic‬ ‭insufficiency,‬ ‭concomitant‬ ‭radiotherapy,‬ ‭live‬ ‭vaccinations,‬ ‭cardiovascular‬ ‭risk,‬
‭pulmonary effects, renal, fertility or sodium control are displayed in the Gemcitabine SmPC.‬
‭7.5.3.‬ ‭Special Precautions for Cisplatin‬
‭This‬‭agent‬‭should‬‭only‬‭be‬‭administered‬‭under‬‭the‬‭direction‬‭of‬‭oncologists‬‭in‬‭specialist‬‭units‬
‭under‬ ‭conditions‬ ‭permitting‬ ‭adequate‬ ‭monitoring‬ ‭and‬ ‭surveillance.‬ ‭Supportive‬ ‭equipment‬
‭should be available to control anaphylactic reactions.‬
‭Cisplatin‬ ‭reacts‬ ‭with‬ ‭metallic‬ ‭aluminium‬ ‭to‬ ‭form‬ ‭a‬ ‭black‬ ‭precipitate‬ ‭of‬ ‭platinum.‬ ‭All‬
‭aluminium‬‭containing‬‭IV‬‭sets,‬‭needles,‬‭catheters‬‭and‬‭syringes‬‭should‬‭be‬‭avoided.‬‭The‬‭solution‬
‭for infusion should not be mixed with other drugs or additives.‬
‭Appropriate‬ ‭monitoring‬ ‭and‬ ‭management‬ ‭of‬ ‭the‬ ‭treatment‬ ‭and‬ ‭its‬ ‭complications‬ ‭are‬ ‭only‬
‭possible if adequate diagnosis and exact treatment conditions are available.‬
‭Further‬ ‭information‬ ‭on‬ ‭particular‬ ‭risks‬ ‭including‬ ‭nephrotoxicity,‬ ‭neuropathies,‬ ‭ototoxicity,‬
‭allergic‬ ‭reactions,‬ ‭hepatic‬ ‭function‬ ‭and‬ ‭haematological‬ ‭formula,‬ ‭carcinogenic‬ ‭potential,‬
‭injection site reactions are displayed in the Cisplatin SmPC.‬
‭7.6.‬
‭Investigational Product Storage‬
‭The‬‭investigational‬‭products‬‭should‬‭be‬‭stored‬‭in‬‭a‬‭secure‬‭area‬‭according‬‭to‬‭local‬‭regulations.‬‭It‬
‭is‬ ‭the‬ ‭responsibility‬ ‭of‬ ‭the‬ ‭investigator‬ ‭to‬ ‭ensure‬ ‭that‬ ‭investigational‬ ‭products‬ ‭are‬ ‭only‬
‭dispensed‬ ‭to‬ ‭study‬ ‭participants.‬ ‭The‬ ‭investigational‬ ‭product‬ ‭must‬ ‭be‬ ‭dispensed‬ ‭only‬ ‭from‬
‭official study sites by authorized personnel according to local regulations.‬
‭The‬ ‭investigator,‬ ‭or‬ ‭an‬ ‭approved‬ ‭representative‬ ‭(eg,‬ ‭pharmacist),‬ ‭will‬ ‭ensure‬ ‭that‬ ‭all‬
‭investigational‬ ‭products‬ ‭are‬ ‭stored‬ ‭in‬ ‭a‬ ‭secured‬ ‭area‬‭with‬‭controlled‬‭access‬‭under‬‭required‬
‭storage conditions and in accordance with applicable regulatory requirements.‬
‭Storage‬‭conditions‬‭stated‬‭in‬‭the‬‭SRSD‬‭(ie,‬‭IB)‬‭will‬‭be‬‭superseded‬‭by‬‭the‬‭storage‬‭conditions‬
‭stated‬‭on‬‭the‬‭label.‬‭Site‬‭systems‬‭must‬‭be‬‭capable‬‭of‬‭measuring‬‭and‬‭documenting‬‭(for‬‭example,‬
‭via‬ ‭a‬ ‭log),‬ ‭at‬ ‭a‬ ‭minimum,‬ ‭daily‬ ‭minimum‬ ‭and‬ ‭maximum‬ ‭temperatures‬ ‭for‬ ‭all‬‭site‬‭storage‬
‭locations‬ ‭(as‬ ‭applicable,‬ ‭including‬ ‭frozen,‬ ‭refrigerated‬ ‭and/or‬ ‭room‬ ‭temperature‬ ‭products).‬
‭This‬‭should‬‭be‬‭captured‬‭from‬‭the‬‭time‬‭of‬‭investigational‬‭product‬‭receipt‬‭throughout‬‭the‬‭study.‬
‭Even‬ ‭for‬ ‭continuous‬ ‭monitoring‬ ‭systems,‬ ‭a‬ ‭log‬ ‭or‬ ‭site‬ ‭procedure‬ ‭that‬ ‭ensures‬‭active‬‭daily‬
‭evaluation‬ ‭for‬ ‭excursions‬‭should‬‭be‬‭available.‬‭The‬‭operation‬‭of‬‭the‬‭temperature‬‭monitoring‬
‭device‬‭and‬‭storage‬‭unit‬‭(for‬‭example,‬‭refrigerator),‬‭as‬‭applicable,‬‭should‬‭be‬‭regularly‬‭inspected‬
‭to ensure it is maintained in working order.‬
‭Any excursions from the product label storage conditions should be reported upon discovery.‬
‭The‬‭site‬‭should‬‭actively‬‭pursue‬‭options‬‭for‬‭returning‬‭the‬‭product‬‭to‬‭the‬‭storage‬‭conditions‬‭as‬
‭described‬ ‭in‬ ‭the‬ ‭labeling,‬ ‭as‬ ‭soon‬ ‭as‬ ‭possible.‬ ‭Deviations‬ ‭from‬ ‭the‬ ‭storage‬ ‭requirements,‬
‭including any actions taken must be documented and reported to the sponsor.‬
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‭Once‬‭an‬‭excursion‬‭is‬‭identified,‬‭the‬‭investigational‬‭product‬‭must‬‭be‬‭quarantined‬‭and‬‭not‬‭used‬
‭until‬‭the‬‭sponsor‬‭provides‬‭documentation‬‭of‬‭permission‬‭to‬‭use‬‭the‬‭investigational‬‭product.‬‭It‬
‭will‬ ‭not‬ ‭be‬ ‭considered‬ ‭a‬ ‭protocol‬ ‭deviation‬ ‭if‬ ‭the‬ ‭sponsor‬ ‭approves‬ ‭the‬ ‭use‬ ‭of‬ ‭the‬
‭investigational‬ ‭product‬ ‭after‬ ‭the‬ ‭temperature‬ ‭excursion.‬ ‭Use‬ ‭of‬ ‭the‬ ‭investigational‬ ‭product‬
‭prior to sponsor approval will be considered a protocol deviation.‬
‭Specific‬ ‭details‬ ‭regarding‬ ‭information‬ ‭the‬ ‭site‬ ‭should‬ ‭report‬ ‭for‬ ‭each‬ ‭excursion‬ ‭will‬ ‭be‬
‭provided to the site.‬
‭Receipt‬‭of‬‭materials,‬‭door‬‭opening‬‭and‬‭closing,‬‭and‬‭other‬‭routine‬‭handling‬‭operations‬‭where‬
‭the‬ ‭product(s)‬ ‭are‬ ‭briefly‬ ‭out‬ ‭of‬ ‭the‬ ‭temperature‬ ‭range‬ ‭described‬ ‭in‬ ‭the‬ ‭labeling‬ ‭are‬ ‭not‬
‭considered excursions.‬
‭Site‬ ‭staff‬ ‭will‬ ‭instruct‬ ‭patients‬ ‭on‬ ‭the‬ ‭proper‬ ‭storage‬ ‭requirements‬ ‭for‬ ‭take-home‬
‭investigational products.‬
‭7.6.1.‬ ‭Atezolizumab storage‬
‭Atezolizumab‬ ‭must‬ ‭be‬ ‭refrigerated‬ ‭at‬ ‭2°C‬ ‭-‬ ‭8°C‬ ‭(36°F‬ ‭-‬ ‭46°F)‬ ‭upon‬ ‭receipt‬ ‭until‬ ‭use.‬
‭Atezolizumab‬‭and‬‭the‬‭diluent‬‭vials‬‭should‬‭not‬‭be‬‭used‬‭beyond‬‭the‬‭expiration‬‭date‬‭provided‬‭by‬
‭the‬ ‭manufacturer.‬‭No‬‭preservative‬‭is‬‭used‬‭in‬‭the‬‭atezolizumab‬‭Drug‬‭Product‬‭or‬‭the‬‭diluent;‬
‭therefore,‬ ‭the‬ ‭vial‬ ‭is‬ ‭intended‬ ‭for‬ ‭single‬ ‭use‬ ‭only.‬ ‭Discard‬ ‭any‬ ‭unused‬ ‭portion‬ ‭of‬ ‭drug‬
‭remaining‬‭in‬‭a‬‭vial.‬‭Vial‬‭contents‬‭should‬‭not‬‭be‬‭frozen‬‭or‬‭shaken‬‭and‬‭should‬‭be‬‭protected‬‭from‬
‭light‬‭by‬‭keeping‬‭the‬‭vial‬‭in‬‭the‬‭outer‬‭carton.‬‭This‬‭information‬‭is‬‭also‬‭available‬‭in‬‭the‬‭pharmacy‬
‭manual.‬
‭7.6.2.‬ ‭Gemcitabine and cisplatin storage‬
‭Gemcitabine and cisplatin must be stored and controlled as specified in the product label.‬
‭7.7.‬
‭Investigational Product Accountability‬
‭The‬‭delegated‬‭investigation‬‭site‬‭staff‬‭must‬‭maintain‬‭adequate‬‭records‬‭documenting‬‭the‬‭receipt,‬
‭use,‬‭loss,‬‭or‬‭other‬‭disposition‬‭of‬‭the‬‭investigational‬‭product‬‭supplies.‬‭All‬‭bottles‬‭of‬‭study‬‭drug‬
‭must‬‭be‬‭returned‬‭to‬‭the‬‭investigator‬‭by‬‭the‬‭patient‬‭at‬‭the‬‭end‬‭of‬‭each‬‭cycle‬‭and‬‭at‬‭the‬‭end‬‭of‬‭the‬
‭trial,‬‭the‬‭sponsor‬‭will‬‭provide‬‭instructions‬‭as‬‭to‬‭the‬‭disposition‬‭of‬‭any‬‭unused‬‭investigational‬
‭product if the investigative site is unable to destroy at site per local procedures.‬
‭7.8.‬
‭Destruction of Investigational Product Supplies‬
‭The‬‭sponsor‬‭or‬‭designee‬‭will‬‭provide‬‭guidance‬‭on‬‭the‬‭destruction‬‭of‬‭unused‬‭investigational‬
‭product‬‭Atezolizumab‬‭(e.g.,‬‭at‬‭the‬‭site).‬‭If‬‭destruction‬‭is‬‭authorized‬‭to‬‭take‬‭place‬‭at‬‭the‬‭study‬
‭site,‬ ‭the‬ ‭investigator‬ ‭must‬ ‭ensure‬ ‭that‬ ‭the‬ ‭materials‬ ‭are‬ ‭destroyed‬ ‭in‬ ‭compliance‬ ‭with‬
‭applicable‬ ‭environmental‬ ‭regulations,‬ ‭institutional‬ ‭policy,‬ ‭and‬ ‭any‬ ‭special‬ ‭instructions‬
‭provided by the Sponsor, and all destruction must be adequately documented.‬
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‭7.9.‬
‭Concomitant Treatments‬
‭Medications‬ ‭or‬ ‭vaccinations‬ ‭specifically‬ ‭prohibited‬ ‭in‬ ‭the‬ ‭Exclusion‬ ‭Criteria‬ ‭are‬ ‭also‬ ‭not‬
‭allowed‬ ‭during‬ ‭the‬ ‭active‬ ‭treatment‬ ‭period,‬ ‭except‬ ‭for‬ ‭the‬ ‭administration‬ ‭of‬ ‭inactivated‬
‭influenza vaccine.‬
‭If‬ ‭there‬ ‭is‬ ‭a‬ ‭clinical‬ ‭indication‬ ‭for‬ ‭one‬ ‭of‬ ‭these‬ ‭or‬ ‭other‬ ‭medications‬ ‭or‬ ‭vaccinations‬
‭specifically‬
‭prohibited‬
‭during‬
‭the‬
‭trial,‬
‭discontinuation‬
‭from‬
‭study‬
‭therapy‬ ‭or‬
‭medication/vaccination‬ ‭may‬ ‭be‬ ‭required.‬ ‭The‬ ‭final‬ ‭decision‬ ‭on‬ ‭any‬ ‭supportive‬ ‭therapy‬ ‭or‬
‭vaccination‬ ‭rests‬ ‭with‬‭the‬‭investigator‬‭and/or‬‭the‬‭patient’s‬‭primary‬‭physician.‬‭However,‬‭the‬
‭decision‬‭to‬‭continue‬‭the‬‭patient‬‭on‬‭study‬‭therapy‬‭or‬‭medication/vaccination‬‭schedule‬‭requires‬
‭the mutual agreement of the investigator, the sponsor, and the patient.‬
‭Concomitant‬‭treatment‬‭considered‬‭necessary‬‭for‬‭the‬‭patient’s‬‭wellbeing‬‭may‬‭be‬‭given‬‭at‬‭the‬
‭discretion‬ ‭of‬ ‭the‬ ‭treating‬ ‭physician.‬‭All‬‭concomitant‬‭treatments,‬‭blood‬‭products,‬‭as‬‭well‬‭as‬
‭non-drug‬‭interventions‬‭received‬‭by‬‭patients‬‭from‬‭screening‬‭until‬‭the‬‭end‬‭of‬‭study‬‭visit‬‭will‬‭be‬
‭recorded on the CRF.‬
‭Concomitant‬‭medications‬‭and‬‭treatments,‬‭including‬‭herbal‬‭supplements,‬‭will‬‭be‬‭recorded‬‭from‬
‭28‬ ‭days‬ ‭prior‬‭to‬‭the‬‭start‬‭of‬‭study‬‭treatment‬‭and‬‭up‬‭to‬‭90‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭study‬
‭treatment.‬‭All‬‭concomitant‬‭medications‬‭should‬‭be‬‭recorded‬‭in‬‭the‬‭CRF‬‭including‬‭supportive‬
‭care‬ ‭drugs‬ ‭(e.g.,‬‭antiemetic‬‭treatment‬‭and‬‭prophylaxis),‬‭and‬‭the‬‭drugs‬‭used‬‭to‬‭treat‬‭adverse‬
‭events or chronic diseases, and non-drug supportive interventions (e.g., transfusions).‬
‭Concurrent‬‭anticancer‬‭therapy‬‭with‬‭agents‬‭other‬‭than‬‭atezolizumab‬‭and‬‭GC‬‭are‬‭not‬‭allowed.‬
‭Medications‬‭intended‬‭solely‬‭for‬‭supportive‬‭care‬‭(i.e.,‬‭antiemetics,‬‭analgesics,‬‭megestrol‬‭acetate‬
‭for anorexia) are allowed.‬
‭7.9.1.‬ ‭Inhibitors and Inducers of CYP Enzymes‬
‭Because‬‭antibodies‬‭are‬‭cleared‬‭principally‬‭by‬‭catabolism‬‭(i.e.,‬‭cleavage‬‭to‬‭small‬‭peptides‬‭and‬
‭amino‬‭acids),‬‭atezolizumab‬‭is‬‭not‬‭expected‬‭to‬‭show‬‭pharmacokinetic‬‭interactions‬‭with‬‭other‬
‭drugs,‬ ‭and‬ ‭is‬ ‭therefore‬ ‭not‬ ‭expected‬ ‭to‬ ‭interact‬ ‭with‬ ‭other‬ ‭drugs‬ ‭through‬ ‭protein‬ ‭binding,‬
‭effects‬ ‭on‬ ‭cytochrome‬ ‭P450‬ ‭activity,‬ ‭renal‬ ‭excretion‬ ‭or‬ ‭competition‬ ‭for‬ ‭common‬ ‭drug‬
‭transporter‬ ‭proteins.‬ ‭No‬ ‭formal‬ ‭pharmacokinetic‬ ‭drug‬ ‭interaction‬ ‭studies‬ ‭have‬ ‭thus‬ ‭been‬
‭undertaken with atezolizumab.‬
‭7.9.2.‬ ‭Concomitant Surgery‬
‭No specific information on the effect of Atezolizumab on wound healing are reported in the‬
‭current version of IB nor SmPC.‬
‭7.9.3.‬ ‭Concomitant Radiotherapy‬
‭Toxicity‬‭of‬‭concurrent‬‭administration‬‭of‬‭gemcitabine‬‭(simultaneous‬‭or‬‭≤‬‭7‬‭days‬‭apart)‬‭depends‬
‭on‬ ‭many‬‭different‬‭factors,‬‭including‬‭the‬‭dose‬‭of‬‭gemcitabine,‬‭the‬‭frequency‬‭of‬‭gemcitabine‬
‭administration,‬ ‭radiation‬ ‭dose,‬ ‭radiotherapy‬ ‭planning‬ ‭technique,‬ ‭tissue‬ ‭to‬ ‭radiate‬ ‭and‬ ‭the‬
‭theoretical‬‭irradiation‬‭volume.‬‭For‬‭the‬‭matter‬‭of‬‭this‬‭study,‬‭radiotherapy‬‭within‬‭4‬‭weeks‬‭prior‬
‭to inclusion is considered an exclusion criteria.‬
‭For‬ ‭non-concurrent‬ ‭gemcitabine‬ ‭administration‬ ‭(administered>‬ ‭7‬ ‭days‬ ‭apart),‬ ‭data‬‭analysis‬
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‭does‬‭not‬‭indicate‬‭an‬‭increased‬‭toxicity‬‭when‬‭gemcitabine‬‭is‬‭administered‬‭at‬‭least‬‭7‬‭days‬‭before‬
‭or‬‭after‬‭radiotherapy,‬‭except‬‭for‬‭late‬‭skin‬‭toxicity.‬‭The‬‭data‬‭that‬‭can‬‭be‬‭started‬‭administration‬‭of‬
‭gemcitabine when the acute effects of radiation therapy have resolved or at least one‬
‭week‬ ‭after‬ ‭radiation‬ ‭therapy.‬ ‭Radiation‬ ‭injury‬ ‭has‬ ‭been‬ ‭detected‬ ‭in‬ ‭irradiated‬ ‭tissues‬ ‭(e.g.‬
‭esophagitis,‬‭colitis,‬‭and‬‭pneumonitis)‬‭in‬‭association‬‭with‬‭both‬‭concurrent‬‭and‬‭non-concurrent‬
‭use‬‭of‬‭gemcitabine.‬‭Further‬‭information‬‭can‬‭be‬‭obtained‬‭in‬‭the‬‭current‬‭version‬‭of‬‭Gemcitabine‬
‭SmPC.‬
‭7.9.4.‬ ‭Other Prohibited Concomitant Medications and Therapies‬
‭Clarifications‬‭about‬‭Steroid‬‭Use:‬‭Data‬‭indicate‬‭that‬‭corticosteroids‬‭have‬‭an‬‭adverse‬‭effect‬‭on‬
‭T-cell‬‭function‬‭and‬‭that‬‭they‬‭inhibit‬‭and‬‭damage‬‭lymphocytes‬‭(‬‭Schleimer‬‭RP,‬‭et‬‭al.‬‭1984;‬‭Khan‬
‭MM, 2008‬‭).‬
‭Furthermore,‬‭as‬‭with‬‭all‬‭immunotherapies‬‭intended‬‭to‬‭augment‬‭cell-mediated‬‭immunity,‬‭there‬
‭is‬‭a‬‭risk‬‭that‬‭concomitant‬‭immunosuppressants‬‭such‬‭as‬‭steroids‬‭will‬‭counteract‬‭the‬‭intended‬
‭benefit‬ ‭of‬ ‭the‬ ‭proposed‬ ‭study‬ ‭treatment.‬ ‭However,‬ ‭studies‬ ‭with‬ ‭anti-CTLA4‬ ‭compounds‬
‭indicate‬ ‭that‬ ‭short-term‬ ‭use‬ ‭of‬ ‭steroids‬ ‭may‬ ‭be‬ ‭employed‬ ‭without‬ ‭compromising‬ ‭clinical‬
‭outcomes (‬‭Weber JS, et al. 2012‬‭).‬
‭Therefore, the use of steroids during this trial is restricted as follows:‬
‭●‬ ‭Therapeutic‬ ‭use:‬ ‭for‬ ‭the‬ ‭treatment‬ ‭of‬ ‭infusion-related‬ ‭reactions‬ ‭and‬ ‭short-term‬
‭treatment‬ ‭of‬ ‭irAEs,‬ ‭steroids‬ ‭are‬ ‭permitted‬ ‭according‬ ‭to‬ ‭the‬ ‭modalities‬‭indicated‬‭in‬
‭Appendix 1‬‭.‬
‭●‬ ‭Physiologic‬‭use:‬‭steroid‬‭replacement‬‭for‬‭adrenal‬‭insufficiency‬‭at‬‭doses‬‭equivalent‬‭to‬
‭≤10 mg prednisone daily is acceptable.‬
‭●‬ ‭Prophylactic‬ ‭use‬‭,‬ ‭e.g.,‬ ‭for‬ ‭the‬ ‭prevention‬ ‭of‬ ‭acute‬ ‭infusion-related‬ ‭reactions,‬ ‭is‬
‭prohibited,‬‭except‬‭prior to CT or MRI.‬
‭7.10.‬ ‭Rescue Medications and Supportive Care‬
‭7.10.1.‬ ‭Supportive Care Guidelines‬
‭Patients‬ ‭should‬ ‭receive‬ ‭appropriate‬ ‭supportive‬ ‭care‬ ‭measures‬ ‭as‬ ‭deemed‬ ‭necessary‬ ‭by‬ ‭the‬
‭treating investigator including but not limited to the items outlined below:‬
‭●‬ ‭Diarrhea:‬ ‭All‬ ‭patients‬ ‭who‬ ‭experience‬ ‭diarrhea‬ ‭should‬ ‭be‬ ‭advised‬ ‭to‬ ‭drink‬‭liberal‬
‭quantities‬ ‭of‬ ‭clear‬ ‭fluids.‬ ‭If‬ ‭sufficient‬ ‭oral‬ ‭fluid‬ ‭intake‬ ‭is‬ ‭not‬ ‭feasible,‬ ‭fluid‬ ‭and‬
‭electrolytes should be substituted via IV infusion.‬
‭●‬ ‭Nausea/Vomiting‬‭:‬ ‭Nausea‬ ‭and‬ ‭vomiting‬ ‭should‬ ‭be‬ ‭treated‬ ‭aggressively,‬ ‭and‬
‭consideration‬ ‭should‬ ‭be‬ ‭given‬ ‭in‬ ‭subsequent‬ ‭cycles‬ ‭to‬ ‭the‬ ‭administration‬ ‭of‬
‭prophylactic‬ ‭antiemetic‬‭therapy‬‭according‬‭to‬‭standard‬‭institutional‬‭practice.‬‭Patients‬
‭should be strongly encouraged to maintain liberal oral fluid intake.‬
‭●‬ ‭Anti-infectives:‬ ‭Patients‬ ‭with‬ ‭a‬ ‭documented‬ ‭infectious‬ ‭complication‬ ‭should‬ ‭receive‬
‭oral‬‭or‬‭IV‬‭antibiotics‬‭or‬‭other‬‭anti-infective‬‭agents‬‭as‬‭considered‬‭appropriate‬‭by‬‭the‬
‭treating‬ ‭investigator‬ ‭for‬ ‭a‬ ‭given‬ ‭infectious‬ ‭condition,‬ ‭according‬ ‭to‬ ‭standard‬
‭institutional‬‭practice.‬‭Prophylactic‬‭administration‬‭should‬‭be‬‭considered‬‭for‬‭the‬‭cases‬
‭outlined in‬‭Appendix 1‬‭.‬
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‭●‬ ‭Anti-inflammatory‬
‭or‬
‭narcotic‬
‭analgesics‬
‭may‬
‭be‬
‭offered‬
‭as‬
‭needed.‬
‭Acetaminophen/paracetamol‬‭to‬‭a‬‭maximum‬‭total‬‭daily‬‭dose‬‭of‬‭2‬‭g‬‭is‬‭permitted.‬‭Daily‬
‭intake over 2 g is prohibited.‬
‭●‬ ‭Patients‬‭who‬‭need‬‭to‬‭be‬‭on‬‭anticoagulant‬‭therapy‬‭during‬‭treatment‬‭should‬‭be‬‭treated‬
‭with‬ ‭low‬ ‭molecular‬ ‭weight‬ ‭heparin.‬ ‭If‬ ‭low‬ ‭molecular‬ ‭weight‬ ‭heparin‬ ‭cannot‬ ‭be‬
‭administered,‬ ‭coumadin‬ ‭or‬ ‭other‬ ‭coumarin‬ ‭derivatives‬ ‭or‬ ‭other‬ ‭anticoagulants‬
‭(including‬‭direct‬‭Xa‬‭inhibitors)‬‭may‬‭be‬‭allowed;‬‭however,‬‭appropriate‬‭monitoring‬‭of‬
‭prothrombin time/international normalized ratio (PT/INR) should be performed.‬
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‭8.‬
‭STUDY PROCEDURES AND EVALUATIONS‬
‭8.1.‬
‭Definition of efficacy variables‬
‭●‬ ‭Overall‬ ‭Response‬ ‭Rate‬ ‭(ORR):‬ ‭Assessed‬ ‭by‬ ‭the‬ ‭investigator‬ ‭using‬ ‭the‬ ‭Response‬
‭Evaluation‬ ‭Criteria‬‭in‬‭Solid‬‭Tumors‬‭(RECIST)‬‭v1.1.‬‭This‬‭will‬‭be‬‭considered‬‭as‬‭the‬
‭percentage/proportion‬ ‭of‬ ‭patients‬‭with‬‭confirmed‬‭complete‬‭response‬‭(CR)‬‭or‬‭partial‬
‭response (PR) as their overall best response throughout the study period.‬
‭●‬ ‭Duration‬‭of‬‭response‬‭(DoR):‬‭Time‬‭from‬‭first‬‭confirmed‬‭response‬‭(CR‬‭or‬‭PR)‬‭to‬‭the‬
‭date‬‭of‬‭the‬‭documented‬‭PD‬‭as‬‭determined‬‭using‬‭RECIST‬‭1.1‬‭criteria‬‭or‬‭death‬‭due‬‭to‬
‭any cause, whichever occurs first.‬
‭●‬ ‭Time‬ ‭to‬‭response‬‭(TtR):‬‭Time‬‭from‬‭first‬‭dosing‬‭date‬‭to‬‭the‬‭date‬‭of‬‭the‬‭documented‬
‭ORR as determined using RECIST 1.1 criteria.‬
‭●‬ ‭Progression-Free‬‭Survival‬‭(PFS):‬‭Time‬‭from‬‭first‬‭dosing‬‭date‬‭to‬‭the‬‭date‬‭of‬‭confirmed‬
‭PD.‬‭A‬‭subject‬‭who‬‭has‬‭not‬‭died‬‭will‬‭be‬‭censored‬‭at‬‭the‬‭last‬‭known‬‭date‬‭alive.‬‭PFS‬‭rate‬
‭will be assessed through the proportion of patients free of PD at the end of follow-up.‬
‭●‬ ‭Clinical‬‭benefit‬‭(CB)‬‭:‬‭Percentage/proportion‬‭of‬‭patients‬‭with‬‭complete‬‭response‬‭(CR)‬
‭or‬ ‭partial‬ ‭response‬ ‭(PR)‬ ‭or‬ ‭maintained‬ ‭stable‬ ‭disease‬ ‭(SD)‬ ‭as‬ ‭their‬ ‭overall‬ ‭best‬
‭response‬‭throughout‬‭the‬‭study‬‭period,‬‭assessed‬‭by‬‭imaging‬‭follow-up‬‭(CT‬‭scan/MRI),‬
‭on week 9, week 18 and then, every 12 weeks.‬
‭●‬ ‭Overall‬ ‭Survival‬ ‭(OS):‬ ‭Time‬ ‭from‬ ‭first‬ ‭dosing‬ ‭date‬ ‭to‬ ‭the‬ ‭date‬ ‭of‬ ‭death‬ ‭and‬ ‭the‬
‭proportion/percentage‬‭of‬‭patients‬‭alive‬‭at‬‭the‬‭end‬‭of‬‭follow-up.‬‭A‬‭subject‬‭who‬‭has‬‭not‬
‭died‬ ‭will‬ ‭be‬ ‭censored‬ ‭at‬ ‭the‬ ‭last‬ ‭known‬ ‭date‬ ‭alive.‬ ‭Survival‬ ‭will‬ ‭be‬ ‭assessed‬ ‭by‬
‭recording‬‭patient‬‭status‬‭at‬‭each‬‭visit‬‭according‬‭to‬‭Table‬‭4‬‭.‬‭Long‬‭term‬‭follow‬‭up‬‭to‬‭be‬
‭performed every 6 months.‬
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‭8.2.‬
‭Safety and tolerability‬
‭Safety‬ ‭assessments:‬ ‭Safety‬ ‭parameters‬ ‭are‬ ‭AE,‬ ‭SAE,‬ ‭AESI,‬ ‭pregnancy,‬ ‭medication‬ ‭error,‬
‭overdose.‬‭Additional‬‭safety‬‭information‬‭could‬‭be‬‭derived‬‭from‬‭ECG,‬‭lab‬‭test,‬‭pregnancy‬‭test,‬
‭or vital sign exam.‬
‭The‬‭assessment‬‭of‬‭adverse‬‭events‬‭will‬‭include‬‭the‬‭type‬‭of‬‭event‬‭(including‬‭symptoms,‬‭physical‬
‭exam‬‭findings‬‭and‬‭laboratory‬‭abnormalities),‬‭the‬‭incidence,‬‭severity,‬‭timing,‬‭seriousness,‬‭and‬
‭relatedness‬‭regarding‬‭the‬‭treatment‬‭under‬‭study.‬‭Adverse‬‭events‬‭will‬‭be‬‭recorded‬‭and‬‭reported‬
‭in‬‭the‬‭corresponding‬‭section‬‭of‬‭the‬‭case‬‭report‬‭form.‬‭The‬‭grade‬‭of‬‭adverse‬‭events‬‭will‬‭be‬‭coded‬
‭according‬ ‭to‬ ‭the‬ ‭National‬ ‭Cancer‬ ‭Institute’s‬ ‭Common‬ ‭Toxicity‬ ‭criteria‬ ‭(NCI-CTCAE‬ ‭v5.0‬
‭scoring‬ ‭system).‬ ‭The‬ ‭worst‬ ‭toxicity‬ ‭score‬ ‭will‬ ‭be‬ ‭recorded.‬ ‭In‬‭case‬‭of‬‭SAE‬‭and‬‭AESI‬‭the‬
‭investigator‬‭should‬‭immediately‬‭fill‬‭in‬‭the‬‭dedicated‬‭SAE‬‭form‬‭and‬‭send‬‭it‬‭by‬‭as‬‭detailed‬‭in‬
‭Section 9.2.‬
‭●‬ ‭Adverse events (AE) assessment:‬‭type, frequency, outcome‬‭of adverse events.‬
‭●‬ ‭Treatment-related‬‭AEs:‬‭An‬‭event‬‭is‬‭assessed‬‭as‬‭related‬‭to‬‭study‬‭treatment‬‭when‬‭there‬
‭is‬ ‭a‬ ‭reasonable‬ ‭possibility‬ ‭that‬ ‭study‬ ‭treatment‬ ‭caused‬ ‭the‬ ‭event.‬ ‭Reasonable‬
‭possibility‬ ‭means‬ ‭there‬ ‭is‬ ‭evidence‬ ‭to‬ ‭suggest‬ ‭a‬ ‭causal‬ ‭relationship‬ ‭between‬‭study‬
‭treatment‬‭and‬‭the‬‭event.‬‭This‬‭event‬‭is‬‭called‬‭a‬‭suspected‬‭adverse‬‭reaction.‬‭A‬‭suspected‬
‭adverse‬ ‭reaction‬ ‭implies‬ ‭a‬ ‭lesser‬ ‭degree‬ ‭of‬ ‭certainty‬ ‭about‬ ‭causality‬ ‭than‬ ‭adverse‬
‭reaction, which means any AE caused by a drug.‬
‭●‬ ‭Serious‬‭adverse‬‭events‬‭(SAEs)‬‭assessment:‬‭type,‬‭frequency,‬‭grade,‬‭outcome,‬‭relation‬
‭with‬ ‭study‬ ‭treatment,‬ ‭all‬ ‭considering‬ ‭the‬‭total‬‭number‬‭and‬‭proportion‬‭based‬‭on‬‭the‬
‭intention-to-treat and per protocol populations.‬
‭8.3.‬
‭Study determinations‬
‭Table 4‬‭details the study determinations to be performed‬‭and the corresponding timeline.‬
‭Table 4. Study determinations‬
‭Visit‬
‭SCR‬
‭Cycle 1‬
‭Cycle 2‬
‭Cycle 3‬
‭Cycle 4‬
‭Cycle 5‬
‭Cycle 6‬
‭Cycle 7‬
‭up to‬
‭Cycle N‬
‭Safety‬
‭Visit‬
‭PFS‬
‭FU‬
‭EOS‬
‭FU‬
‭Timeline‬
‭≤ 28 D‬
‭prior to‬
‭inclusion‬
‭D1‬ ‭D8‬ ‭D1‬ ‭D8‬
‭D1‬
‭D8‬ ‭D1‬ ‭D8‬ ‭D1‬ ‭D8‬
‭D1‬
‭D8‬
‭D1‬
‭within‬
‭30d‬
‭after‬
‭EOT‬
‭Q12W‬
‭Q6‬
‭months‬
‭Visit window‬
‭+/- 3d‬
‭Q3W‬
‭+/-3d‬
‭+/-3d‬
‭+/- 7d‬
‭Clinical Assessments‬
‭Informed consent‬
‭x‬
‭Medical History‬
‭(Medical  and‬
‭oncology specific)‬
‭x‬
‭Physical Exam‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭ECOG‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
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‭Contraception check‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Vital signs (BP, PR)‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Laboratory and biological sample studies‬
‭Archival tumor‬
‭block‬
‭x‬
‭Blood collection‬
‭(biomarkers)‬
‭x‬
‭x‬
‭x‬
‭(D1C7)‬
‭x‬
‭at DP‬
‭Faecal sample‬
‭(biomarkers)‬
‭x‬
‭x‬
‭x‬
‭at DP‬
‭Coagulation‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Hematology*‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Blood chemistry*‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Thyroid function‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭HBV/HCV test‬
‭x‬
‭Pregnancy test‬
‭(serum/urine)‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Urinalysis‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Cardiac monitoring‬
‭ECG‬
‭x‬
‭If clinically indicated‬
‭x‬
‭FEVI‬
‭x‬
‭If clinically indicated‬
‭x‬
‭Disease assessment‬
‭Tumor evaluation‬
‭x‬
‭On week 9 , week 18 (prior starting atezolizumab monotherapy and every 12 weeks +/-7‬
‭days thereafter until the of objective disease progression or death (whichever comes‬
‭first)‬
‭Survival‬
‭assessment‬
‭x‬
‭IMP follow-up‬
‭Treatment dosing‬
‭compliance‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Chemotherapy‬
‭administration‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Atezolizumab‬
‭administration‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Concomitant‬
‭medications‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭New systemic cancer‬
‭treatment‬
‭x‬
‭x‬
‭Safety assessment‬
‭Adverse events‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭D:‬‭Day/s;‬‭Q3W:‬‭Every‬‭3‬‭weeks;‬‭Q12W:‬‭Every‬‭12‬‭weeks;‬‭EOT:‬‭End‬‭of‬‭treatment;‬‭PFS:‬‭Progression-free‬‭survival;‬
‭EOS: End of study.‬
‭Informed‬‭consent:‬‭Informed‬‭consent‬‭of‬‭study‬‭procedures‬‭may‬‭be‬‭obtained‬‭prior‬‭to‬‭the‬‭screening.‬‭If‬‭laboratory‬‭or‬
‭imaging‬‭procedures‬‭were‬‭performed‬‭for‬‭different‬‭reasons‬‭prior‬‭to‬‭signing‬‭consent,‬‭these‬‭can‬‭be‬‭used‬‭for‬‭screening‬
‭purposes‬ ‭with‬ ‭the‬ ‭consent‬ ‭of‬ ‭the‬ ‭patient.‬ ‭However,‬ ‭all‬‭screening‬‭laboratory‬‭and‬‭imaging‬‭results‬‭must‬‭have‬‭been‬
‭obtained within 28 days of inclusion.‬
‭Medical‬‭History:‬‭Should‬‭include‬‭information‬‭on‬‭prior‬‭systemic‬‭adjuvant‬‭or‬‭neoadjuvant‬‭therapy‬‭regimens,‬‭surgery‬
‭and‬ ‭radiation‬ ‭therapy.‬ ‭Comorbidities:‬ ‭cardiovascular‬ ‭disease,‬ ‭previous‬ ‭cancer‬ ‭and‬ ‭diabetes,‬ ‭pulmonary‬ ‭disease,‬
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‭dementia, etc.‬
‭Physical‬‭exam:‬‭Includes‬‭an‬‭examination‬‭of‬‭major‬‭body‬‭systems‬‭and‬‭weight‬‭(height‬‭at‬‭screening‬‭only).‬‭Additional‬
‭PE‬ ‭may‬ ‭be‬ ‭performed‬ ‭as‬ ‭clinically‬ ‭indicated.‬ ‭During‬ ‭the‬ ‭physical‬ ‭examination,‬ ‭a‬ ‭stethoscope‬ ‭will‬ ‭be‬ ‭used‬ ‭to‬
‭carefully‬‭auscultate‬‭the‬‭lungs,‬‭additional‬‭respiratory‬‭functional‬‭tests‬‭should‬‭be‬‭performed‬‭as‬‭per‬‭local‬‭practise‬‭when‬
‭suspecting pneumonitis (more information is provided in annex 1 of this protocol).‬
‭ECOG PS:‬‭ECOG may be recorded by telephone if the‬‭patient is not coming to site for other reasons.‬
‭Contraception‬‭check:‬‭Male‬‭patients‬‭who‬‭are‬‭able‬‭to‬‭father‬‭children‬‭and‬‭female‬‭patients‬‭who‬‭are‬‭of‬‭childbearing‬
‭potential‬‭will‬‭need‬‭to‬‭affirm‬‭that‬‭they‬‭meet‬‭the‬‭criteria‬‭for‬‭correct‬‭use‬‭of‬‭2‬‭of‬‭the‬‭selected‬‭methods‬‭of‬‭contraception.‬
‭The‬‭investigator‬‭or‬‭his‬‭or‬‭her‬‭designee‬‭will‬‭discuss‬‭with‬‭the‬‭patient‬‭the‬‭need‬‭to‬‭use‬‭2‬‭highly‬‭effective‬‭contraception‬
‭methods‬ ‭consistently‬ ‭and‬ ‭correctly‬ ‭and‬ ‭document‬ ‭such‬ ‭conversation‬ ‭in‬ ‭the‬ ‭patient’s‬ ‭chart.‬ ‭In‬ ‭addition,‬ ‭the‬
‭investigator‬‭or‬‭his/her‬‭designee‬‭will‬‭instruct‬‭the‬‭patient‬‭to‬‭call‬‭immediately‬‭if‬‭one‬‭or‬‭both‬‭contraception‬‭methods‬‭are‬
‭discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner.‬
‭Vital signs:‬‭To include blood pressure (BP) and pulse‬‭rate (PR). Body weight is to be recorded at each visit along‬
‭with vital signs.‬
‭*Laboratory‬‭Studies:‬‭Complete‬‭blood‬‭count‬‭that‬‭includes‬‭total‬‭white‬‭blood‬‭cell‬‭count‬‭with‬‭leukocyte‬‭formula,‬‭Hb,‬
‭and‬‭platelet‬‭count.‬‭The‬‭analytical‬‭studies‬‭may‬‭be‬‭performed‬‭up‬‭to‬‭72‬‭hours‬‭before‬‭the‬‭scheduled‬‭visits‬‭in‬‭order‬‭to‬
‭have‬ ‭the‬ ‭results‬ ‭at‬ ‭the‬ ‭time‬ ‭of‬ ‭the‬ ‭patient’s‬ ‭visit.‬ ‭During‬ ‭the‬ ‭first‬ ‭6‬ ‭cycles‬ ‭of‬ ‭treatment‬ ‭with‬ ‭split‬ ‭doses‬ ‭of‬
‭gemcitabine‬ ‭plus‬ ‭cisplatin,‬ ‭complete‬ ‭blood‬ ‭count‬ ‭and‬ ‭biochemistry‬ ‭(liver,‬ ‭renal‬ ‭and‬ ‭electrolytes)‬ ‭on‬ ‭D1‬ ‭and‬
‭D8are‬ ‭mandatory‬ ‭for‬ ‭patient‬‭safety‬‭assurance‬‭and‬‭treatment‬‭continuation‬‭.‬‭Biochemistry‬‭tests‬‭include‬‭albumin,‬
‭alkaline‬ ‭phosphatase,‬ ‭lactate‬ ‭dehydrogenase‬ ‭(LDH),‬ ‭calcium,‬ ‭magnesium,‬ ‭phosphorus,‬ ‭sodium,‬ ‭potassium,‬
‭creatinine,‬‭creatine‬‭kinase,‬‭direct‬‭bilirubin,‬‭indirect‬‭bilirubin,‬‭total‬‭bilirubin,‬‭total‬‭protein,‬‭urea,‬‭uric‬‭acid,‬‭amylase,‬
‭lipase,‬ ‭and‬ ‭glucose‬ ‭tests.‬ ‭Liver‬ ‭test‬ ‭panel‬ ‭functions‬ ‭include‬ ‭alanine‬ ‭transaminase‬ ‭(ALT),‬ ‭aspartate‬‭transaminase‬
‭(AST),‬‭alkaline‬‭phosphatase‬‭(ALP),‬‭and‬‭gamma-glutamyl‬‭transpeptidase‬‭(GGT)‬‭tests.‬‭Tests‬‭for‬‭pancreatic‬‭enzymes‬
‭include‬ ‭lipase,‬ ‭protease‬ ‭(optional),‬ ‭amylase,‬ ‭and‬ ‭trypsinogen‬ ‭(optional)‬ ‭tests.‬‭If‬‭screening‬‭clinical‬‭chemistry‬‭and‬
‭haematology‬ ‭assessments‬ ‭are‬ ‭performed‬ ‭within‬ ‭3‬‭days‬‭prior‬‭to‬‭day‬‭1‬‭(first‬‭infusion‬‭day),‬‭they‬‭do‬‭not‬‭need‬‭to‬‭be‬
‭repeated at day 1.‬
‭Faecal‬ ‭samples:‬ ‭Specimens‬ ‭will‬ ‭be‬ ‭collected‬ ‭at‬ ‭baseline‬ ‭(before‬ ‭start‬ ‭of‬ ‭treatment),‬ ‭Cycle‬ ‭4‬ ‭Day‬ ‭1‬ ‭and‬ ‭after‬
‭progression;‬ ‭the‬ ‭sample‬ ‭must‬ ‭be‬ ‭processed‬ ‭and‬ ‭retained‬ ‭in‬ ‭the‬ ‭local‬ ‭laboratory‬ ‭until‬ ‭Sponsor‬ ‭indications‬ ‭for‬
‭shipment.‬
‭Thyroid Function:‬‭TSH and free T4.‬
‭HBV/HCV test:‬‭Serology including HIV, hepatitis B‬‭(HBsAg and anti-HBc), and hepatitis C virus (HCV).‬
‭Pregnancy‬ ‭test‬ ‭(serum/urine):‬ ‭For‬ ‭women‬ ‭of‬ ‭childbearing‬ ‭potential‬ ‭only.‬ ‭A‬ ‭urine‬ ‭or‬ ‭serum‬ ‭pregnancy‬ ‭test‬ ‭is‬
‭acceptable.‬‭Women‬‭of‬‭childbearing‬‭potential‬‭are‬‭required‬‭to‬‭have‬‭a‬‭pregnancy‬‭test‬‭within‬‭7‬‭days‬‭prior‬‭to‬‭the‬‭first‬
‭dose‬‭of‬‭the‬‭study‬‭drug,‬‭and‬‭every‬‭4‬‭weeks‬‭thereafter.‬‭Pregnancy‬‭tests‬‭may‬‭occur‬‭on‬‭day‬‭1,‬‭but‬‭the‬‭results‬‭must‬‭be‬
‭available and reviewed by the treating physician or investigator prior to commencing an infusion.‬
‭Urinalysis:‬‭Protein,‬‭glucose,‬‭blood,‬‭Urine‬‭dipstick/other‬‭semiquantitative‬‭method,‬‭for‬‭urine‬‭protein:‬‭if‬‭≥‬‭2+,‬‭collect‬
‭24-hour.‬
‭ECG:‬‭12-lead ECG. Any clinically significant abnormalities‬‭detected require triplicate ECG results.‬
‭FEVI:‬‭MUGA‬‭Scan‬‭or‬‭ECHO,‬‭the‬‭technique‬‭used‬‭at‬‭screening‬‭will‬‭be‬‭consistently‬‭used‬‭throughout‬‭the‬‭study,‬‭in‬
‭the following assessments.‬
‭Tumor‬‭assessments:‬‭CT‬‭scan‬‭or‬‭MRI‬‭is‬‭to‬‭be‬‭performed‬‭at‬‭baseline,‬‭on‬‭week‬‭9,‬‭on‬‭week‬‭18‬‭and‬‭q12w‬‭±‬‭1w‬‭until‬
‭the‬ ‭confirmation‬ ‭of‬ ‭objective‬ ‭disease‬ ‭progression‬‭or‬‭death‬‭(whichever‬‭comes‬‭first).‬‭The‬‭same‬‭imaging‬‭technique‬
‭used‬ ‭to‬ ‭characterize‬ ‭each‬ ‭identified‬ ‭and‬ ‭reported‬ ‭lesion‬ ‭at‬ ‭screening‬ ‭will‬ ‭be‬ ‭employed‬ ‭in‬ ‭the‬ ‭following‬ ‭tumor‬
‭assessments.‬ ‭This‬ ‭schedule‬ ‭must‬ ‭be‬ ‭followed‬ ‭regardless‬ ‭of‬ ‭any‬ ‭delays‬ ‭in‬ ‭dosing,‬ ‭in‬ ‭case‬ ‭of‬ ‭suspected‬
‭pseudo-progression;‬ ‭treatment‬ ‭should‬ ‭be‬ ‭continued‬ ‭until‬ ‭progression‬ ‭of‬ ‭disease‬ ‭is‬ ‭confirmed‬ ‭from‬ ‭the‬ ‭imaging‬
‭results.‬‭RECIST‬‭assessments‬‭will‬‭be‬‭performed‬‭on‬‭images‬‭from‬‭CT‬‭scans‬‭(preferred)‬‭or‬‭MRI,‬‭each‬‭preferably‬‭with‬
‭IV‬‭contrast‬‭of‬‭the‬‭neck,‬‭chest,‬‭abdomen‬‭(including‬‭liver‬‭and‬‭adrenal‬‭glands),‬‭and‬‭pelvis.‬‭Additional‬‭anatomy‬‭should‬
‭be‬ ‭imaged‬ ‭based‬ ‭on‬ ‭signs‬ ‭and‬ ‭symptoms‬‭of‬‭individual‬‭patients‬‭at‬‭baseline‬‭and‬‭follow-up.‬ ‭Baseline‬‭assessments‬
‭should‬‭be‬‭performed‬‭no‬‭more‬‭than‬‭28‬‭days‬‭before‬‭the‬‭date‬‭of‬‭inclusion‬‭and,‬‭ideally,‬‭should‬‭be‬‭performed‬‭as‬‭close‬‭as‬
‭possible‬‭to‬‭and‬‭prior‬‭to‬‭the‬‭start‬‭of‬‭treatment.‬‭CR‬‭and‬‭PR‬‭must‬‭be‬‭confirmed‬‭with‬‭repeated‬‭imaging‬‭performed‬‭at‬
‭least‬‭4‬‭weeks‬‭after‬‭initial‬‭documentation‬‭of‬‭response.‬‭Assessment‬‭of‬‭response‬‭will‬‭be‬‭performed‬‭using‬‭RECIST‬‭1.1.‬
‭If‬‭radiologic‬‭imaging‬‭shows‬‭disease‬‭progression,‬‭the‬‭confirmatory‬‭scans‬‭should‬‭be‬‭performed‬‭preferably‬‭at‬‭the‬‭next‬
‭scheduled‬ ‭imaging‬ ‭visit‬ ‭and‬ ‭no‬ ‭less‬ ‭than‬ ‭4‬ ‭weeks‬ ‭after‬ ‭the‬ ‭prior‬‭assessment‬‭of‬‭PD‬‭(in‬‭the‬‭absence‬‭of‬‭clinically‬
‭significant‬ ‭deterioration).‬ ‭If‬ ‭an‬ ‭unscheduled‬‭assessment‬‭was‬‭performed‬‭and‬‭the‬‭patient‬‭has‬‭not‬‭progressed,‬‭every‬
‭attempt should be made to perform the subsequent assessment at the next scheduled visit.‬
‭Treatment‬‭dosing‬‭compliance:‬‭Study‬‭drug‬‭compliance‬‭will‬‭be‬‭assessed‬‭by‬‭the‬‭Investigator‬‭and/or‬‭study‬‭personnel‬
‭at‬ ‭each‬ ‭patient’s‬ ‭visit,‬ ‭and‬ ‭it‬ ‭will‬ ‭be‬ ‭captured‬ ‭in‬ ‭the‬ ‭patient’s‬ ‭records‬ ‭as‬ ‭part‬ ‭of‬ ‭source‬ ‭documentation‬ ‭at‬ ‭each‬
‭patient’s visit. Corresponding drug administration information will be reported also in the eCRF.‬
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‭Chemotherapy‬‭dispensing/administration:‬‭Results‬‭for‬‭LTFs,‬‭electrolytes,‬‭and‬‭creatinine‬‭must‬‭be‬‭available‬‭before‬
‭commencing‬ ‭an‬ ‭infusion‬ ‭(within‬ ‭3‬ ‭days)‬ ‭and‬ ‭reviewed‬ ‭by‬ ‭the‬ ‭treating‬‭physician‬‭or‬‭investigator‬‭prior‬‭to‬‭dosing.‬
‭Specific‬ ‭details‬ ‭on‬ ‭haematological‬ ‭and‬ ‭renal‬ ‭function‬ ‭parameters‬ ‭for‬ ‭treatment‬ ‭interruption‬ ‭and‬ ‭resuming‬ ‭are‬
‭detailed in the gemcitabine and cisplatin administration section.‬
‭Atezolizumab‬ ‭dispensing/administration:‬ ‭Every‬ ‭3‬ ‭weeks‬ ‭until‬ ‭PD‬ ‭or‬ ‭unacceptable‬ ‭toxicity.‬ ‭Continuation‬ ‭of‬
‭atezolizumab‬ ‭treatment‬ ‭could‬ ‭be‬ ‭considered‬ ‭for‬ ‭patients‬ ‭who‬ ‭have‬ ‭been‬ ‭reported‬ ‭with‬ ‭PD‬ ‭on‬ ‭the‬ ‭week‬ ‭9‬
‭radiological evaluation but, according to the PI’s criteria, might be considered as with clinical benefit.‬
‭Adverse‬ ‭events:‬ ‭Adverse‬‭events‬‭should‬‭be‬‭documented‬‭and‬‭recorded‬‭at‬‭each‬‭visit‬‭using‬‭NCI-CTCAE‬‭v5.0.‬‭AEs‬
‭(serious‬‭and‬‭non-serious)‬‭should‬‭be‬‭recorded‬‭in‬‭the‬‭eCRF‬‭and‬‭patient‬‭records,‬‭from‬‭the‬‭time‬‭the‬‭patient‬‭has‬‭taken‬‭at‬
‭least‬‭1‬‭dose‬‭of‬‭study‬‭treatment‬‭through‬‭and‬‭including‬‭90‬‭calendar‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭IMP.‬‭If‬‭a‬‭patent‬‭begins‬
‭a‬‭new‬‭anticancer‬‭therapy,‬‭the‬‭AE‬‭reporting‬‭period‬‭for‬‭non-serious‬‭AEs‬‭ends‬‭at‬‭the‬‭time‬‭the‬‭new‬‭treatment‬‭is‬‭started.‬
‭For‬ ‭SAEs,‬ ‭the‬ ‭active‬ ‭reporting‬‭period‬‭to‬‭Sponsor‬‭or‬‭it‬‭designated,‬‭begins‬‭from‬‭the‬‭time‬‭that‬‭the‬‭patient‬‭provides‬
‭informed‬ ‭consent,‬ ‭which‬ ‭is‬ ‭obtained‬ ‭prior‬ ‭to‬ ‭the‬ ‭patient’s‬ ‭participation‬ ‭in‬ ‭this‬ ‭study,‬ ‭through‬ ‭and‬ ‭including‬ ‭90‬
‭calendar days after the last administration of the investigational products.‬
‭Concomitant‬‭medications:‬‭Concomitant‬‭medication‬‭will‬‭be‬‭recorded‬‭from‬‭28‬‭days‬‭prior‬‭to‬‭start‬‭of‬‭study‬‭treatment‬
‭and‬‭up‬‭to‬‭90‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭study‬‭treatment.‬‭All‬‭concomitant‬‭medications‬‭should‬‭be‬‭recorded‬‭in‬‭the‬‭CRF‬
‭including‬‭supportive‬‭care‬‭drugs‬‭(i.e.,‬‭antiemetics‬‭treatment‬‭and‬‭prophylaxis),‬‭the‬‭drugs‬‭used‬‭to‬‭treat‬‭adverse‬‭events‬
‭or chronic diseases, and non-drug supportive interventions (e.g. transfusions).‬
‭Biomarker‬ ‭study:‬ ‭Archival‬ ‭Tumor‬ ‭block‬ ‭at‬ ‭baseline‬ ‭and‬‭processed‬‭blood‬‭samples‬‭at‬‭baseline,‬‭day‬‭1‬‭of‬‭cycle‬‭7‬
‭(D1),‬ ‭and‬ ‭at‬ ‭EOT/progression.‬ ‭Blood‬ ‭samples‬ ‭should‬ ‭be‬ ‭obtained‬ ‭in‬ ‭all‬ ‭patients‬ ‭at‬ ‭the‬ ‭time‬ ‭of‬ ‭EOT‬ ‭(even‬ ‭by‬
‭toxicity‬‭without‬‭progressing)‬‭and‬‭samples‬‭are‬‭to‬‭be‬‭stored‬‭at‬‭site‬‭at‬‭-80‬‭ºC‬‭and‬‭are‬‭to‬‭be‬‭sent‬‭at‬‭the‬‭end‬‭of‬‭study‬‭(1‬
‭dry ice shipment per site).‬
‭New‬ ‭systemic‬ ‭cancer‬ ‭treatment:‬‭Information‬‭on‬‭subsequent‬‭treatments‬‭should‬‭include‬‭the‬‭list‬‭of‬‭post-treatment‬
‭therapies,‬ ‭drugs‬ ‭administered,‬ ‭and‬ ‭the‬ ‭date‬ ‭of‬‭initiation‬‭and‬‭discontinuation‬‭of‬‭each‬‭drug,‬‭and‬‭the‬‭corresponding‬
‭disease progression date (if applicable). All the data will be recorded in the medical record and in the eCRF.‬
‭Survival‬ ‭assessment‬ ‭(EOS):‬ ‭After‬ ‭progression,‬ ‭the‬ ‭patient‬ ‭will‬ ‭be‬ ‭followed‬ ‭for‬ ‭survival‬ ‭until‬ ‭death,‬ ‭loss‬ ‭of‬
‭follow-up,‬ ‭total‬ ‭patient‬ ‭consent‬ ‭withdrawal‬ ‭(refusing‬ ‭to‬ ‭any‬ ‭trial‬ ‭procedure),‬ ‭or‬ ‭end‬ ‭of‬ ‭study.‬‭Patient‬‭long‬‭term‬
‭follow-up‬‭to‬‭determine‬‭status‬‭(alive,‬‭death,‬‭loss‬‭of‬‭follow‬‭up,‬‭etc.)‬‭may‬‭be‬‭performed‬‭by‬‭phone,‬‭if‬‭the‬‭patient‬‭is‬‭not‬
‭coming‬‭to‬‭the‬‭clinic‬‭due‬‭to‬‭other‬‭reasons.‬‭The‬‭investigator‬‭must‬‭document‬‭in‬‭writing‬‭the‬‭results‬‭of‬‭the‬‭phone‬‭call‬‭in‬
‭the patient records and in the eCRF.‬
‭8.4.‬
‭Determinations‬
‭in‬
‭the‬
‭selection‬
‭phase‬
‭(screening‬
‭and‬
‭baseline‬
‭determinations)‬
‭Within 28 days prior to inclusion:‬
‭●‬ ‭Informed consent‬
‭●‬ ‭Medical History (Medical and oncology specific)‬
‭●‬ ‭Archival tumor block‬
‭●‬ ‭HBV/HCV test‬
‭●‬ ‭ECG‬
‭●‬ ‭FEVI‬
‭●‬ ‭Tumor assessment‬
‭●‬ ‭Thyroid function‬
‭●‬ ‭Urinalysis‬
‭Within‬‭3‬‭days‬‭prior‬‭to‬‭inclusion‬‭(not‬‭needed‬‭to‬‭be‬‭repeated‬‭if‬‭it‬‭is‬‭performed‬‭within‬‭3‬‭days‬‭to‬
‭treatment initiation)‬
‭●‬ ‭Physical Exam‬
‭●‬ ‭ECOG‬
‭●‬ ‭Contraception check‬
‭●‬ ‭Vital signs (BP, PR)‬
‭●‬ ‭Coagulation‬
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‭●‬ ‭Hematology‬
‭●‬ ‭Blood chemistry‬
‭●‬ ‭Pregnancy test (serum/urine)‬
‭●‬ ‭Blood collection (biomarkers)‬
‭●‬ ‭Faecal sample collection (biomarkers)‬
‭●‬ ‭Adverse events‬
‭●‬ ‭Concomitant medications‬
‭8.5.‬
‭Determinations and procedures during the treatment period (up to cycle 6)‬
‭8.5.1.‬ ‭Day 1 (considering 3 week cycles)‬
‭●‬ ‭Physical Exam‬
‭●‬ ‭ECOG‬
‭●‬ ‭Contraception check‬
‭●‬ ‭Vital signs (BP, PR)‬
‭●‬ ‭Coagulation‬
‭●‬ ‭Hematology‬
‭●‬ ‭Blood chemistry‬
‭●‬ ‭Thyroid function‬
‭●‬ ‭Pregnancy test (serum/urine)‬
‭●‬ ‭Urinalysis‬
‭●‬ ‭Adverse events‬
‭●‬ ‭Concomitant medications‬
‭●‬ ‭Treatment dosing compliance‬
‭●‬ ‭Atezolizumab administration‬
‭●‬ ‭Split doses of gemcitabine and cisplatin administration‬
‭8.5.2.‬ ‭Day 8 (considering 3 week cycles)‬
‭●‬ ‭Physical Exam‬
‭●‬ ‭ECOG‬
‭●‬ ‭Vital signs‬
‭●‬ ‭Hematology‬
‭●‬ ‭Blood chemistry‬
‭●‬ ‭Adverse events‬
‭●‬ ‭Treatment dosing compliance‬
‭●‬ ‭Concomitant medication‬
‭●‬ ‭Split doses of gemcitabine and cisplatin administration‬
‭8.5.3.‬ ‭Other determinations during treatment‬
‭●‬ ‭Tumor‬‭assessment:‬‭On‬‭week‬‭9,‬‭week‬‭18‬‭(prior‬‭starting‬‭atezolizumab‬‭monotherapy‬
‭and‬ ‭every‬‭12‬‭weeks‬‭+/-7‬‭days‬‭thereafter‬‭until‬‭the‬‭confirmation‬‭of‬‭objective‬‭disease‬
‭progression or death (whichever comes first).‬
‭●‬ ‭Safety‬ ‭determinations:‬‭Hematology‬‭and‬‭Blood‬‭chemistry‬‭(including‬‭renal‬‭function‬
‭assessment‬ ‭with‬ ‭urea‬ ‭and‬‭creatinine)‬‭should‬‭be‬‭evaluated‬‭weekly‬‭during‬‭the‬‭first‬‭6‬
‭cycles of treatment as per recommendations for gemcitabine treatment.‬
‭●‬ ‭When clinically indicated:‬‭ECG, and FEVI.‬
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‭8.5.4.‬ ‭Determinations‬ ‭and‬ ‭procedures‬ ‭on‬ ‭day‬ ‭1‬ ‭of‬ ‭cycle‬ ‭7‬ ‭(D1-C7)‬ ‭and‬
‭subsequent cycles (D1-Cn)‬
‭●‬ ‭Physical Exam‬
‭●‬ ‭ECOG‬
‭●‬ ‭Contraception check‬
‭●‬ ‭Vital signs (BP, PR)‬
‭●‬ ‭Coagulation‬
‭●‬ ‭Hematology‬
‭●‬ ‭Blood chemistry‬
‭●‬ ‭Thyroid function‬
‭●‬ ‭Pregnancy test (serum/urine)‬
‭●‬ ‭Urinalysis‬
‭●‬ ‭Treatment compliance dosing‬
‭●‬ ‭Atezolizumab administration‬
‭●‬ ‭Concomitant medication‬
‭●‬ ‭Adverse event‬
‭When clinically indicated:‬‭urinalysis, ECG, and FEVI.‬
‭Additionally at D1-C7:‬
‭●‬ ‭Blood collection (biomarkers) only D1 C7.‬
‭●‬ ‭Tumor‬ ‭assessment:‬ ‭CT‬ ‭Scan‬ ‭or‬ ‭MRI‬ ‭prior‬ ‭to‬ ‭D1C7‬ ‭(on‬ ‭week‬ ‭18‬ ‭from‬ ‭treatment‬
‭starting).‬
‭When applicable‬
‭●‬ ‭Tumor‬‭assessment:‬‭CT‬‭Scan‬‭or‬‭MRI‬‭is‬‭to‬‭be‬‭performed‬‭on‬‭week‬‭9,‬‭week‬‭18‬‭and‬‭every‬
‭12‬‭weeks‬‭until‬‭the‬‭confirmation‬‭of‬‭objective‬‭disease‬‭progression‬‭or‬‭death‬‭(whichever‬
‭comes first).‬
‭●‬ ‭When clinically indicated:‬‭ECG, and FEVI.‬
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‭8.6.‬
‭Determinations at safety visit‬
‭●‬ ‭Physical Exam‬
‭●‬ ‭ECOG‬
‭●‬ ‭Contraception check‬
‭●‬ ‭Vital signs (BP, PR)‬
‭●‬ ‭Coagulation‬
‭●‬ ‭Hematology‬
‭●‬ ‭Blood chemistry‬
‭●‬ ‭Thyroid function‬
‭●‬ ‭Pregnancy test (serum/urine)‬
‭●‬ ‭Urinalysis‬
‭●‬ ‭ECG‬
‭●‬ ‭FEVI‬
‭●‬ ‭Adverse events‬
‭●‬ ‭Concomitant medications‬
‭8.7.‬
‭Follow-up determinations‬
‭8.7.1. Follow up after end of treatment (prior PD)‬
‭Every 12 weeks:‬
‭●‬ ‭Tumor‬ ‭assessment:‬ ‭CT‬ ‭Scan‬‭or‬‭MRI‬‭is‬‭to‬‭be‬‭performed‬‭on‬‭week‬‭9,‬‭week‬‭18‬‭and‬
‭every‬ ‭12‬ ‭weeks‬ ‭until‬ ‭the‬ ‭confirmation‬ ‭of‬ ‭objective‬ ‭disease‬ ‭progression‬ ‭or‬ ‭death‬
‭(whichever comes first).‬
‭●‬ ‭New systemic cancer treatment.‬
‭●‬ ‭By the time of disease progression,‬‭Blood collection‬‭(biomarkers)‬
‭8.7.2. Follow up after end of treatment (after PD)‬
‭Every 6 months:‬
‭●‬ ‭New systemic cancer treatment‬
‭●‬ ‭Survival assessment‬
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‭9.‬
‭SAFETY EVALUATION‬
‭ICH‬ ‭GCP‬ ‭requires‬ ‭that‬ ‭both‬ ‭investigators‬ ‭and‬ ‭sponsors‬ ‭follow‬ ‭specific‬ ‭procedures‬ ‭when‬
‭reporting‬ ‭adverse‬ ‭events/reactions‬ ‭in‬ ‭clinical‬ ‭trials.‬ ‭These‬ ‭procedures‬ ‭are‬ ‭described‬‭in‬‭this‬
‭section of the protocol.‬
‭Any‬‭event‬‭involving‬‭adverse‬‭drug‬‭reactions‬‭(ADR),‬‭illnesses‬‭with‬‭onset‬‭during‬‭the‬‭study‬‭or‬
‭exacerbations of pre-existing illnesses should be recorded.‬
‭In‬ ‭addition,‬ ‭clinically‬ ‭significant‬ ‭changes‬ ‭in‬ ‭physical‬ ‭examination‬ ‭findings‬ ‭and‬ ‭abnormal‬
‭objective‬ ‭test‬ ‭findings‬ ‭(e.g.,‬ ‭x-ray,‬ ‭ECG)‬ ‭should‬ ‭also‬ ‭be‬ ‭recorded‬ ‭as‬ ‭AE.‬ ‭The‬ ‭criteria‬ ‭for‬
‭determining‬‭whether‬‭an‬‭abnormal‬‭objective‬‭test‬‭finding‬‭should‬‭be‬‭reported‬‭as‬‭an‬‭AE‬‭are‬‭as‬
‭follows:‬
‭●‬ ‭test result is associated with clinically significant symptoms, and/or‬
‭●‬ ‭test‬ ‭result‬ ‭leads‬ ‭to‬ ‭a‬ ‭change‬ ‭in‬ ‭study‬ ‭dosing‬ ‭or‬ ‭discontinuation‬ ‭from‬ ‭the‬ ‭study,‬
‭significant additional concomitant drug treatment or other therapy, and/or‬
‭●‬ ‭test result leads to any of the outcomes included in the definition of a SAE, and/or test‬
‭result is considered to be an AE by the investigator.‬
‭9.1.‬
‭Definitions‬
‭The definitions from ICH GCP apply in this trial protocol.‬
‭9.1.1.‬ ‭Adverse event (AE)‬
‭An‬ ‭adverse‬ ‭event‬ ‭is‬ ‭any‬‭untoward‬‭medical‬‭occurrence‬‭in‬‭a‬‭patient‬‭or‬‭clinical‬‭investigation‬
‭subject which does not necessarily have a causal relationship with the study treatment.‬
‭Examples of AEs include but are not limited to:‬
‭●‬ ‭Abnormal test findings;‬
‭●‬ ‭Clinically significant symptoms and signs;‬
‭●‬ ‭Changes in physical examination findings;‬
‭●‬ ‭Hypersensitivity;‬
‭●‬ ‭Drug abuse;‬
‭●‬ ‭Drug dependency.‬
‭Additionally, they may include signs or symptoms resulting from:‬
‭●‬ ‭Drug overdose;‬
‭●‬ ‭Drug withdrawal;‬
‭●‬ ‭Drug misuse;‬
‭●‬ ‭Drug interactions;‬
‭●‬ ‭Extravasation;‬
‭●‬ ‭Exposure during pregnancy (EDP);‬
‭●‬ ‭Exposure via breastfeeding;‬
‭●‬ ‭Medication error;‬
‭●‬ ‭Occupational exposure;‬
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‭●‬ ‭Worsening‬‭of‬‭signs‬‭and‬‭symptoms‬‭of‬‭the‬‭malignancy‬‭under‬‭study‬‭should‬‭be‬‭reported‬
‭as‬ ‭AEs‬ ‭in‬ ‭the‬ ‭appropriate‬ ‭section‬ ‭of‬ ‭the‬ ‭CRF.‬ ‭Disease‬ ‭progression‬ ‭assessed‬ ‭by‬
‭measurement‬ ‭of‬ ‭malignant‬ ‭lesions‬ ‭on‬ ‭radiographs‬ ‭or‬ ‭other‬ ‭methods‬ ‭should‬ ‭not‬ ‭be‬
‭reported as AEs.‬
‭9.1.2.‬ ‭Atezolizumab Adverse Event of Special Interest‬
‭Adverse‬‭events‬‭of‬‭special‬‭interest‬‭are‬‭required‬‭to‬‭be‬‭reported‬‭by‬‭the‬‭investigator‬‭to‬‭the‬‭Sponsor‬
‭immediately‬ ‭(i.e.,‬ ‭no‬ ‭more‬ ‭than‬ ‭24‬ ‭hours‬ ‭after‬ ‭learning‬ ‭of‬ ‭the‬ ‭event;‬ ‭see‬ ‭Section‬ ‭9.2‬ ‭for‬
‭reporting instructions).‬
‭Adverse events of special interest for this study are as follows:‬
‭●‬ ‭Cases‬‭of‬‭potential‬‭drug-induced‬‭liver‬‭injury‬‭that‬‭include‬‭an‬‭elevated‬‭ALT‬‭or‬‭AST‬‭in‬
‭combination‬‭with‬‭either‬‭an‬‭elevated‬‭bilirubin‬‭or‬‭clinical‬‭jaundice,‬‭as‬‭defined‬‭by‬‭Hy's‬
‭Law.‬
‭●‬ ‭Suspected transmission of an infectious agent by the study treatment, as defined below‬
‭●‬ ‭Any‬ ‭organism,‬ ‭virus,‬ ‭or‬ ‭infectious‬ ‭particle‬ ‭(e.g.,‬ ‭prion‬ ‭protein‬ ‭transmitting‬
‭transmissible‬ ‭spongiform‬ ‭encephalopathy),‬ ‭pathogenic‬ ‭or‬ ‭non-pathogenic,‬ ‭is‬
‭considered‬ ‭an‬ ‭infectious‬ ‭agent.‬ ‭A‬ ‭transmission‬ ‭of‬ ‭an‬ ‭infectious‬ ‭agent‬ ‭may‬ ‭be‬
‭suspected‬‭from‬‭clinical‬‭symptoms‬‭or‬‭laboratory‬‭findings‬‭that‬‭indicate‬‭an‬‭infection‬‭in‬‭a‬
‭patient‬‭exposed‬‭to‬‭a‬‭medicinal‬‭product.‬‭This‬‭term‬‭applies‬‭only‬‭when‬‭a‬‭contamination‬
‭of study treatment is suspected.‬
‭●‬ ‭Systemic lupus erythematosus‬
‭●‬ ‭Events‬ ‭suggestive‬ ‭of‬ ‭hypersensitivity,‬ ‭infusion-related‬ ‭reactions,‬ ‭cytokine-release‬
‭syndrome, HLH, and MAS‬
‭●‬ ‭Nephritis‬
‭●‬ ‭Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)‬
‭●‬ ‭Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)‬
‭●‬ ‭Vasculitis‬
‭●‬ ‭Autoimmune hemolytic anemia‬
‭●‬ ‭Severe‬‭cutaneous‬‭reactions‬‭(e.g.,‬‭Stevens-Johnson‬‭syndrome,‬‭dermatitis‬‭bullous,‬‭toxic‬
‭epidermal necrolysis)‬
‭9.1.3.‬ ‭Laboratory Abnormalities‬
‭All‬ ‭laboratory‬ ‭data‬ ‭required‬ ‭by‬ ‭this‬ ‭protocol‬ ‭and‬ ‭any‬ ‭other‬ ‭clinical‬ ‭investigations‬ ‭will‬ ‭be‬
‭reviewed.‬ ‭Any‬ ‭abnormal‬ ‭value‬ ‭that‬ ‭leads‬ ‭to‬ ‭a‬ ‭change‬ ‭in‬ ‭subject‬ ‭management‬ ‭(eg,‬ ‭dose‬
‭reduction‬ ‭or‬ ‭delay‬ ‭or‬ ‭requirement‬ ‭for‬ ‭additional‬ ‭medication‬ ‭or‬ ‭monitoring)‬ ‭or‬ ‭that‬ ‭is‬
‭considered‬‭to‬‭be‬‭of‬‭clinical‬‭significance‬‭by‬‭the‬‭Investigator‬‭will‬‭be‬‭reported‬‭as‬‭an‬‭AE‬‭or‬‭SAE‬
‭as‬ ‭appropriate,‬ ‭unless‬ ‭this‬ ‭value‬ ‭is‬ ‭consistent‬ ‭with‬ ‭the‬ ‭subject’s‬‭present‬‭disease‬‭state‬‭or‬‭is‬
‭consistent with values obtained prior to entry into the study.‬
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‭9.1.4.‬ ‭Medication errors‬
‭Medication‬ ‭errors‬ ‭may‬ ‭result,‬ ‭in‬ ‭this‬ ‭study,‬‭from‬‭the‬‭administration‬‭or‬‭consumption‬‭of‬‭the‬
‭wrong product, the wrong patient at the wrong time, or at the wrong dosage strength.‬
‭Such‬‭medication‬‭errors‬‭occurring‬‭to‬‭a‬‭study‬‭participant‬‭are‬‭to‬‭be‬‭captured‬‭on‬‭the‬‭eCRF,‬‭and‬
‭reported‬‭through‬‭the‬‭SAE‬‭form‬‭when‬‭appropriate.‬‭In‬‭the‬‭event‬‭of‬‭medication‬‭dosing‬‭error,‬‭the‬
‭sponsor should be notified immediately.‬
‭Medication‬ ‭errors‬ ‭are‬ ‭reportable‬ ‭irrespective‬ ‭of‬ ‭the‬ ‭presence‬ ‭of‬ ‭an‬ ‭associated‬ ‭AE/SAE,‬
‭including:‬
‭●‬ ‭Medication errors involving patient exposure to the investigational product;‬
‭●‬ ‭Potential‬‭medication‬‭errors‬‭or‬‭uses‬‭outside‬‭of‬‭what‬‭is‬‭foreseen‬‭in‬‭the‬‭protocol‬‭that‬‭do‬
‭or do not involve the participating patient.‬
‭Whether‬ ‭or‬ ‭not‬ ‭the‬ ‭medication‬ ‭error‬ ‭is‬ ‭accompanied‬ ‭by‬ ‭an‬ ‭AE,‬ ‭as‬ ‭determined‬ ‭by‬ ‭the‬
‭investigator,‬‭the‬‭medication‬‭error‬‭is‬‭captured‬‭on‬‭the‬‭medication‬‭error‬‭version‬‭of‬‭the‬‭AE‬‭page‬
‭and, if applicable, any associated AEs are captured on an AE CRF page.‬
‭The guidance on reporting of medication errors also applies to the reporting of overdose.‬
‭9.1.4.1. Atezolizumab overdose‬
‭The‬‭standard‬‭fixed‬‭dose‬‭of‬‭Atezolizumab‬‭is‬‭1200‬‭mg‬‭is‬‭equivalent‬‭to‬‭15‬‭mg/kg‬‭in‬‭a‬‭typical‬
‭patient.‬‭No‬‭dose-limiting‬‭toxicities‬‭were‬‭observed‬‭at‬‭the‬‭20‬‭mg/kg‬‭dose‬‭level‬‭and‬‭the‬‭incidence‬
‭and‬ ‭intensity‬ ‭of‬‭AEs‬‭reported‬‭have‬‭not‬‭been‬‭shown‬‭to‬‭be‬‭dependent‬‭on‬‭dose.‬‭A‬‭maximum‬
‭tolerated dose has not been established.‬
‭Atezolizumab‬‭is‬‭supplied‬‭in‬‭vials‬‭containing‬‭the‬‭fixed‬‭1200‬‭mg‬‭dose‬‭of‬‭drug‬‭substance,‬‭which‬
‭minimizes‬‭the‬‭chance‬‭of‬‭overdose.‬‭Because‬‭the‬‭dose‬‭per‬‭patient‬‭is‬‭not‬‭based‬‭on‬‭weight‬‭or‬‭body‬
‭surface‬‭area,‬‭and‬‭no‬‭dose‬‭calculation‬‭is‬‭required,‬‭the‬‭risk‬‭of‬‭overdose‬‭due‬‭to‬‭medication‬‭errors‬
‭is minimal.‬
‭The data available to date suggest that the potential for harm from overdose is very low.‬
‭9.1.4.2. Gemcitabine overdose‬
‭There‬‭is‬‭no‬‭known‬‭antidote‬‭for‬‭overdose‬‭of‬‭gemcitabine.‬‭Doses‬‭as‬‭high‬‭as‬‭5700‬‭mg/m2‬‭have‬
‭been‬ ‭administered‬ ‭by‬ ‭intravenous‬ ‭infusion‬ ‭over‬ ‭30-minutes‬ ‭every‬ ‭2‬ ‭weeks‬ ‭with‬ ‭clinically‬
‭acceptable‬‭toxicity.‬‭In‬‭the‬‭event‬‭of‬‭suspected‬‭overdose,‬‭the‬‭patient‬‭should‬‭be‬‭monitored‬‭with‬
‭appropriate blood counts and receive supportive therapy, as necessary.‬
‭9.1.4.3. Cisplatin overdose‬
‭An‬ ‭acute‬ ‭overdose‬ ‭of‬ ‭cisplatin‬ ‭may‬ ‭result‬ ‭in‬ ‭renal‬ ‭failure,‬ ‭liver‬ ‭failure,‬ ‭deafness,‬ ‭ocular‬
‭toxicity‬‭(including‬‭detachment‬‭of‬‭the‬‭retina),‬‭significant‬‭myelosuppression,‬‭untreatable‬‭nausea‬
‭and vomiting and/or neuritis. An overdose may be fatal.‬
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‭There‬‭is‬‭no‬‭specific‬‭antidote‬‭in‬‭the‬‭event‬‭of‬‭an‬‭over‬‭dosage‬‭of‬‭cisplatin.‬‭Even‬‭if‬‭haemodialysis‬
‭is‬‭initiated‬‭4‬‭hours‬‭after‬‭the‬‭overdose‬‭it‬‭has‬‭little‬‭effect‬‭on‬‭the‬‭elimination‬‭of‬‭cisplatin‬‭from‬‭the‬
‭body following a strong and rapid fixation of cisplatin to proteins.‬
‭Treatment in the event of an overdose consists of general support measures.‬
‭9.1.5.‬ ‭Adverse reaction (AR)‬
‭All‬‭untoward‬‭and‬‭unintended‬‭responses‬‭to‬‭an‬‭investigational‬‭medicinal‬‭product‬‭related‬‭to‬‭any‬
‭dose administered.‬
‭9.1.6.‬ ‭Serious Adverse Event (SAE)‬
‭Any untoward medical occurrence or effect that at any dose:‬
‭1.‬ ‭Results in death (is fatal),‬
‭2.‬ ‭Is life-threatening,‬
‭3.‬ ‭Requires or prolongs inpatient hospitalization,‬
‭4.‬ ‭Results in persistent or significant disability or incapacity,‬
‭5.‬ ‭Is a congenital anomaly or birth defect, or‬
‭6.‬ ‭Is medically significant.‬
‭Progression‬ ‭of‬ ‭the‬ ‭malignancy‬ ‭under‬ ‭study‬ ‭(including‬‭signs‬‭and‬‭symptoms‬‭of‬‭progression)‬
‭should‬ ‭not‬ ‭be‬ ‭reported‬ ‭as‬ ‭an‬ ‭SAE‬ ‭unless‬ ‭the‬ ‭outcome‬ ‭is‬ ‭fatal‬ ‭within‬ ‭the‬ ‭safety‬‭reporting‬
‭period.‬ ‭Hospitalization‬ ‭due‬ ‭to‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭disease‬ ‭progression‬ ‭should‬ ‭not‬ ‭be‬
‭reported as an SAE.‬
‭Medical‬‭and‬‭scientific‬‭judgement‬‭should‬‭be‬‭exercised‬‭in‬‭deciding‬‭whether‬‭urgent‬‭reporting‬‭is‬
‭appropriate‬‭in‬‭other‬‭situations‬‭such‬‭as‬‭important‬‭medical‬‭events‬‭that‬‭may‬‭not‬‭be‬‭immediately‬
‭life-threatening‬ ‭or‬ ‭result‬ ‭in‬ ‭hospitalization‬ ‭but‬ ‭may‬ ‭jeopardize‬ ‭the‬ ‭patient‬ ‭or‬ ‭may‬ ‭require‬
‭intervention to prevent one of the outcomes listed in the above definition.‬
‭Any‬‭suspected‬‭transmission‬‭of‬‭an‬‭infectious‬‭agent‬‭through‬‭the‬‭medication‬‭is‬‭also‬‭considered‬‭a‬
‭SAE.‬
‭The‬‭terms‬‭"severe"‬‭and‬‭"serious"‬‭are‬‭not‬‭synonymous.‬ ‭Severity‬‭refers‬‭to‬‭the‬‭intensity‬‭of‬‭an‬
‭adverse‬‭event‬‭(e.g.,‬‭rated‬‭as‬‭mild,‬‭moderate,‬‭or‬‭severe,‬‭or‬‭according‬‭to‬‭NCI‬‭CTCAE;‬‭the‬‭event‬
‭itself‬‭may‬‭be‬‭of‬‭relatively‬‭minor‬‭medical‬‭significance‬‭(such‬‭as‬‭severe‬‭headache‬‭without‬‭any‬
‭further findings).‬
‭Severity‬‭and‬‭seriousness‬‭need‬‭to‬‭be‬‭independently‬‭assessed‬‭for‬‭each‬‭adverse‬‭event‬‭recorded‬‭on‬
‭the eCRF.‬
‭Serious‬ ‭adverse‬ ‭events‬ ‭are‬ ‭required‬ ‭to‬ ‭be‬ ‭reported‬ ‭by‬ ‭the‬ ‭investigator‬ ‭to‬ ‭the‬ ‭Sponsor‬
‭immediately‬ ‭(i.e.,‬ ‭no‬ ‭more‬ ‭than‬ ‭24‬ ‭hours‬ ‭after‬ ‭learning‬ ‭of‬ ‭the‬ ‭event;‬ ‭see‬ ‭Section‬ ‭9.2‬ ‭for‬
‭reporting instructions).‬
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‭9.1.7.‬ ‭Protocol-Specified Serious Adverse Events‬
‭There‬ ‭are‬ ‭no‬ ‭protocol-specified‬ ‭SAEs‬ ‭in‬ ‭this‬ ‭study.‬ ‭All‬ ‭SAEs‬ ‭will‬ ‭be‬ ‭reported‬ ‭by‬ ‭the‬
‭investigator‬‭as‬‭described‬‭in‬‭the‬‭previous‬‭sections,‬‭and‬‭will‬‭be‬‭handled‬‭as‬‭SAEs‬‭in‬‭the‬‭safety‬
‭database.‬
‭9.1.8.‬ ‭Life Threatening Event‬
‭It‬‭is‬‭any‬‭event‬‭in‬‭which‬‭the‬‭subject‬‭was‬‭at‬‭risk‬‭of‬‭death‬‭at‬‭the‬‭time‬‭of‬‭the‬‭event;‬‭it‬‭does‬‭not‬
‭refer to an event which hypothetically might have caused death if it were more severe.‬
‭9.1.9.‬ ‭Hospitalization / Prolongation of Hospitalization‬
‭Any‬‭event‬‭requiring‬‭hospitalization‬‭(or‬‭prolongation‬‭of‬‭hospitalization)‬‭that‬‭occurs‬‭or‬‭worsens‬
‭during‬‭a‬‭patient’s‬‭participation‬‭in‬‭a‬‭clinical‬‭study‬‭must‬‭be‬‭reported‬‭as‬‭a‬‭serious‬‭adverse‬‭event.‬
‭Prolongation‬ ‭of‬ ‭hospitalization‬ ‭is‬ ‭defined‬ ‭as‬ ‭any‬ ‭extension‬ ‭of‬ ‭an‬ ‭inpatient‬ ‭hospitalization‬
‭beyond‬‭the‬‭stay‬‭anticipated/required‬‭for‬‭the‬‭initial‬‭admission,‬‭as‬‭determined‬‭by‬‭the‬‭investigator‬
‭or treating physician.‬
‭Hospitalizations that do not meet the criteria for serious adverse event reporting are:‬
‭1.‬ ‭Reasons‬ ‭described‬ ‭in‬ ‭protocol‬ ‭(e.g.,‬ ‭drug‬ ‭administration,‬ ‭protocol-required‬
‭investigations).‬ ‭Hospitalizations‬ ‭or‬ ‭prolonged‬ ‭hospitalization‬ ‭for‬ ‭a‬ ‭complication‬ ‭of‬
‭therapy administration or procedures will be reported as a Serious Adverse Event.‬
‭2.‬ ‭Hospitalization‬‭or‬‭prolonged‬‭hospitalization‬‭for‬‭technical,‬‭practical‬‭or‬‭social‬‭reasons,‬
‭in the absence of an adverse event.‬
‭3.‬ ‭Pre-planned‬ ‭hospitalizations‬ ‭(i.e.,‬ ‭planned‬ ‭before‬ ‭study‬ ‭entry).‬ ‭Any‬ ‭surgery‬ ‭or‬
‭procedure planned before study entry must be documented on the case report form.‬
‭9.1.10.‬ ‭Unexpected adverse event (not listed)‬
‭An‬‭unexpected‬‭AA,‬‭whose‬‭nature‬‭or‬‭severity‬‭does‬‭not‬‭correspond‬‭to‬‭the‬‭product‬‭information.‬
‭The reference documents to establish the expectedness will be:‬
‭●‬ ‭Atezolizumab, last version of Investigator Brochure available for the Sponsor‬
‭●‬ ‭Gemcitabine, last version of the SmPC.‬
‭●‬ ‭Cisplatin, last version of the SmPC.‬
‭9.1.11.‬ ‭Adverse Event Associated With the Use of the Drug (Adverse Reaction)‬
‭The‬ ‭investigator’s‬ ‭assessment‬ ‭of‬ ‭causality‬ ‭must‬ ‭be‬ ‭provided‬ ‭for‬ ‭all‬ ‭AEs‬ ‭(serious‬ ‭and‬
‭non-serious);‬‭the‬‭investigator‬‭must‬‭record‬‭the‬‭causal‬‭relationship‬‭in‬‭the‬‭CRF,‬‭as‬‭appropriate,‬
‭and‬‭report‬‭such‬‭an‬‭assessment‬‭in‬‭accordance‬‭with‬‭the‬‭serious‬‭adverse‬‭reporting‬‭requirements‬‭if‬
‭applicable.‬‭An‬‭investigator’s‬‭causality‬‭assessment‬‭is‬‭the‬‭determination‬‭of‬‭whether‬‭there‬‭exists‬
‭a‬ ‭reasonable‬ ‭possibility‬ ‭that‬ ‭the‬ ‭investigational‬ ‭product‬ ‭caused‬ ‭or‬ ‭contributed‬ ‭to‬ ‭an‬ ‭AE;‬
‭generally‬ ‭the‬ ‭facts‬ ‭(evidence)‬ ‭or‬ ‭arguments‬ ‭to‬ ‭suggest‬ ‭a‬ ‭causal‬ ‭relationship‬ ‭should‬ ‭be‬
‭provided.‬‭If‬‭the‬‭investigator‬‭does‬‭not‬‭know‬‭whether‬‭or‬‭not‬‭the‬‭investigational‬‭product‬‭caused‬
‭the‬‭event,‬‭then‬‭the‬‭event‬‭will‬‭be‬‭handled‬‭as‬‭“related‬‭to‬‭investigational‬‭product”‬‭for‬‭reporting‬
‭purposes,‬ ‭as‬ ‭defined‬ ‭by‬ ‭the‬ ‭sponsor‬ ‭(see‬ ‭the‬ ‭section‬ ‭on‬ ‭Reporting‬ ‭Requirements).‬ ‭If‬ ‭the‬
‭investigator's‬‭causality‬‭assessment‬‭is‬‭“unknown‬‭but‬‭not‬‭related‬‭to‬‭investigational‬‭product”,‬‭this‬
‭should be clearly documented on study records.‬
‭In‬ ‭addition,‬ ‭if‬ ‭the‬ ‭investigator‬ ‭determines‬‭an‬‭SAE‬‭is‬‭associated‬‭with‬‭study‬‭procedures,‬‭the‬
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‭investigator‬ ‭must‬ ‭record‬ ‭this‬ ‭causal‬ ‭relationship‬ ‭in‬ ‭the‬ ‭source‬ ‭documents‬ ‭and‬ ‭CRF,‬ ‭as‬
‭appropriate,‬ ‭and‬ ‭report‬ ‭such‬ ‭an‬ ‭assessment‬ ‭in‬ ‭accordance‬ ‭with‬ ‭the‬ ‭SAE‬ ‭reporting‬
‭requirements, if applicable.‬
‭For‬‭combination‬‭treatments,‬‭causality‬‭assessment‬‭will‬‭be‬‭performed‬‭for‬‭each‬‭of‬‭the‬‭individual‬
‭drugs included in the combination.‬
‭An‬‭adverse‬‭event‬‭is‬‭considered‬‭associated‬‭with‬‭the‬‭use‬‭of‬‭the‬‭drug‬‭(Adverse‬‭Reaction)‬‭if‬‭the‬
‭attribution is possible, probable, or very likely by the definitions listed below.‬
‭9.1.12.‬ ‭Attribution Definitions‬
‭Not Related‬
‭An adverse event that is not related to the use of the drug.‬
‭Doubtful‬
‭An‬‭adverse‬‭event‬‭for‬‭which‬‭an‬‭alternative‬‭explanation‬‭is‬‭more‬‭likely,‬‭e.g.,‬‭concomitant‬‭drug(s),‬
‭concomitant‬ ‭disease(s),‬ ‭or‬ ‭the‬ ‭relationship‬ ‭in‬ ‭time‬ ‭suggests‬ ‭that‬ ‭a‬ ‭causal‬ ‭relationship‬ ‭is‬
‭unlikely.‬
‭Possible‬
‭An‬‭adverse‬‭event‬‭that‬‭might‬‭be‬‭due‬‭to‬‭the‬‭use‬‭of‬‭the‬‭drug.‬‭An‬‭alternative‬‭explanation,‬‭e.g.,‬
‭concomitant‬ ‭drug(s),‬ ‭concomitant‬ ‭disease(s),‬ ‭is‬ ‭inconclusive.‬ ‭The‬ ‭relationship‬ ‭in‬ ‭time‬ ‭is‬
‭reasonable; therefore, the causal relationship cannot be excluded.‬
‭Probable‬
‭An‬ ‭adverse‬ ‭event‬ ‭that‬ ‭might‬ ‭be‬ ‭due‬ ‭to‬ ‭the‬ ‭use‬ ‭of‬ ‭the‬ ‭drug.‬ ‭The‬ ‭relationship‬ ‭in‬ ‭time‬ ‭is‬
‭suggestive‬ ‭(e.g.,‬ ‭confirmed‬ ‭by‬ ‭de-challenge).‬ ‭An‬‭alternative‬‭explanation‬‭is‬‭less‬‭likely,‬‭e.g.,‬
‭concomitant drug(s), concomitant disease(s).‬
‭Very Likely‬
‭An‬ ‭adverse‬ ‭event‬ ‭that‬ ‭is‬ ‭listed‬ ‭as‬ ‭a‬ ‭possible‬ ‭adverse‬ ‭reaction‬ ‭and‬ ‭cannot‬ ‭be‬ ‭reasonably‬
‭explained‬‭by‬‭an‬‭alternative‬‭explanation,‬‭e.g.,‬‭concomitant‬‭drug(s),‬‭concomitant‬‭disease(s).‬‭The‬
‭relationship in time is very suggestive (e.g., it is confirmed by dechallenge and rechallenge).‬
‭9.1.3.‬ ‭Intensity (Severity) Criteria‬
‭The‬‭intensity‬‭of‬‭AEs‬‭will‬‭be‬‭classified‬‭using‬‭the‬‭Common‬‭Terminology‬‭Criteria‬‭for‬‭AEs‬‭of‬‭the‬
‭National‬ ‭Cancer‬ ‭Institute,‬ ‭version‬ ‭5.0‬ ‭(NCI-CTCAE)‬ ‭and‬ ‭will‬ ‭be‬ ‭recorded‬ ‭in‬ ‭detail‬ ‭as‬
‭instructed‬ ‭in‬ ‭the‬ ‭eCRF.‬ ‭If‬ ‭an‬ ‭AE‬ ‭occurs‬ ‭that‬ ‭is‬ ‭not‬ ‭listed‬ ‭in‬ ‭the‬ ‭NCI-CTCAE‬ ‭V5.0‬
‭classification system, the 5-point scale detailed below will be used instead:‬
‭-‬
‭Mild: General malaise, without interruption of normal daily activity.‬
‭-‬
‭Moderate: Sufficient general malaise to reduce or affect normal daily activity.‬
‭-‬
‭Severe: Incapacity for work or the development of normal daily activity.‬
‭-‬
‭Life threatening or disabling: Represents an immediate threat to life.‬
‭-‬
‭Death: AE-related.‬
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‭Grade‬
‭Grade‬
‭Severity‬
‭1‬
‭Mild;‬ ‭asymptomatic‬ ‭or‬ ‭mild‬ ‭symptoms;‬ ‭clinical‬‭or‬‭diagnostic‬‭observations‬‭only;‬‭or‬
‭intervention not indicated‬
‭2‬
‭Moderate;‬ ‭minimal,‬ ‭local,‬ ‭or‬ ‭non-invasive‬ ‭intervention‬ ‭indicated;‬ ‭or‬ ‭limiting‬
‭age-appropriate instrumental activities of daily living‬‭a‬
‭3‬
‭Severe‬‭or‬‭medically‬‭significant,‬‭but‬‭not‬‭immediately‬‭life-threatening;‬‭hospitalization‬
‭or‬‭prolongation‬‭of‬‭hospitalization‬‭indicated;‬‭disabling;‬‭or‬‭limiting self-care‬‭activities‬
‭of daily living‬‭b, c‬
‭4‬
‭Life-threatening consequences or urgent intervention indicated‬‭d‬
‭5‬
‭Death related to adverse event‬‭d‬
‭NCI CTCAE‬‭ ‬‭=‬‭ ‬‭National Cancer Institute Common Terminology‬‭Criteria for Adverse Events.‬
‭Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:‬
‭http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm‬
‭a‬ ‭Instrumental activities of daily living refer to‬‭preparing meals, shopping for groceries or clothes,‬
‭using the telephone, managing money, etc.‬
‭b‬ ‭Examples of self-care activities of daily living‬‭include bathing, dressing and undressing, feeding‬
‭oneself, using the toilet, and taking medications, as performed by patients who are not bedridden.‬
‭c‬ ‭If an event is assessed as a "significant medical‬‭event," it must be reported as a serious adverse event‬
‭(see Section 5.4.2 for reporting instructions), per the definition of serious adverse event in‬
‭Section 5.2.2.‬
‭d‬ ‭Grade 4 and 5 events must be reported as serious‬‭adverse events (see Section 9.2  for reporting‬
‭instructions), per the definition of serious adverse event in Section 9.1.‬
‭9.1.14.‬ ‭Exposure during Pregnancy‬
‭If,‬‭following‬‭initiation‬‭of‬‭the‬‭investigational‬‭product,‬‭it‬‭is‬‭subsequently‬‭discovered‬‭that‬‭a‬‭study‬
‭participant‬ ‭is‬ ‭pregnant‬ ‭or‬ ‭may‬ ‭have‬ ‭been‬ ‭pregnant‬ ‭at‬ ‭the‬ ‭time‬ ‭of‬ ‭investigational‬ ‭product‬
‭exposure,‬‭within‬‭5‬‭months‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭atezolizumab‬‭,‬‭or‬‭within‬‭6‬‭months‬‭after‬‭the‬‭last‬
‭dose‬ ‭of‬ ‭atezolizumab,‬ ‭the‬ ‭investigational‬ ‭product‬ ‭will‬ ‭be‬ ‭permanently‬ ‭discontinued‬ ‭in‬ ‭an‬
‭appropriate manner (e.g., dose tapering if necessary for participant).‬
‭Any‬ ‭pregnancy‬ ‭that‬ ‭occurs‬ ‭in‬ ‭a‬ ‭female‬ ‭partner‬ ‭of‬ ‭a‬‭male‬‭study‬‭participant‬‭should‬‭also‬‭be‬
‭reported‬‭to‬‭the‬‭sponsor‬‭within‬‭24‬‭hours‬‭of‬‭becoming‬‭aware.‬‭Male‬‭patients‬‭will‬‭be‬‭instructed‬
‭through‬ ‭the‬ ‭Informed‬ ‭Consent‬ ‭Form‬ ‭to‬ ‭immediately‬ ‭inform‬ ‭the‬ ‭investigator‬ ‭if‬ ‭his‬ ‭partner‬
‭becomes‬‭pregnant‬‭during‬‭the‬‭chemotherapy‬‭treatment‬‭period‬‭or‬‭within‬‭6‬‭months‬‭after‬‭the‬‭last‬
‭dose‬‭of‬‭chemotherapy.‬‭In‬‭order‬‭for‬‭Sponsor‬‭or‬‭designee‬‭to‬‭collect‬‭any‬‭pregnancy‬‭surveillance‬
‭information‬‭from‬‭the‬‭female‬‭partner,‬‭the‬‭female‬‭partner‬‭must‬‭sign‬‭an‬‭informed‬‭consent‬‭form‬
‭for disclosure of this information.‬
‭In‬‭both‬‭cases,‬‭the‬‭investigator‬‭must‬‭immediately‬‭notify‬‭the‬‭Sponsor‬‭Pharmacovigilance‬‭Office‬
‭by sending the Pregnancy form (see ISF).‬
‭Follow-up‬‭information‬‭regarding‬‭the‬‭course‬‭of‬‭the‬‭pregnancy,‬‭including‬‭perinatal‬‭and‬‭neonatal‬
‭outcome‬‭and,‬‭where‬‭applicable,‬‭offspring‬‭information,‬‭study‬‭discontinuation‬‭must‬‭be‬‭reported‬
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‭following the before procedure described during at least 1 year after child-bearing.‬
‭Any‬‭serious‬‭adverse‬‭events‬‭associated‬‭with‬‭the‬‭pregnancy‬‭(e.g.,‬‭an‬‭event‬‭in‬‭the‬‭fetus,‬‭an‬‭event‬
‭in‬‭the‬‭mother‬‭during‬‭or‬‭after‬‭the‬‭pregnancy,‬‭or‬‭a‬‭congenital‬‭anomaly/birth‬‭defect‬‭in‬‭the‬‭child)‬
‭or abortion should be reported as a SAE.‬
‭9.1.15.‬ ‭Occupational Exposure‬
‭An‬ ‭occupational‬ ‭exposure‬ ‭occurs‬ ‭when,‬ ‭during‬ ‭the‬ ‭performance‬ ‭of‬ ‭job‬ ‭duties,‬ ‭a‬ ‭person‬
‭(whether‬ ‭a‬ ‭healthcare‬ ‭professional‬ ‭or‬ ‭otherwise)‬ ‭gets‬ ‭in‬ ‭unplanned‬ ‭direct‬ ‭contact‬‭with‬‭the‬
‭product, which may or may not lead to the occurrence of an AE.‬
‭An‬ ‭occupational‬ ‭exposure‬ ‭is‬ ‭reported‬ ‭to‬ ‭the‬ ‭drug‬ ‭safety‬ ‭unit‬ ‭within‬ ‭24‬ ‭hours‬ ‭of‬ ‭the‬
‭investigator’s‬ ‭awareness,‬ ‭using‬ ‭the‬ ‭SAE‬ ‭report‬ ‭form,‬ ‭regardless‬ ‭of‬ ‭whether‬ ‭there‬ ‭is‬ ‭an‬
‭associated‬‭AE/SAE.‬‭Since‬‭the‬‭information‬‭does‬‭not‬‭pertain‬‭to‬‭a‬‭patient‬‭enrolled‬‭in‬‭the‬‭study,‬
‭the‬‭information‬‭is‬‭not‬‭reported‬‭on‬‭a‬‭CRF;‬‭however,‬‭a‬‭copy‬‭of‬‭the‬‭completed‬‭SAE‬‭report‬‭form‬
‭is maintained in the investigator site file.‬
‭9.1.16.‬ ‭Expedited reporting‬
‭The‬ ‭sponsor‬ ‭assumes‬ ‭responsibility‬ ‭for‬ ‭appropriate‬ ‭reporting‬ ‭of‬ ‭adverse‬ ‭events‬ ‭to‬ ‭the‬
‭regulatory‬‭authorities.‬‭The‬‭sponsor‬‭will‬‭also‬‭report‬‭all‬‭serious‬‭adverse‬‭events‬‭that‬‭are‬‭unlisted‬
‭(unexpected)‬‭and‬‭be‬‭associated‬‭with‬‭the‬‭use‬‭of‬‭the‬‭study‬‭drug.‬‭The‬‭sponsor‬‭must‬‭report‬‭these‬
‭events to investigators and competent authorities in accordance with current regulations.‬
‭9.2.‬
‭Collection and reporting of Adverse Events information‬
‭The sponsor will collect AEs up to 30 days after administration of the last dose of study drug.‬
‭All‬‭adverse‬‭events‬‭must‬‭be‬‭recorded‬‭using‬‭medical‬‭terminology‬‭in‬‭the‬‭source‬‭document‬‭and‬
‭the‬‭eCRF.‬‭Investigators‬‭must‬‭assess‬‭the‬‭severity‬‭(grade)‬‭of‬‭the‬‭event‬‭following‬‭NCI-CTCAE‬‭V‬
‭5.0‬ ‭Criteria‬ ‭and‬ ‭assign‬ ‭a‬ ‭relationship‬ ‭to‬ ‭study‬ ‭therapy‬ ‭and‬ ‭pursue‬ ‭and‬ ‭obtain‬ ‭information‬
‭adequate‬ ‭both‬ ‭to‬ ‭determine‬ ‭the‬ ‭outcome‬ ‭and‬ ‭to‬ ‭assess‬ ‭whether‬ ‭it‬ ‭meets‬ ‭the‬ ‭criteria‬ ‭for‬
‭classification‬‭as‬‭a‬‭SAE‬‭requiring‬‭immediate‬‭notification.‬‭The‬‭investigator‬‭must‬‭provide‬‭any‬
‭information as requested by the sponsor in addition to that on the eCRF.‬
‭Any‬‭serious‬‭adverse‬‭event‬‭which‬‭occurs‬‭from‬‭patient‬‭informed‬‭consent‬‭signature,‬‭during‬‭the‬
‭clinical‬‭study‬‭or‬‭within‬‭90‬‭days‬‭of‬‭receiving‬‭the‬‭last‬‭dose‬‭of‬‭study‬‭medication,‬‭whether‬‭or‬‭not‬
‭related to the study drug, must be reported by the investigator.‬
‭If‬‭a‬‭patient‬‭begins‬‭a‬‭new‬‭anticancer‬‭therapy,‬‭the‬‭AE‬‭reporting‬‭period‬‭for‬‭non-serious‬‭AEs‬‭ends‬
‭at‬‭the‬‭time‬‭the‬‭new‬‭treatment‬‭is‬‭started.‬‭Death‬‭must‬‭be‬‭reported‬‭if‬‭it‬‭occurs‬‭during‬‭the‬‭SAE‬
‭reporting‬‭period‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭investigational‬‭product,‬‭irrespective‬‭of‬‭any‬‭intervening‬
‭treatment.‬
‭In‬‭addition,‬‭any‬‭SAEs‬‭which‬‭occur‬‭as‬‭a‬‭result‬‭of‬‭protocol‬‭specific‬‭diagnostic‬‭procedures‬‭or‬
‭interventions‬‭must‬‭also‬‭be‬‭reported.‬ ‭Beyond‬‭this‬‭period‬‭of‬‭time,‬‭only‬‭those‬‭SAEs‬‭suspected‬‭to‬
‭be related to the study drug will be reported.‬
‭All‬ ‭SAEs‬ ‭suspected‬ ‭to‬ ‭be‬ ‭related‬ ‭to‬ ‭study‬ ‭treatment‬ ‭should‬ ‭be‬ ‭followed‬ ‭after‬ ‭the‬
‭treatment/study‬ ‭withdrawal‬ ‭until‬‭the‬‭event‬‭or‬‭its‬‭symptoms‬‭have‬‭resolved‬‭or‬‭stabilized‬‭at‬‭a‬
‭grade acceptable to the Investigator, Chief investigator and/or Sponsor.‬
‭Site‬‭staff‬‭should‬‭notify‬‭the‬‭sponsor,‬‭all‬‭the‬‭pregnancies‬‭of‬‭female‬‭subjects‬‭and‬‭female‬‭partners‬
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‭of‬‭male‬‭subjects‬‭that‬‭occurred‬‭during‬‭the‬‭clinical‬‭trial‬‭within‬‭24‬‭hours‬‭from‬‭becoming‬‭aware.‬
‭Site‬‭staff‬‭should‬‭also‬‭communicate‬‭the‬‭outcome‬‭of‬‭the‬‭pregnancy‬‭within‬‭24‬‭hours‬‭since‬‭the‬
‭awareness.‬
‭The‬‭cause‬‭of‬‭death‬‭of‬‭a‬‭deceased‬‭patient‬‭in‬‭a‬‭clinical‬‭trial,‬‭whether‬‭the‬‭case‬‭of‬‭an‬‭expected‬
‭event‬‭or‬‭associated‬‭with‬‭the‬‭investigational‬‭agent,‬‭is‬‭considered‬‭an‬‭SAE‬‭and‬‭therefore‬‭must‬‭be‬
‭communicated‬‭using‬‭the‬‭SAE‬‭form.‬‭The‬‭autopsy‬‭report‬‭should‬‭be‬‭sent‬‭to‬‭Sponsor‬‭identified‬
‭only with the patient inclusion number.‬
‭All serious adverse events, AESIs and pregnancy cases must be reported by fax within 24‬
‭h to MFAR Clinical Research, S.L. by fax (+ 34 93 253 11 68) or e-mail to‬
‭investigacion@mfar.net‬
‭The‬ ‭SAE‬ ‭report‬ ‭should‬ ‭comprise‬ ‭a‬ ‭full‬ ‭written‬ ‭summary,‬ ‭detailing‬ ‭relevant‬‭aspects‬‭of‬‭the‬
‭adverse‬‭events‬‭in‬‭question.‬‭Where‬‭applicable,‬‭information‬‭from‬‭relevant‬‭hospital‬‭case‬‭records‬
‭and‬‭autopsy‬‭reports‬‭should‬‭be‬‭included.‬‭Follow-up‬‭information‬‭should‬‭be‬‭forwarded‬‭to‬‭MFAR‬
‭Clinical‬‭Research,‬‭S.L.‬‭by‬‭fax‬‭(+‬‭34‬‭93‬‭253‬‭11‬‭68)‬‭or‬‭e-mail‬‭to‬‭investigacion@mfar.net‬
‭within 24 hours.‬
‭All‬‭SAEs‬‭suspected‬‭to‬‭be‬‭related‬‭to‬‭study‬‭drug‬‭must‬‭be‬‭followed‬‭up‬‭after‬‭the‬‭time‬‭of‬‭therapy‬
‭discontinuation‬‭until‬‭the‬‭event‬‭or‬‭its‬‭consequences‬‭resolve‬‭or‬‭stabilize‬‭at‬‭an‬‭acceptable‬‭level‬
‭for the investigator, the Trial Chief Investigator and/or Sponsor.‬
‭Non-Serious Adverse Event Reporting Requirements‬
‭All‬‭AEs‬‭will‬‭be‬‭reported‬‭on‬‭the‬‭AE‬‭page(s)‬‭of‬‭the‬‭CRF.‬‭It‬‭should‬‭be‬‭noted‬‭that‬‭the‬‭form‬‭for‬
‭collection‬ ‭of‬ ‭SAE‬ ‭information‬ ‭is‬ ‭not‬ ‭the‬ ‭same‬ ‭as‬ ‭the‬ ‭AE‬ ‭CRF.‬ ‭Where‬ ‭the‬ ‭same‬ ‭data‬‭are‬
‭collected,‬‭the‬‭forms‬‭must‬‭be‬‭completed‬‭in‬‭a‬‭consistent‬‭manner.‬‭For‬‭example,‬‭the‬‭same‬‭AE‬‭term‬
‭should‬‭be‬‭used‬‭on‬‭both‬‭forms.‬‭AEs‬‭should‬‭be‬‭reported‬‭using‬‭concise‬‭medical‬‭terminology‬‭on‬
‭the CRFs as well as on the form for collection of SAE information.‬
‭Sponsor’s Reporting Requirements to Regulatory Authorities‬
‭Adverse‬ ‭event‬ ‭reporting,‬ ‭including‬ ‭suspected‬ ‭unexpected‬‭serious‬‭adverse‬‭reactions,‬‭will‬‭be‬
‭carried out in accordance with applicable local regulations.‬
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‭10.‬
‭STATISTICAL CONSIDERATIONS‬
‭Detailed‬‭methodology‬‭for‬‭summary‬‭and‬‭statistical‬‭analyses‬‭of‬‭the‬‭data‬‭collected‬‭in‬‭this‬‭study‬
‭will‬ ‭be‬ ‭documented‬ ‭in‬ ‭a‬ ‭statistical‬ ‭analysis‬ ‭plan‬ ‭(SAP),‬ ‭which‬ ‭will‬ ‭be‬ ‭maintained‬ ‭by‬ ‭the‬
‭Sponsor.‬
‭This‬ ‭document‬ ‭may‬ ‭modify‬ ‭the‬ ‭plans‬ ‭outlined‬ ‭in‬ ‭the‬ ‭protocol;‬ ‭however,‬ ‭any‬ ‭major‬
‭modifications‬‭of‬‭the‬‭primary‬‭endpoint‬‭and/or‬‭its‬‭analysis‬‭will‬‭also‬‭be‬‭reflected‬‭in‬‭a‬‭protocol‬
‭amendment.‬
‭10.1.‬ ‭Sample size calculation‬
‭Fleming's‬‭phase‬‭II‬‭procedure‬‭(‬‭Fleming‬‭TR,‬‭1982‬‭)‬‭will‬‭be‬‭used.‬‭The‬‭null‬‭hypothesis‬‭that‬‭the‬
‭smallest‬‭response‬‭probability‬‭is‬‭0.3‬‭will‬‭be‬‭tested‬‭against‬‭a‬‭one-sided‬‭alternative.‬‭In‬‭the‬‭first‬
‭stage,‬‭46‬‭patients‬‭will‬‭be‬‭accrued.‬‭An‬‭intermediate‬‭analysis‬‭will‬‭be‬‭performed‬‭once‬‭these‬‭first‬
‭46‬‭patients‬‭reach‬‭6‬‭months‬‭after‬‭study‬‭treatment‬‭initiation.‬‭If‬‭there‬‭are‬‭16‬‭or‬‭fewer‬‭responses‬‭in‬
‭these‬ ‭46‬ ‭patients,‬ ‭the‬ ‭study‬ ‭will‬ ‭be‬ ‭stopped.‬ ‭This‬ ‭intermediate‬‭analysis‬‭is‬‭established‬‭as‬‭a‬
‭cut-off‬‭point‬‭to‬‭stop‬‭the‬‭study‬‭if‬‭the‬‭benefit‬‭for‬‭the‬‭patient‬‭in‬‭terms‬‭of‬‭objective‬‭response‬‭does‬
‭not‬‭justify‬‭its‬‭continuation‬‭with‬‭sufficient‬‭clarity.‬‭If‬‭there‬‭is‬‭no‬‭preliminary‬‭evidence‬‭in‬‭the‬‭first‬
‭46‬‭patients,‬‭which‬‭allows‬‭enough‬‭statistical‬‭power‬‭to‬‭reject‬‭the‬‭null‬‭hypothesis,‬‭the‬‭recruitment‬
‭will‬‭stop‬‭as‬‭it‬‭is‬‭considered‬‭that‬‭the‬‭efficacy‬‭of‬‭the‬‭treatment‬‭is‬‭not‬‭sufficient‬‭to‬‭justify‬‭the‬
‭inclusion‬‭of‬‭more‬‭patients.‬‭Otherwise,‬‭20‬‭additional‬‭patients‬‭will‬‭be‬‭accrued‬‭for‬‭a‬‭total‬‭of‬‭66.‬
‭The‬‭null‬‭hypothesis‬‭will‬‭be‬‭rejected‬‭if‬‭25‬‭or‬‭more‬‭responses‬‭are‬‭observed‬‭in‬‭66‬‭patients.‬‭This‬
‭design yields a type I error rate of 0.05 and power of 0.9 when the true response rate is 0.5.‬
‭Variables‬
‭Descriptions‬
‭α‬
‭Probability of type I error: 0.05‬
‭β‬
‭Probability of type II error: 0.1‬
‭p‬‭0‬
‭Response Probability of Poor Drug (P0) ---> 0.30‬
‭P1‬
‭Response Probability of Good Drug (P1) ---> 0.50‬
‭Nmax‬
‭Maximum number of patients to be recruited: 66‬
‭Numstage‬
‭Number of stages in Phase II clinical trial: 2‬
‭n‬‭i‬
‭Number of patients to be recruited in stage i= 46‬
‭R1‬
‭Upper Limit For 1st Stage Rejection of Drug (r1)= 16‬
‭R‬
‭Upper Limit for 2nd Stage Rejection of Drug (r)= 25‬
‭10.2.‬ ‭Study endpoints‬
‭10.2.1.‬ ‭Primary endpoint‬
‭Overall Response Rate (ORR):‬‭Percentage/proportion‬‭of patients with confirmed complete‬
‭response (CR) or partial response (PR) as their overall best response throughout the study‬
‭period.‬
‭10.2.2. Secondary endpoints‬
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‭Efficacy endpoints:‬
‭●‬ ‭Duration of response‬‭(DoR):‬‭Time from first confirmed‬‭response (CR or PR) to the‬
‭date of the documented PD as determined using RECIST 1.1 criteria or death due to‬
‭any cause, whichever occurs first.‬
‭●‬ ‭Time to response‬‭(TtR):‬‭Time from first dosing date‬‭to the date of the documented‬
‭ORR as determined using RECIST 1.1 criteria.‬
‭●‬ ‭Clinical benefit‬‭:‬‭Percentage/proportion of patients‬‭with confirmed complete response‬
‭(CR) or partial response (PR), or stable disease (SD) as their overall best response‬
‭throughout the study period.‬
‭●‬ ‭Overall Survival‬‭(OS)‬
‭○‬ ‭Time‬‭from‬‭first‬‭dosing‬‭date‬‭to‬‭the‬‭date‬‭of‬‭death.‬‭A‬‭subject‬‭who‬‭has‬‭not‬‭died‬
‭will be censored at the last known date alive.‬
‭○‬ ‭Proportion‬‭of‬‭patients‬‭alive‬‭at‬‭the‬‭end‬‭of‬‭the‬‭atezolizumab‬‭plus‬‭split‬‭dose‬‭of‬
‭gemcitabine and cisplatin combination stage.‬
‭○‬ ‭Proportion of patients alive at the end of follow-up.‬
‭●‬ ‭Progression-Free Survival‬‭(PFS)‬
‭○‬ ‭Time‬‭from‬‭first‬‭dosing‬‭date‬‭to‬‭the‬‭date‬‭of‬‭confirmed‬‭PD.‬‭A‬‭subject‬‭who‬‭has‬
‭not died will be censored at the last known date alive.‬
‭○‬ ‭Proportion of patients free of PD at 6 months since start of treatment.‬
‭○‬ ‭Proportion of patients free of PD at the end of follow-up.‬
‭Safety endpoints‬
‭●‬ ‭Adverse‬‭events‬‭(AE)‬‭assessment:‬‭Type,‬‭frequency,‬‭severity‬‭and‬‭outcome‬‭of‬‭adverse‬
‭events .‬
‭●‬ ‭Treatment-related AEs:‬‭Type, frequency, severity and‬‭outcome.‬
‭Exploratory endpoints‬
‭●‬ ‭Biomarkers and/or genes expression and participant outcomes.‬
‭10.3.‬ ‭Efficacy assessment‬
‭10.3.1.‬ ‭Efficacy variables‬
‭Overall‬‭Response‬‭Rate‬‭(ORR)‬‭at‬‭6‬‭months‬‭from‬‭first‬‭dose:‬‭includes‬‭patients‬‭with‬‭confirmed‬
‭persistent‬‭partial‬‭(PR)‬‭and‬‭complete‬‭response‬‭(CR)‬‭as‬‭best‬‭response‬‭according‬‭to‬‭RECIST‬‭v‬
‭1.1, at 6 months from adaptive the study treatment initiation.‬
‭Overall‬‭Response‬‭Rate‬‭(ORR)‬‭from‬‭first‬‭dose:‬‭includes‬‭patients‬‭with‬‭confirmed‬‭persistent‬
‭partial‬‭(PR)‬‭and‬‭complete‬‭response‬‭(CR)‬‭as‬‭best‬‭response‬‭according‬‭to‬‭RECIST‬‭1.1,‬‭at‬‭the‬‭end‬
‭of their participation in the study.‬
‭Time‬ ‭to‬ ‭response:‬ ‭Time‬ ‭to‬ ‭response‬ ‭(TTR)‬ ‭is‬ ‭defined‬‭as‬‭the‬‭time‬‭from‬‭the‬‭start‬‭of‬‭study‬
‭treatment‬ ‭to‬ ‭the‬ ‭first‬ ‭objective‬ ‭tumor‬ ‭response‬ ‭(tumor‬ ‭shrinkage‬ ‭of‬ ‭≥30%)‬ ‭observed‬ ‭for‬
‭patients who achieved a CR or PR.‬
‭Duration‬ ‭of‬ ‭response‬ ‭(DOR):‬ ‭DOR‬ ‭is‬ ‭calculated‬ ‭as‬ ‭the‬ ‭time‬ ‭from‬ ‭the‬ ‭date‬ ‭of‬ ‭first‬
‭documented‬‭CR‬‭or‬‭PR,‬‭as‬‭per‬‭RECIST‬‭1.1,‬‭to‬‭the‬‭first‬‭documented‬‭progression‬‭or‬‭death‬‭due‬‭to‬
‭underlying cancer.‬
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‭Overall‬‭Survival‬‭(OS):‬‭Median‬‭Overall‬‭Survival‬‭(mOS)‬‭is‬‭calculated‬‭as‬‭the‬‭time‬‭from‬‭the‬
‭date of inclusion to date of death due to any cause.‬
‭Progression-free‬‭Survival‬‭(PFS):‬‭Median‬‭Progression‬‭free‬‭survival‬‭(mPFS)‬‭is‬‭defined‬‭as‬‭the‬
‭time‬‭from‬‭the‬‭date‬‭of‬‭inclusion‬‭to‬‭the‬‭date‬‭of‬‭the‬‭first‬‭documented‬‭disease‬‭progression‬‭or‬‭death‬
‭due‬‭to‬‭any‬‭cause,‬‭whichever‬‭occurs‬‭first.‬‭PFS‬‭will‬‭be‬‭determined‬‭based‬‭on‬‭tumour‬‭assessment‬
‭(RECIST‬‭version‬‭1.1‬‭criteria).‬‭The‬‭local‬‭Investigator's‬‭assessments‬‭will‬‭be‬‭used‬‭for‬‭analyses.‬
‭Patients‬‭who‬‭are‬‭alive‬‭and‬‭have‬‭not‬‭progressed‬‭at‬‭the‬‭last‬‭follow-up‬‭will‬‭be‬‭censored‬‭at‬‭the‬
‭date‬‭of‬‭the‬‭last‬‭available‬‭image‬‭determination‬‭(CT‬‭scan‬‭or‬‭MRI).‬‭Patients‬‭with‬‭no‬‭additional‬
‭image‬ ‭test‬ ‭other‬ ‭than‬ ‭that‬ ‭at‬ ‭baseline‬ ‭will‬ ‭be‬ ‭censored‬ ‭to‬ ‭the‬‭day‬‭after‬‭inclusion.‬‭Patients‬
‭initiating‬‭new‬‭anticancer‬‭therapy‬‭(without‬‭progression‬‭to‬‭the‬‭study‬‭treatment)‬‭will‬‭be‬‭censored‬
‭to the date of new anticancer therapy initiation.‬
‭Clinical‬ ‭Benefit‬ ‭(CB)‬ ‭Rate:‬ ‭Clinical‬ ‭Benefit‬ ‭Rate‬ ‭(CBR)‬ ‭is‬ ‭defined‬ ‭as‬ ‭the‬‭percentage‬‭of‬
‭patients‬‭who‬‭achieved‬‭complete‬‭response,‬‭partial‬‭response‬‭and‬‭stable‬‭disease.‬‭Stable‬‭disease‬
‭should be maintained for at least 6 months to be considered as a CBR event.‬
‭10.4.‬ ‭Safety assessment‬
‭The‬‭safety‬‭population‬‭(SP)‬‭consists‬‭of‬‭all‬‭enrolled‬‭subjects‬‭who‬‭received‬‭at‬‭least‬‭one‬‭dose‬‭of‬
‭study‬‭treatment.‬‭Patients‬‭will‬‭be‬‭monitored‬‭for‬‭safety‬‭during‬‭all‬‭the‬‭stages‬‭of‬‭the‬‭study.‬‭All‬
‭safety and tolerability assessments will be done at pre-dosing time, unless otherwise specified.‬
‭Safety‬‭parameters‬‭are‬‭AE,‬‭SAE,‬‭AESI,‬‭pregnancy,‬‭medication‬‭error,‬‭and‬‭overdose.‬‭Additional‬
‭safety information could be derived from ECG, lab test, pregnancy test, or vital sign exam.‬
‭The‬‭assessment‬‭of‬‭adverse‬‭events‬‭will‬‭include‬‭the‬‭type‬‭of‬‭event‬‭(including‬‭symptoms,‬‭physical‬
‭exam‬‭findings‬‭and‬‭laboratory‬‭abnormalities),‬‭the‬‭incidence,‬‭severity,‬‭timing,‬‭seriousness,‬‭and‬
‭relatedness‬‭regarding‬‭the‬‭treatment‬‭under‬‭study.‬‭Adverse‬‭events‬‭will‬‭be‬‭recorded‬‭and‬‭reported‬
‭in‬‭the‬‭corresponding‬‭section‬‭of‬‭the‬‭case‬‭report‬‭form.‬‭The‬‭grade‬‭of‬‭adverse‬‭events‬‭will‬‭be‬‭coded‬
‭according‬ ‭to‬ ‭the‬ ‭National‬ ‭Cancer‬ ‭Institute’s‬ ‭Common‬ ‭Toxicity‬ ‭criteria‬ ‭(NCI-CTCAE‬ ‭v5.0‬
‭scoring system). The worst toxicity score will be recorded.‬
‭10.5.‬ ‭Definition of study populations‬
‭Data will be analysed in the following populations:‬
‭1.‬ ‭Intent-To-Treat (ITT):‬‭All patients that have been‬‭enrolled in the trial.‬
‭2.‬ ‭Evaluable‬‭population‬‭per‬‭protocol‬‭(PP):‬‭All‬‭patients‬‭fulfilling‬‭all‬‭eligibility‬‭criteria‬
‭without‬‭any‬‭protocol‬‭deviation‬‭that‬‭makes‬‭the‬‭patient‬‭invalid‬‭for‬‭the‬‭primary‬‭endpoint‬
‭evaluation.‬
‭3.‬ ‭Safety population (SP):‬‭All patients receiving at‬‭least one dose of the study treatments.‬
‭10.6.‬ ‭Data quality control‬
‭A‬‭Data‬‭Management‬‭Plan‬‭(DMP)‬‭will‬‭be‬‭elaborated‬‭for‬‭this‬‭trial‬‭in‬‭order‬‭to‬‭outline‬‭the‬‭data‬
‭management‬ ‭procedures‬‭and‬‭the‬‭related‬‭responsibilities‬‭of‬‭trial‬‭staff.‬‭The‬‭DMP‬‭will‬‭clearly‬
‭specify‬ ‭the‬ ‭data‬‭quality‬‭control‬‭tasks‬‭to‬‭be‬‭performed‬‭and‬‭the‬‭corresponding‬‭responsibility,‬
‭timelines, etc., according to international guidelines in the subject and GCPs.‬
‭Following‬‭data‬‭entry‬‭of‬‭the‬‭investigator‬‭staff‬‭into‬‭the‬‭data‬‭capture‬‭system‬‭(eCRF),‬‭the‬‭data‬
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‭entered‬ ‭will‬ ‭be‬ ‭reconciled‬ ‭against‬ ‭the‬ ‭original‬ ‭case‬ ‭report‬ ‭form,‬ ‭review‬ ‭form/clinic‬
‭notes/laboratory‬‭reports‬‭by‬‭CRA‬‭during‬‭monitoring‬‭visits,‬‭according‬‭to‬‭the‬‭monitoring‬‭plan.‬
‭Any‬‭identified‬‭issues‬‭should‬‭be‬‭clarified‬‭with‬‭the‬‭Investigator‬‭staff.‬‭Any‬‭necessary‬‭corrections‬
‭should be made in the corresponding field of the eCRF.‬
‭The‬‭monitoring‬‭plan‬‭will‬‭establish‬‭that‬‭source‬‭data‬‭verification‬‭(SDV)‬‭is‬‭expected‬‭for‬‭a‬‭subset‬
‭of‬ ‭variables,‬ ‭according‬ ‭to‬ ‭study‬ ‭status,‬‭starting‬‭on‬‭the‬‭approval‬‭of‬‭this‬‭DMP‬‭and‬‭the‬‭SDV‬
‭strategy agreed.‬
‭Remote‬ ‭QC‬ ‭activities‬ ‭will‬ ‭be‬ ‭outlined‬ ‭in‬ ‭the‬ ‭Monitoring‬ ‭Plan‬ ‭for‬ ‭relevant‬ ‭variables‬ ‭as‬
‭eligibility, primary endpoints, safety endpoints and relevant secondary endpoints.‬
‭Performance‬‭of‬‭these‬‭checks‬‭is‬‭expected‬‭on‬‭all‬‭the‬‭patients‬‭included‬‭(this‬‭estimate‬‭may‬‭vary‬
‭according to the quality of the data reported by the research team).‬
‭Any‬‭finding‬‭will‬‭be‬‭reflected‬‭in‬‭the‬‭monitoring‬‭report‬‭and‬‭will‬‭be‬‭conveniently‬‭managed‬‭with‬
‭sites‬‭(including‬‭Principal‬‭Investigator)‬‭and‬‭informed‬‭to‬‭the‬‭Coordinating‬‭Investigator,‬‭as‬‭the‬
‭representative‬ ‭of‬ ‭the‬ ‭Sponsor‬ ‭in‬ ‭this‬ ‭study,‬ ‭and‬ ‭when‬ ‭applicable,‬ ‭notified‬ ‭to‬ ‭competent‬
‭authorities according to local regulations.‬
‭10.7.‬ ‭Statistical analysis‬
‭For‬ ‭each‬ ‭categorical‬ ‭variable,‬ ‭the‬ ‭results‬ ‭will‬ ‭be‬ ‭summarised‬ ‭by‬ ‭frequencies‬ ‭and‬
‭percentages/proportions along with 95 % confidence intervals (95% CIs) when applicable.‬
‭For‬‭each‬‭continuous‬‭variable,‬‭the‬‭results‬‭will‬‭be‬‭summarised‬‭by‬‭descriptive‬‭statistics‬‭such‬‭as‬
‭median,‬‭range,‬‭and‬‭range‬‭or‬‭by‬‭means,‬‭standard‬‭deviations,‬‭and‬‭(95%‬‭CIs).‬‭For‬‭time‬‭to‬‭event‬
‭endpoints,‬‭Kaplan-Meier‬‭estimates‬‭at‬‭selected‬‭time‬‭points‬‭and‬‭corresponding‬‭curves‬‭will‬‭be‬
‭presented.‬‭Time‬‭to‬‭event‬‭is‬‭derived‬‭relative‬‭to‬‭the‬‭first‬‭study‬‭treatment‬‭administration‬‭and‬‭will‬
‭be expressed in weeks and/or months.‬
‭Vital‬‭signs,‬‭ECG‬‭parameters,‬‭clinical‬‭laboratory‬‭data‬‭(haematology,‬‭serum‬‭biochemistry,‬‭and‬
‭urinalysis)‬‭will‬‭be‬‭presented‬‭in‬‭tabular‬‭form.‬‭Laboratory‬‭values‬‭will‬‭be‬‭expressed‬‭as‬‭absolute‬
‭values‬ ‭and‬ ‭in‬ ‭grades‬ ‭(ordinal‬ ‭categorical‬ ‭variables),‬ ‭when‬ ‭feasible.‬ ‭In‬ ‭case‬ ‭of‬ ‭laboratory‬
‭findings‬ ‭reported‬ ‭as‬ ‭adverse‬‭events,‬‭values‬‭will‬‭be‬‭presented‬‭and/or‬‭classified‬‭according‬‭to‬
‭NCI CTCAE v 5.0.‬
‭All‬‭adverse‬‭events,‬‭including‬‭treatment-emergent‬‭AE‬‭(AEs‬‭starting‬‭after‬‭the‬‭administration‬‭of‬
‭study‬‭treatment‬‭and‬‭up‬‭to‬‭study‬‭completion)‬‭will‬‭be‬‭summarised‬‭by‬‭system‬‭organ‬‭class‬‭and‬
‭preferred‬‭term.‬‭Grading‬‭will‬‭be‬‭presented‬‭by‬‭type‬‭and‬‭in‬‭tables‬‭showing‬‭the‬‭frequency‬‭and‬
‭percentage‬‭of‬‭the‬‭within-patient‬‭worst‬‭grades.‬‭In‬‭addition,‬‭grade‬‭≥‬‭3‬‭AEs‬‭will‬‭be‬‭summarised‬
‭separately. Further analyses could be performed.‬
‭Analysis‬‭will‬‭be‬‭based‬‭on‬‭observed‬‭data,‬‭and‬‭missing‬‭data‬‭for‬‭drop-outs‬‭are‬‭not‬‭replaced‬‭by‬
‭methods like LOCF (last option carried forward).‬
‭Full analysis details will be outlined in the statistical analysis plan (SAP).‬
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‭11.‬
‭LEGAL AND ETHICS CONSIDERATION‬
‭11.1.‬
‭Ethical conduct of the study‬
‭The‬ ‭study‬ ‭will‬ ‭be‬ ‭conducted‬ ‭in‬ ‭accordance‬‭with‬‭the‬‭principles‬‭of‬‭the‬‭Helsinki‬‭Declaration‬
‭Adopted‬‭by‬‭the‬‭18th‬‭World‬‭Medical‬‭Assembly,‬‭Helsinki,‬‭Finland,‬‭June‬‭1964‬‭updated‬‭to‬‭its‬
‭latest‬ ‭version‬ ‭Fortaleza,‬ ‭Brazil,‬ ‭October‬ ‭2013.‬ ‭With‬ ‭the‬ ‭Good‬ ‭Clinical‬ ‭Practice‬ ‭(GCP)‬
‭standards‬ ‭issued‬ ‭by‬ ‭the‬ ‭Working‬ ‭Party‬ ‭on‬ ‭Medicinal‬ ‭Product‬ ‭Efficacy‬ ‭of‬ ‭the‬ ‭European‬
‭Economic Community (1990) (CPMP / ICH / 135/95).‬
‭And the laws and regulations in force in Spain:‬
‭●‬ ‭The‬‭Oviedo‬‭Convention‬‭of‬‭April‬‭4,‬‭1997‬‭on‬‭human‬‭rights‬‭and‬‭biomedicine,‬‭ratified‬‭in‬
‭the BOE in October 1999.‬
‭●‬ ‭The‬‭rules‬‭for‬‭the‬‭adequate‬‭protection‬‭of‬‭personal‬‭data,‬‭in‬‭accordance‬‭with‬‭Law‬‭3/2018‬
‭Protection of Personal Data and guarantee of digital rights.‬
‭●‬ ‭The‬ ‭rights‬ ‭and‬ ‭obligations‬ ‭regarding‬ ‭information‬ ‭and‬ ‭clinical‬ ‭documentation,‬ ‭as‬
‭provided in Law 41/2002, of November 14, basic regulation of patient autonomy.‬
‭●‬ ‭Royal‬ ‭Decree‬ ‭1090/2015,‬ ‭of‬ ‭4‬ ‭December,‬ ‭regulating‬ ‭clinical‬ ‭trials‬ ‭with‬ ‭medicinal‬
‭products,‬ ‭Ethics‬ ‭Committees‬ ‭for‬ ‭Investigation‬ ‭with‬ ‭medicinal‬ ‭products‬ ‭and‬ ‭the‬
‭Spanish Clinical Studies Registry.‬
‭●‬ ‭Law 14/2007, of July 3, on Biomedical Research.‬
‭11.2.‬
‭Independent Ethical Committee (IEC) Review‬
‭Prior‬ ‭to‬ ‭the‬ ‭commencement‬ ‭of‬ ‭the‬ ‭trial‬ ‭at‬ ‭a‬ ‭given‬ ‭site,‬ ‭this‬ ‭clinical‬ ‭trial‬ ‭protocol‬ ‭will‬‭be‬
‭submitted‬‭together‬‭with‬‭its‬‭associated‬‭documents‬‭to‬‭the‬‭Central‬‭IEC‬‭for‬‭its‬‭approval,‬‭which‬
‭will be filed in the Investigator Site File. A copy will be filed in the Sponsor Trial Master File.‬
‭The‬‭IEC‬‭will‬‭be‬‭asked‬‭to‬‭document‬‭the‬‭date‬‭of‬‭the‬‭meeting‬‭at‬‭which‬‭the‬‭favourable‬‭opinion‬‭or‬
‭approval‬ ‭was‬ ‭given,‬ ‭with‬ ‭the‬ ‭members‬ ‭and‬ ‭voting‬ ‭members‬ ‭present.‬ ‭Written‬ ‭evidence‬ ‭of‬
‭favourable‬‭opinion‬‭or‬‭approval‬‭that‬‭clearly‬‭identifies‬‭the‬‭trial,‬‭the‬‭clinical‬‭trial‬‭protocol‬‭and‬‭the‬
‭version, the Subject Information and Informed Consent Form, should be provided.‬
‭Amendments‬‭to‬‭this‬‭clinical‬‭trial‬‭protocol‬‭will‬‭also‬‭be‬‭submitted‬‭to‬‭the‬‭concerned‬‭IEC,‬‭before‬
‭implementation‬‭of‬‭substantial‬‭changes.‬‭Relevant‬‭safety‬‭information‬‭will‬‭be‬‭submitted‬‭to‬‭the‬
‭IEC during the course of the trial, in accordance with national regulations and requirements.‬
‭Initial‬‭IEC‬‭positive‬‭vote,‬‭and‬‭all‬‭materials‬‭approved‬‭by‬‭the‬‭IEC‬‭for‬‭this‬‭study‬‭including‬‭the‬
‭patient‬ ‭consent‬ ‭form‬ ‭and‬‭recruitment‬‭materials‬‭must‬‭be‬‭maintained‬‭by‬‭the‬‭Investigator‬‭and‬
‭made available for inspection.‬
‭11.3.‬
‭Authorities‬
‭The‬‭study‬‭protocol‬‭and/or‬‭related‬‭documents‬‭will‬‭be‬‭submitted‬‭to‬‭regulatory‬‭authorities‬‭before‬
‭commencement‬ ‭of‬ ‭the‬ ‭clinical‬‭trial,‬‭as‬‭national‬‭authorities‬‭in‬‭the‬‭country‬‭where‬‭the‬‭trial‬‭is‬
‭taking place.‬
‭11.4.‬
‭Informed consent‬
‭The‬‭patient‬‭should‬‭sign‬‭an‬‭informed‬‭consent‬‭that‬‭will‬‭include‬‭the‬‭information‬‭for‬‭the‬‭clinical‬
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‭trial and associated translational research.‬
‭The‬ ‭clinician‬ ‭will‬ ‭have‬ ‭to‬ ‭explain‬ ‭the‬ ‭nature,‬ ‭objectives‬ ‭and‬‭possible‬‭consequences‬‭of‬‭the‬
‭clinical‬‭trial‬‭in‬‭a‬‭manner‬‭that‬‭is‬‭understandable‬‭by‬‭the‬‭patient.‬‭The‬‭patient‬‭must‬‭give‬‭his/her‬
‭consent before being admitted into the study and before biological samples are taken.‬
‭The‬‭study‬‭subject‬‭will‬‭provide‬‭his/her‬‭consent,‬‭signing‬‭by‬‭duplicate‬‭the‬‭appropriate‬‭model.‬‭For‬
‭this‬‭purpose,‬‭each‬‭model‬‭must‬‭carry‬‭the‬‭signature‬‭of‬‭investigator‬‭and‬‭patient.‬‭The‬‭investigator‬
‭will retain one copy of the original of each patient signed consent form.‬
‭The‬‭investigator‬‭will‬‭not‬‭start‬‭any‬‭investigation‬‭related‬‭with‬‭the‬‭study‬‭until‬‭the‬‭written‬‭consent‬
‭has been obtained.‬
‭The‬‭informed‬‭consent‬‭form‬‭used‬‭in‬‭this‬‭study,‬‭and‬‭any‬‭changes‬‭made‬‭during‬‭the‬‭course‬‭of‬‭the‬
‭study, must be prospectively approved by the Ethics Committee.‬
‭11.5.‬
‭Confidentiality‬
‭In‬‭order‬‭to‬‭guarantee‬‭the‬‭confidentiality‬‭of‬‭the‬‭clinical‬‭trial‬‭data‬‭according‬‭to‬‭the‬‭provisions‬‭of‬
‭The‬ ‭rules‬ ‭for‬ ‭the‬ ‭adequate‬ ‭protection‬ ‭of‬ ‭personal‬ ‭data,‬ ‭in‬ ‭accordance‬ ‭with‬ ‭Law‬ ‭3/2018‬
‭Protection‬‭of‬‭Personal‬‭Data‬‭and‬‭guarantee‬‭of‬‭digital‬‭rights,‬‭only‬‭the‬‭personnel‬‭designated‬‭by‬
‭the‬‭Sponsor‬‭will‬‭have‬‭access‬‭to‬‭the‬‭patient‬‭data‬‭for‬‭monitoring/auditing‬‭purposes,‬‭Investigators‬
‭and his/her staff, the Ethic Committee and the pertinent Competent Authorities.‬
‭The‬‭investigator‬‭should‬‭facilitate‬‭access‬‭to‬‭the‬‭source‬‭documents‬‭and‬‭data‬‭for‬‭monitoring‬‭and‬
‭auditing purposes.‬
‭The‬‭content‬‭of‬‭the‬‭case‬‭report‬‭forms‬‭(CRF),‬‭as‬‭well‬‭as‬‭the‬‭documents‬‭generated‬‭during‬‭the‬
‭study‬‭will‬‭be‬‭protected‬‭from‬‭non-permitted‬‭uses‬‭by‬‭persons‬‭not‬‭involved‬‭in‬‭the‬‭investigation,‬
‭and‬‭will‬‭therefore‬‭be‬‭considered‬‭strictly‬‭confidential‬‭and‬‭not‬‭revealed‬‭to‬‭third‬‭parties,‬‭except‬
‭those specified in the previous paragraphs.‬
‭11.6.‬
‭Insurance Policy‬
‭The‬ ‭insurance‬ ‭or‬ ‭indemnity‬ ‭in‬ ‭accordance‬ ‭with‬ ‭pertinent‬ ‭regulatory‬ ‭requirements‬ ‭will‬ ‭be‬
‭provided.‬‭All‬‭patients‬‭in‬‭this‬‭study‬‭are‬‭insured‬‭through‬‭the‬‭corresponding‬‭insurance‬‭policy‬‭that‬
‭satisfies the conditions stipulated by the RD 1090/2015 in Spain.‬
‭11.7.‬
‭End of study definition‬
‭The‬‭end‬‭of‬‭study‬‭is‬‭defined‬‭as‬‭the‬‭Last‬‭Patient‬‭Last‬‭Visit‬‭(LPLV)‬‭and‬‭will‬‭be‬‭considered‬‭at‬‭24‬
‭months‬‭after‬‭last‬‭patient‬‭first‬‭visit‬‭(LPFV),‬‭Sponsor‬‭will‬‭ask‬‭survival‬‭status‬‭of‬‭all‬‭patients‬‭at‬
‭the‬‭final‬‭clinical‬‭trial‬‭database‬‭closing,‬‭in‬‭order‬‭to‬‭maximise‬‭the‬‭median‬‭follow‬‭up‬‭of‬‭patients‬
‭for overall survival data.‬
‭11.8.‬
‭Early study termination‬
‭The‬ ‭clinical‬ ‭trial‬ ‭may‬ ‭be‬ ‭terminated‬ ‭prematurely‬ ‭or‬ ‭suspended‬ ‭at‬ ‭the‬ ‭request‬ ‭of‬ ‭Health‬
‭Authorities‬ ‭or‬ ‭if‬ ‭new‬ ‭safety‬ ‭or‬ ‭efficacy‬ ‭information‬ ‭leads‬ ‭to‬ ‭an‬ ‭unfavourable‬ ‭risk‬ ‭benefit‬
‭judgment‬‭for‬‭any‬‭IMP.‬‭The‬‭Sponsor‬‭may‬‭discontinue‬‭the‬‭trial‬‭if‬‭it‬‭becomes‬‭unjustifiable‬‭for‬
‭medical‬‭or‬‭ethical‬‭reasons,‬‭poor‬‭enrolment,‬‭or‬‭the‬‭discontinuation‬‭of‬‭clinical‬‭development‬‭of‬
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‭the IMP or withdrawal of the IMP from the market for safety reasons.‬
‭Health‬ ‭Authorities‬ ‭and‬ ‭Independent‬ ‭Ethics‬ ‭Committees‬ ‭(IECs)‬ ‭will‬ ‭be‬ ‭informed‬ ‭about‬‭the‬
‭discontinuation of the trial in accordance with applicable regulations.‬
‭In‬ ‭case‬ ‭of‬ ‭early‬‭termination‬‭of‬‭the‬‭study,‬‭all‬‭the‬‭study‬‭material‬‭(study‬‭drugs,‬‭etc.)‬‭must‬‭be‬
‭returned to the Sponsor.‬
‭12.‬
‭STUDY PROCEDURES‬
‭12.1.‬ ‭Responsibilities according to Good Clinical Practice‬
‭Responsibilities‬ ‭of‬ ‭the‬ ‭principal‬ ‭investigator‬ ‭of‬ ‭each‬ ‭participating‬ ‭center‬ ‭includes‬ ‭what‬ ‭is‬
‭detailed in section 4 of the‬‭Guideline for good clinical‬‭practice E6 (R2)‬‭.‬
‭12.2.‬ ‭Instructions for e-CRF completion‬
‭The‬‭data‬‭will‬‭be‬‭recorded‬‭using‬‭the‬‭Electronic‬‭Data‬‭Capture‬‭software‬‭property‬‭of‬‭MFAR‬‭S.L.‬
‭The‬‭MFAR‬‭e-CRF‬‭environment‬‭will‬‭be‬‭used‬‭for‬‭data‬‭collection‬‭in‬‭this‬‭study.‬‭The‬‭database‬‭can‬
‭be‬ ‭accessed‬ ‭through‬ ‭the‬ ‭following‬ ‭link:‬ ‭www.mfar.es/access‬‭.‬ ‭Access‬ ‭to‬ ‭data‬ ‭is‬‭secure‬‭and‬
‭restricted‬‭for‬‭authorised‬‭users.‬‭Each‬‭user‬‭requires‬‭a‬‭username‬‭and‬‭password‬‭for‬‭exclusively‬
‭personal use, as per good clinical practice.‬
‭All‬ ‭the‬ ‭EDC‬ ‭users‬ ‭are‬ ‭uniquely‬‭identified‬‭by‬‭name,‬‭all‬‭the‬‭access‬‭to‬‭the‬‭software‬‭is‬‭made‬
‭through a secure, encrypted connection and all the activities are logged and audited.‬
‭All‬‭the‬‭EDC‬‭forms‬‭are‬‭designed‬‭according‬‭to‬‭the‬‭eCRF‬‭defined‬‭by‬‭the‬‭study‬‭protocol,‬‭and‬‭are‬
‭validated‬ ‭according‬ ‭to‬ ‭the‬ ‭DVP‬ ‭(Data‬ ‭Validation‬ ‭Plan).‬ ‭There‬ ‭will‬‭be‬‭eCRFs‬‭for‬‭different‬
‭visits,‬‭and‬‭whether‬‭these‬‭are‬‭mandatory‬‭(m)‬‭and‬‭non-mandatory‬‭eCRFs‬‭(such‬‭as‬‭laboratory‬
‭testing and the corresponding validation of variables, rules and extraction).‬
‭Data‬ ‭on‬ ‭Adverse‬ ‭Event‬ ‭(AE),‬ ‭Adverse‬ ‭Reactions‬ ‭(AR),‬ ‭Serious‬ ‭Adverse‬ ‭Events‬ ‭(SAEs),‬
‭Serious‬ ‭Adverse‬ ‭Reactions‬ ‭(SARs)‬ ‭and‬ ‭Suspected‬ ‭Unexpected‬ ‭SARs‬ ‭(SUSARs)‬ ‭will‬ ‭be‬
‭undertaken‬‭by‬‭Sites‬‭in‬‭the‬‭eCRF‬‭and‬‭are‬‭transferred‬‭to‬‭the‬‭study‬‭database‬‭along‬‭with‬‭the‬‭rest‬‭of‬
‭variables.‬
‭Electronic‬‭Case‬‭Report‬‭Form‬‭(eCRF)‬‭includes‬‭the‬‭CTCAE‬‭version‬‭5.0‬‭terms‬‭as‬‭a‬‭pulldown‬‭list‬
‭in‬‭order‬‭to‬‭categorise‬‭the‬‭events,‬‭additionally‬‭when‬‭the‬‭variable‬‭“SAE”‬‭is‬‭marked‬‭as‬‭“yes”,‬‭an‬
‭automatic‬‭email‬‭is‬‭sent‬‭to‬‭the‬‭MFAR‬‭Staff‬‭in‬‭order‬‭to‬‭be‬‭aware‬‭of‬‭the‬‭paper‬‭based‬‭SAE‬‭form‬‭is‬
‭expected‬‭to‬‭be‬‭received,‬‭for‬‭regulatory‬‭reporting‬‭purposes.‬‭As‬‭data‬‭cleaning‬‭procedure,‬‭SAE‬
‭received‬‭in‬‭paper‬‭based‬‭form‬‭are‬‭conciliate‬‭with‬‭the‬‭adverse‬‭events‬‭data‬‭collected‬‭in‬‭the‬‭eCRF‬
‭and‬‭is‬‭ensured‬‭that‬‭all‬‭the‬‭events‬‭reported‬‭by‬‭means‬‭of‬‭SAE‬‭form‬‭are‬‭also‬‭collected‬‭in‬‭the‬
‭eCRF,‬‭that‬‭is‬‭the‬‭final‬‭destination‬‭of‬‭any‬‭adverse‬‭event‬‭(whether‬‭be‬‭AE,‬‭AR,‬‭SAE,‬‭SAR‬‭or‬
‭SUSAR).‬
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‭12.3.‬ ‭Drug supply‬
‭AUREA‬ ‭is‬ ‭an‬ ‭Investigator‬ ‭Initiated‬ ‭Study,‬ ‭Atezolizumab‬ ‭will‬ ‭be‬ ‭supplied‬ ‭by‬ ‭the‬‭Sponsor‬
‭through‬‭Roche,‬‭the‬‭Sponsor‬‭will‬‭supply‬‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬‭months‬‭of‬‭treatment‬‭for‬
‭each‬‭patient.‬‭The‬‭treatment‬‭for‬‭patients‬‭not‬‭progressing‬‭at‬‭24‬‭months‬‭will‬‭be‬‭according‬‭to‬‭PI‬
‭criteria,‬‭following‬‭his/her‬‭local‬‭normal‬‭practice.‬‭In‬‭case‬‭that‬‭the‬‭site‬‭cannot‬‭provide‬‭the‬‭drug‬
‭for‬ ‭regulatory‬ ‭reasons‬ ‭(for‬ ‭example,‬ ‭the‬ ‭indication‬ ‭is‬ ‭not‬ ‭financed)‬ ‭and‬ ‭always‬‭with‬‭prior‬
‭approval‬ ‭by‬ ‭the‬ ‭study‬ ‭sponsor‬ ‭(SOGUG)‬ ‭and‬ ‭by‬ ‭Roche,‬ ‭and‬ ‭if‬ ‭it‬ ‭is‬ ‭thus‬ ‭indicated‬‭in‬‭the‬
‭contract‬ ‭between‬ ‭the‬ ‭Sponsor‬ ‭and‬ ‭the‬ ‭Site,‬ ‭the‬ ‭patient‬ ‭could‬ ‭continue‬ ‭in‬ ‭treatment‬ ‭with‬
‭Atezollizumab‬ ‭participating‬ ‭in‬‭a‬‭Post-Trial‬‭Access‬‭(PTA)‬‭Program,‬‭previously‬‭approved‬‭by‬
‭Roche. The maximum duration of the PTA will be 1 year.‬
‭If‬‭as‬‭per‬‭Treating‬‭Physician‬‭criteria,‬‭the‬‭best‬‭option‬‭for‬‭the‬‭patient‬‭would‬‭be‬‭to‬‭continue‬‭with‬
‭Atezolizumab,‬ ‭the‬ ‭administration‬ ‭may‬ ‭continue‬‭but‬‭following‬‭Site’s‬‭supply‬‭channels‬‭(other‬
‭than‬‭those‬‭provided‬‭by‬‭Sponsor),‬‭after‬‭managing‬‭local‬‭administrative‬‭approvals‬‭Gemcitabine‬
‭and Cisplatin will be provided by the sites as per standard care criteria.‬
‭12.3.1. Packaging and labelling‬
‭Packaging‬ ‭and‬ ‭labeling‬ ‭of‬ ‭study‬ ‭treatment‬ ‭will‬ ‭be‬ ‭in‬ ‭accordance‬ ‭with‬ ‭applicable‬ ‭local‬
‭regulatory requirements and applicable Good Manufacturing Practice (GMP) guidelines.‬
‭12.4.‬ ‭Final report and Publications‬
‭As‬‭stated‬‭in‬‭article‬‭42‬‭of‬‭RD‬‭1090/2015‬‭of‬‭clinical‬‭trials,‬‭the‬‭Sponsor‬‭is‬‭obliged‬‭to‬‭publish‬
‭both‬‭positive‬‭and‬‭negative‬‭results‬‭of‬‭the‬‭authorized‬‭clinical‬‭trials‬‭in‬‭scientific‬‭journals‬‭and‬‭with‬
‭mention to the Ethical Committee of Clinical Research that approved the study.‬
‭The‬‭clinical‬‭publication‬‭will‬‭be‬‭carried‬‭out‬‭by‬‭the‬‭Coordinating‬‭Investigator‬‭in‬‭collaboration‬
‭and‬ ‭Principal‬ ‭Investigators.‬ ‭Coordinating‬ ‭Investigator‬ ‭and‬ ‭Principal‬ ‭Investigators‬ ‭who‬
‭contributed‬ ‭with‬ ‭at‬ ‭least‬ ‭3%‬ ‭of‬ ‭the‬ ‭patients‬ ‭will‬ ‭be‬‭the‬‭authors.‬‭The‬‭order‬‭of‬‭authors‬‭will‬
‭strictly depend on the number of patients included by the Investigators.‬
‭The‬‭anonymity‬‭of‬‭the‬‭source‬‭subjects‬‭of‬‭the‬‭data‬‭and‬‭biological‬‭samples‬‭will‬‭be‬‭maintained‬‭at‬
‭all times.‬
‭The‬ ‭results‬ ‭or‬ ‭conclusions‬ ‭of‬ ‭the‬ ‭study‬ ‭will‬ ‭be‬ ‭communicated‬ ‭primarily‬ ‭in‬ ‭scientific‬
‭publications before being released to the non-health public.‬
‭No efficacy study outcome will be reported prematurely or sensationalistically.‬
‭Participating‬ ‭investigators‬ ‭should‬‭not‬‭publish‬‭any‬‭patient‬‭data‬‭that‬‭is‬‭directly‬‭related‬‭to‬‭the‬
‭study objectives until the trial report is published.‬
‭The‬ ‭trial‬ ‭will‬ ‭be‬ ‭registered‬ ‭in‬ ‭the‬ ‭Spanish‬ ‭Registry‬ ‭of‬ ‭Clinical‬ ‭Studies‬ ‭(REEC)‬ ‭and‬
‭www.clinicaltrials.gov‬‭.‬
‭12.5.‬ ‭Monitoring‬
‭The‬‭study‬‭will‬‭be‬‭monitored‬‭through‬‭local‬‭visits,‬‭telephone‬‭calls‬‭and‬‭periodic‬‭inspection‬‭of‬
‭CRFs.‬ ‭During‬ ‭the‬ ‭study,‬ ‭according‬ ‭to‬ ‭monitoring‬ ‭plan,‬ ‭a‬ ‭monitor‬ ‭from‬ ‭MFAR‬ ‭Clinical‬
‭Research‬ ‭or‬ ‭a‬ ‭representative‬ ‭will‬ ‭have‬ ‭regular‬‭contact‬‭with‬‭the‬‭investigational‬‭site,‬‭for‬‭the‬
‭following:‬
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‭●‬ ‭Provide information and support to the investigator(s)‬
‭●‬ ‭Confirm that facilities remain acceptable‬
‭●‬ ‭Confirm‬ ‭that‬ ‭the‬ ‭investigational‬ ‭team‬ ‭is‬ ‭adhering‬ ‭to‬ ‭the‬ ‭protocol,‬ ‭data‬ ‭are‬ ‭being‬
‭accurately‬ ‭recorded‬ ‭in‬ ‭the‬ ‭case‬ ‭report‬ ‭forms,‬ ‭and‬ ‭that‬ ‭investigational‬ ‭product‬
‭accountability checks are being performed‬
‭●‬ ‭Perform‬‭source‬‭data‬‭verification.‬‭This‬‭includes‬‭a‬‭comparison‬‭of‬‭the‬‭data‬‭in‬‭the‬‭case‬
‭report‬‭forms‬‭with‬‭the‬‭patient’s‬‭medical‬‭records‬‭at‬‭the‬‭hospital‬‭or‬‭practice,‬‭and‬‭other‬
‭records‬‭relevant‬‭to‬‭the‬‭study.‬‭This‬‭will‬‭require‬‭direct‬‭access‬‭to‬‭all‬‭original‬‭records‬‭for‬
‭each patient (e.g., clinic charts).‬
‭●‬ ‭Record‬ ‭and‬ ‭report‬ ‭any‬ ‭protocol‬ ‭deviations‬ ‭not‬ ‭previously‬ ‭sent‬ ‭to‬ ‭MFAR‬ ‭Clinical‬
‭Research.‬
‭●‬ ‭Confirm‬‭that‬‭AEs‬‭and‬‭SAEs‬‭have‬‭been‬‭properly‬‭documented‬‭on‬‭eCRFs,‬‭all‬‭SAEs‬‭have‬
‭been‬ ‭forwarded‬ ‭to‬ ‭MFAR‬‭Clinical‬‭Research,‬‭and‬‭all‬‭the‬‭SAEs‬‭that‬‭met‬‭criteria‬‭for‬
‭reporting have been forwarded to the IEC‬
‭The‬‭monitor‬‭will‬‭be‬‭available‬‭between‬‭visits‬‭if‬‭the‬‭investigator(s)‬‭or‬‭other‬‭staff‬‭members‬‭need‬
‭information or advice.‬
‭12.6.‬ ‭Clinical Study Report‬
‭According‬‭to‬‭local‬‭regulation,‬‭the‬‭summary‬‭of‬‭results‬‭of‬‭the‬‭trial‬‭will‬‭be‬‭sent‬‭to‬‭the‬‭AEMPS‬
‭and‬‭the‬‭CEIm‬‭no‬‭later‬‭than‬‭one‬‭year‬‭after‬‭the‬‭date‬‭of‬‭the‬‭end‬‭of‬‭the‬‭trial‬‭globally.‬‭The‬‭summary‬
‭of results will follow the European format required for EudraCT.‬
‭12.7.‬ ‭Protocol Amendments‬
‭Supplements‬‭and‬‭changes‬‭to‬‭the‬‭protocol‬‭can‬‭be‬‭performed‬‭exclusively‬‭by‬‭the‬‭Sponsor,‬‭who‬
‭must‬ ‭submit‬ ‭them‬ ‭to‬ ‭the‬ ‭Ethics‬ ‭Committee‬ ‭and‬ ‭the‬ ‭local‬ ‭Regulatory‬ ‭Authority‬ ‭protocol‬
‭amendments.‬
‭Relevant‬ ‭safety‬ ‭information‬ ‭will‬ ‭be‬ ‭submitted‬ ‭to‬‭the‬‭IEC‬‭during‬‭the‬‭course‬‭of‬‭the‬‭trial,‬‭in‬
‭accordance with national regulations and requirements.‬
‭Initial‬‭IEC‬‭positive‬‭vote,‬‭and‬‭all‬‭materials‬‭approved‬‭by‬‭the‬‭IEC‬‭for‬‭this‬‭study‬‭including‬‭the‬
‭patient‬ ‭consent‬ ‭form‬ ‭and‬‭recruitment‬‭materials‬‭must‬‭be‬‭maintained‬‭by‬‭the‬‭Investigator‬‭and‬
‭made available for inspection.‬
‭12.8.‬ ‭Data Handling‬
‭The‬‭data‬‭will‬‭be‬‭recorded‬‭using‬‭the‬‭Electronic‬‭Data‬‭Capture‬‭software‬‭property‬‭of‬‭MFAR‬‭S.L.,‬
‭which‬ ‭is‬ ‭developed‬ ‭and‬ ‭maintained‬ ‭with‬ ‭strict‬ ‭observance‬ ‭of‬ ‭the‬ ‭regulatory‬ ‭standards‬ ‭for‬
‭Clinical EDC systems, with special observance of the guidelines specified at:‬
‭●‬
‭CPMP/ICH/135/95. ICH E6. Note for Guidance on Good Clinical Practice.‬
‭●‬
‭Good‬ ‭Clinical‬ ‭Data‬ ‭Management‬ ‭Practice,‬ ‭Version‬ ‭4,‬ ‭Society‬ ‭for‬ ‭Clinical‬ ‭Data‬
‭Management (SCDM), October 2005.‬
‭●‬
‭EMEA.‬‭Reflection‬‭on‬‭expectations‬‭for‬‭electronic‬‭source‬‭documents‬‭used‬‭in‬‭clinical‬
‭trials. London, 17 October 2007.‬
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‭●‬
‭Directive‬ ‭9‬ ‭Guidance‬ ‭for‬ ‭Industry.‬ ‭Part‬ ‭11,‬ ‭Electronic‬ ‭Records;‬ ‭Electronic‬
‭Signatures – Scope and Application (August 2003).‬
‭●‬
‭FDA.‬‭Guidance‬‭for‬‭Industry.‬‭Computerised‬‭Systems‬‭Used‬‭in‬‭Clinical‬‭Investigations‬
‭(May 2007).‬
‭●‬
‭FDA.‬‭Guidance‬‭for‬‭Industry.‬‭Part‬‭11,‬‭Electronic‬‭Records;‬‭Electronic‬‭Signatures‬‭–‬
‭Scope and Application (August 2003)‬
‭●‬
‭Organic‬‭Law‬‭3/2018,‬‭of‬‭December‬‭5,‬‭Protection‬‭of‬‭Personal‬‭Data‬‭and‬‭guarantee‬‭of‬
‭digital rights‬
‭The‬‭EDC‬‭database‬‭is‬‭hosted‬‭at‬‭a‬‭data‬‭server‬‭located‬‭at‬‭the‬‭Data‬‭Centre‬‭maintained‬‭by‬‭Claranet‬
‭SAU‬‭located‬‭at‬‭“‬‭Calle‬‭Juan‬‭Gris,‬‭10-18,‬‭08014‬‭Barcelona‬‭”‬‭.‬‭The‬‭physical‬‭access‬‭to‬‭the‬‭Data‬
‭Centre‬ ‭is‬ ‭restricted‬ ‭to‬ ‭authorised‬ ‭Claranet‬ ‭personnel,‬ ‭and‬ ‭logical‬ ‭access‬ ‭to‬‭the‬‭database‬‭is‬
‭restricted to named MFAR personnel.‬
‭All‬ ‭the‬ ‭EDC‬ ‭users‬ ‭are‬ ‭uniquely‬‭identified‬‭by‬‭name,‬‭all‬‭the‬‭access‬‭to‬‭the‬‭software‬‭is‬‭made‬
‭through a secure, encrypted connection and all the activities are logged and audited.‬
‭All‬‭the‬‭EDC‬‭forms‬‭are‬‭designed‬‭according‬‭to‬‭the‬‭eCRF‬‭defined‬‭by‬‭the‬‭study‬‭protocol,‬‭and‬‭are‬
‭validated according to the DVP (Data Validation Plan).‬
‭12.9.‬ ‭Documentation‬
‭The‬ ‭Investigator/Institution‬ ‭should‬ ‭maintain‬ ‭trial‬ ‭documents‬ ‭according‬ ‭to‬ ‭ICH‬ ‭Topic‬ ‭E6‬
‭Section‬‭8‬‭,‬‭and‬‭as‬‭required‬‭by‬‭pertinent‬‭regulatory‬‭requirements.‬‭According‬‭to‬‭RD‬‭1090/2015‬
‭on Clinical trial, the archive period for all essential documents is 25 years.‬
‭Essential‬‭documents‬‭should‬‭be‬‭stored‬‭according‬‭to‬‭ICH‬‭GCP‬‭guidelines‬‭for‬‭a‬‭longer‬‭period‬‭of‬
‭time,‬‭if‬‭required‬‭by‬‭pertinent‬‭regulations.‬‭The‬‭original‬‭patient‬‭data‬‭(clinical‬‭record)‬‭must‬‭be‬
‭kept archived for the time stipulated by the study centre regulations.‬
‭All‬ ‭original‬ ‭subject‬ ‭files‬ ‭(medical‬ ‭records)‬ ‭must‬ ‭be‬ ‭stored‬ ‭at‬ ‭the‬ ‭site‬ ‭(hospital,‬ ‭research‬
‭institution,‬‭or‬‭practice)‬‭for‬‭the‬‭longest‬‭possible‬‭time‬‭permitted‬‭by‬‭the‬‭applicable‬‭regulations,‬
‭and/or‬‭as‬‭per‬‭ICH‬‭GCP‬‭guidelines,‬‭whichever‬‭is‬‭longer‬‭(In‬‭Spain‬‭25‬‭years).‬‭In‬‭any‬‭case,‬‭the‬
‭Investigator‬ ‭should‬ ‭ensure‬ ‭that‬ ‭no‬ ‭destruction‬ ‭of‬‭medical‬‭records‬‭is‬‭performed‬‭without‬‭the‬
‭written approval of the Sponsor.‬
‭12.10.‬ ‭Audits and inspections‬
‭Authorised‬ ‭representatives‬ ‭of‬ ‭Sponsor,‬ ‭a‬ ‭regulatory‬ ‭authority,‬ ‭an‬ ‭Independent‬ ‭Ethics‬
‭Committee‬ ‭may‬ ‭visit‬ ‭the‬ ‭site‬ ‭to‬ ‭perform‬ ‭audits‬ ‭or‬ ‭inspections,‬ ‭including‬ ‭source‬ ‭data‬
‭verification.‬ ‭The‬ ‭purpose‬ ‭of‬ ‭a‬ ‭Sponsor‬ ‭audit‬ ‭or‬ ‭inspection‬ ‭is‬ ‭to‬ ‭systematically‬ ‭and‬
‭independently‬‭examine‬‭all‬‭study-related‬‭activities‬‭and‬‭documents‬‭to‬‭determine‬‭whether‬‭these‬
‭activities‬‭were‬‭conducted,‬‭and‬‭data‬‭were‬‭recorded,‬‭analysed,‬‭and‬‭accurately‬‭reported‬‭according‬
‭to‬ ‭the‬ ‭protocol,‬ ‭Good‬ ‭Clinical‬ ‭Practice‬ ‭guidelines‬ ‭of‬ ‭the‬ ‭International‬ ‭Conference‬ ‭on‬
‭Harmonisation,‬‭and‬‭any‬‭applicable‬‭regulatory‬‭requirements.‬‭The‬‭investigator‬‭should‬‭contact‬
‭the‬ ‭Sponsor‬ ‭through‬ ‭MFAR‬ ‭immediately‬ ‭if‬ ‭contacted‬ ‭by‬ ‭a‬ ‭regulatory‬ ‭agency‬ ‭about‬ ‭an‬
‭inspection.‬
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‭13.‬
‭TRANSLATIONAL SUBSTUDIES‬
‭A‬‭key‬‭objective‬‭of‬‭the‬‭biomarker‬‭analyses‬‭that‬‭will‬‭be‬‭performed‬‭in‬‭this‬‭study‬‭is‬‭to‬‭investigate‬
‭candidate‬‭biomarkers‬‭that‬‭may‬‭have‬‭predictive‬‭value‬‭in‬‭identifying‬‭those‬‭patients‬‭who‬‭may‬
‭benefit‬‭from‬‭treatment‬‭with‬‭the‬‭combination‬‭of‬‭atezolizumab‬‭1‬‭and‬‭split‬‭dose‬‭GC.‬‭In‬‭addition,‬
‭analyses‬ ‭of‬ ‭blood‬ ‭biomarkers‬ ‭obtained‬ ‭before,‬ ‭during‬ ‭and‬ ‭after‬ ‭treatment‬ ‭will‬ ‭provide‬ ‭an‬
‭opportunity‬ ‭to‬ ‭investigate‬ ‭pharmacodynamic‬ ‭effects.‬ ‭Samples‬ ‭collected‬ ‭at‬ ‭the‬ ‭End‬ ‭of‬
‭Treatment/Withdrawal‬‭visit‬‭enable‬‭investigation‬‭of‬‭potential‬‭mechanisms‬‭of‬‭resistance‬‭to‬‭the‬
‭drug combination.‬
‭The following biological samples are required:‬
‭●‬ ‭Tumor‬ ‭sample,‬ ‭archive‬ ‭tumor‬ ‭sample‬ ‭in‬ ‭order‬ ‭to‬ ‭evaluate‬ ‭changes‬ ‭in‬ ‭signaling‬
‭molecules in response to study treatment in tumour tissue.‬
‭●‬ ‭Processed‬‭blood‬‭samples‬‭obtained‬‭before‬‭treatment,‬‭at‬‭D1C7‬‭of‬‭treatment,‬‭and‬‭at‬‭the‬
‭end‬‭of‬‭treatment/progression,‬‭in‬‭order‬‭to‬‭evaluate‬‭changes‬‭in‬‭signaling‬‭molecules‬‭in‬
‭response to study treatment in blood.‬
‭●‬ ‭Faecal samples for microbiome analyses.‬
‭13.1.‬ ‭Archived Tumor Biospecimens‬
‭Somatic‬‭alterations‬‭in‬‭tumours‬‭including‬‭proteomics,‬‭transcriptomics‬‭and‬‭metabolics‬‭will‬‭be‬
‭analyzed. No germinal line determinations will be performed.‬
‭Tumor‬‭biological‬‭specimens‬‭from‬‭archived‬‭tissue‬‭samples‬‭will‬‭be‬‭used‬‭to‬‭analyze‬‭candidate‬
‭DNA,‬‭RNA,‬‭or‬‭protein‬‭markers,‬‭or‬‭relevant‬‭signature‬‭of‬‭markers‬‭for‬‭their‬‭ability‬‭to‬‭identify‬
‭those patients who are most likely to benefit from treatment with the study drugs.‬
‭Tumor‬‭tissue‬‭biomarker‬‭analyses,‬‭including‬‭determination‬‭of‬‭PD-L1‬‭status,‬‭will‬‭be‬‭performed‬
‭retrospectively‬‭in‬‭a‬‭central‬‭laboratory.‬‭PD-L1‬‭status‬‭will‬‭be‬‭assessed‬‭using‬‭a‬‭validated‬‭PD-L1‬
‭IHC‬ ‭test‬ ‭kit‬ ‭manufactured‬ ‭under‬ ‭GMP‬ ‭specifications,‬ ‭in‬ ‭conjunction‬ ‭with‬ ‭a‬ ‭pre-specified‬
‭scoring‬ ‭algorithm‬ ‭and‬ ‭cutoff‬ ‭defining‬ ‭PD-L1‬ ‭positive‬ ‭versus‬ ‭negative‬ ‭status‬ ‭that‬ ‭will‬ ‭be‬
‭established prior to initiation of scoring of PD-L1.‬
‭Additional‬‭tumor‬‭tissue‬‭biomarkers‬‭that‬‭may‬‭be‬‭analyzed‬‭include,‬‭but‬‭may‬‭not‬‭necessarily‬‭be‬
‭limited‬ ‭to,‬ ‭gene‬ ‭expression‬ ‭profiles‬ ‭and/or‬ ‭quantitation‬ ‭of‬ ‭tumor-infiltrating‬ ‭CD8+‬ ‭T‬
‭lymphocytes by IHC and/or tissue FoxP3, PD-1, or PD-L2.‬
‭13.2.‬ ‭Peripheral Blood‬
‭Specimens‬‭will‬‭be‬‭processed‬‭and‬‭retained‬‭in‬‭local‬‭laboratories‬‭until‬‭Sponsor‬‭indications‬‭for‬
‭shipments.‬‭It‬‭will‬‭include‬‭whole‬‭blood,‬‭serum‬‭and‬‭plasma‬‭samples‬‭that‬‭will‬‭be‬‭retained‬‭in‬‭the‬
‭central laboratory for exploratory assessments.‬
‭Samples‬‭may‬‭be‬‭used‬‭to‬‭identify‬‭or‬‭characterize‬‭cells,‬‭DNA,‬‭RNA,‬‭or‬‭protein‬‭markers‬‭known‬
‭or‬‭suspected‬‭to‬‭be‬‭of‬‭relevance‬‭to‬‭the‬‭mechanisms‬‭of‬‭action,‬‭or‬‭the‬‭development‬‭of‬‭resistance‬
‭to‬ ‭study‬ ‭treatment.‬ ‭These‬ ‭include‬ ‭biomarkers‬ ‭that‬ ‭may‬ ‭aid‬ ‭in‬ ‭the‬ ‭identification‬ ‭of‬ ‭those‬
‭patients‬‭who‬‭might‬‭preferentially‬‭benefit‬‭from‬‭treatment‬‭with‬‭IMP‬‭1‬‭in‬‭combination‬‭with‬‭IMP‬
‭2,‬‭which‬‭may‬‭include‬‭but‬‭are‬‭not‬‭limited‬‭to‬‭biomarkers‬‭related‬‭to‬‭anti-tumor‬‭immune‬‭response‬
‭or target modulation, such as (not necessarily be limited to) soluble IL-8 or IFNγ.‬
‭Information‬ ‭regarding‬ ‭sample‬ ‭collection,‬ ‭management‬ ‭and‬ ‭shipments‬ ‭are‬ ‭provided‬ ‭in‬ ‭the‬
‭translational research manual.‬
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‭13.3.‬ ‭Fecal‬‭samples‬
‭Specimens‬‭will‬‭be‬‭processed‬‭and‬‭retained‬‭in‬‭local‬‭laboratories‬‭until‬‭Sponsor‬‭indications‬‭for‬
‭shipments.‬‭It‬‭will‬‭include‬‭a‬‭total‬‭of‬‭3‬‭samples:‬‭basal‬‭faecal‬‭sample‬‭collected‬‭prior‬‭treatment‬
‭initiation,‬‭faecal‬‭sample‬‭at‬‭Cycle‬‭4‬‭Day‬‭1‬‭and‬‭after‬‭progression.‬‭ ‬‭Information‬‭regarding‬‭sample‬
‭collection, management and shipments are provided in the translational research manual.‬
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‭14.‬
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‭1‬‭antibody,‬‭in‬‭metastatic‬‭renal‬‭cell‬‭carcinoma:‬‭Long-term‬‭safety,‬‭clinical‬‭activity,‬‭and‬‭immune‬
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‭every‬ ‭two‬ ‭weeks‬ ‭in‬ ‭patients‬ ‭with‬‭locally‬‭advanced‬‭or‬‭metastatic‬‭urothelial‬‭carcinoma‬‭and‬
‭impaired renal function. Eur J Cancer. 2012; 48:1816-21.‬
‭Mu‬‭CY,‬‭Huang‬‭JA,‬‭Chen‬‭Y,‬‭et‬‭al.‬‭High‬‭expression‬‭of‬‭PD-L1‬‭in‬‭lung‬‭cancer‬‭may‬‭contribute‬‭to‬
‭poor‬ ‭prognosis‬ ‭and‬ ‭tumor‬ ‭cells‬ ‭immune‬ ‭escape‬ ‭through‬ ‭suppressing‬ ‭tumor‬ ‭infiltrating‬
‭dendritic cells maturation. Med Oncol 2011;28:682-8.‬
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‭Immunolo 2007;9:813-24.‬
‭Plimack‬ ‭ER,‬ ‭Hoffman-Censits‬ ‭JH,‬‭Viterbo‬‭R,‬‭Trabulsi‬‭EJ,‬‭Ross‬‭EA,‬‭Greenberg‬‭RE,‬‭et‬‭al.‬
‭Accelerated‬ ‭methotrexate,‬ ‭vinblastine,‬ ‭doxorubicin,‬ ‭and‬ ‭cisplatin‬ ‭is‬ ‭safe,‬ ‭effective,‬ ‭and‬
‭efficient‬‭neoadjuvant‬‭treatment‬‭for‬‭muscle-invasive‬‭bladder‬‭cancer:‬‭results‬‭of‬‭a‬‭multicenter‬
‭phase‬ ‭II‬ ‭study‬ ‭with‬ ‭molecular‬ ‭correlates‬ ‭of‬ ‭response‬ ‭and‬ ‭toxicity.‬ ‭J‬ ‭Clin‬ ‭Oncol.‬
‭2014;32(18):1895-901.‬
‭Powles‬ ‭T,‬ ‭Eder‬ ‭JP,‬ ‭Fine‬ ‭GD,‬ ‭et‬ ‭al.‬ ‭MPDL3280A‬‭(anti-PD-L1)‬‭treatment‬‭leads‬‭to‬‭clinical‬
‭activity in metastatic bladder cancer. Nature. 2014; 515:558-62.‬
‭Riegler‬ ‭LL,‬ ‭Jones‬ ‭GP,‬ ‭Lee‬ ‭DW.‬ ‭Current‬ ‭approaches‬ ‭in‬ ‭the‬‭grading‬‭and‬‭management‬‭of‬
‭cytokine‬ ‭release‬ ‭syndrome‬ ‭after‬ ‭chimeric‬ ‭antigen‬ ‭receptor‬ ‭T-cell‬ ‭therapy.‬ ‭Ther‬ ‭Clin‬ ‭Risk‬
‭Manag. 2019;15:323-35.‬
‭Rosenberg‬ ‭JE,‬ ‭Hoffman-Censits‬ ‭J,‬ ‭Powles‬ ‭T,‬ ‭et‬ ‭al.‬ ‭Atezolizumab‬ ‭in‬ ‭patients‬‭with‬‭locally‬
‭advanced‬‭and‬‭metastatic‬‭urothelial‬‭carcinoma‬‭who‬‭have‬‭progressed‬‭following‬‭treatment‬‭with‬
‭platinum-based‬ ‭chemotherapy:‬ ‭A‬ ‭single-arm,‬ ‭multicentre,‬ ‭phase‬ ‭2‬ ‭trial.‬ ‭Lancet.‬ ‭2016;‬
‭387:1909-20.‬
‭Rotz‬‭SJ,‬‭Leino‬‭D,‬‭Szabo‬‭S,‬‭et‬‭al.‬‭Severe‬‭cytokine‬‭release‬‭syndrome‬‭in‬‭a‬‭patient‬‭receiving‬
‭PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642.‬
‭Saxman‬‭SB.,‬‭Propert‬‭KJ,‬‭Einhorn,‬‭LH,‬‭Crawford,‬‭ED.,‬‭Tannock‬‭I,‬‭Raghavan,‬‭D.‬‭Long-term‬
‭follow-up‬ ‭of‬ ‭a‬ ‭phase‬ ‭III‬ ‭intergroup‬ ‭study‬ ‭of‬ ‭cisplatin‬ ‭alone‬ ‭or‬ ‭in‬ ‭combination‬ ‭with‬
‭methotrexate,‬‭vinblastine,‬‭and‬‭doxorubicin‬‭in‬‭patients‬‭with‬‭metastatic‬‭urothelial‬‭carcinoma:‬‭A‬
‭cooperative group study. J Clin Oncol. 1997; 15:2564-69.‬
‭Schleimer‬ ‭RP,‬ ‭Jacques‬ ‭A,‬ ‭Shin‬ ‭HS,‬ ‭et‬ ‭al.‬ ‭Inhibition‬ ‭of‬ ‭T‬ ‭cell-mediated‬ ‭cytotoxicity‬ ‭by‬
‭anti-inflammatory steroids. J Immunol. 1984;132:266-71.‬
‭Sellers‬‭LE,‬‭Harper‬‭A,‬‭Linch‬‭MD,‬‭et‬‭al.‬‭Split‬‭dose‬‭gemcitabine/cisplatin‬‭(GC)‬‭in‬‭urothelial‬
‭carcinoma of the bladder: Review of toxicity and response. J Clin Oncol. 2016;34:15_suppl.‬
‭Spiess‬‭PE,‬‭Agarwal‬‭N,‬‭Bangs‬‭R,‬‭Boorjian‬‭SA,‬‭Buyyounouski‬‭MK,‬‭Clark‬‭PE,‬‭et‬‭al.‬‭Bladder‬
‭Cancer,‬ ‭Version‬ ‭5.2017,‬ ‭NCCN‬ ‭Clinical‬ ‭Practice‬ ‭Guidelines‬ ‭in‬ ‭Oncology.‬ ‭J‬ ‭Natl‬ ‭Compr‬
‭Cancer Netw. 2017;15:1240-67.‬
‭Sternberg‬‭CN,‬‭de‬‭Mulder‬‭P,‬‭Schornagel‬‭JH,‬‭et‬‭al.‬‭Seven‬‭year‬‭update‬‭of‬‭an‬‭EORTC‬‭phase‬‭III‬
‭trial‬ ‭of‬ ‭high-dose‬ ‭intensity‬ ‭M-VAC‬ ‭chemotherapy‬ ‭and‬ ‭G-CSF‬ ‭versus‬ ‭classic‬ ‭M-VAC‬ ‭in‬
‭advanced urothelial tract tumours. Eur J Cancer. 2006;42:50-54.‬
‭Summary‬ ‭of‬ ‭Product‬ ‭Characteristics‬ ‭Atezolizumab,‬ ‭last‬ ‭updated‬ ‭23/10/2019‬ ‭available‬ ‭at:‬
‭https://www.ema.europa.eu/en/medicines/human/EPAR/tecentriq‬
‭Thompson‬ ‭RH,‬ ‭Kuntz‬ ‭SM,‬ ‭Leibovich‬ ‭BC,‬ ‭et‬ ‭al.‬ ‭Tumor‬ ‭B7-H1‬ ‭is‬ ‭associated‬ ‭with‬ ‭poor‬
‭prognosis‬ ‭in‬ ‭renal‬ ‭cell‬ ‭carcinoma‬ ‭patients‬ ‭with‬ ‭long-term‬ ‭follow-up.‬ ‭Cancer‬ ‭Res.‬
‭2006;66:3381-5.‬
‭van‬‭Leenders‬‭GJLH.‬‭PD-L1‬‭testing‬‭in‬‭urothelial‬‭carcinoma:‬‭are‬‭we‬‭there‬‭yet?‬‭Transl‬‭Androl‬
‭Urol. 2019;8:S466-8.‬
‭Von‬ ‭der‬ ‭Maase‬ ‭H,‬ ‭Hansen‬ ‭SW,‬ ‭Roberts‬ ‭PI,‬ ‭et‬ ‭al.‬ ‭Gemcitabine‬ ‭and‬ ‭cisplatin‬ ‭versus‬
‭methotrexate,‬ ‭vinblastine,‬ ‭doxorubicin,‬ ‭and‬ ‭cisplatin‬ ‭in‬ ‭advanced‬ ‭or‬ ‭metastatic‬ ‭bladder‬
‭cancer:‬ ‭results‬ ‭of‬ ‭a‬ ‭large,‬ ‭randomized,‬ ‭multinational,‬ ‭phase‬ ‭III‬ ‭study.‬ ‭J‬ ‭Clin‬ ‭Oncol.‬
‭2000;18:3068-77.‬
‭Witjes‬ ‭AJ,‬‭Lebret‬‭T,‬‭Compérat‬‭EM,‬‭Cowan‬‭NC,‬‭De‬‭Santis‬‭M,‬‭Bruins‬‭HM,‬‭et‬‭al.‬‭Updated‬
‭2016‬ ‭EAU‬ ‭Guidelines‬ ‭on‬ ‭Muscle-invasive‬ ‭and‬ ‭Metastatic‬ ‭Bladder‬ ‭Cancer.‬ ‭Eur‬ ‭Urol.‬
‭2017;71:462-75.‬
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‭APPENDICES‬
‭Appendix 1. Management of Atezolizumab-specific Adverse Events‬
‭Toxicities‬‭associated‬‭or‬‭possibly‬‭associated‬‭with‬‭atezolizumab‬‭treatment‬‭should‬‭be‬‭managed‬
‭according‬ ‭to‬ ‭standard‬ ‭medical‬ ‭practice.‬ ‭Additional‬ ‭tests,‬‭such‬‭as‬‭autoimmune‬‭serology‬‭or‬
‭biopsies, should be used to evaluate for a possible immunogenic etiology.‬
‭Although‬‭most‬‭immune-related‬‭adverse‬‭events‬‭observed‬‭with‬‭immunomodulatory‬‭agents‬‭have‬
‭been‬‭mild‬‭and‬‭self-limiting,‬‭such‬‭events‬‭should‬‭be‬‭recognized‬‭early‬‭and‬‭treated‬‭promptly‬‭to‬
‭avoid‬ ‭potential‬ ‭major‬ ‭complications.‬ ‭Discontinuation‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭not‬ ‭have‬ ‭an‬
‭immediate‬‭therapeutic‬‭effect,‬‭and‬‭in‬‭severe‬‭cases,‬‭immune-related‬‭toxicities‬‭may‬‭require‬‭acute‬
‭management‬
‭with‬
‭topical‬
‭corticosteroids,‬
‭systemic‬
‭corticosteroids,‬
‭or‬
‭other‬
‭immunosuppressive agents.‬
‭The‬‭following‬‭are‬‭general‬‭recommendations‬‭for‬‭management‬‭of‬‭any‬‭other‬‭adverse‬‭events‬‭that‬
‭may occur and are not specifically listed in the following subsections.‬
‭●‬ ‭Patients‬‭and‬‭family‬‭caregivers‬‭should‬‭receive‬‭timely‬‭and‬‭up-to-date‬‭information‬‭about‬
‭immunotherapies,‬ ‭their‬ ‭mechanism‬ ‭of‬ ‭action,‬ ‭and‬ ‭the‬ ‭clinical‬ ‭profile‬ ‭of‬ ‭possible‬
‭immune-related‬‭adverse‬‭events‬‭prior‬‭to‬‭initiating‬‭therapy‬‭and‬‭throughout‬‭treatment‬‭and‬
‭survival‬‭follow-up.‬‭There‬‭should‬‭be‬‭a‬‭high‬‭level‬‭of‬‭suspicion‬‭that‬‭new‬‭symptoms‬‭are‬
‭treatment related.‬
‭●‬ ‭In‬‭general,‬‭atezolizumab‬‭therapy‬‭should‬‭be‬‭continued‬‭with‬‭close‬‭monitoring‬‭for‬‭Grade‬
‭1 toxicities, with the exception of some neurologic toxicities.‬
‭●‬ ‭Consider‬ ‭holding‬ ‭atezolizumab‬ ‭for‬ ‭most‬ ‭Grade‬ ‭2‬ ‭toxicities‬ ‭and‬ ‭resume‬ ‭when‬
‭symptoms‬‭and/or‬‭laboratory‬‭values‬‭resolve‬‭to‬‭Grade‬‭1‬‭or‬‭better.‬‭Corticosteroids‬‭(initial‬
‭dose of 0.51 mg/kg/day of prednisone or equivalent) may be administered.‬
‭●‬ ‭For‬‭Grade‬‭2‬‭recurrent‬‭or‬‭persistent‬‭(lasting‬‭for‬‭more‬‭than‬‭5‬‭days)‬‭events,‬‭treat‬‭as‬‭a‬
‭Grade 3 event.‬
‭●‬ ‭Hold‬ ‭atezolizumab‬ ‭for‬ ‭Grade‬ ‭3‬ ‭toxicities‬ ‭and‬ ‭initiate‬ ‭treatment‬ ‭with‬ ‭high-dose‬
‭corticosteroids‬ ‭(12‬ ‭mg/kg/day‬ ‭prednisone‬ ‭or‬ ‭equivalent).‬ ‭Corticosteroids‬ ‭should‬ ‭be‬
‭tapered‬‭over‬‭1‬‭month‬‭to‬‭10‬‭mg/day‬‭oral‬‭prednisone‬‭or‬‭equivalent,‬‭before‬‭atezolizumab‬
‭can‬ ‭be‬ ‭resumed.‬ ‭If‬ ‭symptoms‬ ‭do‬ ‭not‬ ‭improve‬ ‭within‬ ‭48‬ ‭to‬‭72‬‭hours‬‭of‬‭high-dose‬
‭corticosteroid use, other immunosuppressants may be offered for some toxicities.‬
‭●‬ ‭In‬ ‭general,‬ ‭Grade‬ ‭4‬ ‭toxicities‬ ‭warrant‬ ‭permanent‬ ‭discontinuation‬ ‭of‬ ‭atezolizumab‬
‭treatment,‬ ‭with‬ ‭the‬ ‭exception‬ ‭of‬ ‭endocrinopathies‬ ‭that‬ ‭are‬ ‭controlled‬ ‭by‬
‭hormone-replacement therapy.‬
‭●‬ ‭The‬‭investigator‬‭should‬‭consider‬‭the‬‭benefit‬‭risk‬‭balance‬‭for‬‭a‬‭given‬‭patient‬‭prior‬‭to‬
‭further‬ ‭administration‬ ‭of‬ ‭atezolizumab.‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬
‭considered‬ ‭in‬ ‭patients‬ ‭who‬ ‭are‬ ‭deriving‬ ‭benefit‬ ‭and‬ ‭have‬‭fully‬‭recovered‬‭from‬‭the‬
‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭should‬ ‭be‬ ‭based‬ ‭on‬ ‭the‬ ‭investigator's‬ ‭assessment‬ ‭of‬ ‭the‬ ‭benefits‬ ‭and‬ ‭risks‬ ‭and‬
‭documented by the investigator. The Medical Monitor is available to advise as needed.‬
‭Guidelines‬‭for‬‭managing‬‭patients‬‭who‬‭experience‬‭selected‬‭adverse‬‭events‬‭are‬‭provided‬‭in‬‭the‬
‭following‬‭sections.‬‭Management‬‭guidelines‬‭are‬‭presented‬‭by‬‭adverse‬‭event‬‭severity‬‭based‬‭on‬
‭the‬ ‭National‬ ‭Cancer‬ ‭Institute‬ ‭Common‬ ‭Terminology‬ ‭Criteria‬ ‭for‬ ‭Adverse‬ ‭Events‬ ‭(NCI‬
‭CTCAE).‬
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‭A)‬ ‭Management Guidelines for Pulmonary Events, Including Pneumonitis‬
‭Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, fatigue,‬
‭hypoxia, pneumonitis, and pulmonary infiltrates. Patients will be assessed for pulmonary signs‬
‭and symptoms throughout the study and will have CT scans of the chest performed at every‬
‭tumor assessment.‬
‭All pulmonary events should be thoroughly evaluated for other commonly reported etiologies,‬
‭such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism,‬
‭heart failure, chronic obstructive pulmonary disease, or pulmonary hypertension. COVID-19‬
‭evaluation should be performed per institutional guidelines where relevant. Management‬
‭guidelines for pulmonary events are provided in the next table.‬
‭B)‬ ‭Management Guidelines for Pulmonary Events, Including Pneumonitis table‬
‭Event‬
‭Management‬
‭Pulmonary event, Grade 1‬
‭●‬
‭Continue atezolizumab and monitor closely.‬
‭●‬
‭Re-evaluate on serial imaging.‬
‭●‬
‭Consider patient referral to pulmonary specialist.‬
‭●‬
‭For Grade 1 pneumonitis, consider withholding atezolizumab.‬
‭Pulmonary event, Grade 2‬
‭●‬
‭Withhold atezolizumab for up to 12 weeks after event onset.‬‭a‬
‭●‬
‭Refer‬ ‭patient‬‭to‬‭pulmonary‬‭and‬‭infectious‬‭disease‬‭specialists‬
‭and‬ ‭consider‬ ‭bronchoscopy‬ ‭or‬ ‭BAL‬ ‭with‬ ‭or‬ ‭without‬
‭transbronchial biopsy.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone or equivalent.‬
‭●‬
‭If event resolves to Grade 1 or better, resume atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact the Medical Monitor.‬‭c‬
‭●‬
‭For‬ ‭recurrent‬ ‭events‬ ‭or‬ ‭events‬ ‭with‬ ‭no‬ ‭improvement‬ ‭after‬
‭48–72 hours of corticosteroids, treat as a Grade 3 or 4 event.‬
‭Pulmonary event, Grade 3 or 4‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭Medical‬
‭Monitor.‬‭c‬
‭●‬
‭Oral‬‭or‬‭IV‬‭broad-spectrum‬‭antibiotics‬‭should‬‭be‬‭administered‬
‭in parallel to the immunosuppressive treatment.‬
‭●‬
‭Bronchoscopy‬‭or‬‭BAL‬‭with‬‭or‬‭without‬‭transbronchial‬‭biopsy‬
‭is recommended.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day IV methylprednisolone.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭improve‬ ‭within‬ ‭48‬ ‭hours‬ ‭after‬ ‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭taper‬ ‭corticosteroids‬
‭over ≥ 1 month.‬
‭BAL = bronchoscopic alveolar lavage.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭based‬ ‭on‬ ‭the‬ ‭investigator's‬ ‭benefit-risk‬
‭assessment‬‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬‭by‬
‭the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬ ‭corticosteroids‬ ‭have‬ ‭been‬ ‭initiated,‬ ‭they‬ ‭must‬ ‭be‬ ‭tapered‬ ‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
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‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭should‬‭be‬‭based‬‭on‬‭the‬‭investigator's‬‭benefit-risk‬‭assessment‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate).Medical Monitor is available to advise as needed.‬
‭d‬‭In case of pneumonitis, atezolizumab should not‬‭be resumed after permanent discontinuation.‬
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‭C)‬ ‭Management Guidelines for Hepatic Events‬
‭Patients‬ ‭eligible‬ ‭for‬ ‭study‬ ‭treatment‬ ‭must‬ ‭have‬ ‭adequate‬ ‭liver‬ ‭function,‬ ‭as‬ ‭manifested‬ ‭by‬
‭measurements‬ ‭of‬‭total‬‭bilirubin‬‭and‬‭hepatic‬‭transaminases;‬‭liver‬‭function‬‭will‬‭be‬‭monitored‬
‭throughout‬‭study‬‭treatment.‬‭Management‬‭guidelines‬‭for‬‭hepatic‬‭events‬‭are‬‭provided‬‭in‬‭the‬‭next‬
‭table.‬
‭Patients‬ ‭with‬ ‭right‬ ‭upper-quadrant‬ ‭abdominal‬ ‭pain‬ ‭and/or‬ ‭unexplained‬ ‭nausea‬ ‭or‬ ‭vomiting‬
‭should‬ ‭have‬ ‭liver‬ ‭function‬ ‭tests‬ ‭(LFTs)‬ ‭performed‬ ‭immediately‬ ‭and‬ ‭reviewed‬ ‭before‬
‭administration of the next dose of study drug.‬
‭For‬‭patients‬‭with‬‭elevated‬‭LFTs,‬‭concurrent‬‭medication,‬‭viral‬‭hepatitis,‬‭and‬‭toxic‬‭or‬‭neoplastic‬
‭etiologies should be considered and addressed, as appropriate.‬
‭Event‬
‭Management‬
‭Hepatic event,‬
‭Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Monitor‬ ‭LFTs‬ ‭until‬ ‭values‬‭resolve‬‭to‬‭within‬‭normal‬‭limits‬‭or‬
‭to baseline values.‬
‭Hepatic event,‬
‭Grade 2‬
‭All events:‬
‭●‬
‭Monitor LFTs more frequently until return to baseline values.‬
‭Events of  5 days’ duration:‬
‭●‬
‭Withhold atezolizumab for up to 12 weeks after event onset. a‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If event resolves to Grade 1 or better, resume atezolizumab. b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Hepatic event,‬
‭Grade 3 or 4‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭Medical‬
‭Monitor.‬‭c‬
‭●‬
‭Consider‬ ‭patient‬ ‭referral‬ ‭to‬ ‭gastrointestinal‬ ‭specialist‬ ‭for‬
‭evaluation‬ ‭and‬ ‭liver‬ ‭biopsy‬ ‭to‬ ‭establish‬ ‭etiology‬ ‭of‬ ‭hepatic‬
‭injury.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭improve‬ ‭within‬ ‭48‬ ‭hours‬ ‭after‬ ‭initiating‬
‭corticosteroids, consider adding an immunosuppressive agent.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭taper‬ ‭corticosteroids‬
‭over 1 month.‬
‭In patients with HCC‬
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‭AST/ALT is within normal‬
‭limits at baseline and‬
‭increases to  ≥3 x ULN to‬
‭≤10 x ULN‬
‭or‬
‭AST/ALT is ≥ ULN to ≤ 3 x‬
‭ULN at baseline and‬
‭increases to ≥5 x ULN to‬
‭≤10 x ULN‬
‭or‬
‭AST/ALT is ≥3xULN to ≤ 5‬
‭x ULN at baseline and‬
‭increases to ≥ 8 x ULN to  ≤‬
‭10 x ULN‬
‭●‬ ‭Monitor LFTs more frequently until return to baseline values.‬
‭●‬ ‭Withhold atezolizumab for up to 12 weeks after event onset. a‬
‭Events of > 5 days' duration:‬
‭●‬ ‭Consider initiating treatment with corticosteroids equivalent to 12‬
‭mg/kg/day oral prednisone.‬
‭●‬ ‭If event resolves to baseline or to Grade 1 or better, resume‬
‭atezolizumab. b‬
‭●‬ ‭If event does not resolve to baseline or to Grade 1 or better while‬
‭withholding atezolizumab, permanently discontinue atezolizumab‬
‭and contact Medical Monitor. c‬
‭AST or ALT increases to ≥‬
‭10 x ULN or total bilirubin‬
‭increases to ≥ 3 x ULN‬
‭Permanently discontinue atezolizumab and contact the Medical‬
‭Monitor. c‬
‭Consider patient referral to GI specialist for evaluation and liver‬
‭biopsy to establish etiology of hepatic injury.‬
‭Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day‬
‭oral prednisone.‬
‭If event does not improve within 48 hours after initiating‬
‭corticosteroids, consider adding an immunosuppressive agent.‬
‭If event resolves to baseline, taper corticosteroids over ≥ 1 month.‬
‭GI=gastrointestinal; HCC=hepatocellular carcinoma; LFT=liver function test; ULN=upper limit of‬
‭normal.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>‬‭12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭based‬ ‭on‬ ‭the‬ ‭investigator’s‬ ‭benefit-risk‬
‭assessment‬‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬‭by‬
‭the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬‭atezolizumab‬
‭should‬‭be‬‭based‬‭on‬‭the‬‭investigator’s‬‭benefit-risk‬‭assessment‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate). Medical Monitor is available to advise as needed.‬
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‭D)‬ ‭Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis)‬
‭Management guidelines for diarrhea or colitis are provided in the next table.‬
‭All‬ ‭events‬ ‭of‬ ‭diarrhea‬ ‭or‬ ‭colitis‬ ‭should‬ ‭be‬ ‭thoroughly‬ ‭evaluated‬ ‭for‬ ‭other‬ ‭more‬ ‭common‬
‭etiologies.‬
‭For‬ ‭events‬ ‭of‬ ‭significant‬ ‭duration‬ ‭or‬ ‭magnitude‬ ‭or‬ ‭associated‬ ‭with‬ ‭signs‬ ‭of‬
‭systemic‬ ‭inflammation‬ ‭or‬ ‭acute-phase‬ ‭reactants‬ ‭(e.g., increased‬ ‭C-reactive‬ ‭protein,‬ ‭platelet‬
‭count,‬ ‭or‬‭bandemia):‬ ‭Perform‬‭sigmoidoscopy‬‭(or‬‭colonoscopy,‬‭if‬‭appropriate)‬‭with‬‭colonic‬
‭biopsy,‬‭with‬‭three‬‭to‬‭five‬‭specimens‬‭for‬‭standard‬‭paraffin‬‭block‬‭to‬‭check‬‭for‬‭inflammation‬‭and‬
‭lymphocytic infiltrates to confirm colitis diagnosis.‬
‭Event‬
‭Management‬
‭Diarrhea or colitis,‬
‭Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Initiate symptomatic treatment.‬
‭●‬
‭Endoscopy is recommended if symptoms persist for 7 days.‬
‭●‬
‭Monitor closely.‬
‭Diarrhea or colitis,‬
‭Grade 2‬
‭●‬
‭Withhold atezolizumab for up to 12 weeks after event onset.‬‭a‬
‭●‬
‭Initiate symptomatic treatment.‬
‭●‬
‭If strong clinical suspicion for immune-mediated colitis, start‬
‭empiric IV steroids while waiting for definitive diagnosis.‬
‭●‬
‭Patient referral to GI specialist is recommended.‬
‭●‬
‭For‬ ‭recurrent‬ ‭events‬ ‭or‬ ‭events‬ ‭that‬ ‭persist‬ ‭>‬ ‭5‬ ‭days,‬ ‭initiate‬
‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬ ‭mg/kg/day‬
‭oral prednisone.‬
‭●‬
‭If event resolves to Grade 1 or better, resume atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Diarrhea or colitis,‬
‭Grade 3‬
‭●‬
‭Withhold atezolizumab for up to 12 weeks after event onset.‬‭a‬
‭●‬
‭Refer‬‭patient‬‭to‬‭GI‬‭specialist‬‭for‬‭evaluation‬‭and‬‭confirmatory‬
‭biopsy.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone or equivalent upon improvement.‬
‭●‬
‭If event resolves to Grade 1 or better, resume atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Diarrhea or colitis,‬
‭Grade 4‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭Medical‬
‭Monitor.‬‭c‬
‭●‬
‭Refer‬ ‭patient‬‭to‬‭GI‬‭specialist‬‭for‬‭evaluation‬‭and‬‭confirmation‬
‭biopsy.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone or equivalent upon improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭improve‬ ‭within‬ ‭48‬ ‭hours‬ ‭after‬ ‭initiating‬
‭corticosteroids, consider adding an immunosuppressive agent.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭taper‬ ‭corticosteroids‬
‭over 1 month.‬
‭GI=gastrointestinal.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>‬‭12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭based‬ ‭on‬ ‭the‬ ‭investigator’s‬ ‭benefit-risk‬
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‭assessment‬‭and‬‭in‬‭alignment‬‭with‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬‭by‬‭the‬
‭investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭should‬‭be‬‭based‬‭on‬‭the‬‭investigator’s‬‭benefit-risk‬‭assessment‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate). Medical Monitor is available to advise as needed.‬
‭E)‬ ‭Management Guidelines for Endocrine Events‬
‭Management guidelines for endocrine events are provided in the next table.‬
‭Patients‬ ‭with‬ ‭unexplained‬ ‭symptoms‬ ‭such‬ ‭as‬ ‭headache,‬ ‭fatigue,‬ ‭myalgias,‬ ‭impotence,‬
‭constipation,‬ ‭or‬ ‭mental‬ ‭status‬ ‭changes‬ ‭should‬ ‭be‬ ‭investigated‬ ‭for‬ ‭the‬ ‭presence‬ ‭of‬ ‭thyroid,‬
‭pituitary,‬‭or‬‭adrenal‬‭endocrinopathies.‬‭Patients‬‭should‬‭be‬‭referred‬‭to‬‭an‬‭endocrinologist‬‭if‬‭an‬
‭endocrinopathy‬‭is‬‭suspected.‬ ‭Thyroid-stimulating‬‭hormone‬‭(TSH)‬‭and‬‭free‬‭triiodothyronine‬
‭and‬ ‭thyroxine‬ ‭levels‬ ‭should‬ ‭be‬ ‭measured‬ ‭to‬ ‭determine‬ ‭whether‬ ‭ thyroid‬ ‭abnormalities‬ ‭are‬
‭present.‬ ‭Pituitary‬‭hormone‬‭levels‬‭and‬‭function‬‭tests‬‭ (e.g., TSH,‬‭growth‬‭hormone,‬‭luteinizing‬
‭hormone,‬ ‭follicle-stimulating‬ ‭hormone,‬ ‭testosterone,‬ ‭prolactin,‬‭adrenocorticotropic‬‭hormone‬
‭[ACTH]‬ ‭levels,‬‭and‬‭ACTH‬‭stimulation‬‭test)‬‭and‬‭magnetic‬‭resonance‬‭imaging‬‭(MRI)‬‭of‬‭the‬
‭brain‬‭(with‬‭detailed‬‭pituitary‬‭sections)‬‭may‬‭help‬‭to‬‭differentiate‬‭primary‬‭pituitary‬‭insufficiency‬
‭from primary adrenal insufficiency.‬
‭Event‬
‭Management‬
‭Grade 1‬
‭hypothyroidism‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Initiate treatment with thyroid replacement hormone.‬
‭●‬
‭Monitor TSH closely.‬
‭Grade 2‬
‭hypothyroidism‬
‭●‬
‭Consider withholding atezolizumab.‬
‭●‬
‭Initiate treatment with thyroid replacement hormone.‬
‭●‬
‭Monitor TSH closely.‬
‭●‬
‭Consider a patient referral to an endocrinologist.‬
‭●‬
‭Resume‬ ‭atezolizumab‬ ‭when‬ ‭symptoms‬ ‭are‬ ‭controlled‬ ‭and‬
‭thyroid function is improving.‬
‭Grade 3 and 4‬
‭hypothyroidism‬
‭●‬
‭Withhold atezolizumab.‬
‭●‬
‭Initiate treatment with thyroid replacement hormone.‬
‭●‬
‭Monitor TSH closely.‬
‭●‬
‭Refer to an endocrinologist.‬
‭●‬
‭Admit‬ ‭patient‬ ‭to‬ ‭the‬ ‭hospital‬ ‭for‬ ‭developing‬ ‭myxedema‬
‭(bradycardia, hypothermia and altered mental status).‬
‭●‬
‭Resume‬ ‭atezolizumab‬ ‭when‬ ‭symptoms‬ ‭are‬ ‭controlled‬ ‭and‬
‭thyroid function is improving.‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭the‬
‭Medical‬
‭monitor‬ ‭for‬ ‭life-threatening‬ ‭immune-mediated‬
‭hypothyroidism.‬
‭Grade 1‬
‭hyperthyroidism‬
‭TSH‬‭≥‬‭0.1 mU/L and < 0.5 mU/L:‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Monitor TSH every 4 weeks.‬
‭●‬
‭Consider patient referral to endocrinologist.‬
‭TSH < 0.1 mU/L:‬
‭●‬
‭Follow guidelines for symptomatic hyperthyroidism.‬
‭●‬
‭Consider patient referral to endocrinologist.‬
‭Grade 2‬
‭●‬
‭Consider withholding atezolizumab.‬
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‭hyperthyroidism‬
‭●‬
‭Initiate‬ ‭treatment‬‭with‬‭anti-thyroid‬‭drug‬‭such‬‭as‬‭methimazole‬
‭or carbimazole as needed.‬
‭●‬
‭Consider patient referral to endocrinologist.‬
‭●‬
‭Resume‬ ‭atezolizumab‬ ‭when‬ ‭symptoms‬ ‭are‬ ‭controlled‬ ‭and‬
‭thyroid function is improving.‬
‭Grade 3 and 4‬
‭hyperthyroidism‬
‭●‬
‭Withhold atezolizumab.‬
‭●‬
‭Initiate‬
‭treatment‬
‭with‬
‭anti-thyroid‬
‭drugs‬
‭such‬
‭as‬
‭methimazole or carbimazole as needed.‬
‭●‬
‭Refer to endocrinologist.‬
‭●‬
‭Resume‬ ‭atezolizumab‬ ‭when‬ ‭symptoms‬ ‭are‬ ‭controlled‬ ‭and‬
‭thyroid function is improving.‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭the‬
‭Coordinating‬
‭Investigator‬
‭for‬
‭life-threatening‬
‭immune-mediated hyperthyroidism.‬‭c‬
‭Symptomatic adrenal‬
‭insufficiency,‬
‭Grade 2 - 4‬
‭●‬
‭Withhold atezolizumab for up to 12 weeks after event onset.‬‭a‬
‭●‬
‭Refer patient to endocrinologist.‬
‭●‬
‭Perform appropriate imaging.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone or equivalent upon improvement.‬
‭●‬
‭If‬ ‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better‬‭and‬‭patient‬‭is‬‭stable‬‭on‬
‭replacement therapy, resume atezolizumab.‬‭b‬
‭●‬
‭If‬‭event‬‭does‬‭not‬‭resolve‬‭to‬‭Grade‬‭1‬‭or‬‭better‬‭or‬‭patient‬‭is‬‭not‬
‭stable‬
‭on‬
‭replacement‬
‭therapy‬
‭while‬
‭withholding‬
‭atezolizumab,‬ ‭permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬
‭contact Medical Monitor.‬‭c‬
‭Hyperglycemia,‬
‭Grade 1 or 2‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Investigate‬‭for‬‭diabetes.‬‭If‬‭patient‬‭has‬‭Type‬‭1‬‭diabetes,‬‭treat‬‭as‬
‭a‬‭Grade‬‭3‬‭event.‬‭If‬‭patient‬‭does‬‭not‬‭have‬‭Type‬‭1‬‭diabetes,‬‭treat‬
‭as per institutional guidelines.‬
‭●‬
‭Monitor for glucose control.‬
‭Hyperglycemia,‬
‭Grade 3 or 4‬
‭●‬
‭Withhold atezolizumab.‬
‭●‬
‭Initiate treatment with insulin.‬
‭●‬
‭Evaluate‬ ‭for‬ ‭diabetic‬ ‭ketoacidosis‬ ‭and‬ ‭manage‬ ‭as‬ ‭per‬
‭institutional guidelines.‬
‭●‬
‭Monitor for glucose control.‬
‭●‬
‭Resume‬ ‭atezolizumab‬ ‭when‬ ‭symptoms‬ ‭resolve‬ ‭and‬ ‭glucose‬
‭levels are stable.‬
‭Hypophysitis‬
‭(pan-hypopituitarism),‬
‭Grade 2 or 3‬
‭●‬
‭Withhold atezolizumab for up to 12 weeks after event onset. a‬
‭●‬
‭Refer patient to endocrinologist.‬
‭●‬
‭Perform brain MRI (pituitary protocol).‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone or equivalent upon improvement.‬
‭●‬
‭Initiate hormone replacement if clinically indicated.‬
‭●‬
‭If event resolves to Grade 1 or better, resume atezolizumab. b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭●‬
‭For recurrent hypophysitis, treat as a Grade 4 event.‬
‭Hypophysitis‬
‭(pan-hypopituitarism),‬
‭Grade 4‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭Medical‬
‭Monitor. c‬
‭●‬
‭Refer patient to endocrinologist.‬
‭●‬
‭Perform brain MRI (pituitary protocol).‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
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‭mg/kg/day oral prednisone or equivalent upon improvement.‬
‭●‬
‭Initiate hormone replacement if clinically indicated.‬
‭MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭based‬ ‭on‬ ‭the‬ ‭investigator’s‬ ‭benefit-risk‬
‭assessment‬‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬‭by‬
‭the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭should‬‭be‬‭based‬‭on‬‭the‬‭investigator’s‬‭benefit-risk‬‭assessment‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate). Medical Monitor is available to advise as needed.‬
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‭F)‬ ‭Management Guidelines for Ocular Events‬
‭An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).‬
‭Management guidelines for ocular events are provided in the next Table.‬
‭Event‬
‭Management‬
‭Ocular event,‬
‭Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Patient referral to ophthalmologist is strongly recommended.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭topical‬ ‭corticosteroid‬ ‭eye‬ ‭drops‬ ‭and‬
‭topical immunosuppressive therapy.‬
‭●‬
‭If symptoms persist, treat as a Grade 2 event.‬
‭Ocular event,‬
‭Grade 2‬
‭●‬
‭Withhold atezolizumab for up to 12 weeks after event onset.a‬
‭●‬
‭Patient referral to ophthalmologist is strongly recommended.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭topical‬ ‭corticosteroid‬ ‭eye‬ ‭drops‬ ‭and‬
‭topical immunosuppressive therapy.‬
‭●‬
‭If event resolves to Grade 1 or better, resume atezolizumab.b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Ocular event,‬
‭Grade 3 or 4‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭Medical‬
‭Monitor. c Refer patient to ophthalmologist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭taper‬ ‭corticosteroids‬
‭over 1 month.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭based‬ ‭on‬ ‭the‬ ‭investigator’s‬ ‭benefit-risk‬
‭assessment‬‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬‭by‬
‭the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭should‬‭be‬‭based‬‭on‬‭the‬‭investigator’s‬‭benefit-risk‬‭assessment‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate). Medical Monitor is available to advise as needed.‬
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‭G)‬ ‭Management Guidelines for Immune-Mediated Cardiac Events‬
‭Management guidelines for cardiac events are provided in the following table.‬
‭Immune-Mediated Myocarditis‬
‭Immune-related‬ ‭myocarditis‬ ‭should‬ ‭be‬ ‭suspected‬ ‭in‬ ‭any‬ ‭patient‬ ‭presenting‬ ‭with‬ ‭signs‬ ‭or‬
‭symptoms‬ ‭suggestive‬ ‭of‬ ‭myocarditis,‬ ‭including,‬ ‭but‬ ‭not‬‭limited‬‭to,‬‭laboratory‬‭(e.g.,‬‭B-type‬
‭natriuretic‬‭peptide)‬‭or‬‭cardiac‬‭imaging‬‭abnormalities,‬‭dyspnea,‬‭chest‬‭pain,‬‭palpitations,‬‭fatigue,‬
‭decreased‬‭exercise‬‭tolerance,‬‭or‬‭syncope.‬ ‭Myocarditis‬‭may‬‭also‬‭be‬‭a‬‭clinical‬‭manifestation‬‭of‬
‭myositis‬‭or‬‭associated‬‭with‬‭pericarditis‬‭and‬‭should‬‭be‬‭managed‬‭accordingly.‬‭Immune-related‬
‭myocarditis‬‭needs‬‭to‬‭be‬‭distinguished‬‭from‬‭myocarditis‬‭resulting‬‭from‬‭infection‬‭(commonly‬
‭viral,‬‭e.g.,‬‭in‬‭a‬‭patient‬‭who‬‭reports‬‭a‬‭recent‬‭history‬‭of‬‭gastrointestinal‬‭illness),‬‭ischemic‬‭events,‬
‭underlying‬ ‭arrhythmias,‬ ‭exacerbation‬ ‭of‬ ‭preexisting‬ ‭cardiac‬ ‭conditions,‬ ‭or‬ ‭progression‬ ‭of‬
‭malignancy.‬
‭All‬ ‭patients‬ ‭with‬ ‭possible‬ ‭myocarditis‬ ‭should‬ ‭be‬ ‭urgently‬ ‭evaluated‬‭by‬‭performing‬‭cardiac‬
‭enzyme‬ ‭assessment,‬ ‭an‬ ‭ECG,‬ ‭a‬ ‭chest‬ ‭X-ray,‬ ‭an‬ ‭echocardiogram,‬ ‭and‬ ‭a‬ ‭cardiac‬ ‭MRI‬ ‭as‬
‭appropriate‬ ‭per‬ ‭institutional‬ ‭guidelines.‬
‭A‬ ‭cardiologist‬ ‭should‬ ‭be‬ ‭consulted.‬
‭An‬
‭endomyocardial‬ ‭biopsy‬ ‭may‬ ‭be‬ ‭considered‬‭to‬‭enable‬‭a‬‭definitive‬‭diagnosis‬‭and‬‭appropriate‬
‭treatment, if clinically indicated.‬
‭Patients‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭myocarditis,‬ ‭in‬‭the‬‭absence‬‭of‬‭an‬‭identified‬‭alternate‬
‭etiology, should be treated according to the guidelines in the following Table.‬
‭Immune-mediated pericardial disorders‬
‭Immune-Immune-mediated‬ ‭pericarditis‬ ‭should‬ ‭be‬ ‭suspected‬ ‭in‬ ‭any‬ ‭patient‬ ‭presenting‬ ‭with‬
‭chest pain and may be associated with immune-mediated myocarditis.‬
‭Immune-mediated‬ ‭pericardial‬ ‭effusion‬ ‭and‬ ‭cardiac‬ ‭tamponade‬ ‭should‬ ‭be‬ ‭suspected‬ ‭in‬ ‭any‬
‭patient presenting with chest pain associated with dyspnea or hemodynamic instability.‬
‭Patients‬ ‭should‬ ‭be‬ ‭evaluated‬ ‭for‬ ‭other‬ ‭causes‬ ‭of‬ ‭pericardial‬ ‭disorders‬ ‭such‬ ‭as‬ ‭infection‬
‭(commonly‬ ‭viral),‬ ‭cancer‬ ‭related‬ ‭(metastatic‬ ‭disease‬ ‭or‬ ‭chest‬ ‭radiotherapy),‬ ‭cardiac‬ ‭injury‬
‭related‬‭(post‬‭myocardial‬‭infarction‬‭or‬‭iatrogenic),‬‭and‬‭autoimmune‬‭disorders,‬‭and‬‭should‬‭be‬
‭managed accordingly.‬
‭All‬‭patients‬‭with‬‭suspected‬‭pericardial‬‭disorders‬‭should‬‭be‬‭urgently‬‭evaluated‬‭by‬‭performing‬
‭an‬ ‭ECG,‬ ‭chest‬ ‭X-ray,‬ ‭transthoracic‬ ‭echocardiogram,‬ ‭and‬ ‭cardiac‬ ‭MRI‬ ‭as‬ ‭appropriate‬ ‭per‬
‭institutional guidelines. A cardiologist should be consulted.‬
‭Pericardiocentesis‬ ‭should‬ ‭be‬ ‭considered‬ ‭for‬‭diagnostic‬‭or‬‭therapeutic‬‭purposes,‬‭if‬‭clinically‬
‭indicated.‬
‭Patients‬‭with‬‭signs‬‭and‬‭symptoms‬‭of‬‭pericarditis,‬‭pericardial‬‭effusion,‬‭or‬‭cardiac‬‭tamponade,‬‭in‬
‭the‬‭absence‬‭of‬‭an‬‭identified‬‭alternate‬‭etiology,‬‭should‬‭be‬‭treated‬‭according‬‭to‬‭the‬‭guidelines‬‭in‬
‭the next Table.‬
‭Event‬
‭Management‬
‭Immune-mediated‬
‭myocarditis, Grade 2-4‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭Medical‬
‭Monitor.‬
‭●‬
‭Refer patient to cardiologist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭as‬ ‭per‬ ‭institutional‬ ‭guidelines‬‭and‬‭consider‬
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‭Immune-mediated pericardial‬
‭disorders, Grades 2-4‬
‭antiarrhythmic‬‭drugs,‬‭temporary‬‭pacemaker,‬‭ECMO,‬‭VAD,‬‭or‬
‭pericardiocentesis as appropriate.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone or equivalent upon improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭improve‬ ‭within‬ ‭48‬ ‭hours‬ ‭after‬ ‭initiating‬
‭corticosteroids, consider adding an immunosuppressive agent.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭taper‬ ‭corticosteroids‬
‭over ≥ 1 month.‬
‭ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device.‬
‭H)‬ ‭Management‬ ‭Guidelines‬ ‭for‬ ‭Infusion-Related‬ ‭Reactions‬ ‭and‬ ‭Cytokine-Release‬
‭Syndrome‬
‭No premedication is indicated for the administration of Cycle 1 of atezolizumab.‬
‭However, patients who experience an infusion-related reaction (IRR) or cytokine-release‬
‭syndrome (CRS) with atezolizumab may receive premedication with antihistamines,‬
‭antipyretic medications, and/or analgesics (e.g., acetaminophen) for subsequent infusions.‬
‭Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of its‬
‭potential for causing agranulocytosis.‬
‭IRRs‬ ‭are‬ ‭known‬ ‭to‬ ‭occur‬ ‭with‬ ‭the‬‭administration‬‭of‬‭monoclonal‬‭antibodies‬‭and‬‭have‬‭been‬
‭reported‬ ‭with‬ ‭atezolizumab.‬ ‭These‬ ‭reactions,‬ ‭which‬ ‭are‬ ‭thought‬ ‭to‬ ‭be‬ ‭due‬ ‭to‬ ‭release‬ ‭of‬
‭cytokines‬ ‭and/or‬ ‭other‬ ‭chemical‬ ‭mediators,‬ ‭occur‬ ‭within‬ ‭24‬ ‭hours‬ ‭of‬ ‭atezolizumab‬
‭administration and are generally mild to moderate in severity.‬
‭CRS‬ ‭is‬ ‭defined‬ ‭as‬ ‭a‬ ‭supraphysiologic‬ ‭response‬ ‭following‬ ‭administration‬ ‭of‬ ‭any‬ ‭immune‬
‭therapy‬‭that‬‭results‬‭in‬‭activation‬‭or‬‭engagement‬‭of‬‭endogenous‬‭or‬‭infused‬‭T‬‭cells‬‭and/or‬‭other‬
‭immune‬‭effector‬‭cells.‬‭Symptoms‬‭can‬‭be‬‭progressive,‬‭always‬‭include‬‭fever‬‭at‬‭the‬‭onset,‬‭and‬
‭may‬ ‭include‬ ‭hypotension,‬ ‭capillary‬ ‭leak‬ ‭(hypoxia),‬ ‭and‬ ‭end-organ‬ ‭dysfunction‬ ‭(Lee‬ ‭et‬ ‭al.‬
‭2019).‬ ‭CRS‬ ‭has‬ ‭been‬ ‭well‬‭documented‬‭with‬‭chimeric‬‭antigen‬‭receptor‬‭T-cell‬‭therapies‬‭and‬
‭bispecific‬‭T-cell‬‭engager‬‭antibody‬‭therapies‬‭but‬‭has‬‭also‬‭been‬‭reported‬‭with‬‭immunotherapies‬
‭that‬ ‭target‬ ‭PD-L1‬ ‭or‬ ‭PD-1‬ ‭(Rotz‬ ‭et‬ ‭al.‬ ‭2017;‬ ‭Adashek‬ ‭and‬ ‭Feldman‬ ‭2019),‬ ‭including‬
‭atezolizumab.‬
‭There‬‭may‬‭be‬‭significant‬‭overlap‬‭in‬‭signs‬‭and‬‭symptoms‬‭of‬‭IRRs‬‭and‬‭CRS,‬‭and‬‭in‬‭recognition‬
‭of‬‭the‬‭challenges‬‭in‬‭clinically‬‭distinguishing‬‭between‬‭the‬‭two,‬‭consolidated‬‭guidelines‬‭for‬‭the‬
‭medical management of IRRs and CRS are provided in the next Table.‬
‭Severe‬ ‭SARS-COV-2‬ ‭Infection‬ ‭appears‬ ‭to‬ ‭be‬ ‭associated‬ ‭with‬ ‭a‬ ‭CRS‬ ‭involving‬ ‭the‬
‭inflammatory‬‭cytokines‬‭interleukin‬‭(IL)-6,‬‭IL-10,‬‭IL-2,‬‭and‬‭interferonƔ-‬‭(Merad‬‭and‬‭Martin‬
‭2020).‬‭If‬‭a‬‭patient‬‭develops‬‭suspected‬‭CRS‬‭during‬‭the‬‭study,‬‭a‬‭differential‬‭diagnosis‬‭should‬
‭include‬ ‭COVID-19,‬ ‭which‬ ‭should‬ ‭be‬‭confirmed‬‭or‬‭refuted‬‭through‬‭assessment‬‭of‬‭exposure‬
‭history,‬ ‭appropriate‬ ‭laboratory‬ ‭testing,‬ ‭and‬ ‭clinical‬ ‭or‬ ‭radiologic‬ ‭evaluations‬ ‭per‬ ‭the‬
‭investigator’s‬ ‭judgment.‬ ‭If‬ ‭a‬ ‭diagnosis‬ ‭of‬ ‭COVID-19‬ ‭is‬ ‭confirmed,‬ ‭the‬ ‭disease‬ ‭should‬ ‭be‬
‭managed as per local or institutional guidelines.‬
‭Event‬
‭Management‬
‭Grade 1‬‭a‬
‭Fever‬‭b‬‭with or‬
‭without‬
‭constitutional‬
‭●‬
‭Immediately interrupt infusion.‬
‭●‬
‭Upon‬ ‭symptom‬ ‭resolution,‬ ‭wait‬ ‭for‬ ‭30‬ ‭minutes‬ ‭and‬ ‭then‬
‭restart‬‭infusion‬‭at‬‭half‬‭the‬‭rate‬‭being‬‭given‬‭at‬‭the‬‭time‬‭of‬‭event‬
‭onset.‬
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‭symptoms‬
‭●‬
‭If‬‭the‬‭infusion‬‭is‬‭tolerated‬‭at‬‭the‬‭reduced‬‭rate‬‭for‬‭30‬‭minutes,‬
‭the infusion rate may be increased to the original rate.‬
‭●‬
‭If symptoms recur, discontinue infusion of this dose.‬
‭●‬
‭Administer‬‭symptomatic‬‭treatment,‬‭c‬‭including‬‭maintenance‬‭of‬
‭IV fluids for hydration.‬
‭●‬
‭In‬ ‭case‬ ‭of‬ ‭rapid‬ ‭decline‬ ‭or‬ ‭prolonged‬ ‭CRS‬ ‭(>‬ ‭2‬ ‭days)‬ ‭or‬ ‭in‬
‭patients‬ ‭with‬ ‭significant‬ ‭symptoms‬ ‭and/or‬ ‭comorbidities,‬
‭consider managing as per Grade 2.‬
‭●‬
‭For‬ ‭subsequent‬ ‭infusions,‬ ‭consider‬ ‭administration‬ ‭of‬ ‭oral‬
‭premedication‬ ‭with‬ ‭antihistamines,‬ ‭antipyretic‬ ‭medication,‬
‭and/or analgesics, and monitor closely for IRRs and/or CRS.‬
‭Grade 2‬‭a‬
‭Fever‬‭b‬‭with‬
‭hypotension not‬
‭requiring‬
‭vasopressors‬
‭and/or‬
‭Hypoxia requiring‬
‭low-flow oxygen d‬
‭by nasal cannula or‬
‭blow-by‬
‭●‬
‭Immediately interrupt infusion.‬
‭●‬
‭Upon‬ ‭symptom‬ ‭resolution,‬ ‭wait‬ ‭for‬ ‭30‬ ‭minutes‬ ‭and‬ ‭then‬
‭restart‬‭infusion‬‭at‬‭half‬‭the‬‭rate‬‭being‬‭given‬‭at‬‭the‬‭time‬‭of‬‭event‬
‭onset.‬
‭●‬
‭If symptoms recur, discontinue infusion of this dose.‬
‭●‬
‭Administer symptomatic treatment.‬‭c‬
‭●‬
‭For hypotension, administer IV fluid bolus as needed.‬
‭●‬
‭Monitor‬‭cardiopulmonary‬‭and‬‭other‬‭organ‬‭function‬‭closely‬‭(in‬
‭the‬ ‭ICU,‬ ‭if‬ ‭appropriate).‬ ‭Administer‬ ‭IV‬ ‭fluids‬ ‭as‬ ‭clinically‬
‭indicated,‬ ‭and‬ ‭manage‬ ‭constitutional‬ ‭symptoms‬ ‭and‬ ‭organ‬
‭toxicities as per institutional practice.‬
‭●‬
‭Rule‬ ‭out‬ ‭other‬ ‭inflammatory‬ ‭conditions‬‭that‬‭can‬‭mimic‬‭CRS‬
‭(e.g.,‬ ‭sepsis).‬ ‭If‬ ‭no‬ ‭improvement‬ ‭within‬ ‭24‬ ‭hours,‬ ‭initiate‬
‭workup and assess for signs and symptoms of HLH or MAS.‬
‭●‬
‭Consider‬ ‭IV‬ ‭corticosteroids‬ ‭(e.g.,‬ ‭methylprednisolone‬ ‭2‬
‭mg/kg/day or dexamethasone 10 mg every 6 hours).‬
‭●‬
‭Consider anti-cytokine therapy.‬‭e‬
‭●‬
‭Consider‬
‭hospitalization‬
‭until‬
‭complete‬
‭resolution‬ ‭of‬
‭symptoms.‬‭If‬‭no‬‭improvement‬‭within‬‭24‬‭hours,‬‭manage‬‭as‬‭per‬
‭Grade‬‭3,‬‭that‬‭is,‬‭hospitalize‬‭patient‬‭(monitoring‬‭in‬‭the‬‭ICU‬‭is‬
‭recommended),‬ ‭permanently‬ ‭discontinue‬ ‭atezolizumab,‬ ‭and‬
‭contact Medical Monitor.‬
‭●‬
‭If‬ ‭symptoms‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭for‬ ‭3‬ ‭consecutive‬
‭days,‬‭the‬‭next‬‭dose‬‭of‬‭atezolizumab‬‭may‬‭be‬‭administered.‬‭For‬
‭subsequent‬
‭infusions,‬
‭consider‬ ‭administration‬ ‭of‬ ‭oral‬
‭premedication‬ ‭with‬ ‭antihistamines,‬ ‭antipyretic‬ ‭medication,‬
‭and/or analgesics and monitor closely for IRRs and/or CRS.‬
‭●‬
‭If‬ ‭symptoms‬ ‭do‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭for‬ ‭3‬
‭consecutive days, contact Medical Monitor.‬
‭Grade 3‬‭a‬
‭Fever‬‭b‬‭with‬
‭hypotension‬
‭requiring a‬
‭vasopressor (with‬
‭or without‬
‭vasopressin)‬
‭and/or‬
‭Hypoxia requiring‬
‭high-flow oxygen d‬
‭by nasal cannula,‬
‭face mask,‬
‭non-rebreather‬
‭mask, or venturi‬
‭mask‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭Medical‬
‭Monitor.‬‭f‬
‭●‬
‭Administer symptomatic treatment.‬‭c‬
‭●‬
‭For‬‭hypotension,‬‭administer‬‭IV‬‭fluid‬‭bolus‬‭and‬‭vasopressor‬‭as‬
‭needed.‬
‭●‬
‭Monitor‬ ‭cardiopulmonary‬ ‭and‬ ‭other‬ ‭organ‬ ‭function‬ ‭closely;‬
‭monitoring‬‭in‬‭the‬‭ICU‬‭is‬‭recommended.‬‭Administer‬‭IV‬‭fluids‬
‭as‬ ‭clinically‬ ‭indicated,‬ ‭and‬ ‭manage‬ ‭constitutional‬ ‭symptoms‬
‭and organ toxicities as per institutional practice.‬
‭●‬
‭Rule‬ ‭out‬ ‭other‬ ‭inflammatory‬ ‭conditions‬‭that‬‭can‬‭mimic‬‭CRS‬
‭(e.g.,‬ ‭sepsis).‬ ‭If‬ ‭no‬ ‭improvement‬ ‭within‬ ‭24‬ ‭hours,‬ ‭initiate‬
‭workup and assess for signs and symptoms of HLH or MAS.‬
‭●‬
‭Administer‬ ‭IV‬ ‭corticosteroids‬ ‭(e.g.,‬ ‭methylprednisolone‬ ‭2‬
‭mg/kg/day or dexamethasone 10 mg every 6 hours).‬
‭●‬
‭Consider anti-cytokine therapy.‬‭e‬
‭●‬
‭Hospitalize‬ ‭patient‬ ‭until‬‭complete‬‭resolution‬‭of‬‭symptoms.‬‭If‬
‭no‬‭improvement‬‭within‬‭24‬‭hours,‬‭manage‬‭as‬‭per‬‭Grade‬‭4,‬‭that‬
‭is,‬‭admit‬‭patient‬‭to‬‭ICU‬‭and‬‭initiate‬‭hemodynamic‬‭monitoring,‬
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‭mechanical‬ ‭ventilation,‬ ‭and/or‬ ‭IV‬ ‭fluids‬ ‭and‬ ‭vasopressors‬‭as‬
‭needed;‬ ‭for‬ ‭patients‬ ‭who‬ ‭are‬ ‭refractory‬ ‭to‬ ‭anti-cytokine‬
‭therapy,‬ ‭experimental‬ ‭treatments‬ ‭may‬ ‭be‬ ‭considered‬ ‭at‬ ‭the‬
‭discretion‬ ‭of‬ ‭the‬ ‭investigator‬ ‭and‬ ‭in‬ ‭consultation‬ ‭with‬ ‭the‬
‭Medical Monitor.‬
‭Grade 4‬‭a‬
‭Fever‬‭b‬‭with‬
‭hypotension‬
‭requiring multiple‬
‭vasopressors‬
‭(excluding‬
‭vasopressin)‬
‭and/or‬
‭Hypoxia requiring‬
‭oxygen by positive‬
‭pressure (e.g.,‬
‭CPAP, BiPAP,‬
‭intubation and‬
‭mechanical‬
‭ventilation)‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭Medical‬
‭Monitor.‬‭f‬
‭●‬
‭Administer symptomatic treatment.‬‭c‬
‭●‬
‭Admit‬ ‭patient‬ ‭to‬ ‭ICU‬ ‭and‬ ‭initiate‬ ‭hemodynamic‬‭monitoring,‬
‭mechanical‬ ‭ventilation,‬ ‭and/or‬ ‭IV‬ ‭fluids‬ ‭and‬ ‭vasopressors‬‭as‬
‭needed.‬ ‭Monitor‬ ‭other‬ ‭organ‬ ‭function‬ ‭closely.‬ ‭Manage‬
‭constitutional‬
‭symptoms‬ ‭and‬ ‭organ‬ ‭toxicities‬ ‭as‬ ‭per‬
‭institutional practice.‬
‭●‬
‭Rule‬ ‭out‬ ‭other‬ ‭inflammatory‬ ‭conditions‬‭that‬‭can‬‭mimic‬‭CRS‬
‭(e.g.,‬ ‭sepsis).‬ ‭If‬ ‭no‬ ‭improvement‬ ‭within‬ ‭24‬ ‭hours,‬ ‭initiate‬
‭workup and assess for signs and symptoms of HLH or MAS.‬
‭●‬
‭Administer‬ ‭IV‬ ‭corticosteroids‬ ‭(e.g.,‬ ‭methylprednisolone‬ ‭2‬
‭mg/kg/day or dexamethasone 10 mg every 6 hours).‬
‭●‬
‭Consider‬ ‭anti-cytokine‬ ‭therapy.‬
‭e‬ ‭For‬ ‭patients‬ ‭who‬ ‭are‬
‭refractory‬ ‭to‬ ‭anti-cytokine‬ ‭therapy,‬ ‭experimental‬‭treatments‬‭g‬
‭may‬‭be‬‭considered‬‭at‬‭the‬‭discretion‬‭of‬‭the‬‭investigator‬‭and‬‭in‬
‭consultation with the Medical Monitor.‬
‭●‬
‭Hospitalize patient until complete resolution of symptoms.‬
‭ASTCT‬‭=‬‭American‬‭Society‬‭for‬‭Transplantation‬‭and‬‭Cellular‬‭Therapy;‬‭BiPAP‬‭=‬‭bi-level‬‭positive‬‭airway‬
‭pressure;‬ ‭CAR‬ ‭=‬ ‭chimeric‬ ‭antigen‬ ‭receptor;‬ ‭CPAP‬ ‭=‬ ‭continuous‬ ‭positive‬ ‭airway‬ ‭pressure;‬ ‭CRS‬ ‭=‬
‭cytokine-release‬ ‭syndrome;‬ ‭CTCAE‬ ‭=‬ ‭Common‬ ‭Terminology‬ ‭Criteria‬ ‭for‬ ‭Adverse‬ ‭Events;‬ ‭eCRF‬ ‭=‬
‭electronic‬‭Case‬‭Report‬‭Form;‬‭HLH‬‭=‬‭hemophagocytic‬‭lymphohistiocytosis;‬‭ICU‬‭=‬‭intensive‬‭care‬‭unit;‬
‭IRR‬ ‭=‬ ‭infusion-related‬ ‭reaction;‬ ‭MAS‬ ‭=‬ ‭macrophage‬ ‭activation‬‭syndrome;‬‭NCCN‬‭=‬‭National‬‭Cancer‬
‭Comprehensive Network; NCI  National Cancer Institute.‬
‭Note:‬‭The‬‭management‬‭guidelines‬‭have‬‭been‬‭adapted‬‭from‬‭NCCN‬‭guidelines‬‭for‬‭management‬‭of‬‭CAR‬
‭T-cell-related toxicities (Version 2.2019).‬
‭a‬ ‭Grading‬ ‭system‬ ‭for‬ ‭management‬ ‭guidelines‬ ‭is‬‭based‬‭on‬‭ASTCT‬‭Consensus‬‭Grading‬‭Scale‬‭for‬‭CRS.‬
‭NCI‬ ‭CTCAE‬ ‭(version‬ ‭as‬ ‭specified‬ ‭in‬ ‭the‬ ‭protocol)‬ ‭should‬ ‭be‬ ‭used‬ ‭when‬ ‭reporting‬ ‭severity‬ ‭of‬‭IRRs,‬
‭CRS,‬‭or‬‭organ‬‭toxicities‬‭associated‬‭with‬‭CRS‬‭on‬‭the‬‭Adverse‬‭Event‬‭eCRF.‬‭Organ‬‭toxicities‬‭associated‬
‭with CRS should not influence overall CRS grading.‬
‭b‬ ‭Fever‬ ‭is‬ ‭defined‬ ‭as‬ ‭temperature‬ ‭≥‬ ‭38ºC‬‭not‬‭attributable‬‭to‬‭any‬‭other‬‭cause.‬‭In‬‭patients‬‭who‬‭develop‬
‭CRS‬ ‭and‬ ‭then‬ ‭receive‬‭anti-pyretic,‬‭anti-cytokine,‬‭or‬‭corticosteroid‬‭therapy,‬‭fever‬‭is‬‭no‬‭longer‬‭required‬
‭when‬‭subsequently‬‭determining‬‭event‬‭severity‬‭(grade).‬‭In‬‭this‬‭case,‬‭the‬‭grade‬‭is‬‭driven‬‭by‬‭the‬‭presence‬
‭of hypotension and/or hypoxia.‬
‭c‬ ‭Symptomatic‬ ‭treatment‬ ‭may‬ ‭include‬ ‭oral‬ ‭or‬ ‭IV‬ ‭antihistamines,‬ ‭antipyretic‬ ‭medications,‬ ‭analgesics,‬
‭bronchodilators,‬ ‭and/or‬ ‭oxygen.‬ ‭For‬‭bronchospasm,‬‭urticaria,‬‭or‬‭dyspnea,‬‭additional‬‭treatment‬‭may‬‭be‬
‭administered as per institutional practice.‬
‭d‬ ‭Low‬‭flow‬‭is‬‭defined‬‭as‬‭oxygen‬‭delivered‬‭at‬‭≤‬‭6‬‭L/min,‬‭and‬‭high‬‭flow‬‭is‬‭defined‬‭as‬‭oxygen‬‭delivered‬‭at‬
‭> 6 L/min.‬
‭e‬ ‭There‬‭are‬‭case‬‭reports‬‭where‬‭anti-cytokine‬‭therapy‬‭has‬‭been‬‭used‬‭for‬‭treatment‬‭of‬‭CRS‬‭with‬‭immune‬
‭checkpoint‬ ‭inhibitors/ICI‬‭(‬‭Rotz‬‭et‬‭al.‬‭2017‬‭;‬‭Adashek‬‭and‬‭Feldman‬‭2019‬‭),‬‭but‬‭data‬‭are‬‭limited,‬‭and‬‭the‬
‭role of such treatment in the setting of antibody-associated CRS has not been established.‬
‭f‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬ ‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬‭from‬‭the‬‭event.‬‭The‬‭decision‬‭to‬‭rechallenge‬‭patients‬‭with‬‭atezolizumab‬‭should‬‭be‬‭based‬‭on‬‭the‬
‭investigator’s‬‭benefit-risk‬‭assessment‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬‭appropriate‬‭delegate).‬
‭Medical‬ ‭Monitor‬ ‭is‬ ‭available‬ ‭to‬ ‭advise‬ ‭as‬ ‭needed.‬ ‭For‬ ‭subsequent‬ ‭infusions,‬ ‭administer‬ ‭oral‬
‭premedication‬ ‭with‬ ‭antihistamines,‬ ‭antipyretic‬‭medications,‬‭and/or‬‭analgesics,‬‭and‬‭monitor‬‭closely‬‭for‬
‭IRRs‬ ‭and/or‬ ‭CRS.‬ ‭Premedication‬ ‭with‬ ‭corticosteroids‬ ‭and‬ ‭extending‬ ‭the‬ ‭infusion‬ ‭time‬ ‭may‬ ‭also‬ ‭be‬
‭considered after assessing the benefit-risk ratio.‬
‭g‬‭Refer to‬‭Riegler et al. (2019)‬‭.‬
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‭I)‬ ‭Management Guidelines for Pancreatic Events, Including Pancreatitis‬
‭The‬‭differential‬‭diagnosis‬‭of‬‭acute‬‭abdominal‬‭pain‬‭should‬‭include‬‭pancreatitis.‬ ‭Appropriate‬
‭work-up‬‭should‬‭include‬‭an‬‭evaluation‬‭for‬‭ductal‬‭obstruction,‬‭as‬‭well‬‭as‬‭serum‬‭amylase‬‭and‬
‭lipase‬‭tests.‬ ‭Management‬‭guidelines‬‭for‬‭pancreatic‬‭events,‬‭including‬‭pancreatitis,‬‭are‬‭provided‬
‭in the next Table.‬
‭Event‬
‭Management‬
‭Amylase and/or lipase‬
‭elevation, Grade 2‬
‭Amylase and/or lipase > 1.5 - 2.0 ULN:‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Monitor amylase and lipase weekly.‬
‭●‬
‭For prolonged elevation (e.g., > 3 weeks), consider treatment‬
‭●‬
‭with corticosteroids equivalent to 10 mg/day oral prednisone.‬
‭Asymptomatic with amylase and/or lipase > 2.0 - 5.0 x ULN:‬
‭●‬
‭Treat as a Grade 3 event.‬
‭Amylase and/or lipase‬
‭elevation, Grade 3 or 4‬
‭●‬
‭Withhold atezolizumab for up to 12 weeks after event onset.‬‭a‬
‭●‬
‭Refer patient to GI specialist.‬
‭●‬
‭Monitor amylase and lipase every other day.‬
‭●‬
‭If‬ ‭no‬ ‭improvement,‬ ‭consider‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬
‭equivalent to 1-2 mg/kg/day oral prednisone.‬
‭●‬
‭If event resolves to Grade 1 or better, resume atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭●‬
‭For‬ ‭recurrent‬ ‭events,‬ ‭permanently‬ ‭discontinue‬ ‭atezolizumab‬
‭and contact Medical Monitor.‬‭c‬
‭Immune-mediated‬
‭pancreatitis, Grade 2 or 3‬
‭●‬
‭Withhold atezolizumab for up to 12 weeks after event onset.‬‭a‬
‭●‬
‭Refer patient to GI specialist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone or equivalent upon improvement.‬
‭●‬
‭If event resolves to Grade 1 or better, resume atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭●‬
‭For‬ ‭recurrent‬ ‭events,‬ ‭permanently‬ ‭discontinue‬ ‭atezolizumab‬
‭and contact Medical Monitor.‬‭c‬
‭Immune-mediated‬
‭pancreatitis, Grade 4‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭Medical‬
‭Monitor.‬‭c‬
‭●‬
‭Refer patient to GI specialist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone or equivalent upon improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭improve‬ ‭within‬ ‭48‬ ‭hours‬ ‭after‬ ‭initiating‬
‭corticosteroids, consider adding an immunosuppressive agent.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭taper‬ ‭corticosteroids‬
‭over‬‭≥‬‭1 month.‬
‭GI = gastrointestinal.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭based‬ ‭on‬ ‭the‬ ‭investigator’s‬ ‭benefit-risk‬
‭assessment‬‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬‭by‬
‭the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
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‭should‬ ‭be‬ ‭based‬ ‭on‬ ‭the‬ ‭investigator’s‬ ‭benefit-risk‬ ‭assessment‬ ‭and‬ ‭documented‬ ‭by‬ ‭the‬ ‭investigator.‬
‭Medical Monitor is available to advise as needed.‬
‭J)‬ ‭Management Guidelines for Dermatologic Events‬
‭The‬‭majority‬‭of‬‭cases of‬‭rash‬‭reported‬‭with‬‭the‬‭use‬‭of‬‭atezolizumab‬‭were‬‭mild‬‭in‬‭severity‬‭and‬
‭self‬‭limited,‬‭with‬‭or‬‭without‬‭pruritus.‬ ‭Although‬‭uncommon,‬‭cases‬‭of‬‭severe‬‭cutaneous‬‭adverse‬
‭reactions‬ ‭such‬ ‭as‬ ‭Stevens-Johnson‬ ‭syndrome‬ ‭and‬ ‭toxic‬ ‭epidermal‬ ‭necrolysis‬ ‭have‬ ‭been‬
‭reported‬‭with‬‭atezolizumab.‬‭A‬‭dermatologist‬‭should‬‭evaluate‬‭persistent‬‭and/or‬‭severe‬‭rash‬‭or‬
‭pruritus.‬ ‭A‬‭biopsy‬‭should‬‭be‬‭considered‬‭unless‬‭contraindicated.‬ ‭Management‬‭guidelines‬‭for‬
‭dermatologic events are provided in the next Table.‬
‭Event‬
‭Management‬
‭Dermatologic‬
‭event, Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Consider‬ ‭treatment‬ ‭with‬ ‭topical‬ ‭corticosteroids‬ ‭and/or‬ ‭other‬
‭symptomatic therapy (e.g., antihistamines).‬
‭Dermatologic‬
‭event, Grade 2‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Consider‬ ‭patient‬ ‭referral‬ ‭to‬‭dermatologist‬‭for‬‭evaluation‬‭and,‬
‭if indicated, biops.‬
‭●‬
‭Initiate treatment with topical corticosteroids.‬
‭●‬
‭Consider‬‭treatment‬‭with‬‭higher-potency‬‭topical‬‭corticosteroids‬
‭if event does not improve.‬
‭●‬
‭If‬ ‭unresponsive‬ ‭to‬ ‭topical‬ ‭corticosteroids,‬ ‭consider‬ ‭oral‬
‭prednisone 0.5 mg/kg/day.‬
‭Dermatologic‬
‭event, Grade 3‬
‭●‬
‭Withhold atezolizumab for up to 12 weeks after event onset.‬‭a‬
‭●‬
‭Refer‬‭patient‬‭to‬‭dermatologist‬‭for‬‭evaluation‬‭and,‬‭if‬‭indicated,‬
‭biopsy.‬
‭●‬
‭Initiate‬‭treatment‬‭with‬‭corticosteroids‬‭equivalent‬‭to‬‭10‬‭mg/day‬
‭oral‬ ‭prednisone,‬ ‭increasing‬ ‭dose‬ ‭to‬ ‭1-2‬ ‭mg/kg/day‬ ‭if‬ ‭event‬
‭does not improve within 48-72 hours.‬
‭●‬
‭If event resolves to Grade 1 or better, resume atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Dermatologic‬
‭event, Grade 4‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭Medical‬
‭Monitor.‬‭c‬
‭Stevens-Johnson syndrome or‬
‭toxic epidermal necrolysis,‬
‭(any grade)‬
‭Additional‬ ‭guidance‬ ‭for‬ ‭Stevens-Johnson‬ ‭syndrome‬ ‭or‬ ‭toxic‬
‭epidermal necrolysis:‬
‭●‬
‭Withhold‬
‭atezolizumab‬
‭for‬
‭suspected‬ ‭Stevens-Johnson‬
‭syndrome or toxic epidermal necrolysis.‬
‭●‬
‭Confirm‬ ‭diagnosis‬ ‭by‬ ‭referring‬ ‭patient‬ ‭to‬ ‭a‬ ‭specialist‬
‭(dermatologist,‬ ‭ophthalmologist‬ ‭or‬ ‭urologist‬ ‭as‬ ‭relevant)‬ ‭for‬
‭evaluation and, if indicated, biopsy.‬
‭●‬
‭Follow‬ ‭the‬ ‭applicable‬ ‭treatment‬ ‭and‬ ‭management‬ ‭guidelines‬
‭above.‬
‭●‬
‭If‬‭Stevens-Johnson‬‭syndrome‬‭or‬‭toxic‬‭epidermal‬‭necrolysis‬‭is‬
‭confirmed, permanently discontinue atezolizumab.‬
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‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>‬‭12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬ ‭10‬ ‭mg/day‬ ‭oral‬ ‭prednisone.‬ ‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭based‬ ‭on‬ ‭the‬ ‭investigator’s‬ ‭benefit-risk‬
‭assessment‬‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬‭by‬
‭the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬ ‭corticosteroids‬ ‭have‬ ‭been‬ ‭initiated,‬ ‭they‬ ‭must‬ ‭be‬ ‭tapered‬ ‭over‬ ‭1‬ ‭month‬ ‭to‬ ‭the‬‭equivalent‬‭of‬ ‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭should‬‭be‬‭based‬‭on‬‭the‬‭investigator’s‬‭benefit-risk‬‭assessment‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate). Medical Monitor is available to advise as needed..‬
‭K)‬ ‭Management Guidelines for Neurologic Disorders‬
‭Patients‬ ‭may‬ ‭present‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭sensory‬ ‭and/or‬ ‭motor‬ ‭neuropathy.‬
‭Diagnostic‬ ‭work-up‬ ‭is‬ ‭essential‬ ‭for‬ ‭an‬ ‭accurate‬ ‭characterization‬ ‭to‬ ‭differentiate‬ ‭between‬
‭alternative‬ ‭etiologies.‬ ‭Management‬ ‭guidelines‬‭for‬‭neurologic‬‭disorders‬‭are‬‭provided‬‭in‬‭the‬
‭next Table.‬
‭Event‬
‭Management‬
‭Immune-mediated neuropathy,‬
‭Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Investigate etiology‬
‭Immune-mediated, including‬
‭facial paresis, neuropathy,‬
‭Grade 2‬
‭●‬
‭Withhold atezolizumab for up to 12 weeks after event onset.‬‭a‬
‭●‬
‭Investigate etiology and refer patient to neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭●‬
‭For general immune-mediated neuropathy‬
‭o‬ ‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭o‬‭If‬‭event‬‭does‬‭not‬‭resolve‬‭to‬‭Grade‬‭1‬‭or‬‭better‬‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinueatezolizumab‬ ‭and‬ ‭contact‬ ‭the‬ ‭Medical‬
‭Monitor.‬‭c‬
‭●‬
‭For facial paresis:‬
‭o If event resolves fully, resume atezolizumab‬‭b‬
‭o‬ ‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭fully‬ ‭while‬ ‭withholding‬
‭atezolizumab,‬‭permanently‬‭discontinue‬‭atezolizumab‬
‭and contact the Medical Monitor.‬‭c‬
‭Immune-mediated neuropathy,‬
‭including facial paresis,‬
‭Grade 3 or 4‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭Medical‬
‭Monitor.‬‭c‬
‭●‬
‭Refer patient to neurologist‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭Myasthenia gravis and‬
‭Guillain-Barré syndrome (any‬
‭grade)‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭Medical‬
‭Monitor.‬‭c‬
‭●‬
‭Refer patient to neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭●‬
‭Consider‬ ‭initiation‬ ‭of‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral or IV prednisone.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭based‬ ‭on‬ ‭the‬ ‭investigator’s‬ ‭benefit-risk‬
‭assessment‬‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬‭by‬
‭the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
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‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭based‬ ‭on‬ ‭the‬ ‭investigator’s‬ ‭benefit-risk‬ ‭assessment‬ ‭and‬ ‭documented‬ ‭by‬ ‭the‬ ‭investigator‬ ‭(or‬ ‭an‬
‭appropriate delegate). Medical Monitor is available to advise as needed.‬
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‭L)‬ ‭Management Guidelines for Immune-Mediated Meningoencephalitis‬
‭Immune-related‬‭meningoencephalitis‬‭should‬‭be‬‭suspected‬‭in‬‭any‬‭patient‬‭presenting‬‭with‬‭signs‬
‭or‬‭symptoms‬‭suggestive‬‭of‬‭meningitis‬‭or encephalitis,‬‭including,‬‭but‬‭not‬‭limited‬‭to,‬‭headache,‬
‭neck‬‭pain,‬‭confusion,‬‭seizure,‬‭motor‬‭or‬‭sensory‬‭dysfunction,‬‭and‬‭altered‬‭or‬‭depressed‬‭level‬‭of‬
‭consciousness.‬
‭Encephalopathy‬ ‭from‬ ‭metabolic‬ ‭or‬ ‭electrolyte‬ ‭imbalances‬ ‭needs‬ ‭to‬ ‭be‬
‭distinguished‬‭from potential‬‭meningoencephalitis‬‭resulting‬‭from‬‭infection‬‭(bacterial,‬‭viral,‬‭or‬
‭fungal) or progression of malignancy, or secondary to a paraneoplastic process.‬
‭All‬‭patients‬‭being‬‭considered‬‭for‬‭meningoencephalitis‬‭should‬‭be‬‭urgently‬‭evaluated‬‭with‬‭a‬‭CT‬
‭scan‬ ‭and/or‬ ‭MRI‬ ‭scan‬ ‭of‬ ‭the‬ ‭brain‬ ‭to‬ ‭evaluate‬‭for‬‭metastasis,‬‭inflammation,‬‭or‬‭edema.‬ ‭If‬
‭deemed‬ ‭safe‬ ‭by‬ ‭the‬ ‭treating‬ ‭physician,‬ ‭a‬ ‭lumbar‬ ‭puncture‬ ‭should‬ ‭be‬ ‭performed‬ ‭and‬ ‭a‬
‭neurologist should be consulted.‬
‭Patients‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭meningoencephalitis,‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬ ‭an‬‭identified‬
‭alternate etiology, should be treated according to the guidelines in the next Table.‬
‭Event‬
‭Management‬
‭Immune-mediated‬
‭meningoencephalitis, all‬
‭grades‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭Medical‬
‭Monitor.‬‭a‬
‭●‬
‭Refer‬ ‭patient‬ ‭to‬ ‭neurologist.‬
‭Initiate‬ ‭treatment‬ ‭with‬
‭corticosteroids‬
‭equivalent‬
‭to‬
‭1-2‬
‭mg/kg/day‬
‭IV‬
‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬ ‭mg/kg/day‬ ‭oral‬
‭prednisone or equivalent upon improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭improve‬ ‭within‬ ‭48‬ ‭hours‬ ‭after‬ ‭initiating‬
‭corticosteroids, consider adding an immunosuppressive agent.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭taper‬ ‭corticosteroids‬
‭over‬‭≥‬‭1 month‬
‭M)‬‭Management Guidelines for Renal Events‬
‭Eligible‬ ‭patients‬ ‭must‬ ‭have‬ ‭adequate‬ ‭renal‬ ‭function,‬ ‭and‬ ‭renal‬ ‭function,‬ ‭including‬ ‭serum‬
‭creatinine,‬ ‭should‬ ‭be‬ ‭monitored‬ ‭throughout‬ ‭study‬ ‭treatment.‬ ‭Patients‬ ‭with‬‭abnormal‬‭renal‬
‭function‬‭should‬‭be‬‭evaluated‬‭and‬‭treated‬‭for‬‭other‬‭more‬‭common‬‭etiologies‬‭(including‬‭prerenal‬
‭and‬ ‭postrenal‬ ‭causes,‬ ‭and‬‭concomitant‬‭medications‬‭such‬‭as‬‭non-steroidal‬‭anti-inflammatory‬
‭drugs).‬ ‭Refer‬‭the‬‭patient‬‭to‬‭a‬‭renal‬‭specialist‬‭if‬‭clinically‬‭indicated.‬ ‭A‬‭renal‬‭biopsy‬‭may‬‭be‬
‭required to enable a definitive diagnosis and appropriate treatment.‬
‭Patients‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭nephritis,‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬ ‭an‬ ‭identified‬ ‭alternate‬
‭etiology, should be treated according to the guidelines in the next‬‭Tabl‬‭e.‬
‭Event‬
‭Management‬
‭Renal event, Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Monitor‬ ‭kidney‬ ‭function,‬ ‭including‬ ‭creatinine‬ ‭and‬ ‭urine‬
‭protein,‬‭closely‬‭until‬‭values‬‭resolve‬‭to‬‭within‬‭normal‬‭limits‬‭or‬
‭to baseline values.‬
‭Renal event, Grade 2‬
‭●‬
‭Withhold atezolizumab for up to 12 weeks after event onset.‬‭a‬
‭●‬
‭Refer patient to renal specialist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If event resolves to Grade 1 or better, resume atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
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‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Renal event, Grade 3 or 4‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭Medical‬
‭Monitor.‬
‭●‬
‭Refer patient to renal specialist and consider renal biopsy.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭improve‬ ‭within‬ ‭48‬ ‭hours‬ ‭after‬ ‭initiating‬
‭corticosteroids,‬‭consider‬‭adding‬‭an‬‭immunosuppressive‬‭agent.‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭taper‬ ‭corticosteroids‬
‭over‬‭≥‬‭1 month.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭based‬ ‭on‬ ‭the‬ ‭investigator’s‬ ‭benefit-risk‬
‭assessment‬‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬‭by‬
‭the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭should‬‭be‬‭based‬‭on‬‭the‬‭investigator’s‬‭benefit-risk‬‭assessment‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate). Medical Monitor is available to advise as needed.‬
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‭N)‬ ‭Management Guidelines for Immune-Mediated Myositis‬
‭Myositis‬‭or‬‭inflammatory‬‭myopathies‬‭are‬‭a‬‭group‬‭of‬‭disorders‬‭sharing‬‭the‬‭common‬‭feature‬‭of‬
‭inflammatory‬‭muscle‬‭injury;‬‭dermatomyositis‬‭and‬‭polymyositis‬‭are‬‭among‬‭the‬‭most‬‭common‬
‭disorders.‬‭Initial‬‭diagnosis‬‭is‬‭based‬‭on‬‭clinical‬‭(muscle‬‭weakness,‬‭muscle‬‭pain,‬‭skin‬‭rash‬‭in‬
‭dermatomyositis),‬
‭biochemical‬
‭(serum‬
‭creatine‬
‭kinase‬
‭increase),‬
‭and‬
‭imaging‬
‭(electromyography/MRI) features, and is confirmed with a muscle biopsy.‬
‭Patients‬‭with‬‭possible‬‭myositis‬‭should‬‭be‬‭referred‬‭to‬‭a‬‭rheumatologist‬‭or‬‭neurologist.‬‭Patients‬
‭with possible myositis should be monitored for signs of myocarditis.‬
‭Patients‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭myositis,‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬ ‭an‬ ‭identified‬ ‭alternate‬
‭etiology, should be treated according to the guidelines in the next Table.‬
‭Event‬
‭Management‬
‭Immune-mediated myositis,‬
‭Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Refer patient to rheumatologist or neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭Immune-mediated myositis,‬
‭Grade 2‬
‭●‬
‭Withhold‬‭atezolizumab‬‭for‬‭up‬‭to‬‭12‬‭weeks‬‭after‬‭event‬‭onset‬‭a‬
‭and contact Medical Monitor.‬
‭●‬
‭Refer patient to rheumatologist or neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭●‬
‭Consider‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone or equivalent upon improvement.‬
‭●‬
‭If‬ ‭corticosteroids‬ ‭are‬ ‭initiated‬ ‭and‬ ‭event‬ ‭does‬ ‭not‬ ‭improve‬
‭within‬ ‭48‬ ‭hours‬ ‭after‬ ‭initiating‬ ‭corticosteroids,‬ ‭consider‬
‭adding an immunosuppressive agent.‬
‭●‬
‭If event resolves to Grade 1 or better, resume atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Immune-mediated myositis,‬
‭Grade 3‬
‭●‬
‭Withhold‬‭atezolizumab‬‭for‬‭up‬‭to‬‭12‬‭weeks‬‭after‬‭event‬‭onset‬‭a‬
‭and contact Medical Monitor.‬
‭●‬
‭Refer patient to rheumatologist or neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭●‬
‭Respiratory support may be required in more severe cases.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone,‬ ‭or‬ ‭higher-dose‬ ‭bolus‬ ‭if‬
‭patient‬ ‭is‬ ‭severely‬ ‭compromised‬ ‭(e.g.,‬ ‭cardiac‬ ‭or‬ ‭respiratory‬
‭symptoms,‬ ‭dysphagia,‬ ‭or‬ ‭weakness‬ ‭that‬ ‭severely‬ ‭limits‬
‭mobility);‬ ‭convert‬ ‭to‬ ‭1-2‬ ‭mg/kg/day‬ ‭oral‬ ‭prednisone‬ ‭or‬
‭equivalent upon improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭improve‬ ‭within‬ ‭48‬ ‭hours‬ ‭after‬ ‭initiating‬
‭corticosteroids,‬‭consider‬‭adding‬‭an‬‭immunosuppressive‬‭agent.‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭resume‬‭atezolizumab.‬‭b‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭●‬
‭For recurrent events, treat as a Grade 4 event.‬
‭Immune-mediated myositis,‬
‭Grade 4‬
‭(CTCAE v5.0 guidelines‬
‭only)‬
‭●‬
‭Permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬ ‭contact‬ ‭Medical‬
‭Monitor.‬‭c‬
‭●‬
‭Refer patient to rheumatologist or neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭●‬
‭Respiratory‬ ‭support‬ ‭may‬ ‭be‬ ‭required‬ ‭in‬ ‭more‬ ‭severe‬ ‭cases.‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
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‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone,‬ ‭or‬ ‭higher-dose‬ ‭bolus‬ ‭if‬
‭patient‬ ‭is‬ ‭severely‬ ‭compromised‬ ‭(e.g.,‬ ‭cardiac‬ ‭or‬ ‭respiratory‬
‭symptoms,‬ ‭dysphagia,‬ ‭or‬ ‭weakness‬ ‭that‬ ‭severely‬ ‭limits‬
‭mobility);‬ ‭convert‬ ‭to‬ ‭12‬ ‭mg/kg/day‬ ‭oral‬ ‭prednisone‬ ‭or‬
‭equivalent upon improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭improve‬ ‭within‬ ‭48‬ ‭hours‬ ‭after‬ ‭initiating‬
‭corticosteroids, consider adding an immunosuppressive agent.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭taper‬ ‭corticosteroids‬
‭over‬‭≥‬‭1 month.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭based‬ ‭on‬ ‭the‬ ‭investigator’s‬ ‭benefit-risk‬
‭assessment‬‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬‭by‬
‭the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭should‬ ‭be‬ ‭based‬ ‭on‬ ‭the‬ ‭investigator’s‬ ‭benefit-risk‬ ‭assessment‬ ‭and‬ ‭documented‬ ‭by‬ ‭the‬ ‭investigator.‬
‭Medical Monitor is available to advise as needed.‬
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‭O)‬ ‭Management‬
‭Guidelines‬
‭for‬
‭Hemophagocytic‬
‭Lymphohistiocytosis‬
‭and‬
‭Macrophage Activation Syndrome‬
‭Immune-mediated‬‭reactions‬‭may‬‭involve‬‭any‬‭organ‬‭system‬‭and‬‭may‬‭lead‬‭to‬‭hemophagocytic‬
‭lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS).‬
‭Clinical‬ ‭and‬ ‭laboratory‬ ‭features‬ ‭of‬ ‭severe‬ ‭CRS‬ ‭overlap‬ ‭with‬ ‭HLH,‬ ‭and‬ ‭HLH‬ ‭should‬ ‭be‬
‭considered when CRS presentation is atypical or prolonged.‬
‭Patients‬‭with‬‭suspected‬‭HLH‬‭should‬‭be‬‭diagnosed‬‭according‬‭to‬‭published‬‭criteria‬‭by‬‭McClain‬
‭and‬‭Eckstein‬‭(2014).‬‭A‬‭patient‬‭should‬‭be‬‭classified‬‭as‬‭having‬‭HLH‬‭if‬‭five‬‭of‬‭the‬‭following‬
‭eight criteria are met:‬
‭●‬ ‭Fever  ≥ 38.5°C‬
‭●‬ ‭Splenomegaly‬
‭●‬ ‭Peripheral blood cytopenia consisting of at least two of the following:‬
‭-‬
‭Hemoglobin‬‭<‬‭90‬‭g/L‬‭(9‬‭g/dL)‬‭(<‬‭100‬‭g/L‬‭[10‬‭g/dL]‬‭for‬‭infants‬‭<‬‭4‬
‭weeks old)‬
‭-‬
‭Platelet count < 100 x 109/L (100,000/μL)‬
‭-‬
‭ANC < 1.0 x 109/L (1000/μL)‬
‭●‬ ‭Fasting‬‭triglycerides‬‭>‬‭2.992‬‭mmol/L‬‭(265‬‭mg/dL)‬‭and/or‬‭fibrinogen‬‭<‬‭1.5‬‭g/L‬‭(150‬
‭mg/dL)‬
‭●‬ ‭Hemophagocytosis in bone marrow, spleen, lymph node, or liver‬
‭●‬ ‭Low or absent natural killer cell activity‬
‭●‬ ‭Ferritin  > 500 mg/L (500 ng/mL)‬
‭●‬ ‭Soluble‬‭interleukin‬‭2‬‭(IL-2)‬‭receptor‬‭(soluble‬‭CD25)‬‭elevated‬‭≥ 2‬‭standard‬‭deviations‬
‭above age-adjusted laboratory-specific norms‬
‭Patients‬‭with‬‭suspected‬‭MAS‬‭should‬‭be‬‭diagnosed‬‭according‬‭to‬‭published‬‭criteria‬‭for‬‭systemic‬
‭juvenile‬‭idiopathic‬‭arthritis‬‭by‬‭Ravelli‬‭et‬‭al.‬‭(2016).‬‭A‬‭febrile‬‭patient‬‭should‬‭be‬‭classified‬‭as‬
‭having MAS if the following criteria are met:‬
‭Ferritin > 684 mg/L (684 ng/mL)‬
‭At least two of the following:‬
‭-‬
‭Platelet count  ≤181 x 109/L (181,000μ/L)‬
‭-‬
‭AST ≥ 48 U/L‬
‭-‬
‭Triglycerides > 1.761 mmol/L (156 mg/dL)‬
‭-‬
‭Fibrinogen ≤ 3.6 g/L (360 mg/dL)‬
‭Patients‬‭with‬‭suspected‬‭HLH‬‭or‬‭MAS‬‭should‬‭be‬‭treated‬‭according‬‭to‬‭the‬‭guidelines‬‭in‬‭the‬‭next‬
‭Table.‬
‭Event‬
‭Management‬
‭Suspected HLH or MAS‬
‭●‬
‭Permanently discontinue atezolizumab and contact the‬
‭Medical Monitor.‬
‭●‬
‭Consider patient referral to hematologist.‬
‭●‬
‭Initiate supportive care, including intensive care monitoring if‬
‭indicated per institutional guidelines.‬
‭●‬
‭Consider initiation of IV corticosteroids, an‬
‭immunosuppressive agent, and/or anti-cytokine therapy.‬
‭●‬
‭If event does not respond to treatment within 24 hours, contact‬
‭Medical Monitor and initiate treatment as appropriate‬
‭according to published guidelines.‬
‭●‬
‭If event resolves to Grade 1 or better, taper corticosteroids‬
‭over  ≥1 month.‬
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‭HLH=hemophagocytic lymphohistiocytosis; IV=intravenous; MAS=macrophage activation syndrome.‬
‭P)‬ ‭Management Guidelines for Immune-Mediated Myelitis‬
‭Event‬
‭Management‬
‭Immune-mediated myelitis,‬
‭Grade 1‬
‭●‬
‭Continue atezolizumab unless symptoms worsen or do not‬
‭improve.‬
‭●‬
‭Investigate etiology and refer patient to a neurologist‬
‭Immune-mediated myelitis,‬
‭Grade 2‬
‭●‬
‭Permanently discontinue atezolizumab and contact the‬
‭Medical Monitor.‬
‭●‬
‭Investigate etiology and refer patients to a neurologist.‬
‭●‬
‭Rule out infection.‬
‭●‬
‭Initiate treatment with corticosteroids equivalent to 1-2‬
‭mg/kg/day oral prednisone‬
‭Immune-mediated myelitis,‬
‭Grade 3 or 4‬
‭●‬
‭Permanently discontinue atezolizumab and contact the‬
‭Medical Monitor.‬
‭●‬
‭Refer a patient to a neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines‬
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‭Clinical Trial Protocol‬
‭Protocol Number:‬
‭SOGUG-2020-IEC(VEJ)-1‬
‭Title:‬
‭Phase‬ ‭II,‬ ‭multicenter,‬ ‭non-randomized,‬ ‭single-arm,‬ ‭open-label‬ ‭trial‬ ‭of‬
‭atezolizumab‬‭in‬‭combination‬‭of‬‭split-doses‬‭of‬‭gemcitabine‬‭plus‬‭cisplatin‬‭in‬
‭patients with locally advanced or metastatic urothelial carcinoma‬
‭Short title:‬
‭Study‬‭of‬‭atezolizumab‬‭combined‬‭with‬‭split-dose‬‭gemcitabine‬‭plus‬‭cisplatin‬
‭in urothelial carcinoma‬
‭Acronym:‬
‭AUREA‬
‭Nº EudraCT:‬
‭2020-001326-65‬
‭Sponsor:‬
‭Spanish Oncology Genitourinary Group (SOGUG)‬
‭Velázquez, 7, 3a. planta, 28001‬
‭Madrid, Spain‬
‭Coordinating:‬
‭Investigator:‬
‭Guillermo de Velasco, M.D., PhD.‬
‭Medical Oncology Department‬
‭Hospital Universitario 12 de Octubre,‬
‭Av Córdoba s/n 28041,‬
‭Madrid, Spain‬
‭VERSION 2.0 - 08MAR2022‬
‭Confidentiality Statement‬
‭The‬ ‭information‬ ‭contained‬ ‭in‬‭this‬‭document‬‭is‬‭the‬‭property‬‭of‬‭the‬‭sponsor‬‭and‬‭therefore‬‭is‬
‭provided‬‭confidentially‬‭for‬‭review‬‭by‬‭you,‬‭your‬‭investigative‬‭team,‬‭the‬‭Investigational‬‭Ethics‬
‭Committee,‬‭and‬‭the‬‭competent‬‭authorities.‬‭This‬‭information‬‭must‬‭not‬‭be‬‭revealed‬‭to‬‭any‬‭other‬
‭party‬‭without‬‭previous‬‭authorization‬‭in‬‭writing‬‭by‬‭the‬‭sponsor,‬‭except‬‭as‬‭needed‬‭to‬‭obtain‬‭the‬
‭informed consent of the subjects who may be given the medicinal product.‬
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‭SPONSOR’S PROTOCOL SIGNATURE PAGE‬
‭I‬‭approve‬‭the‬‭design‬‭of‬‭the‬‭clinical‬‭trial‬‭and‬‭I‬‭understand‬‭and‬‭will‬‭conduct‬‭the‬‭trial‬‭according‬
‭to‬‭the‬‭clinical‬‭trial‬‭protocol,‬‭any‬‭approved‬‭protocol‬‭amendments,‬‭International‬‭Conference‬‭on‬
‭Harmonization‬‭Good‬‭Clinical‬‭Practice,‬‭and‬‭all‬‭applicable‬‭Health‬‭Authority‬‭requirements‬‭and‬
‭national laws.‬
‭Dra. Aránzazu González del Alba‬
‭SOGUG Chairman‬
‭Signature‬
‭Signature date‬
‭(DD-mm-YYYY)‬
‭Dr. Guillermo de Velasco‬
‭Coordinating Investigator‬
‭Signature‬
‭Signature date‬
‭(DD-mm-YYYY)‬
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‭Page‬‭110‬‭of‬‭315‬


‭PRINCIPAL INVESTIGATOR’S PROTOCOL SIGNATURE PAGE‬
‭I have read this protocol and agree to conduct this clinical trial in accordance with all the‬
‭provisions of the Protocol, any approved protocol amendments, International Conference on‬
‭Harmonization‬ ‭Good‬ ‭Clinical‬ ‭Practice,‬ ‭Helsinki‬ ‭Declaration‬ ‭and‬ ‭all‬ ‭applicable‬ ‭Health‬
‭Authority  requirements and national laws‬
‭Site‬‭: _______________________________________________‬
‭Name:‬‭__________________________________________‬
‭Date:‬‭_________________________________________‬
‭Principal Investigator Signature:‬‭__________________________________‬
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‭Page‬‭111‬‭of‬‭315‬


‭SPONSOR’S PROTOCOL SIGNATURE PAGE‬
‭1‬
‭PRINCIPAL INVESTIGATOR’S PROTOCOL SIGNATURE PAGE‬
‭3‬
‭1. SUMMARY‬
‭9‬
‭1.1. Type of application‬
‭9‬
‭1.2. Study Title‬
‭9‬
‭1.3. Protocol Number and Version‬
‭9‬
‭1.4. Nº EudraCT‬
‭9‬
‭1.5. Sponsor Data‬
‭9‬
‭1.6. Coordinating Investigator‬
‭9‬
‭1.7. Principal Investigators‬
‭9‬
‭1.8. Study Sites‬
‭9‬
‭1.9. Monitoring Organization‬
‭9‬
‭1.10. Disease under study‬
‭9‬
‭1.11. Study Phase‬
‭9‬
‭1.12. Study Treatments‬
‭9‬
‭1.13. Objectives‬
‭10‬
‭1.14. Endpoints‬
‭11‬
‭1.15. Sample Size‬
‭11‬
‭1.16. Eligibility and withdrawal criteria‬
‭11‬
‭1.17. Planned trial period‬
‭15‬
‭2. GENERAL INFORMATION‬
‭20‬
‭2.1. Study Identification‬
‭20‬
‭2.2. Monitoring Organization‬
‭20‬
‭2.3. Sponsor information‬
‭20‬
‭2.4. Coordinating investigator‬
‭20‬
‭2.5. Investigators and study centres‬
‭20‬
‭3. INVESTIGATIONAL MEDICINAL PRODUCT (IMP) DESCRIPTION‬
‭21‬
‭3.1. Study medication‬
‭21‬
‭4. RATIONALE AND OBJECTIVES‬
‭22‬
‭4.1. Rationale‬
‭22‬
‭4.1.1. Current state of the art‬
‭22‬
‭4.1.2. Split-Dose Cisplatin‬
‭22‬
‭4.1.3. PD-L1 and the role of atezolizumab in mUC‬
‭23‬
‭4.2. Hypothesis‬
‭24‬
‭4.3. Rationale for dose selection‬
‭24‬
‭4.4. Study Objectives‬
‭25‬
‭4.4.1. Primary Objectives‬
‭25‬
‭4.4.2. Secondary Objectives‬
‭25‬
‭4.4.3. Exploratory objectives‬
‭25‬
‭5. STUDY DESIGN‬
‭26‬
‭5.1. Study design‬
‭26‬
‭5.2. Patient selection‬
‭27‬
‭5.3. Screening period and screening failure‬
‭27‬
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‭Page‬‭112‬‭of‬‭315‬


‭5.4. Patient registration/enrollment‬
‭28‬
‭5.5. Treatment description, doses and schedules‬
‭28‬
‭5.6. Duration of study, recruitment, treatment and follow-up‬
‭29‬
‭5.7. Determinations during the study‬
‭29‬
‭5.7.1. Screening phase‬
‭29‬
‭5.7.2. Treatment phase‬
‭29‬
‭5.7.3. Safety visit (after the end of treatment by any reason)‬
‭30‬
‭5.7.4. Follow up until progression‬
‭30‬
‭5.7.5. Follow up after progression‬
‭30‬
‭5.8. End of study (EoS)‬
‭30‬
‭5.9. Outcome assessments‬
‭30‬
‭5.9.1. Response evaluation according RECIST 1.1‬
‭30‬
‭5.9.2. Safety assessments‬
‭31‬
‭6. STUDY POPULATION‬
‭32‬
‭6.1. Inclusion criteria‬
‭32‬
‭6.2. Exclusion criteria‬
‭33‬
‭6.3. Criteria for withdrawal from the treatment and study‬
‭36‬
‭6.3.1. Permanent Interruption of study treatments‬
‭36‬
‭6.3.2. Withdrawal from the study‬
‭37‬
‭7. TREATMENT DESCRIPTION‬
‭38‬
‭7.1. Study medication‬
‭38‬
‭7.1.1. Atezolizumab‬
‭38‬
‭7.1.2.   Gemcitabine and Cisplatin‬
‭38‬
‭7.2. Treatment accountability and compliance‬
‭38‬
‭7.2.1. Atezolizumab accountability and compliance‬
‭38‬
‭7.2.2. Gemcitabine and Cisplatin accountability and compliance‬
‭39‬
‭7.3. Preparation and Dispensing‬
‭39‬
‭7.3.1. Atezolizumab preparation and dispensing‬
‭39‬
‭7.3.2. Gemcitabine plus cisplatin preparation and dispensing‬
‭39‬
‭7.4. Investigational Medical Products Administration‬
‭39‬
‭7.4.1. Atezolizumab administration‬
‭39‬
‭7.4.1.1. Intrapatient Atezolizumab Dose Reduction‬
‭40‬
‭7.4.2. Gemcitabine and cisplatin administration‬
‭40‬
‭7.4.2.1. Gemcitabine administration‬
‭40‬
‭7.4.2.2. Cisplatin administration‬
‭41‬
‭7.4.2.3. Intrapatient Gemcitabine and Cisplatin Dose Reduction‬
‭41‬
‭7.5. Special Precautions for Investigational Medical Products‬
‭42‬
‭7.5.1. Special Precautions for Atezolizumab‬
‭42‬
‭7.5.1.1. Hepatic impairment‬
‭43‬
‭7.5.1.2. Renal impairment‬
‭43‬
‭7.5.1.3. Reproductive and Developmental Toxicity‬
‭43‬
‭7.5.1.4. Immune-mediated adverse reactions‬
‭43‬
‭7.5.2. Special Precautions for Gemcitabine‬
‭48‬
‭7.5.3. Special Precautions for Cisplatin‬
‭48‬
‭7.6. Investigational Product Storage‬
‭48‬
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‭Page‬‭113‬‭of‬‭315‬


‭7.6.1. Atezolizumab storage‬
‭49‬
‭7.6.2. Gemcitabine and cisplatin storage‬
‭49‬
‭7.7. Investigational Product Accountability‬
‭50‬
‭7.8. Destruction of Investigational Product Supplies‬
‭50‬
‭7.9. Concomitant Treatments‬
‭50‬
‭7.9.1. Inhibitors and Inducers of CYP Enzymes‬
‭50‬
‭7.9.2. Concomitant Surgery‬
‭51‬
‭7.9.3. Concomitant Radiotherapy‬
‭51‬
‭7.9.4. Other Prohibited Concomitant Medications and Therapies‬
‭51‬
‭7.10. Rescue Medications and Supportive Care‬
‭52‬
‭7.10.1. Supportive Care Guidelines‬
‭52‬
‭8. STUDY PROCEDURES AND EVALUATIONS‬
‭53‬
‭8.1. Definition of efficacy variables‬
‭53‬
‭8.2. Safety and tolerability‬
‭54‬
‭8.3. Study determinations‬
‭54‬
‭8.4. Determinations in the selection phase (screening and baseline determinations)‬
‭57‬
‭8.5. Determinations and procedures during the treatment period (up to cycle 6)‬
‭58‬
‭8.5.1. Day 1 (considering 3 week cycles)‬
‭58‬
‭8.5.2. Day 8 (considering 3 week cycles)‬
‭58‬
‭8.5.3. Other determinations during treatment‬
‭59‬
‭8.5.4. Determinations and procedures on day 1 of cycle 7 (D1-C7) and subsequent‬
‭cycles (D1-Cn)‬
‭59‬
‭8.6. Determinations at safety visit‬
‭60‬
‭8.7. Follow-up determinations‬
‭60‬
‭8.7.1. Follow up after end of treatment (prior PD)‬
‭60‬
‭8.7.2. Follow up after end of treatment (after PD)‬
‭60‬
‭9. SAFETY EVALUATION‬
‭61‬
‭9.1. Definitions‬
‭61‬
‭9.1.1. Adverse event (AE)‬
‭61‬
‭9.1.2. Atezolizumab Adverse Event of Special Interest‬
‭62‬
‭9.1.3. Laboratory Abnormalities‬
‭62‬
‭9.1.4. Medication errors‬
‭63‬
‭9.1.4.1. Atezolizumab overdose‬
‭63‬
‭9.1.4.2. Gemcitabine overdose‬
‭63‬
‭9.1.4.3. Cisplatin overdose‬
‭63‬
‭9.1.5. Adverse reaction (AR)‬
‭64‬
‭9.1.6. Serious Adverse Event (SAE)‬
‭64‬
‭9.1.7. Protocol-Specified Serious Adverse Events‬
‭64‬
‭9.1.8. Life Threatening Event‬
‭65‬
‭9.1.9. Hospitalization / Prolongation of Hospitalization‬
‭65‬
‭9.1.10. Unexpected adverse event (not listed)‬
‭65‬
‭9.1.11. Adverse Event Associated With the Use of the Drug (Adverse Reaction)‬
‭65‬
‭9.1.12. Attribution Definitions‬
‭66‬
‭9.1.3. Intensity (Severity) Criteria‬
‭66‬
‭9.1.14. Exposure during Pregnancy‬
‭67‬
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‭9.1.15. Occupational Exposure‬
‭68‬
‭9.1.16. Expedited reporting‬
‭68‬
‭9.2. Collection and reporting of Adverse Events information‬
‭68‬
‭10. STATISTICAL CONSIDERATIONS‬
‭70‬
‭10.1. Sample size calculation‬
‭70‬
‭10.2. Study endpoints‬
‭70‬
‭10.2.1. Primary endpoint‬
‭70‬
‭10.2.2. Secondary endpoints‬
‭71‬
‭10.3. Efficacy assessment‬
‭71‬
‭10.3.1. Efficacy variables‬
‭71‬
‭10.4. Safety assessment‬
‭72‬
‭10.5. Definition of study populations‬
‭72‬
‭10.6. Data quality control‬
‭73‬
‭10.7. Statistical analysis‬
‭73‬
‭11. LEGAL AND ETHICS CONSIDERATION‬
‭75‬
‭11.1. Ethical conduct of the study‬
‭75‬
‭11.2. Independent Ethical Committee (IEC) Review‬
‭75‬
‭11.3. Authorities‬
‭75‬
‭11.4. Informed consent‬
‭76‬
‭11.5. Confidentiality‬
‭76‬
‭11.6. Insurance Policy‬
‭76‬
‭11.7. End of study definition‬
‭76‬
‭11.8. Early study termination‬
‭77‬
‭12. STUDY PROCEDURES‬
‭78‬
‭12.1. Responsibilities according to Good Clinical Practice‬
‭78‬
‭12.2. Instructions for e-CRF completion‬
‭78‬
‭12.3. Drug supply‬
‭78‬
‭12.3.1. Packaging and labelling‬
‭79‬
‭12.4. Final report and Publications‬
‭79‬
‭12.5. Monitoring‬
‭79‬
‭12.6. Clinical Study Report‬
‭80‬
‭12.7. Protocol Amendments‬
‭80‬
‭12.8. Data Handling‬
‭80‬
‭12.9. Documentation‬
‭81‬
‭12.10. Audits and inspections‬
‭81‬
‭13. TRANSLATIONAL SUBSTUDIES‬
‭82‬
‭13.1. Archived Tumor Biospecimens‬
‭82‬
‭13.2. Peripheral Blood‬
‭82‬
‭13.3. Faecal samples‬
‭83‬
‭14. REFERENCES‬
‭84‬
‭APPENDICES‬
‭88‬
‭Appendix 1. Management of Atezolizumab-specific Adverse Events‬
‭88‬
‭Management Guidelines for Pulmonary Events, Including Pneumonitis‬
‭88‬
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‭Management Guidelines for Hepatic Events‬
‭89‬
‭Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis)‬
‭90‬
‭Management Guidelines for Endocrine Events‬
‭91‬
‭Management Guidelines for Ocular Events‬
‭93‬
‭Management Guidelines for Immune-Mediated Myocarditis‬
‭94‬
‭Management Guidelines for Infusion-Related Reactions and Cytokine-Release‬
‭Syndrome‬
‭95‬
‭Management Guidelines for Pancreatic Events, Including Pancreatitis‬
‭98‬
‭Management Guidelines for Dermatologic Events‬
‭100‬
‭Management Guidelines for Neurologic Disorders‬
‭102‬
‭Management Guidelines for Immune-Mediated Meningoencephalitis‬
‭103‬
‭Management Guidelines for Renal Events‬
‭104‬
‭Management Guidelines for Immune-Mediated Myositis‬
‭105‬
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‭1.‬
‭SUMMARY‬
‭1.1.‬
‭Type of application‬
‭Clinical trial with approved medications with a potential better regimen.‬
‭1.2.‬
‭Study Title‬
‭Phase‬ ‭II,‬ ‭multicenter,‬ ‭non-randomized,‬ ‭single-arm,‬ ‭open-label‬ ‭trial‬ ‭of‬ ‭atezolizumab‬ ‭in‬
‭combination‬‭of‬‭split-doses‬‭of‬‭gemcitabine‬‭plus‬‭cisplatin‬‭in‬‭patients‬‭with‬‭locally‬‭advanced‬‭or‬
‭metastatic urothelial carcinoma‬
‭1.3.‬
‭Protocol Number and Version‬
‭SOGUG-2020-IEC(VEJ)-1 -  VERSION 2.0 08MAR2022‬
‭1.4.‬
‭Nº EudraCT‬
‭2020-001326-65‬
‭1.5.‬
‭Sponsor Data‬
‭Spanish Oncology Genitourinary Group (SOGUG)‬
‭C/ Velazquez 7, 3a. planta‬
‭28001, Madrid, Spain‬
‭secretaria@sogug.es‬
‭1.6.‬
‭Coordinating Investigator‬
‭Guillermo de Velasco, M.D., PhD.‬
‭Medical Oncology Department‬
‭Hospital Universitario 12 de Octubre‬
‭1.7.‬
‭Principal Investigators‬
‭The‬ ‭list‬ ‭of‬ ‭sites‬ ‭and‬ ‭the‬ ‭corresponding‬ ‭Principal‬ ‭Investigators‬ ‭is‬ ‭provided‬ ‭in‬ ‭the‬ ‭attached‬
‭document.‬
‭1.8.‬
‭Study Sites‬
‭It is expected the participation of 12 Sites in Spain.‬
‭1.9.‬
‭Monitoring Organization‬
‭MFAR Clinical Research‬
‭C/ Sinfonía 28, 2-1, 28001, Madrid, Spain‬
‭investigacion@mfar.net‬
‭1.10.‬ ‭Disease under study‬
‭Locally advanced and metastatic urothelial carcinoma (mUC)‬
‭1.11.‬
‭Study Phase‬
‭Phase II clinical trial; Investigator Initiated Study (IIS)‬
‭1.12.‬ ‭Study Treatments‬
‭All‬‭study‬‭treatments‬‭are‬‭intended‬‭for‬‭administration‬‭as‬‭described‬‭below‬‭(regarding‬‭maximum‬
‭treatment‬‭duration‬‭as‬‭per‬‭protocol),‬‭until‬‭PD,‬‭unacceptable‬‭toxicity,‬‭investigator’s‬‭decision‬‭or‬
‭patient’s consent withdrawal (whichever occurs first).‬
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‭●‬ ‭Atezolizumab‬‭at‬‭a‬‭fixed‬‭dose‬‭of‬‭1200‬‭mg/m‬‭2‬‭by‬‭intravenous‬‭(IV)‬‭infusion‬‭on‬‭D1‬‭of‬
‭each‬ ‭cycle‬ ‭up‬ ‭to‬ ‭disease‬ ‭progression,‬ ‭unacceptable‬ ‭toxicity‬ ‭or‬ ‭absence‬ ‭of‬ ‭clinical‬
‭benefit.‬ ‭AUREA‬ ‭is‬ ‭an‬ ‭Investigator‬ ‭Initiated‬ ‭Study,‬ ‭the‬ ‭Sponsor‬ ‭will‬ ‭supply‬
‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬‭months‬‭of‬‭treatment‬‭for‬‭each‬‭patient.‬‭For‬‭those‬‭patients‬‭in‬
‭which‬‭the‬‭PI‬‭considers‬‭that‬‭the‬‭best‬‭option‬‭for‬‭the‬‭patient‬‭is‬‭continuing‬‭atezolizumab‬
‭for‬ ‭more‬ ‭than‬ ‭24‬ ‭months,‬ ‭available‬‭commercial‬‭Site‬‭supplies‬‭should‬‭be‬‭used,‬‭after‬
‭managed local administrative regulation.‬
‭●‬ ‭Gemcitabine‬‭1000‬‭mg/m‬‭2‬ ‭IV‬‭on‬‭D1‬‭and‬‭1000‬‭mg/m‬‭2‬ ‭IV‬‭on‬‭D8‬‭of‬‭each‬‭21-day‬‭cycle‬
‭plus‬‭Cisplatin‬‭70‬‭mg/m‬‭2‬ ‭by‬‭IV‬‭on‬‭split-dose‬‭schedule‬‭of‬‭35‬‭mg/m‬‭2‬‭on‬‭day‬‭1‬‭(D1)‬‭and‬
‭35 mg/m‬‭2‬‭on day 8 (D8)‬‭for up to 6 cycles.‬
‭1.13.‬ ‭Objectives‬
‭Primary Objective:‬
‭To‬‭evaluate‬‭the‬‭preliminary‬‭efficacy‬‭of‬‭atezolizumab‬‭plus‬‭split-dose‬‭gemcitabine‬‭and‬‭cisplatin‬
‭(GC)‬ ‭for‬ ‭the‬ ‭first-line‬ ‭setting,‬ ‭in‬ ‭patients‬ ‭with‬ ‭histologically‬ ‭confirmed‬ ‭advanced‬ ‭(locally‬
‭advanced‬‭and‬‭metastatic)‬‭urothelial‬‭cancer‬‭in‬‭terms‬‭of‬‭overall‬‭response‬‭rate‬‭(ORR)‬‭assessed‬‭by‬
‭the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.‬
‭Secondary Objectives‬
‭Efficacy:‬
‭●‬ ‭To‬ ‭evaluate‬ ‭the‬ ‭duration‬ ‭of‬ ‭response‬ ‭(DoR)‬ ‭associated‬ ‭with‬ ‭the‬ ‭study‬ ‭treatment,‬
‭understood‬‭as‬‭the‬‭time‬‭from‬‭first‬‭confirmed‬‭response‬‭(CR‬‭or‬‭PR)‬‭to‬‭the‬‭date‬‭of‬‭the‬
‭documented‬‭progressive‬‭disease‬‭as‬‭determined‬‭using‬‭RECIST‬‭1.1‬‭criteria‬‭or‬‭death‬‭due‬
‭to any cause, whichever occurs first.‬
‭●‬ ‭To‬ ‭determine‬ ‭the‬ ‭overall‬ ‭survival‬ ‭(OS)‬ ‭of‬ ‭patients‬ ‭with‬ ‭locally-advanced‬ ‭or‬ ‭mUC‬
‭treated‬‭with‬‭the‬‭intended‬‭treatment‬‭regimen,‬‭understood‬‭as‬‭the‬‭time‬‭from‬‭first‬‭dosing‬
‭date‬‭to‬‭the‬‭date‬‭of‬‭death.‬‭A‬‭subject‬‭who‬‭has‬‭not‬‭died‬‭will‬‭be‬‭censored‬‭at‬‭last‬‭known‬
‭date alive.‬
‭●‬ ‭To‬‭evaluate‬‭the‬‭time‬‭to‬‭response‬‭(TtR)‬‭associated‬‭with‬‭the‬‭study‬‭treatment,‬‭understood‬
‭as‬‭the‬‭time‬‭from‬‭the‬‭first‬‭dose‬‭of‬‭the‬‭study‬‭treatment‬‭and‬‭confirmed‬‭response‬‭(CR‬‭or‬
‭PR) based on RECIST 1.1 criteria.‬
‭●‬ ‭To evaluate the‬‭clinical benefit rate (CBR)‬‭, defined‬‭as the percentage of patients who‬
‭have achieved complete response, partial response and stable disease. Stable disease‬
‭should be maintained for at least 6 months to be considered as CBR event.‬
‭●‬ ‭To‬‭determine‬‭the‬‭progression-free‬‭survival‬‭(PFS)‬‭of‬‭patients‬‭with‬‭locally-advanced‬‭or‬
‭mUC‬ ‭treated‬ ‭with‬ ‭the‬ ‭intended‬ ‭treatment‬ ‭regimen,‬ ‭defined‬ ‭as‬ ‭the‬ ‭time‬ ‭from‬ ‭first‬
‭dosing‬‭date‬‭until‬‭disease‬‭progression‬‭or‬‭death‬‭from‬‭any‬‭cause.‬‭Patients‬‭who‬‭have‬‭not‬
‭progressed and start a new line of treatment will be censored.‬
‭Safety:‬
‭●‬ ‭To‬ ‭evaluate‬ ‭safety‬ ‭of‬ ‭the‬ ‭intended‬ ‭treatment‬ ‭regimen‬ ‭based‬ ‭on‬ ‭the‬ ‭frequency‬ ‭and‬
‭severity of adverse events assessed by NCI CTCAE v5.0.‬
‭Exploratory objectives‬
‭●‬ ‭To‬ ‭explore‬ ‭potential‬ ‭correlation‬ ‭of‬ ‭efficacy‬ ‭with‬ ‭relevant‬ ‭potential‬ ‭prognostic‬
‭factors/stratification factors‬
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‭●‬ ‭To‬‭evaluate‬‭the‬‭relationship‬‭between‬‭the‬‭expression‬‭of‬‭PD-L1‬‭and‬‭microbiome‬‭with‬
‭ORR and PFS during experimental treatment.‬
‭1.14.‬ ‭Endpoints‬
‭Primary endpoint:‬
‭●‬ ‭Overall Response Rate (ORR)‬
‭Secondary endpoints‬
‭●‬ ‭Duration of response‬‭(DoR)‬
‭●‬ ‭Overall Survival‬‭(OS)‬
‭●‬ ‭Time to response‬‭(TtR)‬
‭●‬ ‭Clinical benefit‬‭(CB)‬
‭●‬ ‭Progression-Free Survival‬‭(PFS)‬
‭Safety endpoints‬
‭●‬ ‭Adverse events‬‭(AE)‬
‭●‬ ‭Treatment-related AEs‬‭(TRAEs)‬
‭Exploratory endpoints‬
‭●‬ ‭Biomarkers expression‬
‭1.15.‬ ‭Sample Size‬
‭A minimum of 66 patients will be included in the trial.‬
‭1.16.‬ ‭Eligibility and withdrawal criteria‬
‭Inclusion criteria‬
‭1.‬ ‭Male or female subjects ≥ 18 years old.‬
‭2.‬ ‭Written‬‭informed‬‭consent‬‭approved‬‭by‬‭the‬‭Independent‬‭Ethics‬‭Committee‬‭(IEC),‬‭prior‬
‭to the performance of any trial activities.‬
‭3.‬ ‭Patients‬ ‭with‬ ‭histologically‬ ‭documented,‬ ‭locally‬ ‭advanced‬ ‭(T4B,‬ ‭any‬ ‭N;‬ ‭or‬ ‭any‬‭T,‬
‭N2-3) or metastatic urothelial carcinoma (M1, Stage IV)*.‬
‭*Also‬‭termed‬‭transitional‬‭cell‬‭carcinoma‬‭(TCC)‬‭or‬‭urothelial‬‭cell‬‭carcinoma‬‭[UCC]‬‭of‬
‭the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra).‬
‭4.‬ ‭Patients‬‭should‬‭not‬‭be‬‭eligible‬‭(unfit)‬‭for‬‭full‬‭dose‬‭of‬‭cisplatin,‬‭in‬‭the‬‭investigator’s‬
‭judgement, based on:‬
‭a.‬ ‭Age older than 70 years.‬
‭b.‬ ‭ECOG‬ ‭Performance‬ ‭status‬ ‭(PS)‬ ‭2‬ ‭or‬ ‭Karnofsky‬ ‭PS‬ ‭of‬ ‭60‬ ‭-‬ ‭70%‬ ‭(only‬‭15‬
‭patients will be included with ECOG 2).‬
‭c.‬ ‭Measured‬ ‭creatinine‬ ‭clearance‬ ‭(ClCr)‬ ‭>‬ ‭30‬ ‭and‬ ‭<‬ ‭60‬ ‭mL/min‬ ‭by‬ ‭the‬
‭Cockcroft-Gault‬ ‭formula‬ ‭(Cockcroft‬ ‭and‬ ‭Gault‬ ‭1976)‬ ‭or‬ ‭by‬ ‭24-hour‬ ‭urine‬
‭collection for the determination of creatinine clearance:‬
‭Males:‬
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‭Creatinine CL (mL/min)  =‬
‭Weight (kg) × (140 – Age)‬
‭72 x serum creatinine (mg/dL)‬
‭Females:‬
‭Creatinine CL (mL/min)  =‬
‭Weight (kg) × (140 – Age)‬‭×0.85‬
‭72 x serum creatinine (mg/dL)‬
‭d.‬ ‭Any‬‭other‬‭reason‬‭the‬‭physician‬‭considers‬‭but‬‭should‬‭specify‬‭in‬‭the‬‭CRF‬‭and‬
‭discussed with the PI.‬
‭5.‬ ‭At‬ ‭least‬ ‭one‬ ‭measurable‬ ‭lesion‬ ‭through‬ ‭radiographic‬‭tumor‬‭evaluation‬‭(CT‬‭scan‬‭or‬
‭magnetic‬ ‭resonance‬ ‭imaging/MRI)‬ ‭as‬ ‭defined‬‭by‬‭RECIST‬‭version‬‭1.1,‬‭that‬‭has‬‭not‬
‭been previously irradiated within 4 weeks prior to the study enrolment.‬
‭6.‬ ‭Patients‬ ‭with‬ ‭an‬ ‭archival‬ ‭or‬ ‭de‬ ‭novo‬ ‭tumor‬ ‭biopsy‬ ‭(representative‬ ‭formalin-fixed‬
‭paraffin-embedded/FFPE‬ ‭paraffin‬ ‭block‬ ‭obtained‬ ‭as‬‭close‬‭as‬‭possible‬‭to‬‭the‬‭patient‬
‭inclusion)‬‭with‬‭an‬‭associated‬‭pathology‬‭report,‬‭for‬‭testing‬‭of‬‭PD-L1‬‭expression,‬‭prior‬
‭to‬ ‭study‬ ‭enrollment.‬ ‭Samples‬ ‭in‬ ‭unstained‬ ‭slides‬ ‭could‬ ‭be‬ ‭acceptable‬ ‭(at‬ ‭least‬ ‭15‬
‭slides).‬
‭7.‬ ‭Patients with adequate normal organ and marrow function as defined below:‬
‭a.‬ ‭Haemoglobin ≥ 9.0 g/dL.‬
‭b.‬ ‭Absolute neutrophil count (ANC)‬‭>‬‭1500 per mm‬‭3‬‭.‬
‭c.‬ ‭Platelet count ≥ 100,000 per mm‬‭3‬‭.‬
‭d.‬ ‭Serum‬‭bilirubin‬‭≤‬‭1.5‬‭X‬‭institutional‬‭upper‬‭limit‬‭of‬‭normal‬‭(ULN)‬‭unless‬‭liver‬
‭metastases‬ ‭are‬ ‭present,‬ ‭in‬ ‭which‬ ‭case‬ ‭it‬‭must‬‭be‬‭≤‬‭2X‬‭ULN.‬‭This‬‭will‬‭not‬
‭apply‬‭to‬‭patients‬‭with‬‭confirmed‬‭Gilbert’s‬‭syndrome‬‭(persistent‬‭or‬‭recurrent‬
‭hyperbilirubinemia‬ ‭that‬ ‭is‬ ‭predominantly‬ ‭unconjugated‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬
‭haemolysis‬ ‭or‬ ‭hepatic‬ ‭pathology);‬ ‭however,‬ ‭they‬ ‭will‬ ‭be‬ ‭allowed‬ ‭only‬ ‭in‬
‭consultation with their physician.‬
‭e.‬ ‭Serum‬‭transaminases‬‭(ALT,‬‭AST‬‭and‬‭GGT)‬‭≤‬‭2.5X‬‭institutional‬‭upper‬‭limit‬‭of‬
‭normal‬ ‭unless‬ ‭liver‬ ‭metastases‬ ‭are‬ ‭present,‬ ‭in‬ ‭which‬ ‭case‬‭it‬‭must‬‭be‬‭≤‬‭3X‬
‭ULN.‬
‭8.‬ ‭No major active bleeding.‬
‭9.‬ ‭Female‬ ‭subjects‬ ‭of‬ ‭childbearing‬ ‭potential‬ ‭(not‬ ‭surgically‬ ‭sterile‬ ‭or‬ ‭at‬ ‭least‬‭2‬‭years‬
‭postmenopausal)‬‭must‬‭provide‬‭a‬‭negative‬‭urine‬‭pregnancy‬‭test‬‭at‬‭screening,‬‭and‬‭use‬‭a‬
‭medically‬ ‭accepted‬ ‭double‬ ‭barrier‬ ‭method‬ ‭of‬ ‭contraception‬ ‭(i.e.‬ ‭condom‬ ‭with‬
‭spermicide‬‭+‬‭IUD‬‭or‬‭cervical‬‭caps).‬‭In‬‭addition,‬‭they‬‭must‬‭agree‬‭to‬‭continue‬‭the‬‭use‬‭of‬
‭this‬ ‭double‬ ‭barrier‬ ‭method‬ ‭for‬ ‭the‬ ‭duration‬ ‭of‬ ‭the‬ ‭study‬ ‭and‬ ‭for‬ ‭6‬ ‭months‬ ‭after‬
‭participation in the study.‬
‭10.‬‭Males‬‭should‬‭agree‬‭to‬‭abstain‬‭from‬‭sexual‬‭intercourse‬‭with‬‭a‬‭female‬‭partner‬‭or‬‭agree‬
‭to‬ ‭use‬ ‭a‬ ‭double‬ ‭barrier‬ ‭method‬ ‭of‬ ‭contraception‬ ‭(i.e.‬ ‭condom‬ ‭with‬ ‭spermicide,‬ ‭in‬
‭addition‬‭to‬‭having‬‭their‬‭female‬‭partner‬‭use‬‭some‬‭contraceptive‬‭measures‬‭such‬‭as‬‭oral‬
‭contraceptive‬ ‭drugs,‬ ‭intrauterine‬ ‭device‬ ‭(IUD)‬ ‭hormonal‬ ‭contraception,‬ ‭or‬ ‭cervical‬
‭caps), for the duration of the study and for 6 months after participation in the study‬
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‭11.‬ ‭Willingness‬‭and‬‭ability‬‭of‬‭patients‬‭to‬‭comply‬‭with‬‭the‬‭protocol‬‭for‬‭the‬‭duration‬‭of‬‭the‬
‭study‬‭including‬‭undergoing‬‭treatment‬‭as‬‭well‬‭as‬‭availability‬‭for‬‭scheduled‬‭visits‬‭and‬
‭examinations including follow up.‬
‭Exclusion criteria‬
‭1.‬ ‭Prior‬‭treatment‬‭with‬‭any‬‭immune‬‭checkpoint‬‭inhibitor‬‭therapy‬‭(e.g.,‬‭CTLA4,‬‭PD-1,‬‭or‬
‭PD-L1 targeting agent).*‬
‭*‬‭Note‬‭:‬ ‭Prior‬ ‭adjuvant‬ ‭or‬ ‭neoadjuvant‬ ‭treatment‬ ‭with‬ ‭targeted‬ ‭therapy/checkpoint‬
‭inhibitors‬‭is‬‭allowed,‬‭as‬‭long‬‭as‬‭the‬‭last‬‭dose‬‭was‬‭administered‬‭at‬‭least‬‭12‬‭months‬‭prior‬
‭to the patient inclusion in this trial.‬
‭2.‬ ‭Presence‬‭of‬‭active‬‭second‬‭malignancy‬‭and/or‬‭prior‬‭malignancy‬‭in‬‭the‬‭last‬‭2‬‭years‬‭is‬
‭allowed except for the following:‬
‭a.‬ ‭adequately treated basal cell or squamous cell skin cancer,‬
‭b.‬ ‭adequately‬‭treated‬‭Stage‬‭I‬‭or‬‭II‬‭cancer‬‭from‬‭which‬‭the‬‭patient‬‭is‬‭currently‬‭in‬
‭complete remission per investigators' clinical judgment.‬
‭3.‬ ‭Patient receiving radiation therapy within 4 weeks before inclusion.‬
‭4.‬ ‭Active‬ ‭or‬ ‭prior‬ ‭documented‬ ‭autoimmune‬ ‭disease‬ ‭within‬ ‭the‬ ‭past‬ ‭2‬ ‭years‬ ‭NOTE:‬
‭Subjects‬‭with‬‭vitiligo,‬‭Grave's‬‭disease,‬‭or‬‭psoriasis‬‭not‬‭requiring‬‭systemic‬‭treatment‬
‭(within the past 2 years) are not excluded.‬
‭5.‬ ‭Active‬ ‭or‬ ‭prior‬‭documented‬‭inflammatory‬‭bowel‬‭disease‬‭(e.g..,‬‭Crohn's‬‭disease‬‭and‬
‭ulcerative colitis).‬
‭6.‬ ‭History of allogeneic organ transplant.‬
‭7.‬ ‭Subjects‬ ‭having‬ ‭a‬ ‭diagnosis‬ ‭of‬‭immunodeficiency‬‭or‬‭are‬‭receiving‬‭systemic‬‭steroid‬
‭therapy‬‭or‬‭any‬‭other‬‭form‬‭of‬‭immunosuppressive‬‭therapy‬‭within‬‭28‬‭days‬‭prior‬‭to‬‭the‬
‭first dose of trial treatment.‬
‭8.‬ ‭Current‬ ‭or‬ ‭prior‬ ‭use‬ ‭of‬ ‭immunosuppressive‬ ‭medication‬ ‭within‬ ‭7‬ ‭days‬ ‭prior‬ ‭to‬
‭enrolment, except the following:‬
‭a.‬ ‭Intranasal,‬ ‭inhaled,‬ ‭topical‬ ‭steroids,‬ ‭or‬ ‭local‬ ‭steroid‬ ‭injections‬ ‭(eg,‬
‭intra-articular injection);‬
‭i.‬
‭Systemic‬ ‭corticosteroids‬ ‭at‬ ‭physiologic‬ ‭doses‬ ‭≤10‬ ‭mg/day‬ ‭of‬
‭prednisone or equivalent;‬
‭ii.‬
‭Steroids‬‭as‬‭premedication‬‭for‬‭hypersensitivity‬‭reactions‬‭(eg,‬‭CT‬‭scan‬
‭premedication).‬
‭9.‬ ‭The‬‭subject‬‭has‬‭uncontrolled,‬‭significant‬‭intercurrent‬‭or‬‭recent‬‭illness‬‭(within‬‭6‬‭months‬
‭prior to inclusion) including, but not limited to, the following conditions:‬
‭a.‬ ‭Cardiovascular disorders:‬
‭i.‬
‭Class‬‭3‬‭or‬‭4‬‭congestive‬‭heart‬‭failure‬‭as‬‭defined‬‭by‬‭the‬‭New‬‭York‬‭Heart‬
‭Association,‬
‭unstable‬
‭angina‬
‭pectoris,‬
‭and‬
‭serious‬
‭cardiac‬
‭arrhythmias.‬
‭ii.‬
‭Uncontrolled‬‭hypertension‬‭defined‬‭as‬‭sustained‬‭blood‬‭press‬‭>‬‭150‬‭mm‬
‭hg‬‭systolic‬‭or‬‭>‬‭100‬‭mm‬‭hg‬‭diastolic‬‭despite‬‭optimal‬‭antihypertensive‬
‭treatment.‬
‭iii.‬
‭Stroke‬ ‭(including‬ ‭transient‬ ‭ischemic‬ ‭attack‬ ‭[TIA]),‬ ‭myocardial‬
‭infarction,‬‭other‬‭ischemic‬‭event,‬‭or‬‭thromboembolic‬‭event‬‭(e.g.,‬‭deep‬
‭venous‬‭thrombosis‬‭[DVT]‬‭and‬‭pulmonary‬‭embolism)‬‭within‬‭6‬‭months‬
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‭before‬‭inclusion.‬‭Subjects‬‭with‬‭a‬‭more‬‭recent‬‭diagnosis‬‭of‬‭DVT‬‭are‬
‭allowed‬‭if‬‭stable,‬‭asymptomatic,‬‭and‬‭treated‬‭with‬‭LMWH‬‭for‬‭at‬‭least‬
‭6 weeks before study treatment.‬
‭b.‬ ‭Gastrointestinal‬ ‭disorders‬ ‭(e.g.,‬ ‭malabsorption‬ ‭syndrome‬ ‭or‬ ‭gastric‬ ‭outlet‬
‭obstruction)‬ ‭including‬ ‭those‬ ‭associated‬ ‭with‬ ‭a‬ ‭high‬ ‭risk‬ ‭of‬ ‭perforation‬ ‭or‬
‭fistula formulation:‬
‭i.‬
‭Tumours‬ ‭invading‬ ‭the‬ ‭GI‬ ‭tract,‬ ‭active‬ ‭peptic‬ ‭ulcer‬ ‭disease,‬
‭inflammatory‬
‭bowel‬
‭disease,‬
‭ulcerative‬
‭colitis,‬ ‭diverticulitis,‬
‭cholecystitis,‬
‭symptomatic‬
‭cholangitis‬
‭or‬
‭appendicitis,‬
‭acute‬
‭pancreatitis‬‭or‬‭acute‬‭obstruction‬‭of‬‭the‬‭pancreatic‬‭or‬‭biliary‬‭duct,‬‭or‬
‭gastric outlet obstruction.‬
‭ii.‬
‭Abdominal‬
‭fistula,‬
‭GI‬
‭perforation,‬
‭bowel‬
‭obstruction,‬
‭or‬
‭intra-abdominal‬ ‭abscess‬ ‭within‬ ‭6‬ ‭months‬ ‭before‬ ‭inclusion.‬ ‭Note:‬
‭complete‬ ‭healing‬ ‭of‬ ‭an‬ ‭intra-abdominal‬ ‭abscess‬ ‭must‬‭be‬‭confirmed‬
‭prior to start of the treatment.‬
‭c.‬ ‭Clinically‬‭significant‬‭hematemesis‬‭or‬‭hemoptysis‬‭of‬‭>‬‭0.5‬‭teaspoon‬‭(>‬‭2.5‬‭ml)‬
‭of‬‭red‬‭blood‬‭or‬‭history‬‭of‬‭other‬‭significant‬‭bleeding‬‭within‬‭3‬‭months‬‭before‬
‭treatment.‬
‭d.‬ ‭Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.‬
‭e.‬ ‭Lesions invading major pulmonary blood vessels.‬
‭f.‬
‭Other clinically significant disorders such as:‬
‭i.‬
‭Active‬ ‭infection‬‭requiring‬‭systemic‬‭treatment,‬‭infection‬‭with‬‭human‬
‭immunodeficiency‬
‭virus‬
‭or‬
‭acquired‬
‭immunodeficiency‬
‭syndrome-related illness, or chronic hepatitis B or C infection.‬
‭ii.‬
‭Serious non-healing wound/ulcer/bone fracture.‬
‭iii.‬
‭Malabsorption syndrome.‬
‭iv.‬
‭Moderate to severe hepatic impairment (child-pugh B or C).‬
‭v.‬
‭Requirement for hemodialysis or peritoneal dialysis.‬
‭vi.‬
‭Uncontrolled diabetes mellitus.‬
‭10.‬‭Major‬‭surgery‬‭(e.g.,‬‭GI‬‭surgery‬‭and‬‭removal‬‭or‬‭biopsy‬‭of‬‭brain‬‭metastasis)‬‭within‬‭8‬
‭weeks‬ ‭before‬ ‭inclusion.‬ ‭Complete‬ ‭wound‬ ‭healing‬ ‭from‬ ‭major‬ ‭surgery‬ ‭must‬ ‭have‬
‭occurred‬ ‭4‬ ‭weeks‬ ‭before‬ ‭study‬ ‭treatment‬ ‭and‬ ‭from‬ ‭minor‬ ‭surgery‬ ‭(e.g.,‬ ‭simple‬
‭excision,‬ ‭tooth‬ ‭extraction)‬ ‭at‬ ‭least‬ ‭10‬ ‭days‬ ‭before‬ ‭study‬ ‭treatment.‬ ‭Subjects‬ ‭with‬
‭clinically relevant ongoing complications from prior surgery are not eligible.‬
‭11.‬ ‭Known‬ ‭human‬ ‭immunodeficiency‬ ‭virus‬ ‭(HIV)‬ ‭or‬ ‭acquired‬ ‭immunodeficiency‬
‭syndrome (AIDS)-related illness.‬
‭12.‬‭Any‬‭test‬‭for‬‭hepatitis‬‭B‬‭virus‬‭(HBV)‬‭or‬‭hepatitis‬‭C‬‭virus‬‭(HCV)‬‭indicating‬‭acute‬‭or‬
‭chronic infection.‬
‭13.‬‭Women who are pregnant or are breastfeeding.‬
‭14.‬‭Male‬‭patients‬‭must‬‭be‬‭surgically‬‭sterile‬‭or‬‭must‬‭agree‬‭to‬‭use‬‭effective‬‭contraception‬
‭during the period of therapy.‬
‭15.‬‭Any‬ ‭of‬ ‭the‬ ‭following‬ ‭within‬ ‭6‬ ‭months‬ ‭prior‬ ‭to‬ ‭study‬‭entry:‬‭myocardial‬‭infarction,‬
‭uncontrolled‬ ‭angina,‬ ‭uncontrolled‬ ‭hypertension,‬ ‭coronary/peripheral‬ ‭artery‬ ‭bypass‬
‭graft,‬ ‭symptomatic‬ ‭congestive‬ ‭heart‬ ‭failure,‬ ‭cerebrovascular‬ ‭accident‬ ‭or‬ ‭transient‬
‭ischemic attack.‬
‭16.‬‭Previously‬‭identified‬‭allergy‬‭or‬‭hypersensitivity‬‭to‬‭components‬‭of‬‭the‬‭study‬‭treatment‬
‭formulations.‬
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‭1.17.‬ ‭Planned trial period‬
‭●‬ ‭Enrolment/recruitment period: 12 months‬
‭●‬ ‭First patient first visit (FPFV): 8ENE2021‬
‭●‬ ‭Last patient last visit (LPLV): FPFV + 24 months‬
‭●‬ ‭Treatment period: Up to 24 months of LPFV‬
‭●‬ ‭Follow-up period: 24 months‬
‭●‬ ‭Planned end of study date: FPFV + up to 36 months‬
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‭GLOSSARY OF ABBREVIATIONS‬
‭Abbreviation or‬
‭Specialist Term‬
‭Explanation‬
‭ADR‬
‭Adverse drug reaction‬
‭AE‬
‭Adverse event‬
‭aUC‬
‭Advanced urothelial cancer‬
‭BMI‬
‭Body Mass Index‬
‭BP‬
‭Blood Pressure‬
‭CIs‬
‭Confidence intervals‬
‭CK‬
‭Creatine‬ ‭kinase‬ ‭(CK),‬ ‭also‬ ‭known‬ ‭as‬ ‭creatine‬ ‭phosphokinase‬ ‭(CPK)‬ ‭or‬
‭phosphocreatine kinase‬
‭CB‬
‭Clinical benefit‬
‭CR‬
‭Complete Response‬
‭CRA‬
‭Clinical Research Associate‬
‭CTCAE‬
‭Common Terminology Criteria for Adverse Events‬
‭CT Scan‬
‭Computed Tomography Scan‬
‭DMP‬
‭Data Management Plan‬
‭CYP‬
‭Cytochromes P450 enzymes‬
‭DoR‬
‭Duration of response‬
‭DVP‬
‭Data Validation Plan‬
‭ECHO‬
‭Echocardiogram‬
‭ECG‬
‭Electrocardiogram‬
‭ECOG‬
‭Eastern Cooperative Oncology Group‬
‭eCRF‬
‭Electronic Case Report Form‬
‭EDC‬
‭Electronic Data Capture‬
‭ECG‬
‭Electrocardiogram‬
‭EMA‬
‭European Medicines Agency‬
‭ESMO‬
‭European Society of Medical Oncology‬
‭FBE‬
‭Full blood examination‬
‭FDA‬
‭US Food and Drug Administration‬
‭FFPE‬
‭Formalin-fixed paraffin-embedded‬
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‭FPFV‬
‭First patient first visit‬
‭FU‬
‭Follow-up‬
‭GC‬
‭Gemcitabine plus cisplatin‬
‭GCP‬
‭Good Clinical Practice‬
‭G-CSF‬
‭Granulocyte colony-stimulating factor‬
‭GH‬
‭Growth hormone‬
‭Hb‬
‭Haemoglobin‬
‭IB‬
‭Investigator Brochure‬
‭ICF‬
‭Informed Consent Form‬
‭ICH‬
‭International Conference on Harmonization‬
‭ICI‬
‭Immune Checkpoint Inhibitors‬
‭IEC‬
‭Independent Ethics Committee‬
‭IgG1‬
‭Immunoglobulin G1‬
‭IIS‬
‭Investigator Initiated Study‬
‭IMP‬
‭Investigational Medicinal Product‬
‭ISF‬
‭Investigator Site File‬
‭ITT‬
‭Intention To Treat‬
‭IUD‬
‭Intrauterine device‬
‭LPLV‬
‭Last visit Last patient‬
‭MedDRA‬
‭Medical Dictionary for Regulatory Activities‬
‭MRI‬
‭Magnetic Resonance Imaging‬
‭mUC‬
‭Metastatic urothelial cancer‬
‭MUGA‬
‭Multigated Acquisition Scan‬
‭MVAC‬
‭Dose-dense methotrexate, vinblastine, doxorubicin and cisplatin‬
‭NCI‬
‭National Cancer Institute (USA)‬
‭ORR‬
‭Overall response rate‬
‭OS‬
‭Overall Survival‬
‭PD‬
‭Progression disease‬
‭PE‬
‭Physical Examination‬
‭PFS‬
‭Progression Free Survival‬
‭PI‬
‭Principal Investigator‬
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‭PP‬
‭Per Protocol‬
‭PR‬
‭Partial Response‬
‭PS‬
‭Performance Status‬
‭QD‬
‭Quaque die, every day “once daily”‬
‭QxW‬
‭Every X weeks‬
‭RECIST‬
‭Response Evaluation Criteria In Solid Tumours‬
‭REEC‬
‭Registro Español de Estudios Clínicos (Spanish Registry of Clinical Studies)‬
‭Rx‬
‭Radiography‬
‭SAE‬
‭Serious adverse event‬
‭SAP‬
‭Statistical Analysis Plan‬
‭SAR‬
‭Serious adverse reaction‬
‭SC‬
‭Subcutaneous‬
‭SD‬
‭Stable disease‬
‭SDV‬
‭Source Data Verification‬
‭SmPC‬
‭Summary of Product Characteristics‬
‭SP‬
‭Safety Population‬
‭SUSAR‬
‭Suspected unexpected serious adverse reaction‬
‭PD-1‬
‭Programmed death-1‬
‭PD-L1‬
‭Programmed death ligand-1‬
‭TR‬
‭Translational Research‬
‭UC‬
‭Urothelial cancer‬
‭ULN‬
‭Upper Limit of Normality‬
‭VS‬
‭Vital Signs‬
‭WBC‬
‭White Blood Count‬
‭wGC‬
‭weekly Gemcitabine plus cisplatin‬
‭WHO‬
‭World Health Organization‬
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‭2.‬
‭GENERAL INFORMATION‬
‭2.1.‬
‭Study Identification‬
‭Short‬ ‭title‬‭:‬ ‭Study‬ ‭of‬ ‭atezolizumab‬ ‭and‬ ‭split-dose‬ ‭cisplatin/gemcitabine‬ ‭and‬ ‭in‬ ‭urothelial‬
‭carcinoma‬
‭Protocol number:‬‭SOGUG-2020-IEC (VEJ-1)‬
‭EudraCT No.‬‭: 2020-001326-65‬
‭2.2.‬
‭Monitoring Organization‬
‭MFAR Clinical Research‬
‭C/ Sinfonía 28, 2-1, 28001, Madrid, Spain‬
‭investigacion@mfar.net‬
‭2.3.‬
‭Sponsor information‬
‭Spanish Oncology Genitourinary Group (SOGUG)‬
‭C/ Velazquez 7, 3a planta,‬
‭28001, Madrid, Spain‬
‭secretaria@sogug.es‬
‭2.4.‬
‭Coordinating investigator‬
‭Guillermo de Velasco M.D., PhD.‬
‭Hospital Universitario 12 de Octubre‬
‭Av Córdoba s/n‬
‭28041, Madrid, Spain.‬
‭2.5.‬
‭Investigators and study centres‬
‭It‬‭is‬‭expected‬‭the‬‭participation‬‭of‬‭12‬‭Sites‬‭in‬‭Spain.‬‭The‬‭list‬‭of‬‭Sites‬‭and‬‭the‬‭corresponding‬
‭Principal Investigators is provided in a separated document.‬
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‭3.‬
‭INVESTIGATIONAL MEDICINAL PRODUCT (IMP) DESCRIPTION‬
‭3.1.‬
‭Study medication‬
‭Atezolizumab:‬
‭Pharmacotherapeutic‬ ‭group:‬ ‭Antineoplastic‬ ‭agents,‬ ‭monoclonal‬ ‭antibodies.‬ ‭ATC‬ ‭code:‬
‭L01XC‬
‭Presentation:‬‭60‬‭mg/mL‬‭glass‬‭vials‬‭of‬‭20-mL,‬‭nominal‬‭atezolizumab‬‭amount‬‭per‬‭vial,‬‭1200‬
‭mg. Commercial medication labeled for clinical trial.‬
‭Pharmaceutical‬ ‭form:‬ ‭Concentrate‬ ‭for‬ ‭solution‬ ‭for‬ ‭infusion.‬ ‭Clear,‬ ‭colourless‬ ‭to‬ ‭slightly‬
‭yellowish liquid.‬
‭Supply:‬‭Roche‬‭Pharma‬‭will‬‭supply‬‭atezolizumab‬‭to‬‭the‬‭Sponsor‬‭that‬‭will‬‭supply‬‭this‬‭product‬
‭to the sites pharmacy.‬
‭Gemcitabine‬
‭Pharmacotherapeutic‬‭group:‬‭Antineoplastic‬‭agents‬‭-‬‭Alkylating‬‭agents‬‭-‬‭Antimetabolites‬‭-‬
‭Pyrimidine analogues, ATC code: L01BC05‬
‭Presentation:‬‭;‬ ‭Glass‬ ‭vial:‬ ‭*200‬ ‭mg/5.3‬ ‭mL‬ ‭or‬ ‭200‬ ‭mg/2‬ ‭mL;‬ ‭1000‬ ‭mg/10‬ ‭mL‬ ‭or‬ ‭1000‬
‭mg/26.3mL;‬ ‭1500‬ ‭mg/15‬ ‭mL‬ ‭and‬ ‭*2000‬ ‭mg/52.6‬ ‭mL‬ ‭or‬ ‭2000‬ ‭mg/20‬ ‭mL.‬ ‭Commercial‬
‭medication not-labeled for clinical trial.‬
‭Pharmaceutical‬‭form:‬ ‭*‬‭Concentrate‬ ‭for‬ ‭solution‬ ‭for‬ ‭infusion‬ ‭according‬ ‭to‬ ‭different‬
‭commercial presentations authorized in Spain.‬
‭Supply:‬‭By participating sites under standard treatment‬‭criteria‬
‭Cisplatin‬
‭Pharmacotherapeutic‬‭group:‬‭Antineoplastic‬‭agents‬‭-‬‭Other‬‭antineoplastic‬‭agents,‬‭ATC‬‭code:‬
‭L01XA01‬
‭Presentation:‬‭1‬‭mg/mL‬‭glass‬‭vials‬‭of‬‭10-mL,‬‭50-mL‬‭and‬‭100-mL.‬‭Commercial‬‭medication‬
‭not-labeled for clinical trial.‬
‭Pharmaceutical form:‬‭Concentrate for solution for‬‭infusion.‬
‭Supply:‬‭By participating sites under standard treatment‬‭criteria.‬
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‭4.‬
‭RATIONALE AND OBJECTIVES‬
‭4.1.‬
‭Rationale‬
‭4.1.1.‬ ‭Current state of the art‬
‭Cisplatin-based‬‭chemotherapy‬‭(70 mg/m‬‭2‬‭)‬‭has‬‭been‬‭the‬‭standard‬‭of‬‭care‬‭for‬‭first-line‬‭treatment‬
‭for‬‭surgically‬‭unresectable‬‭and‬‭metastatic‬‭patients‬‭fit‬‭enough‬‭to‬‭tolerate‬‭cisplatin‬‭for‬‭more‬‭than‬
‭30‬ ‭years‬ ‭(‬‭Saxman‬ ‭SB,‬ ‭et‬ ‭al.‬ ‭1997;‬ ‭Von‬ ‭der‬ ‭Maase,‬ ‭et‬ ‭al.‬ ‭2000;‬ ‭Bellmunt‬ ‭J,‬‭et‬‭al.‬‭2016‬‭).‬
‭However,‬‭a‬‭standard‬‭dose‬‭schedule‬‭is‬‭not‬‭feasible‬‭for‬‭a‬‭significant‬‭number‬‭of‬‭patients‬‭(about‬
‭50%).‬‭Age-related‬‭physiological‬‭changes‬‭and‬‭comorbidities‬‭are‬‭common‬‭in‬‭the‬‭uro-oncology‬
‭field‬ ‭and,‬ ‭as‬ ‭expected,‬ ‭affect‬ ‭treatment‬ ‭choices‬ ‭and‬ ‭outcomes.‬‭Renal‬‭function‬‭impairment,‬
‭cardiovascular‬ ‭disease,‬ ‭neuropathy,‬ ‭hearing‬ ‭loss‬ ‭are‬ ‭commonly‬ ‭reported‬ ‭in‬ ‭patients‬ ‭with‬
‭bladder‬‭cancer‬‭(‬‭Bellmunt‬‭J,‬‭et‬‭al.‬‭2016‬‭;‬‭Katz‬‭H,‬‭et‬‭al.‬‭2017‬‭);‬‭but‬‭its‬‭toxicity‬‭(‬‭van‬‭Leenders‬
‭GJLH, 2019‬‭).‬
‭According‬‭to‬‭the‬‭most‬‭recent‬‭update‬‭on‬‭cumulative‬‭evidence‬‭and‬‭as‬‭summarized‬‭in‬‭the‬‭most‬
‭recent‬‭ESMO‬‭Bladder‬‭Cancer‬‭Treatment‬‭Recommendations‬‭published‬‭on‬‭16‬‭December‬‭2019,‬
‭a‬‭number‬‭of‬‭cisplatin-containing‬‭regimens‬‭are‬‭acceptable‬‭although‬‭gemcitabine‬‭and‬‭cisplatin‬
‭[I,‬‭A]‬‭is‬‭the‬‭most‬‭widely‬ ‭accepted‬‭(‬‭Von‬‭der‬‭Maase,‬‭et‬‭al.‬‭2000‬‭).‬ ‭Dose-dense‬‭methotrexate,‬
‭vinblastine,‬ ‭doxorubicin‬ ‭and‬ ‭cisplatin‬ ‭(MVAC)‬ ‭[I,‬ ‭B],‬ ‭MVAC‬ ‭with‬ ‭granulocyte‬
‭colony-stimulating‬‭factor‬‭(G-CSF)‬‭[I,‬‭B],‬‭and‬‭gemcitabine,‬‭cisplatin‬‭and‬‭paclitaxel‬‭[I,‬‭C]‬‭are‬
‭alternatives‬‭which‬‭have‬‭established‬‭themselves‬‭as‬‭options‬‭over‬‭time‬‭(‬‭Loehrer‬‭PJ,‬‭et‬‭al.‬‭1992;‬
‭Sternberg‬ ‭CN,‬‭et‬‭al‬‭2006;‬‭Bellmunt‬‭J,‬‭et‬‭al.‬‭2012;‬‭Grande‬‭E,‬‭et‬‭al.‬‭2019‬‭).‬‭Although‬‭these‬
‭specific‬‭regimens‬‭may‬‭lack‬‭proven‬‭advantage‬‭or‬‭non-inferiority‬‭compared‬‭with‬‭gemcitabine‬
‭and cisplatin, they can be considered as options in selected patients.‬
‭4.1.2.‬ ‭Split-Dose Cisplatin‬
‭For‬‭those‬‭patients‬‭with‬‭mUC‬‭cisplatin-ineligible‬‭or‬‭who‬‭have‬‭progressed‬‭on‬‭a‬‭platinum-based‬
‭regimen‬‭treatment‬‭options‬‭are‬‭limited‬‭(‬‭Koshkin‬‭VS,‬‭et‬‭al.‬‭2018‬‭)‬‭and‬‭are‬‭usually‬‭palliated‬‭with‬
‭carboplatin-based‬ ‭regimen,‬ ‭single-agent‬‭taxane‬‭or‬‭gemcitabine,‬‭or‬‭split-dose‬‭cisplatin-based‬
‭regimens‬‭may‬‭be‬‭employed.‬‭In‬‭fact,‬‭some‬‭studies‬‭have‬‭presented‬‭data‬‭on‬‭up‬‭to‬‭50%‬‭of‬‭patients‬
‭eligible‬‭for‬‭cisplatin‬‭might‬‭be‬‭treated‬‭with‬‭carboplatin-based‬‭chemotherapy‬‭based‬‭on‬‭physician‬
‭criteria (ie. IMvigor 130;‬‭Grande E, et al. 2019‬‭).‬
‭The‬ ‭difficult-to-treat‬ ‭concept‬ ‭of‬ ‭this‬ ‭disease‬ ‭entails‬ ‭the‬ ‭undoubtedly‬ ‭high‬ ‭age‬ ‭of‬ ‭most‬ ‭of‬
‭around 80% of patients with UC (‬‭Gore JL, et al. 2010‬‭).‬
‭Administration‬‭of‬‭cisplatin‬‭35 mg/m2‬‭on‬‭day‬‭1 + 8‬‭or‬‭1 + 2‬‭(i.e.,‬‭split‬‭schedule)‬‭is‬‭a‬‭commonly‬
‭used‬ ‭alternative.‬ ‭Several‬ ‭studies‬‭have‬‭reported‬‭that‬‭split‬‭dose‬‭GC‬‭has‬‭comparable‬‭response‬
‭rates‬‭in‬‭metastatic‬‭disease‬‭to‬‭other‬‭platinum‬‭containing‬‭regimens‬‭(‬‭Morales-Barrera‬‭R,‬‭et‬‭al.‬
‭2012‬‭),‬ ‭but‬ ‭has‬ ‭a‬ ‭favourable‬ ‭toxicity‬‭profile‬‭and‬‭considerably‬‭less‬‭time‬‭burden‬‭on‬‭day‬‭care‬
‭facilities‬ ‭(‬‭Sellers‬‭LE,‬‭et‬‭al.‬‭2016‬‭).‬‭These‬‭led‬‭us‬‭to‬‭consider‬‭that‬‭split‬‭dose‬‭GC‬‭should‬‭be‬‭a‬
‭feasible alternative to the longer more toxic regimens, particularly in metastatic disease.‬
‭4.1.3.‬ ‭PD-L1 and the role of atezolizumab in mUC‬
‭Expression‬‭of‬‭programmed‬‭death‬‭ligand-1‬‭(PD-L1)‬‭is‬‭prevalent‬‭among‬‭many‬‭human‬‭tumors‬
‭(‬‭Dong‬‭et‬‭al.‬‭2002‬‭),‬‭and‬‭its‬‭overexpression‬‭is‬‭associated‬‭with‬‭poor‬‭prognosis‬‭for‬‭patients‬‭with‬
‭certain‬‭cancers‬‭(‬‭Thompson‬‭et‬‭al.‬‭2006;‬‭Hamanishi‬‭et‬‭al.‬‭2007;‬‭Okazaki‬‭T‬‭and‬‭Honjo‬‭T,‬‭2007;‬
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‭Hino‬ ‭et‬ ‭al.‬ ‭2010,‬ ‭Mu‬ ‭et‬ ‭al.‬ ‭2011‬‭).‬ ‭Therefore,‬ ‭interruption‬ ‭of‬ ‭the‬ ‭PD-L1/PD‬ ‭1‬ ‭pathway‬
‭represents an attractive strategy to reinvigorate tumor-specific T cell immunity.‬
‭Since‬ ‭May‬ ‭2016,‬ ‭five‬ ‭different‬ ‭agents‬ ‭targeting‬ ‭the‬ ‭PD-1/PD-L1‬ ‭pathway‬ ‭(atezolizumab,‬
‭pembrolizumab,‬ ‭nivolumab,‬ ‭avelumab,‬ ‭durvalumab)‬ ‭have‬ ‭received‬ ‭FDA‬ ‭approval‬ ‭for‬ ‭the‬
‭treatment‬‭of‬‭aUC‬‭in‬‭the‬‭platinum-refractory‬‭setting,‬‭while‬‭pembrolizumab‬‭and‬‭atezolizumab‬
‭are‬‭FDA-approved‬‭for‬‭cisplatin-ineligible‬‭patients‬‭in‬‭the‬‭first-line‬‭setting‬‭(‬‭Koshkin‬‭VS‬‭2018‬‭).‬
‭For‬ ‭platinum‬ ‭or‬ ‭chemotherapy-ineligible‬ ‭patients‬‭with‬‭mUC,‬‭immune‬‭checkpoint‬‭inhibitors‬
‭(ICI)‬‭such‬‭as‬‭inhibitors‬‭of‬‭programmed‬‭death-1/programmed‬‭death-ligand‬‭1‬‭(PD-1/PD-L1)‬‭are‬
‭approved‬ ‭regardless‬ ‭of‬ ‭PD-L1‬ ‭expression,‬ ‭including‬ ‭pembrolizumab‬ ‭and‬ ‭atezolizumab‬
‭(‬‭Einstein and Sonpavde, 2019‬‭).‬
‭Atezolizumab‬‭is‬‭a‬‭humanized‬‭immunoglobulin‬‭(IgG1)‬‭monoclonal‬‭antibody‬‭that‬‭is‬‭produced‬
‭in‬ ‭Chinese‬ ‭hamster‬ ‭ovary‬ ‭(CHO)‬ ‭cells.‬ ‭Atezolizumab‬ ‭targets‬ ‭programmed‬ ‭death-ligand‬ ‭1‬
‭(PD-L1)‬‭on‬‭tumor-infiltrating‬‭immune‬‭cells‬‭(ICs)‬‭or‬‭tumor‬‭cells‬‭(TCs)‬‭and‬‭prevents‬‭interaction‬
‭with‬‭the‬‭programmed‬‭death-1‬‭(PD-1)‬‭receptor‬‭and‬‭B7.1‬‭(CD80),‬‭both‬‭of‬‭which‬‭function‬‭as‬
‭inhibitory‬‭receptors‬‭expressed‬‭on‬‭T‬‭cells‬‭and‬‭other‬‭immune‬‭cells.‬‭The‬‭PD-1‬‭and‬‭PD-L1:B7.1‬
‭interactions‬ ‭may‬ ‭enhance‬ ‭the‬ ‭magnitude‬ ‭and‬ ‭quality‬ ‭of‬ ‭the‬ ‭tumor-specific‬ ‭T‬‭cell‬‭response‬
‭through‬ ‭increased‬ ‭T‬ ‭cell‬ ‭priming,‬ ‭expansion,‬ ‭and/or‬ ‭effector‬ ‭function.‬ ‭Atezolizumab‬ ‭was‬
‭engineered‬‭to‬‭eliminate‬‭Fc-effector‬‭function‬‭via‬‭a‬‭single‬‭amino‬‭acid‬‭substitution‬‭at‬‭position‬
‭298‬‭on‬‭the‬‭heavy‬‭chain,‬‭which‬‭results‬‭in‬‭a‬‭non-glycosylated‬‭antibody‬‭that‬‭has‬‭minimal‬‭binding‬
‭to‬‭Fc‬‭receptors‬‭and,‬‭consequently,‬‭eliminates‬‭detectable‬‭Fc‬‭effector‬‭function.‬‭By‬‭eliminating‬
‭Fc-effector‬ ‭function‬ ‭and‬ ‭antibody-dependent‬ ‭cell-mediated‬ ‭cytotoxicity,‬ ‭antibody-mediated‬
‭clearance of activated effector T cells is also eliminated.‬
‭Atezolizumab‬‭has‬‭demonstrated‬‭efficacy‬‭and‬‭a‬‭tolerable‬‭safety‬‭profile‬‭in‬‭a‬‭range‬‭of‬‭cancers,‬
‭including‬ ‭locally‬ ‭advanced‬ ‭or‬ ‭mUC‬ ‭(‬‭Herbst‬ ‭RS,‬ ‭et‬ ‭al.‬ ‭2014;‬ ‭Powles‬ ‭T,‬ ‭et‬ ‭al.‬ ‭2014,‬
‭Fehrenbacher‬ ‭L‬ ‭et‬ ‭al.‬ ‭2016;‬ ‭McDermott‬ ‭DF,‬ ‭et‬ ‭al.‬ ‭2016;‬ ‭Rosenberg‬ ‭JE,‬ ‭et‬ ‭al.‬ ‭2016‬‭).‬
‭Cumulative‬ ‭data‬ ‭on‬ ‭efficacy‬ ‭at‬ ‭the‬ ‭time‬ ‭of‬ ‭this‬ ‭study‬ ‭design‬ ‭(March‬ ‭2020)‬ ‭suggest‬ ‭that‬
‭atezolizumab‬‭as‬‭a‬‭single-agent‬‭for‬‭first-line‬‭in‬‭patients‬‭with‬‭mUC‬‭entails‬‭clinical‬‭benefit‬‭in‬
‭terms of objective responses, durable responses, and OS.‬
‭Clinical‬‭data‬‭from‬‭the‬‭first-line‬‭cisplatin-ineligible‬‭IMvigor210‬‭cohort—the‬‭first‬‭report‬‭of‬‭an‬
‭anti–PD-L1/PD-1‬ ‭checkpoint‬ ‭inhibitor‬ ‭in‬ ‭this‬ ‭setting—‬ ‭atezolizumab‬ ‭conferred‬ ‭significant‬
‭clinical‬‭benefit‬‭(‬‭Rosenberg‬‭JE,‬‭et‬‭al.‬‭2016‬‭),‬‭leading‬‭to‬‭accelerated‬‭regulatory‬‭approval,‬‭and‬
‭several‬ ‭biomarkers‬ ‭associated‬ ‭with‬ ‭response‬ ‭were‬ ‭identified.‬ ‭Furthermore,‬ ‭encouraging‬
‭durable‬ ‭response‬ ‭rates,‬ ‭survival‬ ‭and‬ ‭tolerability‬ ‭(‬‭Balar‬ ‭AV,‬ ‭et‬ ‭al.‬ ‭2017‬‭)‬ ‭have‬ ‭been‬ ‭also‬
‭reported.‬
‭Interim‬‭results‬‭(2018)‬‭from‬‭the‬‭ongoing‬‭IMvigor‬‭130‬‭trial‬‭(atezolizumab‬‭vs‬‭atezolizumab‬‭plus‬
‭platinum-based‬‭chemotherapy‬‭in‬‭locally‬‭advanced/mUC‬‭not‬‭previously‬‭treated)‬‭has‬‭shown‬‭a‬
‭reduction‬ ‭on‬ ‭survival‬‭for‬‭those‬‭patients‬‭treated‬‭with‬‭atezolizumab‬‭alone‬‭when‬‭compared‬‭to‬
‭those‬‭who‬‭received‬‭platinum-based‬‭chemotherapy‬‭(carbo-‬‭or‬‭cis-‬‭at‬‭physician‬‭discretion),‬‭not‬
‭previously‬‭treated‬‭and‬‭with‬‭tumors‬‭showing‬‭a‬‭low-PD-L1‬‭expression‬‭(<5%‬‭of‬‭immune‬‭cells‬
‭with positive staining) (‬‭EMA Tecentriq Assessment‬‭Report‬‭).‬
‭4.2.‬
‭Hypothesis‬
‭The‬ ‭results‬ ‭of‬ ‭trials‬ ‭combining‬ ‭checkpoint‬ ‭inhibitors‬‭or‬‭platinum-based‬‭chemotherapy‬‭plus‬
‭PD-1/PD-L1‬ ‭inhibitors‬ ‭are‬ ‭eagerly‬ ‭awaited.‬ ‭The‬ ‭combination‬ ‭of‬ ‭split‬ ‭cisplatin‬ ‭with‬
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‭atezolizumab‬‭is‬‭a‬‭feasible‬‭treatment‬‭that‬‭may‬‭provide‬‭better‬‭outcomes‬‭than‬‭carboplatin/based‬
‭combinations.‬
‭In‬‭the‬‭IMvigor130,‬‭52%‬‭of‬‭patients‬‭considered‬‭cisplatin‬‭eligible‬‭at‬‭the‬‭entry‬‭of‬‭the‬‭study‬‭were‬
‭treated‬‭with‬‭carboplatin.‬‭Subanalysis‬‭presented‬‭at‬‭ESMO‬‭2019‬‭(‬‭Grande‬‭E,‬‭et‬‭al.‬‭2019‬‭)‬‭has‬
‭also‬ ‭shown‬ ‭a‬ ‭longer‬‭median‬‭OS‬‭are‬‭achieved‬‭with‬‭cisplatin-based‬‭chemotherapy‬‭combined‬
‭with‬‭atezolizumab‬‭(21.7‬‭months)‬‭when‬‭compared‬‭to‬‭the‬‭carboplatin-based‬‭chemotherapy‬‭plus‬
‭atezolizumab‬ ‭(14.2‬ ‭months),‬ ‭with‬ ‭similar‬ ‭findings‬ ‭when‬ ‭it‬ ‭comes‬‭to‬‭PFS‬‭8.8‬‭months‬‭with‬
‭cisplatin/gemcitabine/atezolizumab vs 7.1 months carboplatin/gemcitabine/atezolizumab.‬
‭A‬ ‭reasonable‬ ‭strategy‬ ‭may‬ ‭be‬ ‭the‬ ‭use‬ ‭of‬ ‭split‬ ‭cisplatin‬ ‭with‬ ‭atezolizumab‬ ‭to‬ ‭increase‬ ‭the‬
‭number of patients receiving cisplatin.‬
‭4.3.‬
‭Rationale for dose selection‬
‭As‬‭per‬‭Atezolizumab‬‭Investigator’s‬‭Brochure‬‭(IB)‬‭at‬‭the‬‭time‬‭of‬‭this‬‭study‬‭design‬‭(‬‭version‬‭15,‬
‭July‬‭2019‬‭),‬‭the‬‭standard‬‭fixed‬‭dose‬‭of‬‭1200,‬‭equivalent‬‭to‬‭15mg/kg‬‭in‬‭a‬‭typical‬‭patient.‬‭No‬
‭dose-limiting‬ ‭toxicities‬ ‭were‬ ‭observed‬ ‭at‬ ‭the‬ ‭20‬ ‭mg/kg‬ ‭dose‬ ‭level‬ ‭and‬ ‭the‬ ‭incidence‬ ‭and‬
‭intensity‬‭of‬‭AEs‬‭reported‬‭have‬‭not‬‭been‬‭shown‬‭to‬‭be‬‭dependent‬‭on‬‭dose.‬‭A‬‭maximum‬‭tolerated‬
‭dose‬‭has‬‭not‬‭been‬‭established.‬‭Atezolizumab‬‭is‬‭supplied‬‭in‬‭vials‬‭containing‬‭the‬‭fixed‬‭1200‬‭mg‬
‭dose‬‭of‬‭drug‬‭substance,‬‭which‬‭minimizes‬‭the‬‭chance‬‭of‬‭overdose.‬‭Because‬‭the‬‭dose‬‭per‬‭patient‬
‭is‬‭not‬‭based‬‭on‬‭weight‬‭or‬‭body‬‭surface‬‭area,‬‭and‬‭no‬‭dose‬‭calculation‬‭is‬‭required,‬‭the‬‭risk‬‭of‬
‭overdose‬ ‭due‬ ‭to‬ ‭medication‬ ‭errors‬ ‭is‬ ‭minimal.‬ ‭The‬ ‭data‬ ‭available‬ ‭to‬ ‭date‬ ‭suggest‬‭that‬‭the‬
‭potential for harm from overdose is very low.‬
‭Weekly‬ ‭gemcitabine‬ ‭with‬ ‭GC‬ ‭every‬ ‭3-4‬ ‭weeks‬ ‭is‬ ‭considered‬ ‭conventional‬ ‭first-line‬
‭chemotherapy‬‭for‬‭aUC.‬‭Weekly‬‭split-dose‬‭cisplatin‬‭with‬‭wGC‬‭might‬‭be‬‭less‬‭toxic‬‭and‬‭have‬
‭similar‬ ‭activity.‬ ‭Considering‬ ‭the‬ ‭probable‬ ‭lower‬ ‭nephrotoxicity‬ ‭of‬ ‭fractionated‬ ‭cisplatin,‬
‭prospective‬ ‭evaluation‬ ‭of‬ ‭wGC‬ ‭might‬ ‭be‬ ‭warranted‬‭across‬‭cisplatin-eligible‬‭and‬‭-ineligible‬
‭patients‬‭to‬‭develop‬‭a‬‭single‬‭chemotherapy‬‭template‬‭for‬‭the‬‭development‬‭of‬‭combinations‬‭with‬
‭biological agents in a broad population of patients (‬‭Maughan BL, et al. 2013‬‭).‬
‭In‬‭conclusion,‬‭the‬‭proposed‬‭scientific‬‭rationale‬‭and‬‭the‬‭preliminary‬‭benefit-risk‬‭profile‬‭of‬‭the‬
‭study‬ ‭treatments‬ ‭observed‬ ‭in‬ ‭previous‬ ‭trials‬ ‭support‬ ‭the‬ ‭further‬ ‭investigation‬ ‭of‬ ‭the‬
‭combination in the patient population and dosification regimen chosen for this study.‬
‭4.4.‬
‭Study Objectives‬
‭4.4.1. Primary Objectives‬
‭To‬‭evaluate‬‭the‬‭preliminary‬‭efficacy‬‭of‬‭atezolizumab‬‭plus‬‭split-dose‬‭gemcitabine‬‭and‬‭cisplatin‬
‭(GC)‬ ‭for‬ ‭the‬ ‭first-line‬ ‭setting,‬ ‭in‬ ‭patients‬ ‭with‬ ‭histologically‬ ‭confirmed‬ ‭advanced‬ ‭(locally‬
‭advanced‬‭and‬‭metastatic)‬‭urothelial‬‭cancer‬‭in‬‭terms‬‭of‬‭overall‬‭response‬‭rate‬‭(ORR)‬‭assessed‬‭by‬
‭the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.‬
‭4.4.2. Secondary Objectives‬
‭Efficacy:‬
‭●‬ ‭To‬ ‭evaluate‬ ‭the‬ ‭duration‬ ‭of‬ ‭response‬ ‭(DoR)‬ ‭associated‬ ‭with‬ ‭the‬ ‭study‬ ‭treatment,‬
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‭understood‬‭as‬‭the‬‭time‬‭from‬‭first‬‭confirmed‬‭response‬‭(CR‬‭or‬‭PR)‬‭to‬‭the‬‭date‬‭of‬‭the‬
‭documented‬‭progressive‬‭disease‬‭as‬‭determined‬‭using‬‭RECIST‬‭1.1‬‭criteria‬‭or‬‭death‬‭due‬
‭to any cause, whichever occurs first.‬
‭●‬ ‭To‬ ‭determine‬ ‭the‬ ‭overall‬ ‭survival‬ ‭(OS)‬ ‭of‬ ‭patients‬ ‭with‬ ‭locally-advanced‬ ‭or‬ ‭mUC‬
‭treated‬‭with‬‭the‬‭intended‬‭treatment‬‭regimen,‬‭understood‬‭as‬‭the‬‭time‬‭from‬‭first‬‭dosing‬
‭date‬‭to‬‭the‬‭date‬‭of‬‭death.‬‭A‬‭subject‬‭who‬‭has‬‭not‬‭died‬‭will‬‭be‬‭censored‬‭at‬‭the‬‭last‬‭known‬
‭date alive.‬
‭●‬ ‭To‬‭evaluate‬‭the‬‭time‬‭to‬‭response‬‭(TtR)‬‭associated‬‭with‬‭the‬‭study‬‭treatment,‬‭understood‬
‭as‬‭the‬‭time‬‭from‬‭the‬‭first‬‭dose‬‭of‬‭the‬‭study‬‭treatment‬‭and‬‭confirmed‬‭response‬‭(CR‬‭or‬
‭PR) based on RECIST 1.1 criteria.‬
‭●‬ ‭To evaluate the‬‭clinical benefit rate (CBR)‬‭, defined‬‭as the percentage of patients who‬
‭have achieved complete response, partial response and stable disease. Stable disease‬
‭should be maintained for at least 6 months to be considered as a CBR event.‬
‭●‬ ‭To‬‭determine‬‭the‬‭progression-free‬‭survival‬‭(PFS)‬‭of‬‭patients‬‭with‬‭locally-advanced‬‭or‬
‭mUC‬ ‭treated‬ ‭with‬ ‭the‬ ‭intended‬ ‭treatment‬ ‭regimen,‬ ‭defined‬ ‭as‬ ‭the‬ ‭time‬ ‭from‬ ‭first‬
‭dosing‬‭date‬‭until‬‭disease‬‭progression‬‭or‬‭death‬‭from‬‭any‬‭cause.‬‭Patients‬‭who‬‭have‬‭not‬
‭progressed and start a new line of treatment will be censored.‬
‭Safety:‬
‭●‬ ‭To‬ ‭evaluate‬ ‭safety‬ ‭of‬ ‭the‬ ‭intended‬ ‭treatment‬ ‭regimen‬ ‭based‬ ‭on‬ ‭the‬ ‭frequency‬ ‭and‬
‭severity of adverse events assessed by NCI CTCAE v5.0.‬
‭4.‬‭4‬‭.3.‬ ‭Exploratory‬‭objectives‬
‭●‬ ‭To‬ ‭explore‬ ‭potential‬ ‭correlation‬ ‭of‬ ‭efficacy‬ ‭with‬ ‭relevant‬ ‭potential‬ ‭prognostic‬
‭factors/stratification factors‬
‭●‬ ‭To‬ ‭evaluate‬ ‭the‬ ‭relationship‬‭between‬‭the‬‭expression‬‭of‬‭PD-L1and‬‭microbiome‬‭with‬
‭ORR and PFS during experimental treatment.‬
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‭5.‬ ‭STUDY DESIGN‬
‭5.1.‬
‭Study design‬
‭The‬ ‭AUREA‬ ‭study‬ ‭is‬ ‭a‬ ‭multicenter,‬ ‭open‬ ‭labelled,‬‭single‬‭arm,‬‭Phase‬‭II‬‭clinical‬‭trial‬‭of‬‭of‬
‭atezolizumab‬‭in‬‭combination‬‭of‬‭split-dose‬‭cisplatin‬‭plus‬‭gemcitabine‬‭in‬‭patients‬‭with‬‭locally‬
‭advanced‬‭or‬‭metastatic‬‭urothelial‬‭carcinoma‬‭(additional‬‭details‬‭on‬‭the‬‭eligibility‬‭criteria‬‭of‬‭the‬
‭study are found in section 6 of this protocol).‬
‭The‬‭design‬‭includes‬‭screening‬‭phase,‬‭combined‬‭treatment‬‭initial‬‭phase,‬‭monotherapy‬‭treatment‬
‭phase,‬ ‭follow-up‬ ‭phase‬ ‭and‬ ‭translational‬ ‭research‬ ‭with‬ ‭biopsies,‬ ‭blood‬ ‭samples‬ ‭and‬ ‭faecal‬
‭samples.‬
‭The‬ ‭dose‬ ‭scheme‬ ‭includes‬ ‭the‬ ‭initial‬ ‭dose‬ ‭of‬ ‭atezolizumab‬ ‭(1200‬ ‭mg)‬ ‭intravenously‬
‭administered‬ ‭every‬ ‭21‬ ‭days‬ ‭(one‬ ‭cycle)‬‭up‬‭to‬‭disease‬‭progression,‬‭unacceptable‬‭toxicity‬‭or‬
‭absence‬ ‭of‬ ‭clinical‬ ‭benefit.‬ ‭Dose‬ ‭adjustment‬ ‭or‬ ‭dose‬ ‭reductions‬ ‭of‬ ‭atezolizumab‬ ‭are‬ ‭not‬
‭expected.‬‭Additional‬‭information‬‭on‬‭the‬‭treatment,‬‭modifications,‬‭and‬‭dose‬‭delays‬‭is‬‭available‬
‭in‬ ‭section‬ ‭7‬ ‭of‬ ‭this‬ ‭protocol.‬ ‭AUREA‬ ‭is‬ ‭an‬ ‭Investigator‬ ‭Initiated‬ ‭Study,‬ ‭the‬ ‭Sponsor‬ ‭will‬
‭supply‬‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬‭months‬‭of‬‭treatment‬‭for‬‭each‬‭patient.‬‭For‬‭those‬‭patients‬‭in‬
‭which‬‭the‬‭PI‬‭considers‬‭that‬‭the‬‭best‬‭option‬‭for‬‭the‬‭patient‬‭is‬‭continuing‬‭atezolizumab‬‭for‬‭more‬
‭than‬ ‭24‬ ‭months,‬ ‭available‬ ‭commercial‬ ‭Site‬ ‭supplies‬ ‭should‬ ‭be‬ ‭used,‬ ‭after‬ ‭managed‬ ‭local‬
‭administrative regulation.‬
‭Study‬ ‭treatment‬ ‭will‬ ‭begin‬ ‭as‬ ‭soon‬ ‭as‬ ‭possible‬ ‭after‬ ‭signing‬ ‭the‬ ‭informed‬‭consent‬‭(as‬‭per‬
‭section 5.2‬‭of this protocol) and inclusion will be‬‭completed as per‬‭section 5.3‬‭of this protocol.‬
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‭Figure 1. Study design‬
‭5.2.‬
‭Patient selection‬
‭Once‬‭all‬‭regulatory‬‭and‬‭sponsor‬‭requirements‬‭are‬‭completed‬‭confirming‬‭that‬‭the‬‭study‬‭is‬‭fully‬
‭active‬‭in‬‭the‬‭corresponding‬‭site,‬‭informed‬‭consents‬‭can‬‭be‬‭offered‬‭to‬‭potential‬‭patients,‬‭and‬
‭patient selection can start in this site.‬
‭5.3.‬
‭Screening period and screening failure‬
‭Informed‬ ‭consent‬ ‭will‬ ‭be‬ ‭obtained‬ ‭prior‬ ‭to‬ ‭the‬ ‭start‬ ‭of‬ ‭the‬ ‭specified‬ ‭screening‬ ‭window.‬
‭Procedures‬‭conducted‬‭as‬‭part‬‭of‬‭the‬‭subject’s‬‭routine‬‭clinical‬‭management‬‭(e.g..,‬‭blood‬‭count‬
‭determinations‬‭and‬‭imaging‬‭studies)‬‭prior‬‭to‬‭signing‬‭of‬‭ICF‬‭may‬‭be‬‭used‬‭for‬‭screening‬‭or‬‭for‬
‭defining baseline data, provided these procedures are conducted as specified in the protocol.‬
‭Other‬‭procedures‬‭(such‬‭as‬‭the‬‭faecal‬‭sample‬‭collection)‬‭must‬‭be‬‭developed‬‭once‬‭the‬‭patient‬‭has‬
‭provided the signed consent for participation.‬
‭Once‬ ‭ICFs‬ ‭are‬ ‭signed,‬ ‭a‬ ‭trial‬ ‭screening‬ ‭number‬ ‭will‬ ‭be‬ ‭assigned‬ ‭to‬ ‭each‬ ‭patient‬ ‭after‬
‭registering‬ ‭at‬ ‭Electronic‬‭Data‬‭Capture‬‭(EDC)‬‭platform.‬‭Each‬‭site‬‭will‬‭receive‬‭access‬‭to‬‭the‬
‭EDC‬‭platform‬‭to‬‭register‬‭each‬‭screened‬‭case‬‭because‬‭as‬‭per‬‭GCP‬‭guidelines,‬‭it‬‭is‬‭mandatory‬‭to‬
‭register every patient who signs a consent form.‬
‭Furthermore,‬ ‭within‬ ‭the‬ ‭Investigator‬ ‭Site‬ ‭File‬ ‭(ISF),‬ ‭a‬ ‭Patient‬ ‭Identification‬ ‭List‬ ‭will‬ ‭be‬
‭included‬‭in‬‭order‬‭to‬‭identify‬‭patients‬‭according‬‭to‬‭local‬‭normal‬‭practice.‬‭This‬‭document‬‭will‬
‭allow‬ ‭for‬ ‭immediate‬ ‭and‬ ‭unequivocal‬ ‭identification‬ ‭of‬‭patients‬‭participating‬‭in‬‭this‬‭clinical‬
‭trial.‬
‭This‬‭document‬‭will‬‭always‬‭be‬‭stored‬‭under‬‭Investigator‬‭staff‬‭custody‬‭at‬‭the‬‭site.‬‭The‬‭screening‬
‭number‬ ‭will‬ ‭identify‬ ‭patients‬ ‭throughout‬ ‭the‬ ‭screening‬ ‭period‬ ‭while‬ ‭procedures‬ ‭needed‬ ‭to‬
‭confirm‬‭the‬‭subjects’‬‭suitability‬‭for‬‭the‬‭trial‬‭protocol,‬‭such‬‭as‬‭clinical‬‭laboratory‬‭tests,‬‭imaging,‬
‭and others are performed.‬
‭Screening‬‭determinations‬‭should‬‭be‬‭performed‬‭as‬‭per‬‭indications‬‭specified‬‭in‬‭Table‬‭4‬‭include‬
‭ICF‬‭signature,‬‭eligibility‬‭assessments,‬‭tumour‬‭characteristics,‬‭ECG,‬‭clinical‬‭evaluation‬‭(AE,‬
‭PE,‬‭ECOG,‬‭VS,‬‭BMI,‬‭and‬‭symptom‬‭control),‬‭laboratory‬‭determinations‬‭(FBE,‬‭Biochemistry,‬
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‭electrolytes,‬ ‭liver‬ ‭panel‬ ‭TF),‬ ‭Pancreatic‬ ‭enzymes,‬ ‭serology,‬ ‭urinalysis,‬ ‭pregnancy‬ ‭test,‬
‭concomitant‬ ‭medication,‬ ‭biological‬ ‭samples‬ ‭(tumour‬ ‭sample,‬‭biomarkers),‬‭CT‬‭Scan‬‭/‬‭MRI.‬
‭Availability‬ ‭of‬ ‭archival‬ ‭tumor‬ ‭blocks‬ ‭should‬ ‭be‬ ‭verified.‬ ‭Additional‬ ‭information‬ ‭about‬
‭screening procedures can be found in‬‭Section 8.4‬‭of‬‭this protocol.‬
‭5.4.‬
‭Patient registration/enrollment‬
‭After‬ ‭confirming‬ ‭that‬ ‭a‬ ‭patient‬ ‭fulfils‬ ‭all‬ ‭eligibility‬ ‭criteria‬ ‭of‬ ‭the‬ ‭study‬ ‭(‬‭Section‬ ‭6‬‭,‬‭study‬
‭population‬‭),‬ ‭site‬ ‭staff‬ ‭will‬ ‭initiate‬ ‭the‬ ‭electronic‬ ‭case‬ ‭report‬ ‭form‬ ‭(eCRF)‬ ‭registration‬
‭procedure.‬ ‭Once‬ ‭registration‬ ‭has‬ ‭been‬ ‭completed,‬ ‭the‬ ‭site‬ ‭staff‬ ‭will‬ ‭receive‬‭the‬‭“Inclusion‬
‭confirmation‬‭communication”,‬‭and‬‭study‬‭treatment‬‭can‬‭be‬‭initiated‬‭as‬‭per‬‭Section‬‭7‬‭(treatment‬
‭description‬‭).‬
‭5.5.‬
‭Treatment description, doses and schedules‬
‭During‬ ‭treatment,‬ ‭patients‬ ‭should‬ ‭be‬ ‭visited‬ ‭at‬ ‭baseline‬ ‭for‬ ‭administration‬ ‭of‬ ‭the‬ ‭study‬
‭treatment‬‭(Day‬‭1‬‭of‬‭each‬‭cycle)‬‭as‬‭follows:‬‭Atezolizumab‬‭1200‬‭mg,‬‭gemcitabine‬‭1000‬‭mg/m‬‭2‬
‭and‬ ‭cisplatin‬ ‭35‬ ‭mg/m‬‭2‬‭.‬ ‭A‬ ‭second‬ ‭visit‬ ‭on‬ ‭day‬ ‭8‬ ‭(D8)‬ ‭should‬ ‭be‬ ‭compiled‬ ‭in‬ ‭order‬ ‭to‬
‭administer the second dose of gemcitabine 1000 mg/m‬‭2‬‭and cisplatin 35 mg/m‬‭2‬‭cisplatin.‬
‭Atezolizumab‬ ‭will‬ ‭be‬ ‭administered‬ ‭first‬ ‭as‬ ‭a‬ ‭IV‬ ‭infusion‬ ‭according‬ ‭to‬ ‭what‬ ‭is‬ ‭detailed‬‭in‬
‭section‬ ‭7.4‬ ‭of‬ ‭this‬ ‭protocol,‬ ‭followed‬ ‭by‬ ‭the‬ ‭cisplatin‬ ‭infusion‬ ‭and‬ ‭then‬ ‭the‬ ‭gemcitabine‬
‭infusion.‬‭The‬‭GC‬‭infusion‬‭will‬‭start‬‭at‬‭least‬‭30‬‭minutes‬‭after‬‭completion‬‭of‬‭the‬‭atezolizumab‬
‭infusion.‬ ‭At‬ ‭the‬ ‭investigator’s‬ ‭discretion,‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭administered‬‭over‬‭a‬‭longer‬
‭infusion time (60 minutes) if the participant developed a prior infusion reaction.‬
‭This‬‭regimen‬‭will‬‭be‬‭repeated‬‭every‬‭three‬‭weeks‬‭(q3w)‬‭for‬‭up‬‭to‬‭6‬‭cycles.‬‭Once‬‭cycle‬‭6‬‭is‬
‭done,‬ ‭Atezolizumab‬ ‭1200‬ ‭mg/m‬‭2‬ ‭will‬‭be‬‭administered‬‭as‬‭monotherapy‬‭every‬‭3‬‭weeks‬‭until‬
‭disease‬ ‭progression,‬ ‭discontinuation‬ ‭due‬ ‭to‬ ‭unacceptable‬‭toxicity,‬‭withdrawal‬‭of‬‭consent‬‭or‬
‭absence‬‭of‬‭clinical‬‭benefit.‬‭AUREA‬‭is‬‭an‬‭Investigator‬‭Initiated‬‭Study,‬‭the‬‭Sponsor‬‭will‬‭supply‬
‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬‭months‬‭of‬‭treatment‬‭for‬‭each‬‭patient.‬‭For‬‭those‬‭patients‬‭in‬‭which‬
‭the‬‭PI‬‭considers‬‭that‬‭the‬‭best‬‭option‬‭for‬‭the‬‭patient‬‭is‬‭continuing‬‭atezolizumab‬‭for‬‭more‬‭than‬‭24‬
‭months,‬‭available‬‭commercial‬‭Site‬‭supplies‬‭should‬‭be‬‭used,‬‭after‬‭managed‬‭local‬‭administrative‬
‭regulation.‬
‭All‬ ‭chemotherapy‬ ‭agents’‬ ‭preparation,‬ ‭premedication,‬ ‭administration,‬ ‭monitoring,‬ ‭and‬
‭management‬‭of‬‭complications‬‭are‬‭to‬‭follow‬‭local‬‭prescription‬‭guidelines‬‭and‬‭regulations.‬‭The‬
‭dose of chemotherapy may be capped per local standards.‬
‭All‬ ‭participants‬ ‭will‬ ‭be‬ ‭monitored‬ ‭continuously‬ ‭for‬ ‭adverse‬ ‭events‬ ‭(AEs)‬ ‭while‬ ‭on‬ ‭study‬
‭treatment.‬‭Treatment‬‭modifications‬‭(eg,‬‭dose‬‭delay,‬‭reduction,‬‭retreatment,‬‭or‬‭discontinuation)‬
‭will‬‭be‬‭based‬‭on‬‭specific‬‭laboratory‬‭and‬‭adverse‬‭event‬‭criteria,‬‭as‬‭described‬‭in‬‭Section‬‭5.2‬‭and‬
‭Section 5.3‬‭.‬
‭Table 1. AUREA’s trial treatment schedule‬
‭Drug‬
‭Drug‬
‭Frequency‬
‭Administration‬
‭Treatment period‬
‭Use‬
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‭Atezolizumab‬
‭1200 mg‬
‭Q3W‬
‭IV infusion‬
‭Day 1 of each cycle‬
‭Experimental‬
‭Gemcitabine‬
‭1000‬
‭mg/m‬‭2‬‭/day‬
‭Q3W‬
‭IV infusion‬
‭Day 1 and Day 8 of‬
‭each cycle up to 6‬
‭cycles‬
‭Experimental‬
‭Cisplatin‬
‭35 mg/m‬‭2‬‭/day‬
‭Q3W‬
‭IV infusion‬
‭Day 1 and Day 8 of‬
‭each cycle up to 6‬
‭cycles‬
‭Experimental‬
‭5.6.‬
‭Duration of study, recruitment, treatment and follow-up‬
‭●‬ ‭Enrolment/recruitment period: 12 months‬
‭●‬ ‭First patient first visit (FPFV): 8ENE2021‬
‭●‬ ‭Last patient last visit (LPLV): FPFV + 24 months‬
‭●‬ ‭Treatment period: Up to 24 months from LPFV‬
‭●‬ ‭Follow-up period: 24 months‬
‭●‬ ‭Planned end of study date: FPFV + up to 36 months‬
‭5.7.‬
‭Determinations during the study‬
‭Determination‬ ‭during‬ ‭the‬ ‭study‬ ‭will‬ ‭be‬ ‭performed‬ ‭as‬ ‭per‬ ‭Table‬ ‭4‬ ‭and‬ ‭Section‬ ‭8.3‬ ‭of‬‭this‬
‭protocol.‬
‭5.7.1.‬ ‭Screening phase‬
‭The‬ ‭baseline‬ ‭assessments‬ ‭and‬ ‭procedures‬ ‭should‬ ‭be‬ ‭performed‬ ‭within‬ ‭28‬ ‭days‬ ‭before‬
‭inclusion, and when applicable, as close as possible to the start of study treatment.‬
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‭5.7.2.‬ ‭Treatment phase‬
‭Before‬ ‭each‬ ‭treatment‬ ‭administration‬ ‭chemotherapy/atezolizumab‬‭administration‬‭laboratory,‬
‭medical‬ ‭consulting‬ ‭and‬ ‭other‬ ‭determinations‬ ‭will‬ ‭be‬ ‭performed‬ ‭according‬ ‭to‬ ‭Table‬ ‭4‬ ‭and‬
‭Section 8.5‬‭to ensure that treatment can be safely‬‭administered.‬
‭A‬ ‭CT‬ ‭Scan‬ ‭or‬‭MRI‬‭will‬‭be‬‭performed‬‭at‬‭baseline,‬‭on‬‭week‬‭9,‬‭week‬‭18‬‭and‬‭then‬‭every‬‭12‬
‭weeks‬‭(q12w)‬‭±‬‭1w‬‭until‬‭objective‬‭disease‬‭progression‬‭as‬‭per‬‭PI’s‬‭criteria‬‭or‬‭death‬‭(whichever‬
‭comes‬‭first).‬‭Blood‬‭samples‬‭for‬‭biomarkers‬‭studies‬‭should‬‭be‬‭collected‬‭before‬‭administration‬
‭of cycle 4 and at the time of PD (end of treatment if applicable).‬
‭For‬ ‭patients‬ ‭with‬ ‭progression‬ ‭reported‬ ‭as‬ ‭per‬ ‭RECIST‬ ‭criteria‬ ‭at‬ ‭week‬ ‭9,‬ ‭continuity‬ ‭of‬
‭treatment‬‭with‬‭atezolizumab‬‭should‬‭be‬‭evaluated‬‭by‬‭the‬‭PI‬‭of‬‭each‬‭site‬‭as‬‭per‬‭clinical‬‭benefit‬
‭criteria.‬
‭5.7.3.‬ ‭Safety visit (after the end of treatment by any reason)‬
‭Safety‬‭follow-up‬‭visits‬‭will‬‭be‬‭scheduled‬‭up‬‭to‬‭30‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭study‬‭treatment‬
‭(end of treatment).‬
‭5.7.4.‬ ‭Follow up until progression‬
‭After‬‭the‬‭end‬‭of‬‭the‬‭combined‬‭treatment‬‭with‬‭atezolizumab‬‭and‬‭split‬‭dose‬‭of‬‭gemcitabine‬‭and‬
‭cisplatin,‬‭if‬‭the‬‭patient‬‭has‬‭finished‬‭treatment‬‭without‬‭progression‬‭and‬‭does‬‭not‬‭start‬‭a‬‭new‬
‭treatment‬‭line,‬‭will‬‭be‬‭visited‬‭every‬‭12‬‭weeks.‬‭At‬‭the‬‭time‬‭of‬‭progression‬‭blood‬‭samples‬‭should‬
‭be collected for biomarkers studies.‬
‭5.7.5.‬ ‭Follow up after progression‬
‭Overall,‬‭after‬‭progression,‬‭patients‬‭will‬‭continue‬‭the‬‭long-term‬‭follow‬‭up‬‭every‬‭6‬‭months‬‭until‬
‭death‬‭or‬‭end‬‭of‬‭study.‬‭Sponsor‬‭will‬‭ask‬‭the‬‭survival‬‭status‬‭of‬‭all‬‭patients‬‭at‬‭the‬‭final‬‭clinical‬
‭trial‬ ‭database‬ ‭closing,‬ ‭in‬ ‭order‬ ‭to‬ ‭maximise‬ ‭the‬ ‭median‬ ‭follow‬ ‭up‬ ‭of‬ ‭patients‬ ‭for‬ ‭overall‬
‭survival data.‬
‭In‬‭cases‬‭where‬‭atezolizumab‬‭treatment‬‭has‬‭been‬‭maintained‬‭because‬‭of‬‭clinical‬‭benefit,‬‭follow‬
‭up‬‭will‬‭comply‬‭with‬‭the‬‭“Follow‬‭up‬‭until‬‭progression”‬‭conditions,‬‭with‬‭visits‬‭every‬‭12‬‭weeks‬
‭along with radiological evaluation/assessment of the disease.‬
‭5.8.‬
‭End of study (EoS)‬
‭The‬‭end‬‭of‬‭study‬‭is‬‭defined‬‭as‬‭the‬‭Last‬‭Patient‬‭Last‬‭Visit‬‭(LPLV)‬‭and‬‭will‬‭be‬‭considered‬‭at‬‭24‬
‭months‬‭after‬‭last‬‭patient‬‭first‬‭visit‬‭(LPFV),‬‭Sponsor‬‭will‬‭ask‬‭survival‬‭status‬‭of‬‭all‬‭patients‬‭at‬
‭the‬‭final‬‭clinical‬‭trial‬‭database‬‭closing,‬‭in‬‭order‬‭to‬‭maximise‬‭the‬‭median‬‭follow‬‭up‬‭of‬‭patients‬
‭for overall survival data.‬
‭5.9.‬
‭Outcome assessments‬
‭5.9.1. Response evaluation according RECIST 1.1‬
‭All‬‭patients‬‭will‬‭have‬‭their‬‭best‬‭response‬‭according‬‭to‬‭RECIST‬‭criteria‬‭1.1‬‭from‬‭the‬‭start‬‭of‬
‭study treatment until the end of treatment classified as outlined below:‬
‭●‬ ‭Complete‬‭or‬‭partial‬‭responses‬‭may‬‭be‬‭claimed‬‭only‬‭if‬‭the‬‭criteria‬‭for‬‭each‬‭are‬‭met‬‭at‬‭a‬
‭subsequent time point at least 4 weeks later.‬
‭●‬ ‭Complete‬ ‭Response‬ ‭(CR):‬ ‭disappearance‬ ‭of‬ ‭all‬ ‭target‬ ‭and‬ ‭non-target‬ ‭lesions‬ ‭and‬
‭normalization‬ ‭of‬ ‭tumour‬ ‭markers.‬ ‭Pathological‬ ‭lymph‬ ‭nodes‬ ‭must‬ ‭have‬ ‭short‬ ‭axis‬
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‭measures‬ ‭<‬ ‭10‬ ‭mm‬ ‭(‬‭Note‬‭:‬ ‭continue‬ ‭to‬ ‭record‬ ‭the‬ ‭measurement‬‭even‬‭if‬‭<‬‭10‬‭mm‬‭and‬
‭considered‬ ‭CR).‬ ‭Tumour‬ ‭markers‬ ‭must‬ ‭have‬ ‭normalized.‬ ‭Residual‬ ‭lesions‬ ‭(other‬ ‭than‬
‭nodes‬‭<‬‭10‬‭mm)‬‭thought‬‭to‬‭be‬‭non-malignant‬‭should‬‭be‬‭further‬‭investigated‬‭(by‬‭cytology‬
‭or PET scans) before CR can be accepted.‬
‭●‬ ‭Partial‬‭Response‬‭(PR):‬‭at‬‭least‬‭a‬‭30%‬‭decrease‬‭in‬‭the‬‭sum‬‭of‬‭measures‬‭(longest‬‭diameter‬
‭for‬‭tumour‬‭lesions‬‭and‬‭short‬‭axis‬‭measure‬‭for‬‭nodes)‬‭of‬‭target‬‭lesions,‬‭taking‬‭as‬‭reference‬
‭the baseline sum of diameters. Non target lesions must be non-PD.‬
‭●‬ ‭Stable‬‭Disease‬‭(SD):‬‭Neither‬‭sufficient‬‭shrinkage‬‭to‬‭qualify‬‭for‬‭PR‬‭nor‬‭sufficient‬‭increase‬
‭to qualify for PD taking as reference the smallest sum of diameters on study.‬
‭●‬ ‭Progressive‬‭Disease‬‭(PD):‬‭at‬‭least‬‭a‬‭20%‬‭increase‬‭in‬‭the‬‭sum‬‭of‬‭diameters‬‭of‬‭measured‬
‭lesions‬‭taking‬‭as‬‭references‬‭the‬‭smallest‬‭sum‬‭of‬‭diameters‬‭recorded‬‭on‬‭study‬‭(including‬
‭baseline)‬ ‭AND‬ ‭an‬ ‭absolute‬ ‭increase‬ ‭of‬ ‭≥‬ ‭5‬ ‭mm.‬‭Appearance‬‭of‬‭new‬‭lesions‬‭will‬‭also‬
‭constitute‬ ‭PD‬ ‭(including‬ ‭lesions‬ ‭in‬ ‭previously‬ ‭unassessed‬ ‭areas).‬ ‭In‬ ‭exceptional‬
‭circumstances,‬ ‭unequivocal‬ ‭progression‬ ‭of‬ ‭non-target‬ ‭disease‬ ‭may‬ ‭be‬ ‭accepted‬ ‭as‬
‭evidence‬ ‭of‬ ‭disease‬ ‭progression,‬ ‭where‬ ‭the‬ ‭overall‬ ‭tumour‬ ‭burden‬ ‭has‬ ‭increased‬
‭sufficiently‬‭to‬‭merit‬‭discontinuation‬‭of‬‭treatment,‬‭for‬‭example‬‭where‬‭the‬‭tumour‬‭burden‬
‭appears‬‭to‬‭have‬‭increased‬‭by‬‭at‬‭least‬‭73%‬‭in‬‭volume‬‭(which‬‭is‬‭the‬‭increase‬‭in‬‭volume‬
‭when‬‭all‬‭dimensions‬‭of‬‭a‬‭single‬‭lesion‬‭increase‬‭by‬‭20%).‬‭Modest‬‭increases‬‭in‬‭the‬‭size‬‭of‬
‭one‬ ‭or‬ ‭more‬ ‭non-target‬ ‭lesions‬ ‭are‬ ‭NOT‬ ‭considered‬ ‭unequivocal‬ ‭progression.‬ ‭If‬ ‭the‬
‭evidence‬‭of‬‭PD‬‭is‬‭equivocal‬‭(target‬‭or‬‭non-target),‬‭treatment‬‭may‬‭continue‬‭until‬‭the‬‭next‬
‭assessment, but on further documentation, the earlier date must be used.‬
‭5.9.2.‬ ‭Safety assessments‬
‭Safety‬ ‭parameters‬ ‭are‬ ‭AE,‬ ‭SAE,‬ ‭AESI,‬ ‭pregnancy,‬ ‭medication‬ ‭error,‬ ‭overdose.‬ ‭Additional‬
‭safety‬‭information‬‭could‬‭be‬‭derived‬‭from‬‭ECG,‬‭lab‬‭test,‬‭pregnancy‬‭test,‬‭or‬‭vital‬‭sign‬‭exam.‬
‭The‬‭assessment‬‭of‬‭adverse‬‭events‬‭will‬‭include‬‭the‬‭type‬‭of‬‭event‬‭(including‬‭symptoms,‬‭physical‬
‭exam‬‭findings‬‭and‬‭laboratory‬‭abnormalities),‬‭the‬‭incidence,‬‭severity,‬‭timing,‬‭seriousness,‬‭and‬
‭relatedness‬‭regarding‬‭the‬‭treatment‬‭under‬‭study.‬‭Adverse‬‭events‬‭will‬‭be‬‭recorded‬‭and‬‭reported‬
‭in‬‭the‬‭corresponding‬‭section‬‭of‬‭the‬‭case‬‭report‬‭form.‬‭The‬‭grade‬‭of‬‭adverse‬‭events‬‭will‬‭be‬‭coded‬
‭according‬ ‭to‬ ‭the‬ ‭National‬ ‭Cancer‬ ‭Institute’s‬ ‭Common‬ ‭Toxicity‬ ‭criteria‬ ‭(NCI-CTCAE‬ ‭v5.0‬
‭scoring‬ ‭system).‬ ‭The‬ ‭worst‬ ‭toxicity‬ ‭score‬ ‭will‬ ‭be‬ ‭recorded.‬ ‭In‬‭case‬‭of‬‭SAE‬‭and‬‭AESI‬‭the‬
‭investigator‬‭should‬‭immediately‬‭fill‬‭in‬‭the‬‭dedicated‬‭SAE‬‭form‬‭and‬‭send‬‭it‬‭by‬‭as‬‭detailed‬‭in‬
‭Section 9.2‬
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‭6.‬
‭STUDY POPULATION‬
‭6.1.‬
‭Inclusion criteria‬
‭1.‬ ‭Male or female subjects ≥ 18 years old.‬
‭2.‬ ‭Written‬‭informed‬‭consent‬‭approved‬‭by‬‭the‬‭Independent‬‭Ethics‬‭Committee‬‭(IEC),‬‭prior‬
‭to the performance of any trial activities.‬
‭3.‬ ‭Patients‬ ‭with‬ ‭histologically‬ ‭documented,‬ ‭locally‬ ‭advanced‬ ‭(T4B,‬ ‭any‬ ‭N;‬ ‭or‬ ‭any‬‭T,‬
‭N2-3) or metastatic urothelial carcinoma (M1, Stage IV)*.‬
‭*Also‬‭termed‬‭transitional‬‭cell‬‭carcinoma‬‭(TCC)‬‭or‬‭urothelial‬‭cell‬‭carcinoma‬‭[UCC]‬‭of‬
‭the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra).‬
‭4.‬ ‭Patients‬‭should‬‭not‬‭be‬‭eligible‬‭(unfit)‬‭for‬‭full‬‭dose‬‭of‬‭cisplatin,‬‭in‬‭the‬‭investigator’s‬
‭judgement, based on:‬
‭a.‬ ‭Age older than 70 years‬
‭a.‬ ‭ECOG‬ ‭Performance‬ ‭status‬ ‭(PS)‬ ‭2‬ ‭or‬ ‭Karnofsky‬ ‭PS‬‭of‬‭60‬‭-‬‭70%‬ ‭(only‬‭15‬
‭patients will be included with ECOG 2)‬
‭b.‬ ‭Measured‬ ‭creatinine‬ ‭clearance‬ ‭(ClCr)‬ ‭>‬ ‭30‬ ‭and‬ ‭<‬ ‭60‬ ‭mL/min‬ ‭by‬ ‭the‬
‭Cockcroft-Gault‬ ‭formula‬ ‭(Cockcroft‬ ‭and‬ ‭Gault‬ ‭1976)‬ ‭or‬ ‭by‬ ‭24-hour‬ ‭urine‬
‭collection for the determination of creatinine clearance:‬
‭Males:‬
‭Creatinine CL (mL/min)  =‬
‭Weight (kg) × (140 – Age)‬
‭72 x serum creatinine (mg/dL)‬
‭Females:‬
‭Creatinine CL (mL/min)  =‬
‭Weight (kg) × (140 – Age)‬‭×0.85‬
‭72 x serum creatinine (mg/dL)‬
‭c.‬ ‭Any‬‭other‬‭reason‬‭the‬‭physician‬‭considers‬‭but‬‭should‬‭specify‬‭in‬‭the‬‭CRF‬‭and‬
‭discussed with the PI.‬
‭5.‬ ‭At‬ ‭least‬ ‭one‬ ‭measurable‬ ‭lesion‬ ‭through‬ ‭radiographic‬‭tumor‬‭evaluation‬‭(CT‬‭scan‬‭or‬
‭magnetic‬ ‭resonance‬ ‭imaging)‬‭as‬‭defined‬‭by‬‭RECIST‬‭version‬‭1.1,‬‭that‬‭has‬‭not‬‭been‬
‭previously irradiated within 4 weeks prior to the study enrolment.‬
‭6.‬ ‭Patients‬ ‭with‬ ‭an‬ ‭archival‬ ‭or‬ ‭de‬ ‭novo‬ ‭tumor‬ ‭biopsy‬ ‭(representative‬ ‭formalin-fixed‬
‭paraffin-embedded/FFPE‬ ‭paraffin‬ ‭block‬ ‭obtained‬ ‭as‬‭close‬‭as‬‭possible‬‭to‬‭the‬‭patient‬
‭inclusion)‬‭with‬‭an‬‭associated‬‭pathology‬‭report,‬‭for‬‭testing‬‭of‬‭PD-L1‬‭expression‬‭prior‬
‭to‬ ‭study‬ ‭enrollment.‬ ‭Samples‬ ‭in‬ ‭unstained‬ ‭slides‬ ‭could‬ ‭be‬ ‭acceptable‬ ‭(at‬ ‭least‬ ‭15‬
‭slides).‬
‭7.‬ ‭Patients with adequate normal organ and marrow function as defined below:‬
‭a.‬ ‭Haemoglobin (Hb) ≥ 9.0 g/dL.‬
‭b.‬ ‭Absolute neutrophil count (ANC)‬‭>‬‭1500 per mm‬‭3‬‭.‬
‭c.‬ ‭Platelet count ≥ 100,000 per mm‬‭3‬‭.‬
‭d.‬ ‭Serum‬‭bilirubin‬‭≤‬‭1.5‬‭X‬‭institutional‬‭upper‬‭limit‬‭of‬‭normal‬‭(ULN)‬‭unless‬‭liver‬
‭metastases‬ ‭are‬ ‭present,‬ ‭in‬ ‭which‬ ‭case‬ ‭it‬‭must‬‭be‬‭≤‬‭2X‬‭ULN.‬‭This‬‭will‬‭not‬
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‭apply‬‭to‬‭patients‬‭with‬‭confirmed‬‭Gilbert’s‬‭syndrome‬‭(persistent‬‭or‬‭recurrent‬
‭hyperbilirubinemia‬ ‭that‬ ‭is‬ ‭predominantly‬ ‭unconjugated‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬
‭haemolysis‬ ‭or‬ ‭hepatic‬ ‭pathology);‬ ‭however,‬ ‭they‬ ‭will‬ ‭be‬ ‭allowed‬ ‭only‬ ‭in‬
‭consultation with their physician.‬
‭e.‬ ‭Serum‬‭transaminases‬‭(ALT,‬‭AST‬‭and‬‭GGT)‬‭≤‬‭2.5X‬‭institutional‬‭upper‬‭limit‬‭of‬
‭normal‬ ‭unless‬ ‭liver‬ ‭metastases‬ ‭are‬ ‭present,‬ ‭in‬ ‭which‬ ‭case‬‭it‬‭must‬‭be‬‭≤‬‭3X‬
‭ULN.‬
‭8.‬ ‭No major active bleeding.‬
‭9.‬ ‭Female‬ ‭subjects‬ ‭of‬ ‭childbearing‬ ‭potential‬ ‭(not‬ ‭surgically‬ ‭sterile‬ ‭or‬ ‭at‬ ‭least‬‭2‬‭years‬
‭postmenopausal)‬‭must‬‭provide‬‭a‬‭negative‬‭urine‬‭pregnancy‬‭test‬‭at‬‭screening,‬‭and‬‭use‬‭a‬
‭medically‬ ‭accepted‬ ‭double‬ ‭barrier‬ ‭method‬ ‭of‬ ‭contraception‬ ‭(i.e.‬ ‭condom‬ ‭with‬
‭spermicide‬‭+‬‭IUD‬‭or‬‭cervical‬‭caps).‬‭In‬‭addition,‬‭they‬‭must‬‭agree‬‭to‬‭continue‬‭the‬‭use‬‭of‬
‭this‬ ‭double‬ ‭barrier‬ ‭method‬ ‭for‬ ‭the‬ ‭duration‬ ‭of‬ ‭the‬ ‭study‬ ‭and‬ ‭for‬ ‭6‬ ‭months‬ ‭after‬
‭participation in the study.‬
‭10.‬‭Males‬‭should‬‭agree‬‭to‬‭abstain‬‭from‬‭sexual‬‭intercourse‬‭with‬‭a‬‭female‬‭partner‬‭or‬‭agree‬
‭to‬ ‭use‬ ‭a‬ ‭double‬ ‭barrier‬ ‭method‬ ‭of‬ ‭contraception‬ ‭(i.e.‬ ‭condom‬ ‭with‬ ‭spermicide,‬ ‭in‬
‭addition‬‭to‬‭having‬‭their‬‭female‬‭partner‬‭use‬‭some‬‭contraceptive‬‭measures‬‭such‬‭as‬‭oral‬
‭contraceptive‬ ‭drugs,‬ ‭intrauterine‬ ‭device‬ ‭(IUD)‬ ‭hormonal‬ ‭contraception,‬ ‭or‬ ‭cervical‬
‭caps), for the duration of the study and for 6 months after participation in the study‬
‭11.‬ ‭Willingness‬‭and‬‭ability‬‭of‬‭patients‬‭to‬‭comply‬‭with‬‭the‬‭protocol‬‭for‬‭the‬‭duration‬‭of‬‭the‬
‭study‬‭including‬‭undergoing‬‭treatment‬‭as‬‭well‬‭as‬‭availability‬‭for‬‭scheduled‬‭visits‬‭and‬
‭examinations including follow up.‬
‭6.2.‬
‭Exclusion criteria‬
‭1.‬ ‭Prior‬‭treatment‬‭with‬‭any‬‭immune‬‭checkpoint‬‭inhibitor‬‭therapy‬‭(e.g.,‬‭CTLA4,‬‭PD-1,‬‭or‬
‭PD-L1 targeting agent).*‬
‭*‬‭Note‬‭:‬ ‭Prior‬ ‭adjuvant‬ ‭or‬ ‭neoadjuvant‬ ‭treatment‬ ‭with‬ ‭targeted‬ ‭therapy/checkpoint‬
‭inhibitors‬‭is‬‭allowed,‬‭as‬‭long‬‭as‬‭the‬‭last‬‭dose‬‭was‬‭administered‬‭at‬‭least‬‭12‬‭months‬‭prior‬
‭to the patient inclusion in this trial.‬
‭2.‬ ‭Presence‬‭of‬‭active‬‭second‬‭malignancy‬‭and/or‬‭prior‬‭malignancy‬‭in‬‭the‬‭last‬‭2‬‭years‬‭is‬
‭allowed except for the following:‬
‭a.‬ ‭adequately treated basal cell or squamous cell skin cancer,‬
‭b.‬ ‭adequately‬‭treated‬‭Stage‬‭I‬‭or‬‭II‬‭cancer‬‭from‬‭which‬‭the‬‭patient‬‭is‬‭currently‬‭in‬
‭complete remission per investigators' clinical judgment.‬
‭3.‬ ‭Patient receiving radiation therapy within 4 weeks before inclusion.‬
‭4.‬ ‭Active‬ ‭or‬ ‭prior‬ ‭documented‬ ‭autoimmune‬ ‭disease‬ ‭within‬ ‭the‬ ‭past‬ ‭2‬ ‭years‬ ‭NOTE:‬
‭Subjects‬‭with‬‭vitiligo,‬‭Grave's‬‭disease,‬‭or‬‭psoriasis‬‭not‬‭requiring‬‭systemic‬‭treatment‬
‭(within the past 2 years) are not excluded.‬
‭5.‬ ‭Active‬ ‭or‬ ‭prior‬ ‭documented‬ ‭inflammatory‬ ‭bowel‬ ‭disease‬‭(e.g.,‬‭Crohn's‬‭disease‬‭and‬
‭ulcerative colitis).‬
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‭6.‬ ‭History of allogeneic organ transplant.‬
‭7.‬ ‭Subjects‬ ‭having‬ ‭a‬ ‭diagnosis‬ ‭of‬‭immunodeficiency‬‭or‬‭are‬‭receiving‬‭systemic‬‭steroid‬
‭therapy‬‭or‬‭any‬‭other‬‭form‬‭of‬‭immunosuppressive‬‭therapy‬‭within‬‭28‬‭days‬‭prior‬‭to‬‭the‬
‭first dose of trial treatment.‬
‭8.‬ ‭Current‬ ‭or‬ ‭prior‬ ‭use‬ ‭of‬ ‭immunosuppressive‬ ‭medication‬ ‭within‬ ‭7‬ ‭days‬ ‭prior‬ ‭to‬
‭enrolment, except the following:‬
‭a.‬ ‭Intranasal,‬ ‭inhaled,‬ ‭topical‬ ‭steroids,‬ ‭or‬ ‭local‬ ‭steroid‬ ‭injections‬ ‭(eg,‬
‭intra-articular injection);‬
‭i.‬
‭Systemic‬ ‭corticosteroids‬ ‭at‬ ‭physiologic‬ ‭doses‬ ‭≤10‬ ‭mg/day‬ ‭of‬
‭prednisone or equivalent;‬
‭ii.‬
‭Steroids‬‭as‬‭premedication‬‭for‬‭hypersensitivity‬‭reactions‬‭(eg,‬‭CT‬‭scan‬
‭premedication).‬
‭9.‬ ‭The‬‭subject‬‭has‬‭uncontrolled,‬‭significant‬‭intercurrent‬‭or‬‭recent‬‭illness‬‭(within‬‭6‬‭months‬
‭prior to inclusion) including, but not limited to, the following conditions:‬
‭a.‬ ‭Cardiovascular disorders:‬
‭i.‬
‭Class‬‭3‬‭or‬‭4‬‭congestive‬‭heart‬‭failure‬‭as‬‭defined‬‭by‬‭the‬‭New‬‭York‬‭Heart‬
‭Association,‬
‭unstable‬
‭angina‬
‭pectoris,‬
‭and‬
‭serious‬
‭cardiac‬
‭arrhythmias.‬
‭ii.‬
‭Uncontrolled‬‭hypertension‬‭defined‬‭as‬‭sustained‬‭blood‬‭press‬‭>‬‭150‬‭mm‬
‭hg‬‭systolic‬‭or‬‭>‬‭100‬‭mm‬‭hg‬‭diastolic‬‭despite‬‭optimal‬‭antihypertensive‬
‭treatment.‬
‭iii.‬
‭Stroke‬ ‭(including‬ ‭transient‬ ‭ischemic‬ ‭attack‬ ‭[TIA]),‬ ‭myocardial‬
‭infarction,‬‭other‬‭ischemic‬‭event,‬‭or‬‭thromboembolic‬‭event‬‭(e.g.,‬‭deep‬
‭venous‬‭thrombosis‬‭[DVT]‬‭and‬‭pulmonary‬‭embolism)‬‭within‬‭6‬‭months‬
‭before‬‭inclusion.‬‭Subjects‬‭with‬‭a‬‭more‬‭recent‬‭diagnosis‬‭of‬‭DVT‬‭are‬
‭allowed‬‭if‬‭stable,‬‭asymptomatic,‬‭and‬‭treated‬‭with‬‭LMWH‬‭for‬‭at‬‭least‬
‭6 weeks before study treatment.‬
‭b.‬ ‭Gastrointestinal‬ ‭disorders‬ ‭(e.g.,‬ ‭malabsorption‬ ‭syndrome‬ ‭or‬ ‭gastric‬ ‭outlet‬
‭obstruction)‬ ‭including‬ ‭those‬ ‭associated‬ ‭with‬ ‭a‬ ‭high‬ ‭risk‬ ‭of‬ ‭perforation‬ ‭or‬
‭fistula formulation:‬
‭i.‬
‭Tumours‬ ‭invading‬ ‭the‬ ‭GI‬ ‭tract,‬ ‭active‬ ‭peptic‬ ‭ulcer‬ ‭disease,‬
‭inflammatory‬
‭bowel‬
‭disease,‬
‭ulcerative‬
‭colitis,‬ ‭diverticulitis,‬
‭cholecystitis,‬
‭symptomatic‬
‭cholangitis‬
‭or‬
‭appendicitis,‬
‭acute‬
‭pancreatitis‬‭or‬‭acute‬‭obstruction‬‭of‬‭the‬‭pancreatic‬‭or‬‭biliary‬‭duct,‬‭or‬
‭gastric outlet obstruction.‬
‭ii.‬
‭Abdominal‬
‭fistula,‬
‭GI‬
‭perforation,‬
‭bowel‬
‭obstruction,‬
‭or‬
‭intra-abdominal‬ ‭abscess‬ ‭within‬ ‭6‬ ‭months‬ ‭before‬ ‭inclusion.‬ ‭Note:‬
‭complete‬ ‭healing‬ ‭of‬ ‭an‬ ‭intra-abdominal‬ ‭abscess‬ ‭must‬‭be‬‭confirmed‬
‭prior to start of the treatment.‬
‭c.‬ ‭Clinically‬‭significant‬‭hematemesis‬‭or‬‭hemoptysis‬‭of‬‭>‬‭0.5‬‭teaspoon‬‭(>‬‭2.5‬‭ml)‬
‭of‬‭red‬‭blood‬‭or‬‭history‬‭of‬‭other‬‭significant‬‭bleeding‬‭within‬‭3‬‭months‬‭before‬
‭treatment.‬
‭d.‬ ‭Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.‬
‭e.‬ ‭Lesions invading major pulmonary blood vessels.‬
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‭f.‬
‭Other clinically significant disorders such as:‬
‭i.‬
‭Active‬ ‭infection‬‭requiring‬‭systemic‬‭treatment,‬‭infection‬‭with‬‭human‬
‭immunodeficiency‬
‭virus‬
‭or‬
‭acquired‬
‭immunodeficiency‬
‭syndrome-related illness, or chronic hepatitis B or C infection.‬
‭ii.‬
‭Serious non-healing wound/ulcer/bone fracture.‬
‭iii.‬
‭Malabsorption syndrome.‬
‭iv.‬
‭Moderate to severe hepatic impairment (child-pugh B or C).‬
‭v.‬
‭Requirement for hemodialysis or peritoneal dialysis.‬
‭vi.‬
‭Uncontrolled diabetes mellitus.‬
‭10.‬‭Major‬‭surgery‬‭(e.g.,‬‭GI‬‭surgery‬‭and‬‭removal‬‭or‬‭biopsy‬‭of‬‭brain‬‭metastasis)‬‭within‬‭8‬
‭weeks‬ ‭before‬ ‭inclusion.‬ ‭Complete‬ ‭wound‬ ‭healing‬ ‭from‬ ‭major‬ ‭surgery‬ ‭must‬ ‭have‬
‭occurred‬ ‭4‬ ‭weeks‬ ‭before‬ ‭study‬ ‭treatment‬ ‭and‬ ‭from‬ ‭minor‬ ‭surgery‬ ‭(e.g.,‬ ‭simple‬
‭excision,‬ ‭tooth‬ ‭extraction)‬ ‭at‬ ‭least‬ ‭10‬ ‭days‬ ‭before‬ ‭study‬ ‭treatment.‬ ‭Subjects‬ ‭with‬
‭clinically relevant ongoing complications from prior surgery are not eligible.‬
‭11.‬ ‭Known‬ ‭human‬ ‭immunodeficiency‬ ‭virus‬ ‭(HIV)‬ ‭or‬ ‭acquired‬ ‭immunodeficiency‬
‭syndrome (AIDS)-related illness.‬
‭12.‬‭Any‬‭test‬‭for‬‭hepatitis‬‭B‬‭virus‬‭(HBV)‬‭or‬‭hepatitis‬‭C‬‭virus‬‭(HCV)‬‭indicating‬‭acute‬‭or‬
‭chronic infection.‬
‭13.‬‭Women who are pregnant or are breastfeeding.‬
‭14.‬‭Male‬‭patients‬‭must‬‭be‬‭surgically‬‭sterile‬‭or‬‭must‬‭agree‬‭to‬‭use‬‭effective‬‭contraception‬
‭during the period of therapy.‬
‭15.‬‭Any‬ ‭of‬ ‭the‬ ‭following‬ ‭within‬ ‭6‬ ‭months‬ ‭prior‬ ‭to‬ ‭study‬‭entry:‬‭myocardial‬‭infarction,‬
‭uncontrolled‬ ‭angina,‬ ‭uncontrolled‬ ‭hypertension,‬ ‭coronary/peripheral‬ ‭artery‬ ‭bypass‬
‭graft,‬ ‭symptomatic‬ ‭congestive‬ ‭heart‬ ‭failure,‬ ‭cerebrovascular‬ ‭accident‬ ‭or‬ ‭transient‬
‭ischemic attack.‬
‭16.‬‭Previously‬‭identified‬‭allergy‬‭or‬‭hypersensitivity‬‭to‬‭components‬‭of‬‭the‬‭study‬‭treatment‬
‭formulations.‬
‭6.3.‬
‭Criteria for withdrawal from the treatment and study‬
‭6.3.1. Permanent Interruption of study treatments‬
‭Any‬ ‭reason‬ ‭for‬ ‭discontinuing‬ ‭investigational‬ ‭products‬ ‭must‬ ‭be‬ ‭clearly‬ ‭recorded‬ ‭on‬ ‭the‬
‭electronic case report forms (eCRF).‬
‭Patients‬‭will‬‭receive‬‭the‬‭product‬‭under‬‭investigation‬‭as‬‭per‬‭schedule‬‭described‬‭in‬‭section‬‭5.5‬‭of‬
‭this protocol or until any of the following occurs:‬
‭●‬ ‭Objective‬‭disease‬‭progression‬‭.‬‭However,‬‭patients‬‭with‬‭disease‬‭progression‬‭at‬
‭week‬‭9‬‭who‬‭are‬‭continuing‬‭to‬‭derive‬‭clinical‬‭benefit‬‭from‬‭the‬‭study‬‭treatment‬‭will‬‭be‬
‭eligible‬ ‭to‬ ‭continue‬ ‭with‬ ‭single-agent‬ ‭atezolizumab,‬ ‭provided‬ ‭that‬ ‭the‬ ‭treating‬
‭physician has determined that the benefit/risk for doing so is favorable;‬
‭●‬ ‭Global deterioration of health status requiring discontinuation‬‭;‬
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‭●‬ ‭Unacceptable‬‭toxicity.‬‭If‬‭the‬‭unacceptable‬‭toxicity‬‭is‬‭attributed‬‭to‬‭one‬‭of‬‭the‬
‭two‬‭study‬‭treatments,‬‭the‬‭investigator‬‭(in‬‭discussion‬‭with‬‭the‬‭sponsor)‬‭may‬‭continue‬
‭treatment with the other study treatment;‬
‭●‬ ‭Investigator’s decision;‬
‭●‬ ‭Pregnancy;‬
‭●‬ ‭Protocol‬‭violation,‬‭only‬‭when‬‭non-compliance‬‭might‬‭significantly‬‭impact‬‭in‬
‭patients‬ ‭safety‬ ‭and/or‬ ‭trial‬ ‭results‬ ‭validity,‬ ‭as‬ ‭per‬ ‭case‬ ‭by‬ ‭case‬ ‭Sponsor‬
‭assessment/criteria;‬
‭●‬ ‭Lost to follow-up;‬
‭●‬ ‭Patient refused further treatment (follow-up permitted by patient);‬
‭●‬ ‭Study terminated by sponsor;‬
‭●‬ ‭Death.‬
‭For‬‭all‬‭participants,‬‭global‬‭deterioration‬‭of‬‭health‬‭status‬‭requiring‬‭discontinuation‬‭of‬
‭treatment‬‭without‬‭objective‬‭evidence‬‭of‬‭disease‬‭progression‬‭at‬‭that‬‭time‬‭should‬‭be‬‭reported‬‭as‬
‭‘symptomatic deterioration’ in the source data and in the eCRF.‬
‭A‬‭temporary‬‭interruption‬‭in‬‭study‬‭medication‬‭due‬‭to‬‭an‬‭AE‬‭is‬‭not‬‭considered‬‭to‬‭be‬‭permanent‬
‭discontinuation from investigational product.‬
‭Tumor‬‭assessments‬‭for‬‭participants,‬‭who‬‭discontinue‬‭study‬‭treatment‬‭without‬‭radiographic‬
‭progression, should continue as per protocol until radiographic progression is determined.‬
‭Chemotherapy‬ ‭dose‬ ‭reduction‬ ‭is‬ ‭allowed‬‭in‬‭study.‬‭Any‬‭participant‬‭with‬‭two‬‭prior‬‭dose‬
‭reductions‬‭to‬‭one‬‭agent‬‭who‬‭experiences‬‭a‬‭toxicity‬‭that‬‭would‬‭cause‬‭a‬‭third‬‭dose‬‭reduction‬
‭must‬ ‭be‬ ‭discontinued‬ ‭from‬ ‭that‬ ‭agent.‬ ‭A‬ ‭participant‬ ‭who‬ ‭is‬ ‭discontinued‬ ‭from‬ ‭the‬
‭chemotherapy treatment will remain on the study and receive atezolizumab.‬
‭If‬ ‭a‬ ‭participant‬ ‭meets‬ ‭criteria‬ ‭for‬ ‭discontinuation‬ ‭and‬ ‭the‬ ‭investigator‬ ‭is‬ ‭unable‬‭to‬
‭determine‬‭whether‬‭the‬‭event‬‭is‬‭related‬‭to‬‭atezolizumab‬‭or‬‭chemotherapy,‬‭the‬‭participant‬‭should‬
‭discontinue all treatments.‬
‭The‬‭assessment‬‭for‬‭discontinuation‬‭of‬‭atezolizumab‬‭should‬‭be‬‭made‬‭separately‬‭from‬
‭the‬‭assessment‬‭made‬‭for‬‭discontinuation‬‭of‬‭chemotherapy.‬‭If‬‭criteria‬‭for‬‭discontinuation‬‭for‬
‭atezolizumab‬‭are‬‭met‬‭before‬‭the‬‭first‬‭6‬‭atezolizumab‬‭+‬‭split-doses‬‭of‬‭gemcitabine‬‭and‬‭cisplatin‬
‭chemotherapy‬ ‭cycles‬ ‭have‬ ‭been‬ ‭completed,‬ ‭the‬ ‭split-dose‬ ‭GC‬ ‭chemotherapy‬‭may‬‭continue‬
‭until 6 cycles have been completed.‬
‭6.3.2. Withdrawal from the study‬
‭Subjects‬ ‭will‬ ‭be‬ ‭encouraged‬ ‭to‬ ‭complete‬ ‭the‬ ‭study;‬‭however,‬‭they‬‭may‬‭voluntarily‬
‭withdraw at any time.‬
‭The‬ ‭investigator‬ ‭may‬ ‭also,‬ ‭at‬ ‭his/her‬ ‭discretion,‬ ‭withdraw‬ ‭the‬ ‭subject‬ ‭from‬
‭participating in this study at any time, or the sponsor may discontinue the study.‬
‭Reasons for early withdrawal from the study should be documented in the eCRF as:‬
‭●‬ ‭Study closed/terminated by sponsor;‬
‭●‬ ‭Lost to follow-up;‬
‭●‬ ‭Investigator’s decision;‬
‭●‬ ‭Subject withdrew consent (refused further follow-up);‬
‭●‬ ‭Major‬‭protocol‬‭non-compliance.‬‭Protocol‬‭violation,‬‭only‬‭when‬‭non-compliance‬‭might‬
‭significantly‬‭impact‬‭in‬‭patients‬‭safety‬‭and/or‬‭trial‬‭results‬‭validity,‬‭as‬‭per‬‭case‬‭by‬‭case‬
‭Sponsor assessment/criteria;‬
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‭●‬ ‭Death.‬
‭If‬‭a‬‭patient‬‭does‬‭not‬‭return‬‭for‬‭a‬‭scheduled‬‭visit,‬‭every‬‭effort‬‭should‬‭be‬‭made‬‭to‬‭contact‬‭the‬
‭patient.‬‭All‬‭attempts‬‭to‬‭contact‬‭the‬‭patient‬‭and‬‭information‬‭received‬‭during‬‭contact‬‭attempts‬
‭must‬‭be‬‭documented‬‭in‬‭the‬‭patient’s‬‭medical‬‭record.‬‭In‬‭any‬‭circumstances,‬‭every‬‭effort‬‭should‬
‭be‬‭made‬‭to‬‭document‬‭patient‬‭outcomes,‬‭if‬‭possible.‬‭The‬‭investigator‬‭should‬‭inquire‬‭about‬‭the‬
‭reason‬ ‭for‬ ‭withdrawal,‬ ‭request‬ ‭the‬ ‭patient‬ ‭to‬ ‭return‬ ‭all‬ ‭unused‬ ‭investigational‬ ‭product(s),‬
‭request‬‭that‬‭the‬‭patient‬‭return‬‭for‬‭a‬‭final‬‭visit,‬‭if‬‭applicable,‬‭and‬‭follow‬‭up‬‭with‬‭the‬‭patient‬
‭regarding any unresolved AEs.‬
‭If‬‭the‬‭patient‬‭withdraws‬‭from‬‭the‬‭study,‬‭and‬‭also‬‭withdraws‬‭consent‬‭for‬‭disclosure‬‭of‬‭future‬
‭information,‬ ‭no‬ ‭further‬ ‭evaluations‬ ‭should‬ ‭be‬ ‭performed,‬ ‭and‬‭no‬‭additional‬‭data‬‭should‬‭be‬
‭collected.‬ ‭The‬ ‭sponsor‬ ‭may‬ ‭retain‬ ‭and‬ ‭continue‬ ‭to‬ ‭use‬ ‭any‬ ‭data‬ ‭collected‬ ‭before‬ ‭such‬
‭withdrawal of consent.‬
‭Date‬‭of‬‭withdrawal‬‭from‬‭the‬‭study,‬‭with‬‭reason‬‭for‬‭withdrawal,‬‭will‬‭be‬‭recorded‬‭on‬‭the‬‭eCRF.‬
‭In‬‭the‬‭case‬‭of‬‭death,‬‭a‬‭death‬‭certificate‬‭should‬‭be‬‭obtained‬‭if‬‭possible,‬‭with‬‭the‬‭cause‬‭of‬‭death‬
‭evaluated and documented.‬
‭Note: Patients withdrawn the trial for any reason, cannot enter again.‬
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‭7.‬
‭TREATMENT DESCRIPTION‬
‭For‬‭the‬‭purpose‬‭of‬‭this‬‭study,‬‭the‬‭investigational‬‭products‬‭as‬‭defined‬‭by‬‭(ICH‬‭E6‬‭1.33)‬‭are‬
‭atezolizumab, cisplatin and gemcitabine.‬
‭7.1.‬
‭Study medication‬
‭​‬
‭7.1.1.‬ ‭Atezolizumab‬
‭Atezolizumab‬ ‭will‬ ‭be‬ ‭supplied‬ ‭as‬ ‭60‬ ‭mg/mL‬ ‭glass‬ ‭vials‬ ‭of‬ ‭20-mL,‬ ‭nominal‬ ‭atezolizumab‬
‭amount per vial, 1200 mg.‬
‭Packaging‬ ‭and‬‭labeling‬‭will‬‭be‬‭in‬‭accordance‬‭with‬‭applicable‬‭local‬‭regulatory‬‭requirements‬
‭and applicable Good Manufacturing Practice (GMP) guidelines.‬
‭The‬ ‭information‬ ‭on‬ ‭the‬ ‭study‬ ‭treatment‬ ‭will‬ ‭be‬ ‭in‬ ‭accordance‬ ‭with‬ ‭approved‬ ‭submission‬
‭documents.‬
‭AUREA‬‭is‬‭an‬‭Investigator‬‭Initiated‬‭Study,‬‭the‬‭Sponsor‬‭will‬‭supply‬‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬
‭months‬‭of‬‭treatment‬‭for‬‭each‬‭patient.‬‭For‬‭those‬‭patients‬‭in‬‭which‬‭the‬‭PI‬‭considers‬‭that‬‭the‬‭best‬
‭option‬ ‭for‬ ‭the‬ ‭patient‬ ‭is‬ ‭continuing‬ ‭atezolizumab‬ ‭for‬ ‭more‬ ‭than‬ ‭24‬ ‭months,‬ ‭available‬
‭commercial Site supplies should be used, after managed local administrative regulation.‬
‭7.1.2.‬
‭Gemcitabine and Cisplatin‬
‭Gemcitabine and cisplatin will be supplied as per site clinical standards.‬
‭Packaging‬ ‭and‬‭labeling‬‭will‬‭be‬‭in‬‭accordance‬‭with‬‭applicable‬‭local‬‭regulatory‬‭requirements‬
‭and‬ ‭applicable‬ ‭Good‬ ‭Manufacturing‬ ‭Practice‬ ‭(GMP)‬ ‭guidelines,‬ ‭under‬ ‭commercial‬
‭presentation and each site availability.‬
‭The‬ ‭information‬ ‭on‬ ‭the‬ ‭study‬ ‭treatment‬ ‭will‬ ‭be‬ ‭in‬ ‭accordance‬ ‭with‬ ‭approved‬ ‭submission‬
‭documents.‬
‭7.2.‬
‭Treatment accountability and compliance‬
‭According‬ ‭to‬ ‭local‬ ‭legislation,‬ ‭the‬ ‭investigator‬ ‭will‬ ‭record‬ ‭in‬ ‭the‬ ‭medical‬ ‭history‬ ‭that‬ ‭the‬
‭patient is taking the medication as prescribed for each new cycle in the study.‬
‭7.2.1.‬ ‭Atezolizumab accountability and compliance‬
‭Atezolizumab‬ ‭will‬ ‭be‬ ‭dosed‬ ‭at‬ ‭the‬ ‭investigational‬ ‭site,‬ ‭compliance‬ ‭will‬ ‭be‬ ‭assessed‬ ‭by‬
‭reviewing‬‭the‬‭consistency‬‭of‬‭information‬‭in‬‭the‬‭IWRS,‬‭the‬‭eCRF,‬‭patient‬‭records,‬‭nurse‬‭sheets,‬
‭and in the pharmacy source documentation.‬
‭7.2.2.‬ ‭Gemcitabine and Cisplatin accountability and compliance‬
‭Compliance‬‭of‬‭the‬‭split-dose‬‭GC‬‭chemotherapy‬‭will‬‭be‬‭assessed‬‭by‬‭reviewing‬‭the‬‭consistency‬
‭of‬ ‭information‬ ‭in‬ ‭the‬ ‭eCRF,‬ ‭patient‬ ‭records,‬ ‭nurse‬ ‭sheets,‬ ‭and‬ ‭in‬ ‭the‬ ‭pharmacy‬ ‭source‬
‭documentation.‬
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‭7.3.‬
‭Preparation and Dispensing‬
‭Only‬‭qualified‬‭personnel‬‭who‬‭are‬‭familiar‬‭with‬‭procedures‬‭that‬‭minimize‬‭undue‬‭exposure‬‭to‬
‭them‬‭and‬‭to‬‭the‬‭environment‬‭should‬‭undertake‬‭the‬‭preparation,‬‭handling,‬‭and‬‭safe‬‭disposal‬‭of‬
‭chemotherapeutic agents.‬
‭Investigational‬‭products‬‭should‬‭be‬‭prepared‬‭and‬‭dispensed‬‭by‬‭an‬‭appropriately‬‭qualified‬‭and‬
‭experienced‬ ‭member‬ ‭of‬ ‭the‬ ‭study‬ ‭staff‬ ‭(e.g.,‬ ‭physician,‬ ‭nurse,‬ ‭physician’s‬ ‭assistant,‬
‭practitioner, or pharmacist) as allowed by local, state, and institutional guidance.‬
‭7.3.1.‬ ‭Atezolizumab preparation and dispensing‬
‭Atezolizumab‬‭will‬‭be‬‭dosed‬‭at‬‭the‬‭investigational‬‭site.‬‭Atezolizumab‬‭must‬‭not‬‭be‬‭used‬‭for‬‭any‬
‭purpose‬‭other‬‭than‬‭the‬‭trial.‬‭The‬‭administration‬‭of‬‭trial‬‭investigational‬‭products‬‭to‬‭patients‬‭who‬
‭have not been enrolled into the trial is not covered by the trial insurance.‬
‭7.3.2.‬ ‭Gemcitabine plus cisplatin preparation and dispensing‬
‭The‬‭GC‬‭treatment‬‭will‬‭be‬‭administered‬‭in‬‭quantities‬‭appropriate‬‭for‬‭the‬‭study‬‭visit‬‭schedule‬
‭and‬‭according‬‭to‬‭local‬‭practice.‬‭A‬‭qualified‬‭staff‬‭member‬‭will‬‭record‬‭all‬‭the‬‭study‬‭treatment‬
‭using‬ ‭the‬ ‭local‬ ‭practise.‬ ‭Procedures‬ ‭described‬ ‭in‬ ‭each‬ ‭institution’s‬ ‭pharmacy‬ ‭or‬ ‭hospital‬
‭standard operating procedure manual should be followed when handling hazardous drugs.‬
‭7.4.‬
‭Investigational Medical Products Administration‬
‭7.4.1.‬ ‭Atezolizumab administration‬
‭Atezolizumab‬‭will‬‭be‬‭administered‬‭after‬‭all‬‭procedures/assessments‬‭have‬‭been‬‭completed‬‭as‬
‭described‬‭in‬‭the‬‭Schedule‬‭of‬‭Activities‬‭(‬‭Table‬‭4‬‭),‬‭as‬‭a‬‭1-hour‬‭IV‬‭infusion‬‭once‬‭every‬‭3‬‭weeks‬
‭until‬‭disease‬‭progression,‬‭unacceptable‬‭toxicity‬‭or‬‭absence‬‭of‬‭clinical‬‭benefitt.‬‭AUREA‬‭is‬‭an‬
‭Investigator‬ ‭Initiated‬ ‭Study,‬ ‭the‬ ‭Sponsor‬ ‭will‬‭supply‬‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬‭months‬‭of‬
‭treatment‬‭for‬‭each‬‭patient.‬‭For‬‭those‬‭patients‬‭in‬‭which‬‭the‬‭PI‬‭considers‬‭that‬‭the‬‭best‬‭option‬‭for‬
‭the‬ ‭patient‬ ‭is‬ ‭continuing‬‭atezolizumab‬‭for‬‭more‬‭than‬‭24‬‭months,‬‭available‬‭commercial‬‭Site‬
‭supplies should be used, after managed local administrative regulation.‬
‭The‬‭infusions‬‭must‬‭not‬‭be‬‭administered‬‭as‬‭an‬‭intravenous‬‭push‬‭or‬‭bolus.‬‭The‬‭initial‬‭dose‬‭of‬
‭atezolizumab‬‭must‬‭be‬‭administered‬‭over‬‭60‬‭minutes.‬‭If‬‭the‬‭first‬‭infusion‬‭is‬‭well‬‭tolerated,‬‭all‬
‭subsequent infusions may be administered over 30 minutes.‬
‭Atezolizumab‬ ‭will‬ ‭be‬ ‭administered‬ ‭in‬ ‭IV‬ ‭infusion‬ ‭bags‬ ‭containing‬ ‭0.9%‬ ‭sodium‬ ‭chloride‬
‭(NaCl)‬ ‭and‬ ‭infusion‬ ‭lines‬ ‭equipped‬ ‭with‬ ‭0.2‬ ‭or‬ ‭0.22‬‭m‬‭in-line‬‭filters.‬‭The‬‭IV‬‭bag‬‭may‬‭be‬
‭constructed‬‭of‬‭polyvinyl‬‭chloride,‬‭polyolefin,‬‭polyethylene,‬‭or‬‭polypropylene.‬‭The‬‭IV‬‭infusion‬
‭line‬‭may‬‭be‬‭constructed‬‭of‬‭polyvinyl‬‭chloride,‬‭polyethylene,‬‭polybutadiene,‬‭or‬‭polyurethane‬
‭and‬‭the‬‭0.2‬‭or‬‭0.22‬‭m‬‭in-line‬‭filter‬‭may‬‭be‬‭constructed‬‭of‬‭polyethersulfone‬‭or‬‭polysulfone.‬‭The‬
‭use‬‭of‬‭administration‬‭supplies‬‭composed‬‭of‬‭materials‬‭other‬‭than‬‭those‬‭listed‬‭should‬‭be‬‭avoided‬
‭if‬ ‭possible.‬ ‭Atezolizumab‬ ‭can‬ ‭be‬ ‭diluted‬ ‭to‬ ‭concentrations‬ ‭between‬ ‭3.2‬ ‭mg/mL‬ ‭and‬ ‭16.8‬
‭mg/mL‬ ‭in‬ ‭IV‬ ‭bags‬ ‭containing‬ ‭0.9%‬ ‭NaCl.‬ ‭Atezolizumab‬ ‭must‬ ‭be‬ ‭prepared/diluted‬ ‭under‬
‭appropriate aseptic conditions as it does not contain antimicrobial preservatives.‬
‭The‬‭prepared‬‭solution‬‭for‬‭infusion‬‭should‬‭be‬‭used‬‭immediately‬‭to‬‭limit‬‭microbial‬‭growth‬‭in‬
‭case‬‭of‬‭potential‬‭accidental‬‭contamination.‬‭If‬‭not‬‭used‬‭immediately,‬‭in-use‬‭storage‬‭time‬‭and‬
‭conditions‬‭prior‬‭to‬‭use‬‭are‬‭the‬‭responsibility‬‭of‬‭the‬‭user.‬‭For‬‭flat‬‭or‬‭fixed‬‭dosing‬‭(1200‬‭mg‬‭for‬
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‭this‬‭clinical‬‭trial)‬‭in‬ ‭IV‬‭infusion‬‭bags,‬‭the‬‭dose‬‭solution‬‭may‬‭be‬‭stored‬‭at‬‭2°C–8°C‬‭(36°F‬‭–‬
‭46°F)‬‭for‬‭24‬‭hours‬‭or‬‭at‬‭ambient‬‭temperature‬‭≤‬‭25°C‬‭(77°F)‬‭for‬‭8‬‭hours.‬‭This‬‭time‬‭includes‬
‭storage‬ ‭and‬ ‭time‬ ‭for‬ ‭administration‬ ‭for‬ ‭infusion..‬ ‭Do‬ ‭not‬ ‭shake‬ ‭or‬ ‭freeze‬ ‭infusion‬ ‭bags‬
‭containing the dose solution.‬
‭Detailed‬‭information‬‭on‬‭infusion‬‭bags‬‭and‬‭medical‬‭devices‬‭to‬‭be‬‭used‬‭for‬‭the‬‭preparation‬‭of‬
‭the‬‭dilutions‬‭and‬‭subsequent‬‭administration‬‭will‬‭be‬‭provided‬‭in‬‭the‬‭Dosage‬‭and‬‭Administration‬
‭Instruction‬ ‭contained‬ ‭in‬ ‭the‬ ‭Summary‬ ‭of‬ ‭Product‬‭Characteristics,‬‭and‬‭when‬‭applicable,‬‭the‬
‭corresponding Pharmacy Guidelines.‬
‭Any‬‭unused‬‭portion‬‭of‬‭the‬‭solution‬‭should‬‭be‬‭discarded‬‭in‬‭biohazard‬‭waste‬‭disposal‬‭with‬‭final‬
‭disposal by accepted local and national standards of incineration.‬
‭No‬ ‭premedication‬‭is‬‭indicated‬‭for‬‭the‬‭administration‬‭of‬‭Cycle‬‭1‬‭of‬‭atezolizumab.‬‭However,‬
‭patients‬ ‭who‬ ‭experience‬ ‭an‬ ‭infusion-related‬ ‭reaction‬ ‭(IRR)‬ ‭or‬ ‭cytokine-release‬ ‭syndrome‬
‭(CRS)‬‭with‬‭atezolizumab‬‭may‬‭receive‬‭premedication‬‭with‬‭antihistamines,‬‭antipyretics,‬‭and/or‬
‭analgesics‬‭(e.g.,‬‭acetaminophen)‬‭for‬‭subsequent‬‭infusions.‬‭See‬‭more‬‭information‬‭in‬‭Appendix‬
‭1‬‭.‬
‭7.4.1.1.‬‭Intrapatient Atezolizumab Dose Reduction‬
‭The‬‭dose‬‭amount‬‭required‬‭to‬‭prepare‬‭the‬‭atezolizumab‬‭infusion‬‭solution‬‭will‬‭be‬‭based‬‭on‬‭the‬
‭corresponding‬‭flat‬‭dose‬‭of‬‭1200‬‭mg‬‭established‬‭in‬‭this‬‭protocol.‬‭Overall,‬‭Atezolizumab‬‭dose‬
‭reduction‬ ‭for‬ ‭toxicity‬ ‭management‬ ‭is‬ ‭not‬ ‭permitted.‬ ‭Toxicity‬ ‭management‬ ‭(dose‬ ‭delay‬ ‭or‬
‭discontinuation) in case of immune-mediated events is described in‬‭Appendix 1‬‭.‬
‭7.4.2.‬ ‭Gemcitabine and cisplatin administration‬
‭The‬‭infusions‬‭must‬‭not‬‭be‬‭administered‬‭as‬‭an‬‭intravenous‬‭push‬‭or‬‭bolus.‬‭The‬‭estimated‬‭total‬
‭infusion‬‭time‬‭for‬‭this‬‭treatment‬‭takes‬‭up‬‭to‬‭two‬‭hours‬‭for‬‭Day‬‭1‬‭and‬‭Day‬‭8‬‭of‬‭each‬‭21-days‬
‭cycle.‬‭Typically,‬‭IV‬‭hydration‬‭is‬‭given‬‭both‬‭before‬‭and‬‭after‬‭cisplatin‬‭and‬‭can‬‭add‬‭up‬‭to‬‭two‬
‭hours‬‭on‬‭administration‬‭days.‬‭Infusion‬‭times‬‭may‬‭vary‬‭depending‬‭on‬‭physician‬‭preference‬‭or‬
‭patient tolerability.‬
‭7.4.2.1. Gemcitabine administration‬
‭Gemcitabine‬ ‭will‬ ‭be‬ ‭administered‬ ‭after‬ ‭all‬‭procedures/assessments‬‭have‬‭been‬‭completed‬‭as‬
‭described‬‭in‬‭the‬‭Schedule‬‭of‬‭Activities‬‭(‬‭Table‬‭4‬‭),‬‭as‬‭a‬‭30-minutes‬‭IV‬‭infusion‬‭on‬‭days‬‭1‬‭and‬‭8‬
‭once every 3 weeks for a maximum of 6 cycles.‬
‭Gemcitabine‬ ‭is‬ ‭tolerated‬ ‭well‬ ‭during‬ ‭infusion‬ ‭and‬ ‭may‬ ‭be‬ ‭administered‬ ‭ambulant.‬ ‭If‬
‭extravasation‬‭occurs,‬‭generally‬‭the‬‭infusion‬‭must‬‭be‬‭stopped‬‭immediately‬‭and‬‭started‬‭again‬‭in‬
‭another‬ ‭blood‬ ‭vessel.‬ ‭The‬ ‭patient‬ ‭should‬ ‭be‬ ‭monitored‬ ‭carefully‬ ‭after‬ ‭the‬ ‭administration.‬
‭Treatment‬‭omitted‬‭will‬‭not‬‭be‬‭reinstated‬‭within‬‭a‬‭cycle.‬‭Treatment‬‭will‬‭start‬‭on‬‭day‬‭1‬‭of‬‭the‬
‭next‬‭cycle‬‭once‬‭the‬‭absolute‬‭granulocyte‬‭count‬‭reaches‬‭at‬‭least‬‭1,500‬‭(x10‬‭6‬‭/l)‬‭and‬‭the‬‭platelet‬
‭count reaches 100,000 (x10‬‭6‬‭/l)‬‭.‬
‭7.4.2.2.‬‭Cisplatin administration‬
‭Cisplatin‬‭should‬‭be‬‭administered‬‭by‬‭intravenous‬‭infusion‬‭over‬‭a‬‭period‬‭of‬‭2‬‭hours‬‭(up‬‭to‬‭8‬
‭hours)‬‭on‬‭days‬‭1‬‭and‬‭8‬‭once‬‭every‬‭3‬‭weeks‬‭for‬‭a‬‭maximum‬‭of‬‭6‬‭cycles.‬‭Adequate‬‭hydration‬
‭must‬‭be‬‭maintained‬‭from‬‭2‬‭to‬‭12‬‭hours‬‭prior‬‭to‬‭administration‬‭until‬‭minimum‬‭6‬‭hours‬‭after‬‭the‬
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‭administration‬‭of‬‭cisplatin.‬‭Hydration‬‭is‬‭necessary‬‭to‬‭cause‬‭sufficient‬‭diuresis‬‭during‬‭and‬‭after‬
‭treatment‬‭with‬‭cisplatin.‬‭It‬‭is‬‭realised‬‭by‬‭intravenous‬‭infusion‬‭of‬‭one‬‭of‬‭the‬‭following‬‭solutions‬
‭specified on the SmPC.‬
‭7.4.2.3.‬‭Intrapatient Gemcitabine and Cisplatin Dose Reduction‬
‭According‬ ‭to‬ ‭the‬ ‭current‬ ‭version‬ ‭of‬ ‭Gemcitabine‬ ‭Summary‬ ‭of‬ ‭Product‬ ‭Characteristics‬
‭(‬‭Gemcitabine‬‭SmPC‬‭)‬‭at‬‭the‬‭time‬‭of‬‭this‬‭study‬‭design‬‭(March‬‭2020),‬‭dose‬‭modifications‬‭are‬
‭considered‬‭in‬‭case‬‭of‬‭haematological‬‭toxicity‬‭as‬‭described‬‭below.‬‭For‬‭the‬‭matter‬‭of‬‭this‬‭study,‬
‭information‬‭on‬‭dose‬‭modification‬‭recommendations‬‭for‬‭gemcitabine‬‭given‬‭in‬‭monotherapy‬‭or‬
‭in combination with cisplatin for bladder cancer are described.‬
‭Dose modifications due to haematological toxicity: Initiation of a cycle‬
‭For‬‭all‬‭indications,‬‭the‬‭patient‬‭must‬‭be‬‭monitored‬‭before‬‭each‬‭dose‬‭for‬‭platelet‬‭and‬‭granulocyte‬
‭counts.‬ ‭Patients‬ ‭should‬ ‭have‬ ‭an‬ ‭absolute‬‭granulocyte‬‭count‬‭of‬‭at‬‭least‬‭1,500‬‭(x‬‭10‬‭6‬ ‭/l)‬‭and‬
‭platelet account of 100,000 (x 10‬‭6‬‭/l) prior to the‬‭initiation of a cycle.‬
‭Dose modifications due to haematological toxicity: Within a cycle‬
‭Dose modifications of gemcitabine within a cycle should be performed according to‬‭Table 2‬‭:‬
‭Table‬‭2.‬‭Dose‬‭modification‬‭of‬‭gemcitabine‬‭within‬‭a‬‭cycle‬‭for‬‭bladder‬‭cancer,‬‭NSCLC‬‭and‬
‭pancreatic cancer, given in monotherapy or in combination with cisplatin‬
‭Absolute granulocyte count‬
‭(x 10‬‭6‬‭/l)‬
‭Platelet count‬
‭(x 10‬‭6‬‭/l)‬
‭Percentage of standard dose‬
‭of Gemcitabine (%)‬
‭> 1,000                              and‬
‭> 100,000‬
‭100‬
‭500 - 1,000                        or‬
‭50,000-100,000‬
‭75‬
‭<500                                  or‬
‭< 50,000‬
‭Omit dose*‬
‭*Treatment‬‭omitted‬‭will‬‭not‬‭be‬‭reinstated‬‭within‬‭a‬‭cycle‬‭before‬‭the‬‭absolute‬‭granulocyte‬‭count‬‭reaches‬
‭at least 500 (x106 /l) and the platelet count reaches 50,000 (x10‬‭6‬‭/l).‬
‭Dose modifications due to haematological toxicity: Subsequent cycles for all indications‬
‭The‬‭gemcitabine‬‭dose‬‭should‬‭be‬‭reduced‬‭to‬‭75%‬‭of‬‭the‬‭original‬‭cycle‬‭initiation‬‭dose,‬‭in‬‭the‬
‭case of the following hematologic toxicities (‬‭Table‬‭3‬‭):‬
‭Table 3. Dose modification of gemcitabine in subsequent cycles for all indications‬
‭Count‬
‭(x 10‬‭6‬‭/l)‬
‭Time‬
‭Percentage of standard‬
‭dose of Gemcitabine (%)‬
‭Absolute granulocyte‬
‭< 500‬
‭> 5 days‬
‭75‬
‭< 100‬
‭> 3 days‬
‭75‬
‭Platelet count‬
‭< 25,000‬
‭Not applicable‬
‭75‬
‭Febrile neutropenia‬
‭-‬
‭-‬
‭75‬
‭Cycle delay > 1 week to toxicity‬
‭-‬
‭-‬
‭75‬
‭Patients‬ ‭will‬ ‭be‬ ‭monitored‬ ‭closely‬ ‭for‬ ‭toxicity;‬ ‭Gemcitabine‬ ‭may‬ ‭be‬ ‭adjusted‬ ‭by‬ ‭dosing‬
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‭interruption with or without dose reduction as indicated in‬‭Table 2‬‭and‬‭Table‬‭3.‬
‭Management‬‭of‬‭patients‬‭requiring‬‭more‬‭than‬‭2‬‭dose‬‭reductions‬‭of‬‭any‬‭of‬‭the‬‭IMPs‬‭(one‬‭dose‬
‭level decrease at a time) should be discussed with the Coordinating Investigator.‬
‭Patients‬‭who‬‭have‬‭undergone‬‭dose‬‭reduction‬‭may‬‭also‬‭undergo‬‭dose‬‭re-escalation‬‭back‬‭to‬‭the‬
‭previous‬ ‭dose‬ ‭level‬ ‭at‬ ‭the‬ ‭discretion‬ ‭of‬ ‭the‬ ‭Investigator‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬ ‭Grade‬ ‭≥2‬
‭non-hematologic treatment-related toxicity for at least 28 days.‬
‭Cisplatin‬ ‭reduction‬ ‭will‬ ‭be‬ ‭followed‬ ‭as‬ ‭indicated‬ ‭for‬ ‭Gemcitabine‬ ‭reduction‬ ‭following‬ ‭the‬
‭current version of Cisplatin Summary of Product Characteristics (Cisplatin SmPC).‬
‭No chemotherapy reduction as allowed in Cycle 1 Day 1.‬
‭7.5.‬
‭Special Precautions for Investigational Medical Products‬
‭7.5.1.‬ ‭Special Precautions for Atezolizumab‬
‭In‬‭order‬‭to‬‭improve‬‭the‬‭traceability‬‭of‬‭biological‬‭medicinal‬‭products,‬‭the‬‭trade‬‭name‬‭and‬‭the‬
‭batch‬‭number‬‭of‬‭the‬‭administered‬‭product‬‭should‬‭be‬‭clearly‬‭recorded‬‭(or‬‭stated)‬‭in‬‭the‬‭patient‬
‭file.‬
‭Pneumonitis‬ ‭secondary‬ ‭to‬ ‭PD1/PDL1‬ ‭inhibitor‬ ‭drugs‬ ‭is‬ ‭a‬ ‭rare‬ ‭but‬ ‭potentially‬ ‭serious‬ ‭side‬
‭effect,‬‭patients‬‭should‬‭be‬‭monitored‬‭for‬‭signs‬‭and‬‭symptoms‬‭of‬‭pneumonitis‬‭during‬‭physical‬
‭examination‬‭(PE),‬‭and‬‭causes‬‭other‬‭than‬‭immune-mediated‬‭pneumonitis‬‭should‬‭be‬‭ruled‬‭out‬‭in‬
‭the case of findings during PE.‬
‭7.5.1.1.‬‭Hepatic impairment‬
‭No‬ ‭dedicated‬ ‭studies‬ ‭of‬ ‭atezolizumab‬ ‭have‬ ‭been‬ ‭conducted‬ ‭in‬ ‭patients‬ ‭with‬ ‭hepatic‬
‭impairment.‬ ‭In‬ ‭the‬ ‭population‬ ‭pharmacokinetic‬ ‭analysis,‬‭there‬‭were‬‭no‬‭clinically‬‭important‬
‭differences‬‭in‬‭the‬‭clearance‬‭of‬‭atezolizumab‬‭between‬‭patients‬‭with‬‭mild‬‭hepatic‬‭impairment‬
‭(bilirubin‬ ‭≤‬ ‭ULN‬ ‭and‬ ‭AST‬ ‭>‬ ‭ULN‬ ‭or‬ ‭bilirubin‬ ‭1.0‬ ‭to‬‭1.5‬‭ULN‬‭and‬‭any‬‭AST,‬‭n=71)‬‭and‬
‭normal‬‭hepatic‬‭function‬‭(bilirubin‬‭and‬‭AST‬‭≤‬‭ULN,‬‭n=401).‬‭No‬‭data‬‭are‬‭available‬‭in‬‭patients‬
‭with‬‭either‬‭moderate‬‭(bilirubin‬‭>‬‭1.5‬‭to‬‭3.0‬‭x‬‭ULN‬‭and‬‭any‬‭AST)‬‭or‬‭severe‬‭(bilirubin‬‭>‬‭3.0‬
‭ULN‬ ‭and‬ ‭any‬ ‭AST)‬ ‭hepatic‬ ‭impairment.‬ ‭Hepatic‬ ‭impairment‬ ‭was‬ ‭defined‬‭by‬‭the‬‭National‬
‭Cancer‬ ‭Institute‬ ‭criteria‬ ‭of‬ ‭hepatic‬ ‭dysfunction.‬ ‭More‬ ‭information‬ ‭available‬ ‭in‬ ‭the‬ ‭current‬
‭version of Atezolizumab Investigator’s Brochure.‬
‭7.5.1.2.‬‭Renal impairment‬
‭No‬‭dedicated‬‭studies‬‭of‬‭atezolizumab‬‭have‬‭been‬‭conducted‬‭in‬‭patients‬‭with‬‭renal‬‭impairment.‬
‭More information available in the current version of Atezolizumab Investigator’s Brochure.‬
‭7.5.1.3.‬‭Reproductive and Developmental Toxicity‬
‭Reproductive‬‭and‬‭developmental‬‭toxicity‬‭studies‬‭with‬‭atezolizumab‬‭have‬‭not‬‭been‬‭conducted.‬
‭The‬‭PD-L1/‬‭programmed‬‭death‬‭1‬‭(PD-1)‬‭signaling‬‭pathway‬‭is‬‭well‬‭established‬‭as‬‭essential‬‭in‬
‭maternal/fetal‬ ‭tolerance‬ ‭and‬ ‭embryo-fetal‬ ‭survival‬ ‭during‬ ‭gestation‬ ‭(‬‭Guleria‬ ‭et‬ ‭al.‬ ‭2005;‬
‭Habicht‬‭et‬‭al.‬‭2007;‬‭D’Addio‬‭et‬‭al.‬‭2011‬‭).‬‭Administration‬‭of‬‭atezolizumab‬‭is‬‭expected‬‭to‬‭have‬
‭an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality.‬
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‭7.5.1.4.‬‭Immune-mediated adverse reactions‬
‭Most‬‭immune-mediated‬‭adverse‬‭reactions‬‭that‬‭occur‬‭during‬‭treatment‬‭with‬‭atezolizumab‬‭are‬
‭reversible‬ ‭with‬ ‭the‬ ‭interruptions‬ ‭of‬ ‭atezolizumab‬ ‭and‬ ‭initiation‬ ‭of‬ ‭corticosteroids‬ ‭and/or‬
‭supportive‬ ‭care.‬ ‭Immune-mediated‬ ‭adverse‬ ‭reactions‬ ‭affecting‬ ‭more‬ ‭than‬ ‭one‬‭body‬‭system‬
‭have been observed; these may occur after the last dose of atezolizumab.‬
‭For‬‭suspected‬‭immune-mediated‬‭adverse‬‭reactions,‬‭thorough‬‭evaluation‬‭to‬‭confirm‬‭aetiology‬
‭or‬‭exclude‬‭other‬‭causes‬‭should‬‭be‬‭performed.‬‭Based‬‭on‬‭the‬‭severity‬‭of‬‭the‬‭adverse‬‭reaction,‬
‭atezolizumab‬ ‭should‬ ‭be‬ ‭withheld‬ ‭and‬ ‭corticosteroids‬ ‭administered.‬ ‭Upon‬ ‭improvement‬ ‭to‬
‭Grade‬ ‭≤‬ ‭1,‬ ‭corticosteroid‬ ‭should‬ ‭be‬ ‭tapered‬ ‭over‬ ‭≥‬ ‭1‬ ‭month.‬ ‭Based‬ ‭on‬ ‭limited‬ ‭data‬‭from‬
‭clinical‬‭studies‬‭in‬‭patients‬‭whose‬‭immune-mediated‬‭adverse‬‭reactions‬‭could‬‭not‬‭be‬‭controlled‬
‭with‬ ‭systemic‬ ‭corticosteroid‬ ‭use,‬ ‭the‬ ‭administration‬ ‭of‬ ‭other‬‭systemic‬‭immunosuppressants‬
‭may be considered.‬
‭Atezolizumab‬‭must‬‭be‬‭permanently‬‭discontinued‬‭for‬‭any‬‭Grade‬‭3‬‭immune-mediated‬‭adverse‬
‭reaction‬ ‭that‬ ‭recurs‬ ‭and‬ ‭for‬ ‭any‬ ‭Grade‬ ‭4‬ ‭immune-mediated‬ ‭adverse‬ ‭reactions,‬ ‭except‬ ‭for‬
‭endocrinopathies‬‭that‬‭are‬‭controlled‬‭with‬‭replacement‬‭hormones.‬‭Specific‬‭guidelines‬‭for‬‭the‬
‭management of atezolizumab-specific adverse events is available in‬‭Appendix 1‬‭.‬
‭1)‬
‭Pulmonary events‬
‭Pneumonitis‬ ‭secondary‬ ‭to‬ ‭PD1/PDL1‬ ‭inhibitor‬ ‭drugs‬ ‭is‬ ‭a‬ ‭rare‬ ‭but‬ ‭potentially‬ ‭serious‬ ‭side‬
‭effect,‬‭patients‬‭should‬‭be‬‭monitored‬‭for‬‭signs‬‭and‬‭symptoms‬‭of‬‭pneumonitis‬‭during‬‭physical‬
‭examination‬‭(PE),‬‭and‬‭causes‬‭other‬‭than‬‭immune-mediated‬‭pneumonitis‬‭should‬‭be‬‭ruled‬‭out‬‭in‬
‭the case of findings during PE.‬
‭Cases‬‭of‬‭pulmonary‬‭events,‬‭including‬‭dyspnea,‬‭cough,‬‭fatigue‬‭and‬‭pulmonary‬‭infiltrates,‬‭have‬
‭been‬‭observed‬‭in‬‭clinical‬‭trials‬‭with‬‭atezolizumab.‬‭Patients‬‭should‬‭be‬‭monitored‬‭for‬‭pulmonary‬
‭signs and symptoms.‬
‭Treatment‬ ‭with‬ ‭atezolizumab‬ ‭should‬ ‭be‬ ‭withheld‬ ‭for‬ ‭Grade‬ ‭2‬ ‭pulmonary‬ ‭event‬ ‭,‬ ‭and‬
‭corticosteroids‬ ‭equivalent‬‭1‬‭to‬‭2‬‭mg/kg/day‬‭oral‬‭prednisone‬‭should‬‭be‬‭started.‬‭If‬‭symptoms‬
‭improve‬ ‭to‬ ‭≤‬ ‭Grade‬ ‭1,‬ ‭corticosteroids‬ ‭should‬ ‭be‬ ‭tapered‬ ‭over‬ ‭≥‬ ‭1‬ ‭month.‬ ‭Treatment‬‭with‬
‭atezolizumab‬ ‭may‬ ‭be‬ ‭resumed‬ ‭if‬ ‭the‬ ‭event‬ ‭improves‬ ‭to‬ ‭≤‬ ‭Grade‬ ‭1‬ ‭within‬ ‭12‬ ‭weeks,‬ ‭and‬
‭corticosteroids‬‭have‬‭been‬‭reduced‬‭to‬‭≤‬‭10‬‭mg‬‭prednisone‬‭or‬‭equivalent‬‭per‬‭day.‬‭Treatment‬‭with‬
‭atezolizumab must be permanently discontinued for Grade 3 or 4 pulmonary events.‬
‭2)‬
‭Hepatic events‬
‭Immune-mediated‬ ‭hepatitis‬ ‭has‬ ‭been‬ ‭associated‬ ‭with‬ ‭the‬ ‭administration‬ ‭of‬ ‭atezolizumab.‬
‭Eligible‬‭patients‬‭must‬‭have‬‭adequate‬‭liver‬‭function,‬‭as‬‭manifested‬‭by‬‭measurements‬‭of‬‭total‬
‭bilirubin‬ ‭and‬ ‭hepatic‬ ‭transaminases,‬ ‭and‬ ‭liver‬ ‭function‬‭will‬‭be‬‭monitored‬‭throughout‬‭study‬
‭treatment. Management guidelines for hepatic events are provided in‬‭Appendix 1‬‭.‬
‭3)‬
‭Gastrointestinal events‬
‭Immune-mediated‬ ‭colitis‬ ‭has‬ ‭been‬ ‭associated‬ ‭with‬ ‭the‬ ‭administration‬ ‭of‬ ‭atezolizumab.‬‭All‬
‭events‬‭of‬‭diarrhea‬‭or‬‭colitis‬‭should‬‭be‬‭thoroughly‬‭evaluated‬‭for‬‭other‬‭common‬‭etiologies.‬‭For‬
‭events‬ ‭of‬ ‭significant‬ ‭duration‬ ‭or‬ ‭or‬ ‭magnitude‬ ‭or‬ ‭associated‬ ‭with‬ ‭signs‬ ‭of‬ ‭systemic‬
‭inflammation‬ ‭or‬ ‭acute-phase‬ ‭reactants‬ ‭(e.g.,‬ ‭increased‬ ‭C-reactive‬‭protein,‬‭platelet‬‭count,‬‭or‬
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‭bandemia):‬‭Perform‬‭sigmoidoscopy‬‭(or‬‭colonoscopy,‬‭if‬‭appropriate)‬‭with‬‭colonic‬‭biopsy,‬‭with‬
‭three‬‭to‬‭five‬‭specimens‬‭for‬‭standard‬‭paraffin‬‭block‬‭to‬‭check‬‭for‬‭inflammation‬‭and‬‭lymphocytic‬
‭infiltrates to confirm colitis diagnosis. More information provided in‬‭Appendix 1‬‭.‬
‭4)‬
‭Endocrine events‬
‭Thyroid‬‭disorders,‬‭adrenal‬‭insufficiency,‬‭diabetes‬‭mellitus,‬‭and‬‭pituitary‬‭disorders‬‭have‬‭been‬
‭associated with the administration of atezolizumab.‬
‭Patients‬ ‭with‬ ‭unexplained‬ ‭symptoms‬ ‭such‬ ‭as‬ ‭headache,‬ ‭fatigue,‬ ‭myalgias,‬ ‭impotence,‬
‭constipation,‬ ‭or‬ ‭mental‬ ‭status‬ ‭changes‬ ‭should‬ ‭be‬ ‭investigated‬ ‭for‬ ‭the‬ ‭presence‬ ‭of‬ ‭thyroid,‬
‭pituitary,‬‭or‬‭adrenal‬‭endocrinopathies.‬‭The‬‭patient‬‭should‬‭be‬‭referred‬‭to‬‭an‬‭endocrinologist‬‭if‬
‭an endocrinopathy is suspected.‬
‭Thyroid-stimulating‬‭hormone‬‭(TSH)‬‭and‬‭free‬‭triiodothyronine‬‭(T3)‬‭and‬‭thyroxine‬‭(T4)‬‭levels‬
‭should‬‭be‬‭measured‬‭to‬‭determine‬‭whether‬‭thyroid‬‭abnormalities‬‭are‬‭present.‬‭Pituitary‬‭hormone‬
‭levels‬‭and‬‭function‬‭tests‬‭(e.g.,‬‭TSH,‬‭GH,‬‭luteinizing‬‭hormone,‬‭follicle-stimulating‬‭hormone,‬
‭testosterone,‬ ‭prolactin,‬ ‭adrenocorticotropic‬‭hormone‬‭[ACTH]‬‭levels,‬‭and‬‭ACTH‬‭stimulation‬
‭test)‬‭and‬‭magnetic‬‭resonance‬‭imaging‬‭(MRI)‬‭of‬‭the‬‭brain‬‭(with‬‭detailed‬‭pituitary‬‭sections)‬‭may‬
‭help‬‭to‬‭differentiate‬‭primary‬‭pituitary‬‭insufficiency‬‭from‬‭primary‬‭adrenal‬‭insufficiency.‬‭More‬
‭information provided in‬‭Appendix 1‬‭.‬
‭5)‬
‭Ocular events‬
‭An‬ ‭ophthalmologist‬ ‭should‬ ‭evaluate‬ ‭visual‬ ‭complaints‬ ‭(e.g.,‬ ‭uveitis,‬ ‭retinal‬ ‭events).‬ ‭More‬
‭information provided in‬‭Appendix 1‬‭.‬
‭6)‬
‭Immune-Mediated Myocarditis‬
‭Immune-mediated‬ ‭myocarditis‬ ‭has‬ ‭been‬ ‭associated‬‭with‬‭the‬‭administration‬‭of‬‭atezolizumab‬
‭and‬ ‭should‬ ‭be‬ ‭suspected‬ ‭in‬ ‭any‬ ‭patient‬ ‭presenting‬ ‭with‬ ‭signs‬ ‭or‬ ‭symptoms‬ ‭suggestive‬ ‭of‬
‭myocarditis,‬ ‭including,‬ ‭but‬ ‭not‬ ‭limited‬ ‭to,‬ ‭laboratory‬ ‭(e.g.,‬ ‭B-type‬ ‭Natriuretic‬ ‭Peptide])‬ ‭or‬
‭cardiac‬‭imaging‬‭abnormalities,‬‭dyspnea,‬‭chest‬‭pain,‬‭palpitations,‬‭fatigue,‬‭decreased‬‭exercise‬
‭tolerance, or syncope.‬
‭Immune-mediated‬ ‭myocarditis‬ ‭needs‬ ‭to‬ ‭be‬ ‭distinguished‬ ‭from‬ ‭myocarditis‬ ‭resulting‬ ‭from‬
‭infection‬ ‭(commonly‬‭viral,‬‭e.g.,‬‭in‬‭a‬‭patient‬‭who‬‭reports‬‭a‬‭recent‬‭history‬‭of‬‭gastrointestinal‬
‭illness),‬ ‭ischemic‬ ‭events,‬ ‭underlying‬ ‭arrhythmias,‬ ‭exacerbation‬ ‭of‬ ‭pre-existing‬ ‭cardiac‬
‭conditions, or progression of malignancy.‬
‭All‬ ‭patients‬ ‭with‬ ‭possible‬ ‭myocarditis‬ ‭should‬ ‭be‬ ‭urgently‬ ‭evaluated‬‭by‬‭performing‬‭cardiac‬
‭enzyme‬ ‭assessment,‬ ‭an‬ ‭ECG,‬ ‭a‬ ‭chest‬ ‭X-ray,‬ ‭an‬ ‭echocardiogram,‬ ‭and‬ ‭a‬ ‭cardiac‬ ‭MRI‬ ‭as‬
‭appropriate‬ ‭per‬ ‭institutional‬ ‭guidelines.‬ ‭A‬ ‭cardiologist‬ ‭should‬ ‭be‬ ‭consulted.‬ ‭An‬
‭endomyocardial‬ ‭biopsy‬ ‭may‬ ‭be‬ ‭considered‬‭to‬‭enable‬‭a‬‭definitive‬‭diagnosis‬‭and‬‭appropriate‬
‭treatment,‬ ‭if‬ ‭clinically‬ ‭indicated.‬ ‭Patients‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭myocarditis,‬ ‭in‬ ‭the‬
‭absence‬ ‭of‬ ‭an‬ ‭identified‬‭alternate‬‭etiology,‬‭should‬‭be‬‭treated‬‭according‬‭to‬‭the‬‭guidelines‬‭in‬
‭Appendix 1‬‭.‬
‭7)‬
‭Infusion-Related Reactions and Cytokine-Release Syndrome‬
‭No‬ ‭premedication‬‭is‬‭indicated‬‭for‬‭the‬‭administration‬‭of‬‭Cycle‬‭1‬‭of‬‭atezolizumab.‬‭However,‬
‭patients‬ ‭who‬ ‭experience‬ ‭an‬ ‭infusion-related‬ ‭reaction‬ ‭(IRR)‬ ‭or‬ ‭cytokine-release‬ ‭syndrome‬
‭(CRS)‬‭with‬‭atezolizumab‬‭may‬‭receive‬‭premedication‬‭with‬‭antihistamines,‬ ‭antipyretics,‬‭and/or‬
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‭analgesics‬‭(e.g.,‬‭acetaminophen)‬‭for‬‭subsequent‬‭infusions.‬‭Metamizole‬‭(dipyrone)‬‭is‬‭prohibited‬
‭in‬ ‭treating‬ ‭atezolizumab-associated‬ ‭infusion-related‬ ‭reactions,‬ ‭due‬ ‭to‬ ‭IRRs‬ ‭because‬ ‭of‬ ‭its‬
‭potential for causing agranulocytosis.‬
‭IRRs‬ ‭are‬ ‭known‬ ‭to‬ ‭occur‬ ‭with‬ ‭the‬‭administration‬‭of‬‭monoclonal‬‭antibodies‬‭and‬‭have‬‭been‬
‭reported‬ ‭with‬ ‭atezolizumab.‬ ‭These‬ ‭reactions,‬ ‭which‬ ‭are‬ ‭thought‬ ‭to‬ ‭be‬ ‭due‬ ‭to‬ ‭release‬ ‭of‬
‭cytokines‬ ‭and/or‬ ‭other‬ ‭chemical‬ ‭mediators,‬ ‭occur‬ ‭within‬ ‭24‬ ‭hours‬ ‭of‬ ‭atezolizumab‬
‭administration and are generally mild to moderate in severity.‬
‭CRS‬ ‭is‬ ‭defined‬ ‭as‬ ‭a‬ ‭supraphysiologic‬ ‭response‬ ‭following‬ ‭administration‬ ‭of‬ ‭any‬ ‭immune‬
‭therapy‬‭that‬‭results‬‭in‬‭activation‬‭or‬‭engagement‬‭of‬‭endogenous‬‭or‬‭infused‬‭T‬‭cells‬‭and/or‬‭other‬
‭immune‬‭effector‬‭cells.‬‭Symptoms‬‭can‬‭be‬‭progressive,‬‭always‬‭include‬‭fever‬‭at‬‭the‬‭onset,‬‭and‬
‭may‬ ‭include‬ ‭hypotension,‬ ‭capillary‬ ‭leak‬ ‭(hypoxia),‬ ‭and‬ ‭end‬ ‭-organ‬ ‭dysfunction‬‭(Lee‬‭et‬‭al.‬
‭2019).‬ ‭CRS‬ ‭has‬ ‭been‬ ‭well‬‭documented‬‭with‬‭chimeric‬‭antigen‬‭receptor‬‭T-cell‬‭therapies‬‭and‬
‭bispecific‬‭T-cell‬‭engager‬‭antibody‬‭therapies‬‭but‬‭has‬‭also‬‭been‬‭reported‬‭with‬‭immunotherapies‬
‭that‬ ‭target‬ ‭PD-1‬ ‭or‬ ‭PD-L1‬ ‭(‬‭Rotz‬ ‭et‬ ‭al.‬ ‭2017‬‭;‬ ‭Adashek‬ ‭and‬ ‭Feldman‬ ‭2019‬‭),‬ ‭including‬
‭atezolizumab.‬
‭There‬‭may‬‭be‬‭significant‬‭overlap‬‭in‬‭signs‬‭and‬‭symptoms‬‭of‬‭IRRs‬‭and‬‭CRS,‬‭and‬‭in‬‭recognition‬
‭of‬ ‭the‬ ‭challenges‬ ‭in‬ ‭clinically‬ ‭distinguishing‬ ‭between‬ ‭the‬ ‭two,‬ ‭consolidated‬ ‭guidelines‬ ‭for‬
‭medical management of IRRs during Cycle 1 and CRS are provided in‬‭Appendix 1‬‭.‬
‭Severe‬‭COVID-19‬‭appears‬‭to‬‭be‬‭associated‬‭with‬‭a‬‭cytokine-release‬‭syndrome‬‭(CRS)‬‭involving‬
‭the‬‭inflammatory‬‭cytokines‬‭interleukin‬‭(IL)-6,‬‭IL-10,‬‭IL-2,‬‭and‬‭interferon-‬‭(Merad‬‭and‬‭Martin‬
‭2020).‬‭If‬‭a‬‭patient‬‭develops‬‭suspected‬‭CRS‬‭during‬‭the‬‭study,‬‭a‬‭differential‬‭diagnosis‬‭should‬
‭include‬ ‭COVID-19,‬ ‭which‬ ‭should‬ ‭be‬‭confirmed‬‭or‬‭refuted‬‭through‬‭assessment‬‭of‬‭exposure‬
‭history,‬‭appropriate‬‭laboratory‬‭testing,‬‭and‬‭clinical‬‭or‬‭radiologic‬‭evaluations‬‭per‬‭investigator‬
‭judgment.‬‭If‬‭a‬‭diagnosis‬‭of‬‭COVID-19‬‭is‬‭confirmed,‬‭the‬‭disease‬‭should‬‭be‬‭managed‬‭as‬‭per‬
‭local or institutional guidelines.‬
‭8)‬
‭Pancreatic events‬
‭Symptoms‬‭of‬‭abdominal‬‭pain‬‭associated‬‭with‬‭elevations‬‭of‬‭amylase‬‭and‬‭lipase,‬‭suggestive‬‭of‬
‭pancreatitis,‬ ‭have‬ ‭been‬ ‭associated‬ ‭with‬‭the‬‭administration‬‭of‬‭atezolizumab.‬‭The‬‭differential‬
‭diagnosis‬ ‭of‬ ‭acute‬ ‭abdominal‬‭pain‬‭should‬‭include‬‭pancreatitis.‬‭Appropriate‬‭work-up‬‭should‬
‭include‬ ‭an‬ ‭evaluation‬ ‭for‬ ‭ductal‬ ‭obstruction,‬ ‭as‬ ‭well‬ ‭as‬ ‭serum‬ ‭amylase‬ ‭and‬ ‭lipase‬ ‭tests.‬
‭Management‬‭guidelines‬‭for‬‭pancreatic‬‭events,‬‭including‬‭pancreatitis,‬‭are‬‭provided‬‭in‬‭Appendix‬
‭1‬‭.‬
‭9)‬
‭Dermatologic events‬
‭Treatment-emergent‬‭rash‬‭has‬‭been‬‭associated‬‭with‬‭atezolizumab.‬‭The‬‭majority‬‭of‬‭cases‬‭of‬‭rash‬
‭were‬‭mild‬‭in‬‭severity‬‭and‬‭self-limited,‬‭with‬‭or‬‭without‬‭pruritus.‬‭Although‬‭uncommon,‬‭cases‬‭of‬
‭severe‬ ‭cutaneous‬ ‭adverse‬ ‭reactions‬‭such‬‭as‬‭Stevens-Johnson‬‭syndrome‬‭and‬‭toxic‬‭epidermal‬
‭necrolysis‬‭have‬‭been‬‭reported‬‭with‬‭atezolizumab.‬‭A‬‭dermatologist‬‭should‬‭evaluate‬‭persistent‬
‭and/or‬ ‭severe‬ ‭rash‬ ‭or‬ ‭pruritus.‬ ‭A‬ ‭biopsy‬ ‭should‬ ‭be‬ ‭considered‬ ‭unless‬ ‭contraindicated.‬
‭Management guidelines for dermatologic events are provided in‬‭Appendix 1‬‭.‬
‭10)‬
‭Neurologic Disorders‬
‭Myasthenia‬ ‭gravis‬ ‭and‬ ‭Guillain-Barré‬ ‭syndrome‬ ‭have‬ ‭been‬ ‭observed‬ ‭with‬ ‭single-agent‬
‭atezolizumab.‬ ‭Patients‬ ‭may‬ ‭present‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭sensory‬ ‭and/or‬ ‭motor‬
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‭neuropathy.‬ ‭Diagnostic‬ ‭work-up‬ ‭is‬‭essential‬‭for‬‭an‬‭accurate‬‭characterization‬‭to‬‭differentiate‬
‭between‬‭alternative‬‭etiologies.‬‭Management‬‭guidelines‬‭for‬‭neurologic‬‭disorders‬‭are‬‭provided‬
‭in‬‭Appendix 1‬‭.‬
‭11)‬
‭Immune-Mediated Meningoencephalitis‬
‭Immune-mediated‬‭meningoencephalitis‬‭is‬‭an‬‭identified‬‭risk‬‭associated‬‭with‬‭the‬‭administration‬
‭of‬ ‭atezolizumab.‬ ‭Immune-mediated‬‭meningoencephalitis‬‭should‬‭be‬‭suspected‬‭in‬‭any‬‭patient‬
‭presenting‬‭with‬‭signs‬‭or‬‭symptoms‬‭suggestive‬‭of‬‭meningitis‬‭or‬‭encephalitis,‬‭including,‬‭but‬‭not‬
‭limited‬‭to,‬‭headache,‬‭neck‬‭pain,‬‭confusion,‬‭seizure,‬‭motor‬‭or‬‭sensory‬‭dysfunction,‬‭and‬‭altered‬
‭or depressed level of consciousness.‬
‭Encephalopathy‬ ‭from‬ ‭metabolic‬ ‭or‬ ‭electrolyte‬ ‭imbalances‬ ‭needs‬ ‭to‬ ‭be‬ ‭distinguished‬ ‭from‬
‭potential‬ ‭meningoencephalitis‬ ‭resulting‬ ‭from‬ ‭infection‬ ‭(bacterial,‬ ‭viral,‬ ‭or‬ ‭fungal)‬ ‭or‬
‭progression‬ ‭of‬ ‭malignancy,‬ ‭or‬ ‭secondary‬ ‭to‬ ‭a‬ ‭paraneoplastic‬ ‭process.‬ ‭All‬ ‭patients‬ ‭being‬
‭considered‬‭for‬‭meningoencephalitis‬‭should‬‭be‬‭urgently‬‭evaluated‬‭with‬‭a‬‭CT‬‭scan‬‭and/or‬‭MRI‬
‭scan‬‭of‬‭the‬‭brain‬‭to‬‭evaluate‬‭for‬‭metastasis,‬‭inflammation,‬‭or‬‭edema.‬‭If‬‭deemed‬‭safe‬‭by‬‭the‬
‭treating‬ ‭physician,‬ ‭a‬ ‭lumbar‬ ‭puncture‬ ‭should‬ ‭be‬ ‭performed‬ ‭and‬ ‭a‬ ‭neurologist‬ ‭should‬ ‭be‬
‭consulted.‬
‭Patients‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭meningoencephalitis,‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬ ‭an‬‭identified‬
‭alternate etiology, should be treated according to the guidelines in‬‭Appendix 1‬
‭12)‬
‭Renal events‬
‭Immune-mediated‬ ‭nephritis‬ ‭has‬ ‭been‬ ‭associated‬ ‭with‬ ‭the‬ ‭administration‬ ‭of‬ ‭atezolizumab.‬
‭Eligible‬‭patients‬‭must‬‭have‬‭adequate‬‭renal‬‭function,‬‭and‬‭renal.‬‭Renal‬‭function,‬‭including‬‭serum‬
‭creatinine,‬ ‭should‬ ‭be‬ ‭monitored‬ ‭throughout‬ ‭study‬ ‭treatment.‬ ‭Patients‬ ‭with‬ ‭abnormal‬ ‭renal‬
‭function‬‭should‬‭be‬‭evaluated‬‭and‬‭treated‬‭for‬‭other‬‭more‬‭common‬‭etiologies‬‭(including‬‭prerenal‬
‭and‬ ‭postrenal‬ ‭causes,‬ ‭and‬‭concomitant‬‭medications‬‭such‬‭as‬‭non-steroidal‬‭anti-inflammatory‬
‭drugs).‬ ‭Refer‬‭the‬‭patient‬‭to‬‭a‬‭renal‬‭specialist‬‭if‬‭clinically‬‭indicated.‬‭A‬‭renal‬‭biopsy‬‭may‬‭be‬
‭required to enable a definitive diagnosis and appropriate treatment.‬
‭Patients‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭nephritis,‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬ ‭an‬ ‭identified‬ ‭alternate‬
‭etiology, should be treated according to the guidelines in‬‭Appendix 1‬‭.‬
‭13)‬
‭Immune-Mediated Myositis‬
‭Immune-mediated‬ ‭myositis‬ ‭has‬ ‭been‬ ‭associated‬ ‭with‬ ‭the‬ ‭administration‬ ‭of‬ ‭atezolizumab.‬
‭Myositis‬‭or‬‭inflammatory‬‭myopathies‬‭are‬‭a‬‭group‬‭of‬‭disorders‬‭sharing‬‭the‬‭common‬‭feature‬‭of‬
‭inflammatory‬‭muscle‬‭injury;‬‭dermatomyositis‬‭and‬‭polymyositis‬‭are‬‭among‬‭the‬‭most‬‭common‬
‭disorders.‬‭Initial‬‭diagnosis‬‭is‬‭based‬‭on‬‭clinical‬‭(muscle‬‭weakness,‬‭muscle‬‭pain,‬‭skin‬‭rash‬‭in‬
‭dermatomyositis),‬
‭biochemical‬
‭(serum‬
‭creatine‬ ‭kinase/CK‬ ‭increase),‬ ‭and‬ ‭imaging‬
‭(electromyography/MRI) features, and is confirmed with a muscle biopsy.‬
‭Patients‬‭with‬‭possible‬‭myositis‬‭should‬‭be‬‭referred‬‭to‬‭a‬‭rheumatologist‬‭or‬‭neurologist.‬‭Patients‬
‭with possible myositis should be monitored for signs of myocarditis.‬
‭14)‬
‭Severe Cutaneous Adverse Reactions (SCAR)‬
‭SCARs‬ ‭are‬ ‭a‬ ‭heterogeneous‬ ‭group‬ ‭of‬ ‭immunologically‬ ‭mediated‬ ‭drug‬‭eruptions.‬‭Although‬
‭rare,‬‭these‬‭events‬‭are‬‭potentially‬‭fatal,‬‭and‬‭mainly‬‭constituted‬‭by‬‭erythema‬‭multiforme,‬‭acute‬
‭generalised‬ ‭exanthematous‬ ‭pustulosis,‬ ‭Stevens-Johnson‬ ‭syndrome‬ ‭(SJS),‬ ‭Toxic‬ ‭Epidermal‬
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‭Necrolysis‬‭(TEN)‬‭and‬‭drug‬‭rash‬‭with‬‭eosinophilia‬‭and‬‭systemic‬‭symptoms‬‭(DRESS).‬‭As‬‭per‬
‭epidemiology‬ ‭data,‬ ‭the‬ ‭incidence‬‭of‬‭SJS‬‭and‬‭TEN‬‭ranges‬‭from‬‭0.8‬‭to‬‭5.3‬‭and‬‭1.2‬‭to‬‭6‬‭per‬
‭million person-years respectively.‬
‭A‬‭cumulative‬‭analysis‬‭of‬‭the‬‭company‬‭safety‬‭database‬‭across‬‭the‬‭TECENTRIQ‬‭(atezolizumab)‬
‭program‬ ‭identified‬ ‭at‬ ‭total‬ ‭of‬ ‭99‬ ‭cases‬ ‭of‬ ‭SCARs,‬ ‭of‬ ‭which‬ ‭36‬ ‭were‬ ‭confirmed‬ ‭by‬
‭histopathology‬ ‭or‬ ‭specialist‬ ‭diagnosis,‬ ‭in‬ ‭patients‬ ‭who‬ ‭have‬ ‭received‬ ‭TECENTRIQ‬
‭(atezolizumab).‬ ‭Approximately‬ ‭23,654‬ ‭clinical‬ ‭trial‬ ‭patients‬ ‭and‬ ‭106,316‬ ‭patients‬ ‭in‬
‭post-marketing‬ ‭settings‬ ‭have‬ ‭been‬ ‭exposed‬ ‭to‬ ‭TECENTRIQ‬ ‭(atezolizumab)‬ ‭as‬ ‭of‬ ‭17‬ ‭May‬
‭2020.‬ ‭The‬ ‭incidence‬ ‭rates‬ ‭of‬ ‭SCAR,‬ ‭regardless‬ ‭of‬ ‭severity,‬ ‭from‬ ‭pooled‬ ‭atezolizumab‬
‭monotherapy‬ ‭(N=3178)‬ ‭and‬ ‭combination‬ ‭therapy‬ ‭(N=4371)‬ ‭company‬ ‭sponsored‬ ‭clinical‬
‭studies‬‭were‬‭0.7%‬‭and‬‭0.6%‬‭respectively.‬‭One‬‭fatal‬‭case‬‭of‬‭TEN‬‭was‬‭reported‬‭in‬‭a‬‭77‬‭year‬‭old‬
‭female patient who received atezolizumab monotherapy.‬
‭Patients‬‭with‬‭signs‬‭and‬‭symptoms‬‭of‬‭SCAR‬‭should‬‭be‬‭treated‬‭according‬‭to‬‭the‬‭guidelines‬‭in‬
‭Appendix 1‬‭.‬
‭7.5.2.‬ ‭Special Precautions for Gemcitabine‬
‭Prolongation‬‭of‬‭the‬‭infusion‬‭time‬‭and‬‭increased‬‭dosing‬‭frequency‬‭have‬‭been‬‭shown‬‭to‬‭increase‬
‭toxicity.‬‭Further‬‭information‬‭on‬‭particular‬‭risk‬‭for‬‭toxicity‬‭(including‬‭haematological‬‭toxicity,‬
‭hepatic‬ ‭insufficiency,‬ ‭concomitant‬ ‭radiotherapy,‬ ‭live‬ ‭vaccinations,‬ ‭cardiovascular‬ ‭risk,‬
‭pulmonary effects, renal, fertility or sodium control are displayed in the Gemcitabine SmPC.‬
‭7.5.3.‬ ‭Special Precautions for Cisplatin‬
‭This‬‭agent‬‭should‬‭only‬‭be‬‭administered‬‭under‬‭the‬‭direction‬‭of‬‭oncologists‬‭in‬‭specialist‬‭units‬
‭under‬ ‭conditions‬ ‭permitting‬ ‭adequate‬ ‭monitoring‬ ‭and‬ ‭surveillance.‬ ‭Supportive‬ ‭equipment‬
‭should be available to control anaphylactic reactions.‬
‭Cisplatin‬ ‭reacts‬ ‭with‬ ‭metallic‬ ‭aluminium‬ ‭to‬ ‭form‬ ‭a‬ ‭black‬ ‭precipitate‬ ‭of‬ ‭platinum.‬ ‭All‬
‭aluminium‬‭containing‬‭IV‬‭sets,‬‭needles,‬‭catheters‬‭and‬‭syringes‬‭should‬‭be‬‭avoided.‬‭The‬‭solution‬
‭for infusion should not be mixed with other drugs or additives.‬
‭Appropriate‬ ‭monitoring‬ ‭and‬ ‭management‬ ‭of‬ ‭the‬ ‭treatment‬ ‭and‬ ‭its‬ ‭complications‬ ‭are‬ ‭only‬
‭possible if adequate diagnosis and exact treatment conditions are available.‬
‭Further‬ ‭information‬ ‭on‬ ‭particular‬ ‭risks‬ ‭including‬ ‭nephrotoxicity,‬ ‭neuropathies,‬ ‭ototoxicity,‬
‭allergic‬ ‭reactions,‬ ‭hepatic‬ ‭function‬ ‭and‬ ‭haematological‬ ‭formula,‬ ‭carcinogenic‬ ‭potential,‬
‭injection site reactions are displayed in the Cisplatin SmPC.‬
‭7.6.‬
‭Investigational Product Storage‬
‭The‬‭investigational‬‭products‬‭should‬‭be‬‭stored‬‭in‬‭a‬‭secure‬‭area‬‭according‬‭to‬‭local‬‭regulations.‬‭It‬
‭is‬ ‭the‬ ‭responsibility‬ ‭of‬ ‭the‬ ‭investigator‬ ‭to‬ ‭ensure‬ ‭that‬ ‭investigational‬ ‭products‬ ‭are‬ ‭only‬
‭dispensed‬ ‭to‬ ‭study‬ ‭participants.‬ ‭The‬ ‭investigational‬ ‭product‬ ‭must‬ ‭be‬ ‭dispensed‬ ‭only‬ ‭from‬
‭official study sites by authorized personnel according to local regulations.‬
‭The‬ ‭investigator,‬ ‭or‬ ‭an‬ ‭approved‬ ‭representative‬ ‭(eg,‬ ‭pharmacist),‬ ‭will‬ ‭ensure‬ ‭that‬ ‭all‬
‭investigational‬ ‭products‬ ‭are‬ ‭stored‬ ‭in‬ ‭a‬ ‭secured‬ ‭area‬‭with‬‭controlled‬‭access‬‭under‬‭required‬
‭storage conditions and in accordance with applicable regulatory requirements.‬
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‭Storage‬‭conditions‬‭stated‬‭in‬‭the‬‭SRSD‬‭(ie,‬‭IB)‬‭will‬‭be‬‭superseded‬‭by‬‭the‬‭storage‬‭conditions‬
‭stated‬‭on‬‭the‬‭label.‬‭Site‬‭systems‬‭must‬‭be‬‭capable‬‭of‬‭measuring‬‭and‬‭documenting‬‭(for‬‭example,‬
‭via‬ ‭a‬ ‭log),‬ ‭at‬ ‭a‬ ‭minimum,‬ ‭daily‬ ‭minimum‬ ‭and‬ ‭maximum‬ ‭temperatures‬ ‭for‬ ‭all‬‭site‬‭storage‬
‭locations‬ ‭(as‬ ‭applicable,‬ ‭including‬ ‭frozen,‬ ‭refrigerated‬ ‭and/or‬ ‭room‬ ‭temperature‬ ‭products).‬
‭This‬‭should‬‭be‬‭captured‬‭from‬‭the‬‭time‬‭of‬‭investigational‬‭product‬‭receipt‬‭throughout‬‭the‬‭study.‬
‭Even‬ ‭for‬ ‭continuous‬ ‭monitoring‬ ‭systems,‬ ‭a‬ ‭log‬ ‭or‬ ‭site‬ ‭procedure‬ ‭that‬ ‭ensures‬‭active‬‭daily‬
‭evaluation‬ ‭for‬ ‭excursions‬‭should‬‭be‬‭available.‬‭The‬‭operation‬‭of‬‭the‬‭temperature‬‭monitoring‬
‭device‬‭and‬‭storage‬‭unit‬‭(for‬‭example,‬‭refrigerator),‬‭as‬‭applicable,‬‭should‬‭be‬‭regularly‬‭inspected‬
‭to ensure it is maintained in working order.‬
‭Any excursions from the product label storage conditions should be reported upon discovery.‬
‭The‬‭site‬‭should‬‭actively‬‭pursue‬‭options‬‭for‬‭returning‬‭the‬‭product‬‭to‬‭the‬‭storage‬‭conditions‬‭as‬
‭described‬ ‭in‬ ‭the‬ ‭labeling,‬ ‭as‬ ‭soon‬ ‭as‬ ‭possible.‬ ‭Deviations‬ ‭from‬ ‭the‬ ‭storage‬ ‭requirements,‬
‭including any actions taken must be documented and reported to the sponsor.‬
‭Once‬‭an‬‭excursion‬‭is‬‭identified,‬‭the‬‭investigational‬‭product‬‭must‬‭be‬‭quarantined‬‭and‬‭not‬‭used‬
‭until‬‭the‬‭sponsor‬‭provides‬‭documentation‬‭of‬‭permission‬‭to‬‭use‬‭the‬‭investigational‬‭product.‬‭It‬
‭will‬ ‭not‬ ‭be‬ ‭considered‬ ‭a‬ ‭protocol‬ ‭deviation‬ ‭if‬ ‭the‬ ‭sponsor‬ ‭approves‬ ‭the‬ ‭use‬ ‭of‬ ‭the‬
‭investigational‬ ‭product‬ ‭after‬ ‭the‬ ‭temperature‬ ‭excursion.‬ ‭Use‬ ‭of‬ ‭the‬ ‭investigational‬ ‭product‬
‭prior to sponsor approval will be considered a protocol deviation.‬
‭Specific‬ ‭details‬ ‭regarding‬ ‭information‬ ‭the‬ ‭site‬ ‭should‬ ‭report‬ ‭for‬ ‭each‬ ‭excursion‬ ‭will‬ ‭be‬
‭provided to the site.‬
‭Receipt‬‭of‬‭materials,‬‭door‬‭opening‬‭and‬‭closing,‬‭and‬‭other‬‭routine‬‭handling‬‭operations‬‭where‬
‭the‬ ‭product(s)‬ ‭are‬ ‭briefly‬ ‭out‬ ‭of‬ ‭the‬ ‭temperature‬ ‭range‬ ‭described‬ ‭in‬ ‭the‬ ‭labeling‬ ‭are‬ ‭not‬
‭considered excursions.‬
‭Site‬ ‭staff‬ ‭will‬ ‭instruct‬ ‭patients‬ ‭on‬ ‭the‬ ‭proper‬ ‭storage‬ ‭requirements‬ ‭for‬ ‭take-home‬
‭investigational products.‬
‭7.6.1.‬ ‭Atezolizumab storage‬
‭Atezolizumab‬ ‭must‬ ‭be‬ ‭refrigerated‬ ‭at‬ ‭2°C‬ ‭-‬ ‭8°C‬ ‭(36°F‬ ‭-‬ ‭46°F)‬ ‭upon‬ ‭receipt‬ ‭until‬ ‭use.‬
‭Atezolizumab‬‭and‬‭the‬‭diluent‬‭vials‬‭should‬‭not‬‭be‬‭used‬‭beyond‬‭the‬‭expiration‬‭date‬‭provided‬‭by‬
‭the‬ ‭manufacturer.‬‭No‬‭preservative‬‭is‬‭used‬‭in‬‭the‬‭atezolizumab‬‭Drug‬‭Product‬‭or‬‭the‬‭diluent;‬
‭therefore,‬ ‭the‬ ‭vial‬ ‭is‬ ‭intended‬ ‭for‬ ‭single‬ ‭use‬ ‭only.‬ ‭Discard‬ ‭any‬ ‭unused‬ ‭portion‬ ‭of‬ ‭drug‬
‭remaining‬‭in‬‭a‬‭vial.‬‭Vial‬‭contents‬‭should‬‭not‬‭be‬‭frozen‬‭or‬‭shaken‬‭and‬‭should‬‭be‬‭protected‬‭from‬
‭light‬‭by‬‭keeping‬‭the‬‭vial‬‭in‬‭the‬‭outer‬‭carton.‬‭This‬‭information‬‭is‬‭also‬‭available‬‭in‬‭the‬‭pharmacy‬
‭manual.‬
‭7.6.2.‬ ‭Gemcitabine and cisplatin storage‬
‭Gemcitabine and cisplatin must be stored and controlled as specified in the product label.‬
‭7.7.‬
‭Investigational Product Accountability‬
‭The‬‭delegated‬‭investigation‬‭site‬‭staff‬‭must‬‭maintain‬‭adequate‬‭records‬‭documenting‬‭the‬‭receipt,‬
‭use,‬‭loss,‬‭or‬‭other‬‭disposition‬‭of‬‭the‬‭investigational‬‭product‬‭supplies.‬‭All‬‭bottles‬‭of‬‭study‬‭drug‬
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‭must‬‭be‬‭returned‬‭to‬‭the‬‭investigator‬‭by‬‭the‬‭patient‬‭at‬‭the‬‭end‬‭of‬‭each‬‭cycle‬‭and‬‭at‬‭the‬‭end‬‭of‬‭the‬
‭trial,‬‭the‬‭sponsor‬‭will‬‭provide‬‭instructions‬‭as‬‭to‬‭the‬‭disposition‬‭of‬‭any‬‭unused‬‭investigational‬
‭product if the investigative site is unable to destroy at site per local procedures.‬
‭7.8.‬
‭Destruction of Investigational Product Supplies‬
‭The‬‭sponsor‬‭or‬‭designee‬‭will‬‭provide‬‭guidance‬‭on‬‭the‬‭destruction‬‭of‬‭unused‬‭investigational‬
‭product‬‭Atezolizumab‬‭(e.g.,‬‭at‬‭the‬‭site).‬‭If‬‭destruction‬‭is‬‭authorized‬‭to‬‭take‬‭place‬‭at‬‭the‬‭study‬
‭site,‬ ‭the‬ ‭investigator‬ ‭must‬ ‭ensure‬ ‭that‬ ‭the‬ ‭materials‬ ‭are‬ ‭destroyed‬ ‭in‬ ‭compliance‬ ‭with‬
‭applicable‬ ‭environmental‬ ‭regulations,‬ ‭institutional‬ ‭policy,‬ ‭and‬ ‭any‬ ‭special‬ ‭instructions‬
‭provided by the Sponsor, and all destruction must be adequately documented.‬
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‭7.9.‬
‭Concomitant Treatments‬
‭Medications‬ ‭or‬ ‭vaccinations‬ ‭specifically‬ ‭prohibited‬ ‭in‬ ‭the‬ ‭Exclusion‬ ‭Criteria‬ ‭are‬ ‭also‬ ‭not‬
‭allowed‬ ‭during‬ ‭the‬ ‭active‬ ‭treatment‬ ‭period,‬ ‭except‬ ‭for‬ ‭the‬ ‭administration‬ ‭of‬ ‭inactivated‬
‭influenza vaccine.‬
‭If‬ ‭there‬ ‭is‬ ‭a‬ ‭clinical‬ ‭indication‬ ‭for‬ ‭one‬ ‭of‬ ‭these‬ ‭or‬ ‭other‬ ‭medications‬ ‭or‬ ‭vaccinations‬
‭specifically‬
‭prohibited‬
‭during‬
‭the‬
‭trial,‬
‭discontinuation‬
‭from‬
‭study‬
‭therapy‬ ‭or‬
‭medication/vaccination‬ ‭may‬ ‭be‬ ‭required.‬ ‭The‬ ‭final‬ ‭decision‬ ‭on‬ ‭any‬ ‭supportive‬ ‭therapy‬ ‭or‬
‭vaccination‬ ‭rests‬ ‭with‬‭the‬‭investigator‬‭and/or‬‭the‬‭patient’s‬‭primary‬‭physician.‬‭However,‬‭the‬
‭decision‬‭to‬‭continue‬‭the‬‭patient‬‭on‬‭study‬‭therapy‬‭or‬‭medication/vaccination‬‭schedule‬‭requires‬
‭the mutual agreement of the investigator, the sponsor, and the patient.‬
‭Concomitant‬‭treatment‬‭considered‬‭necessary‬‭for‬‭the‬‭patient’s‬‭wellbeing‬‭may‬‭be‬‭given‬‭at‬‭the‬
‭discretion‬ ‭of‬ ‭the‬ ‭treating‬ ‭physician.‬‭All‬‭concomitant‬‭treatments,‬‭blood‬‭products,‬‭as‬‭well‬‭as‬
‭non-drug‬‭interventions‬‭received‬‭by‬‭patients‬‭from‬‭screening‬‭until‬‭the‬‭end‬‭of‬‭study‬‭visit‬‭will‬‭be‬
‭recorded on the CRF.‬
‭Concomitant‬‭medications‬‭and‬‭treatments,‬‭including‬‭herbal‬‭supplements,‬‭will‬‭be‬‭recorded‬‭from‬
‭28‬ ‭days‬ ‭prior‬‭to‬‭the‬‭start‬‭of‬‭study‬‭treatment‬‭and‬‭up‬‭to‬‭90‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭study‬
‭treatment.‬‭All‬‭concomitant‬‭medications‬‭should‬‭be‬‭recorded‬‭in‬‭the‬‭CRF‬‭including‬‭supportive‬
‭care‬ ‭drugs‬ ‭(e.g.,‬‭antiemetic‬‭treatment‬‭and‬‭prophylaxis),‬‭and‬‭the‬‭drugs‬‭used‬‭to‬‭treat‬‭adverse‬
‭events or chronic diseases, and non-drug supportive interventions (e.g., transfusions).‬
‭Concurrent‬‭anticancer‬‭therapy‬‭with‬‭agents‬‭other‬‭than‬‭atezolizumab‬‭and‬‭GC‬‭are‬‭not‬‭allowed.‬
‭Medications‬‭intended‬‭solely‬‭for‬‭supportive‬‭care‬‭(i.e.,‬‭antiemetics,‬‭analgesics,‬‭megestrol‬‭acetate‬
‭for anorexia) are allowed.‬
‭7.9.1.‬ ‭Inhibitors and Inducers of CYP Enzymes‬
‭Because‬‭antibodies‬‭are‬‭cleared‬‭principally‬‭by‬‭catabolism‬‭(i.e.,‬‭cleavage‬‭to‬‭small‬‭peptides‬‭and‬
‭amino‬‭acids),‬‭atezolizumab‬‭is‬‭not‬‭expected‬‭to‬‭show‬‭pharmacokinetic‬‭interactions‬‭with‬‭other‬
‭drugs,‬ ‭and‬ ‭is‬ ‭therefore‬ ‭not‬ ‭expected‬ ‭to‬ ‭interact‬ ‭with‬ ‭other‬ ‭drugs‬ ‭through‬ ‭protein‬ ‭binding,‬
‭effects‬ ‭on‬ ‭cytochrome‬ ‭P450‬ ‭activity,‬ ‭renal‬ ‭excretion‬ ‭or‬ ‭competition‬ ‭for‬ ‭common‬ ‭drug‬
‭transporter‬ ‭proteins.‬ ‭No‬ ‭formal‬ ‭pharmacokinetic‬ ‭drug‬ ‭interaction‬ ‭studies‬ ‭have‬ ‭thus‬ ‭been‬
‭undertaken with atezolizumab.‬
‭7.9.2.‬ ‭Concomitant Surgery‬
‭No specific information on the effect of Atezolizumab on wound healing are reported in the‬
‭current version of IB nor SmPC.‬
‭7.9.3.‬ ‭Concomitant Radiotherapy‬
‭Toxicity‬‭of‬‭concurrent‬‭administration‬‭of‬‭gemcitabine‬‭(simultaneous‬‭or‬‭≤‬‭7‬‭days‬‭apart)‬‭depends‬
‭on‬ ‭many‬‭different‬‭factors,‬‭including‬‭the‬‭dose‬‭of‬‭gemcitabine,‬‭the‬‭frequency‬‭of‬‭gemcitabine‬
‭administration,‬ ‭radiation‬ ‭dose,‬ ‭radiotherapy‬ ‭planning‬ ‭technique,‬ ‭tissue‬ ‭to‬ ‭radiate‬ ‭and‬ ‭the‬
‭theoretical‬‭irradiation‬‭volume.‬‭For‬‭the‬‭matter‬‭of‬‭this‬‭study,‬‭radiotherapy‬‭within‬‭4‬‭weeks‬‭prior‬
‭to inclusion is considered an exclusion criteria.‬
‭For‬ ‭non-concurrent‬ ‭gemcitabine‬ ‭administration‬ ‭(administered>‬ ‭7‬ ‭days‬ ‭apart),‬ ‭data‬‭analysis‬
‭does‬‭not‬‭indicate‬‭an‬‭increased‬‭toxicity‬‭when‬‭gemcitabine‬‭is‬‭administered‬‭at‬‭least‬‭7‬‭days‬‭before‬
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‭or‬‭after‬‭radiotherapy,‬‭except‬‭for‬‭late‬‭skin‬‭toxicity.‬‭The‬‭data‬‭that‬‭can‬‭be‬‭started‬‭administration‬‭of‬
‭gemcitabine when the acute effects of radiation therapy have resolved or at least one‬
‭week‬ ‭after‬ ‭radiation‬ ‭therapy.‬ ‭Radiation‬ ‭injury‬ ‭has‬ ‭been‬ ‭detected‬ ‭in‬ ‭irradiated‬ ‭tissues‬ ‭(e.g.‬
‭esophagitis,‬‭colitis,‬‭and‬‭pneumonitis)‬‭in‬‭association‬‭with‬‭both‬‭concurrent‬‭and‬‭non-concurrent‬
‭use‬‭of‬‭gemcitabine.‬‭Further‬‭information‬‭can‬‭be‬‭obtained‬‭in‬‭the‬‭current‬‭version‬‭of‬‭Gemcitabine‬
‭SmPC.‬
‭7.9.4.‬ ‭Other Prohibited Concomitant Medications and Therapies‬
‭Clarifications‬‭about‬‭Steroid‬‭Use:‬‭Data‬‭indicate‬‭that‬‭corticosteroids‬‭have‬‭an‬‭adverse‬‭effect‬‭on‬
‭T-cell‬‭function‬‭and‬‭that‬‭they‬‭inhibit‬‭and‬‭damage‬‭lymphocytes‬‭(‬‭Schleimer‬‭RP,‬‭et‬‭al.‬‭1984;‬‭Khan‬
‭MM, 2008‬‭).‬
‭Furthermore,‬‭as‬‭with‬‭all‬‭immunotherapies‬‭intended‬‭to‬‭augment‬‭cell-mediated‬‭immunity,‬‭there‬
‭is‬‭a‬‭risk‬‭that‬‭concomitant‬‭immunosuppressants‬‭such‬‭as‬‭steroids‬‭will‬‭counteract‬‭the‬‭intended‬
‭benefit‬ ‭of‬ ‭the‬ ‭proposed‬ ‭study‬ ‭treatment.‬ ‭However,‬ ‭studies‬ ‭with‬ ‭anti-CTLA4‬ ‭compounds‬
‭indicate‬ ‭that‬ ‭short-term‬ ‭use‬ ‭of‬ ‭steroids‬ ‭may‬ ‭be‬ ‭employed‬ ‭without‬ ‭compromising‬ ‭clinical‬
‭outcomes (‬‭Weber JS, et al. 2012‬‭).‬
‭Therefore, the use of steroids during this trial is restricted as follows:‬
‭●‬ ‭Therapeutic‬ ‭use:‬ ‭for‬ ‭the‬ ‭treatment‬ ‭of‬ ‭infusion-related‬ ‭reactions‬ ‭and‬ ‭short-term‬
‭treatment‬ ‭of‬ ‭irAEs,‬ ‭steroids‬ ‭are‬ ‭permitted‬ ‭according‬ ‭to‬ ‭the‬ ‭modalities‬‭indicated‬‭in‬
‭Appendix 1‬‭.‬
‭●‬ ‭Physiologic‬‭use:‬‭steroid‬‭replacement‬‭for‬‭adrenal‬‭insufficiency‬‭at‬‭doses‬‭equivalent‬‭to‬
‭≤10 mg prednisone daily is acceptable.‬
‭●‬ ‭Prophylactic‬ ‭use‬‭,‬ ‭e.g.,‬ ‭for‬ ‭the‬ ‭prevention‬ ‭of‬ ‭acute‬ ‭infusion-related‬ ‭reactions,‬ ‭is‬
‭prohibited,‬‭except‬‭prior to CT or MRI.‬
‭7.10.‬ ‭Rescue Medications and Supportive Care‬
‭7.10.1.‬ ‭Supportive Care Guidelines‬
‭Patients‬ ‭should‬ ‭receive‬ ‭appropriate‬ ‭supportive‬ ‭care‬ ‭measures‬ ‭as‬ ‭deemed‬ ‭necessary‬ ‭by‬ ‭the‬
‭treating investigator including but not limited to the items outlined below:‬
‭●‬ ‭Diarrhea:‬ ‭All‬ ‭patients‬ ‭who‬ ‭experience‬ ‭diarrhea‬ ‭should‬ ‭be‬ ‭advised‬ ‭to‬ ‭drink‬‭liberal‬
‭quantities‬ ‭of‬ ‭clear‬ ‭fluids.‬ ‭If‬ ‭sufficient‬ ‭oral‬ ‭fluid‬ ‭intake‬ ‭is‬ ‭not‬ ‭feasible,‬ ‭fluid‬ ‭and‬
‭electrolytes should be substituted via IV infusion.‬
‭●‬ ‭Nausea/Vomiting‬‭:‬ ‭Nausea‬ ‭and‬ ‭vomiting‬ ‭should‬ ‭be‬ ‭treated‬ ‭aggressively,‬ ‭and‬
‭consideration‬ ‭should‬ ‭be‬ ‭given‬ ‭in‬ ‭subsequent‬ ‭cycles‬ ‭to‬ ‭the‬ ‭administration‬ ‭of‬
‭prophylactic‬ ‭antiemetic‬‭therapy‬‭according‬‭to‬‭standard‬‭institutional‬‭practice.‬‭Patients‬
‭should be strongly encouraged to maintain liberal oral fluid intake.‬
‭●‬ ‭Anti-infectives:‬ ‭Patients‬ ‭with‬ ‭a‬ ‭documented‬ ‭infectious‬ ‭complication‬ ‭should‬ ‭receive‬
‭oral‬‭or‬‭IV‬‭antibiotics‬‭or‬‭other‬‭anti-infective‬‭agents‬‭as‬‭considered‬‭appropriate‬‭by‬‭the‬
‭treating‬ ‭investigator‬ ‭for‬ ‭a‬ ‭given‬ ‭infectious‬ ‭condition,‬ ‭according‬ ‭to‬ ‭standard‬
‭institutional‬‭practice.‬‭Prophylactic‬‭administration‬‭should‬‭be‬‭considered‬‭for‬‭the‬‭cases‬
‭outlined in‬‭Appendix 1‬‭.‬
‭●‬ ‭Anti-inflammatory‬
‭or‬
‭narcotic‬
‭analgesics‬
‭may‬
‭be‬
‭offered‬
‭as‬
‭needed.‬
‭Acetaminophen/paracetamol‬‭to‬‭a‬‭maximum‬‭total‬‭daily‬‭dose‬‭of‬‭2‬‭g‬‭is‬‭permitted.‬‭Daily‬
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‭intake over 2 g is prohibited.‬
‭●‬ ‭Patients‬‭who‬‭need‬‭to‬‭be‬‭on‬‭anticoagulant‬‭therapy‬‭during‬‭treatment‬‭should‬‭be‬‭treated‬
‭with‬ ‭low‬ ‭molecular‬ ‭weight‬ ‭heparin.‬ ‭If‬ ‭low‬ ‭molecular‬ ‭weight‬ ‭heparin‬ ‭cannot‬ ‭be‬
‭administered,‬ ‭coumadin‬ ‭or‬ ‭other‬ ‭coumarin‬ ‭derivatives‬ ‭or‬ ‭other‬ ‭anticoagulants‬
‭(including‬‭direct‬‭Xa‬‭inhibitors)‬‭may‬‭be‬‭allowed;‬‭however,‬‭appropriate‬‭monitoring‬‭of‬
‭prothrombin time/international normalized ratio (PT/INR) should be performed.‬
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‭8.‬
‭STUDY PROCEDURES AND EVALUATIONS‬
‭8.1.‬
‭Definition of efficacy variables‬
‭●‬ ‭Overall‬ ‭Response‬ ‭Rate‬ ‭(ORR):‬ ‭Assessed‬ ‭by‬ ‭the‬ ‭investigator‬ ‭using‬ ‭the‬ ‭Response‬
‭Evaluation‬ ‭Criteria‬‭in‬‭Solid‬‭Tumors‬‭(RECIST)‬‭v1.1.‬‭This‬‭will‬‭be‬‭considered‬‭as‬‭the‬
‭percentage/proportion‬ ‭of‬ ‭patients‬‭with‬‭confirmed‬‭complete‬‭response‬‭(CR)‬‭or‬‭partial‬
‭response (PR) as their overall best response throughout the study period.‬
‭●‬ ‭Duration‬‭of‬‭response‬‭(DoR):‬‭Time‬‭from‬‭first‬‭confirmed‬‭response‬‭(CR‬‭or‬‭PR)‬‭to‬‭the‬
‭date‬‭of‬‭the‬‭documented‬‭PD‬‭as‬‭determined‬‭using‬‭RECIST‬‭1.1‬‭criteria‬‭or‬‭death‬‭due‬‭to‬
‭any cause, whichever occurs first.‬
‭●‬ ‭Time‬ ‭to‬‭response‬‭(TtR):‬‭Time‬‭from‬‭first‬‭dosing‬‭date‬‭to‬‭the‬‭date‬‭of‬‭the‬‭documented‬
‭ORR as determined using RECIST 1.1 criteria.‬
‭●‬ ‭Progression-Free‬‭Survival‬‭(PFS):‬‭Time‬‭from‬‭first‬‭dosing‬‭date‬‭to‬‭the‬‭date‬‭of‬‭confirmed‬
‭PD.‬‭A‬‭subject‬‭who‬‭has‬‭not‬‭died‬‭will‬‭be‬‭censored‬‭at‬‭the‬‭last‬‭known‬‭date‬‭alive.‬‭PFS‬‭rate‬
‭will be assessed through the proportion of patients free of PD at the end of follow-up.‬
‭●‬ ‭Clinical‬‭benefit‬‭(CB)‬‭:‬‭Percentage/proportion‬‭of‬‭patients‬‭with‬‭complete‬‭response‬‭(CR)‬
‭or‬ ‭partial‬ ‭response‬ ‭(PR)‬ ‭or‬ ‭maintained‬ ‭stable‬ ‭disease‬ ‭(SD)‬ ‭as‬ ‭their‬ ‭overall‬ ‭best‬
‭response‬‭throughout‬‭the‬‭study‬‭period,‬‭assessed‬‭by‬‭imaging‬‭follow-up‬‭(CT‬‭scan/MRI),‬
‭on week 9, week 18 and then, every 12 weeks.‬
‭●‬ ‭Overall‬ ‭Survival‬ ‭(OS):‬ ‭Time‬ ‭from‬ ‭first‬ ‭dosing‬ ‭date‬ ‭to‬ ‭the‬ ‭date‬ ‭of‬ ‭death‬ ‭and‬ ‭the‬
‭proportion/percentage‬‭of‬‭patients‬‭alive‬‭at‬‭the‬‭end‬‭of‬‭follow-up.‬‭A‬‭subject‬‭who‬‭has‬‭not‬
‭died‬ ‭will‬ ‭be‬ ‭censored‬ ‭at‬ ‭the‬ ‭last‬ ‭known‬ ‭date‬ ‭alive.‬ ‭Survival‬ ‭will‬ ‭be‬ ‭assessed‬ ‭by‬
‭recording‬‭patient‬‭status‬‭at‬‭each‬‭visit‬‭according‬‭to‬‭Table‬‭4‬‭.‬‭Long‬‭term‬‭follow‬‭up‬‭to‬‭be‬
‭performed every 6 months.‬
‭8.2.‬
‭Safety and tolerability‬
‭Safety‬ ‭assessments:‬ ‭Safety‬ ‭parameters‬ ‭are‬ ‭AE,‬ ‭SAE,‬ ‭AESI,‬ ‭pregnancy,‬ ‭medication‬ ‭error,‬
‭overdose.‬‭Additional‬‭safety‬‭information‬‭could‬‭be‬‭derived‬‭from‬‭ECG,‬‭lab‬‭test,‬‭pregnancy‬‭test,‬
‭or vital sign exam.‬
‭The‬‭assessment‬‭of‬‭adverse‬‭events‬‭will‬‭include‬‭the‬‭type‬‭of‬‭event‬‭(including‬‭symptoms,‬‭physical‬
‭exam‬‭findings‬‭and‬‭laboratory‬‭abnormalities),‬‭the‬‭incidence,‬‭severity,‬‭timing,‬‭seriousness,‬‭and‬
‭relatedness‬‭regarding‬‭the‬‭treatment‬‭under‬‭study.‬‭Adverse‬‭events‬‭will‬‭be‬‭recorded‬‭and‬‭reported‬
‭in‬‭the‬‭corresponding‬‭section‬‭of‬‭the‬‭case‬‭report‬‭form.‬‭The‬‭grade‬‭of‬‭adverse‬‭events‬‭will‬‭be‬‭coded‬
‭according‬ ‭to‬ ‭the‬ ‭National‬ ‭Cancer‬ ‭Institute’s‬ ‭Common‬ ‭Toxicity‬ ‭criteria‬ ‭(NCI-CTCAE‬ ‭v5.0‬
‭scoring‬ ‭system).‬ ‭The‬ ‭worst‬ ‭toxicity‬ ‭score‬ ‭will‬ ‭be‬ ‭recorded.‬ ‭In‬‭case‬‭of‬‭SAE‬‭and‬‭AESI‬‭the‬
‭investigator‬‭should‬‭immediately‬‭fill‬‭in‬‭the‬‭dedicated‬‭SAE‬‭form‬‭and‬‭send‬‭it‬‭by‬‭as‬‭detailed‬‭in‬
‭Section 9.2.‬
‭●‬ ‭Adverse events (AE) assessment:‬‭type, frequency, outcome‬‭of adverse events.‬
‭●‬ ‭Treatment-related‬‭AEs:‬‭An‬‭event‬‭is‬‭assessed‬‭as‬‭related‬‭to‬‭study‬‭treatment‬‭when‬‭there‬
‭is‬ ‭a‬ ‭reasonable‬ ‭possibility‬ ‭that‬ ‭study‬ ‭treatment‬ ‭caused‬ ‭the‬ ‭event.‬ ‭Reasonable‬
‭possibility‬ ‭means‬ ‭there‬ ‭is‬ ‭evidence‬ ‭to‬ ‭suggest‬ ‭a‬ ‭causal‬ ‭relationship‬ ‭between‬‭study‬
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‭treatment‬‭and‬‭the‬‭event.‬‭This‬‭event‬‭is‬‭called‬‭a‬‭suspected‬‭adverse‬‭reaction.‬‭A‬‭suspected‬
‭adverse‬ ‭reaction‬ ‭implies‬ ‭a‬ ‭lesser‬ ‭degree‬ ‭of‬ ‭certainty‬ ‭about‬ ‭causality‬ ‭than‬ ‭adverse‬
‭reaction, which means any AE caused by a drug.‬
‭●‬ ‭Serious‬‭adverse‬‭events‬‭(SAEs)‬‭assessment:‬‭type,‬‭frequency,‬‭grade,‬‭outcome,‬‭relation‬
‭with‬ ‭study‬ ‭treatment,‬ ‭all‬ ‭considering‬ ‭the‬‭total‬‭number‬‭and‬‭proportion‬‭based‬‭on‬‭the‬
‭intention-to-treat and per protocol populations.‬
‭8.3.‬
‭Study determinations‬
‭Table 4‬‭details the study determinations to be performed‬‭and the corresponding timeline.‬
‭Table 4. Study determinations‬
‭Visit‬
‭SCR‬
‭Cycle 1‬
‭Cycle 2‬
‭Cycle 3‬
‭Cycle 4‬
‭Cycle 5‬
‭Cycle 6‬
‭Cycle 7‬
‭up to‬
‭Cycle N‬
‭Safety‬
‭Visit‬
‭PFS‬
‭FU‬
‭EOS‬
‭FU‬
‭Timeline‬
‭≤ 28 D‬
‭prior to‬
‭inclusion‬
‭D1‬ ‭D8‬ ‭D1‬ ‭D8‬
‭D1‬
‭D8‬ ‭D1‬ ‭D8‬ ‭D1‬ ‭D8‬
‭D1‬
‭D8‬
‭D1‬
‭within‬
‭30d‬
‭after‬
‭EOT‬
‭Q12W‬
‭Q6‬
‭months‬
‭Visit window‬
‭+/- 3d‬
‭Q3W‬
‭+/-3d‬
‭+/-3d‬
‭+/- 7d‬
‭Clinical Assessments‬
‭Informed consent‬
‭x‬
‭Medical History‬
‭(Medical  and‬
‭oncology specific)‬
‭x‬
‭Physical Exam‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭ECOG‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Contraception check‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Vital signs (BP, PR)‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Laboratory and biological sample studies‬
‭Archival tumor‬
‭block‬
‭x‬
‭Blood collection‬
‭(biomarkers)‬
‭x‬
‭x‬
‭x‬
‭(D1C7)‬
‭x‬
‭at DP‬
‭Faecal sample‬
‭(biomarkers)‬
‭x‬
‭x‬
‭x‬
‭at DP‬
‭Coagulation‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Hematology*‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Blood chemistry*‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Thyroid function‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭HBV/HCV test‬
‭x‬
‭Pregnancy test‬
‭(serum/urine)‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Urinalysis‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Cardiac monitoring‬
‭ECG‬
‭x‬
‭If clinically indicated‬
‭x‬
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‭FEVI‬
‭x‬
‭If clinically indicated‬
‭x‬
‭Disease assessment‬
‭Tumor evaluation‬
‭x‬
‭On week 9 , week 18 (prior starting atezolizumab monotherapy and every 12 weeks +/-7‬
‭days thereafter until the of objective disease progression or death (whichever comes‬
‭first)‬
‭Survival‬
‭assessment‬
‭x‬
‭IMP follow-up‬
‭Treatment dosing‬
‭compliance‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Chemotherapy‬
‭administration‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Atezolizumab‬
‭administration‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Concomitant‬
‭medications‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭New systemic cancer‬
‭treatment‬
‭x‬
‭x‬
‭Safety assessment‬
‭Adverse events‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭D:‬‭Day/s;‬‭Q3W:‬‭Every‬‭3‬‭weeks;‬‭Q12W:‬‭Every‬‭12‬‭weeks;‬‭EOT:‬‭End‬‭of‬‭treatment;‬‭PFS:‬‭Progression-free‬‭survival;‬
‭EOS: End of study.‬
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‭Informed‬‭consent:‬‭Informed‬‭consent‬‭of‬‭study‬‭procedures‬‭may‬‭be‬‭obtained‬‭prior‬‭to‬‭the‬‭screening.‬‭If‬‭laboratory‬‭or‬
‭imaging‬‭procedures‬‭were‬‭performed‬‭for‬‭different‬‭reasons‬‭prior‬‭to‬‭signing‬‭consent,‬‭these‬‭can‬‭be‬‭used‬‭for‬‭screening‬
‭purposes‬ ‭with‬ ‭the‬ ‭consent‬ ‭of‬ ‭the‬ ‭patient.‬ ‭However,‬ ‭all‬‭screening‬‭laboratory‬‭and‬‭imaging‬‭results‬‭must‬‭have‬‭been‬
‭obtained within 28 days of inclusion.‬
‭Medical‬‭History:‬‭Should‬‭include‬‭information‬‭on‬‭prior‬‭systemic‬‭adjuvant‬‭or‬‭neoadjuvant‬‭therapy‬‭regimens,‬‭surgery‬
‭and‬ ‭radiation‬ ‭therapy.‬ ‭Comorbidities:‬ ‭cardiovascular‬ ‭disease,‬ ‭previous‬ ‭cancer‬ ‭and‬ ‭diabetes,‬ ‭pulmonary‬ ‭disease,‬
‭dementia, etc.‬
‭Physical‬‭exam:‬‭Includes‬‭an‬‭examination‬‭of‬‭major‬‭body‬‭systems‬‭and‬‭weight‬‭(height‬‭at‬‭screening‬‭only).‬‭Additional‬
‭PE‬ ‭may‬ ‭be‬ ‭performed‬ ‭as‬ ‭clinically‬ ‭indicated.‬ ‭During‬ ‭the‬ ‭physical‬ ‭examination,‬ ‭a‬ ‭stethoscope‬ ‭will‬ ‭be‬ ‭used‬ ‭to‬
‭carefully‬‭auscultate‬‭the‬‭lungs,‬‭additional‬‭respiratory‬‭functional‬‭tests‬‭should‬‭be‬‭performed‬‭as‬‭per‬‭local‬‭practise‬‭when‬
‭suspecting pneumonitis (more information is provided in annex 1 of this protocol).‬
‭ECOG PS:‬‭ECOG may be recorded by telephone if the‬‭patient is not coming to site for other reasons.‬
‭Contraception‬‭check:‬‭Male‬‭patients‬‭who‬‭are‬‭able‬‭to‬‭father‬‭children‬‭and‬‭female‬‭patients‬‭who‬‭are‬‭of‬‭childbearing‬
‭potential‬‭will‬‭need‬‭to‬‭affirm‬‭that‬‭they‬‭meet‬‭the‬‭criteria‬‭for‬‭correct‬‭use‬‭of‬‭2‬‭of‬‭the‬‭selected‬‭methods‬‭of‬‭contraception.‬
‭The‬‭investigator‬‭or‬‭his‬‭or‬‭her‬‭designee‬‭will‬‭discuss‬‭with‬‭the‬‭patient‬‭the‬‭need‬‭to‬‭use‬‭2‬‭highly‬‭effective‬‭contraception‬
‭methods‬ ‭consistently‬ ‭and‬ ‭correctly‬ ‭and‬ ‭document‬ ‭such‬ ‭conversation‬ ‭in‬ ‭the‬ ‭patient’s‬ ‭chart.‬ ‭In‬ ‭addition,‬ ‭the‬
‭investigator‬‭or‬‭his/her‬‭designee‬‭will‬‭instruct‬‭the‬‭patient‬‭to‬‭call‬‭immediately‬‭if‬‭one‬‭or‬‭both‬‭contraception‬‭methods‬‭are‬
‭discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner.‬
‭Vital signs:‬‭To include blood pressure (BP) and pulse‬‭rate (PR). Body weight is to be recorded at each visit along‬
‭with vital signs.‬
‭*Laboratory‬‭Studies:‬‭Complete‬‭blood‬‭count‬‭that‬‭includes‬‭total‬‭white‬‭blood‬‭cell‬‭count‬‭with‬‭leukocyte‬‭formula,‬‭Hb,‬
‭and‬‭platelet‬‭count.‬‭The‬‭analytical‬‭studies‬‭may‬‭be‬‭performed‬‭up‬‭to‬‭72‬‭hours‬‭before‬‭the‬‭scheduled‬‭visits‬‭in‬‭order‬‭to‬
‭have‬ ‭the‬ ‭results‬ ‭at‬ ‭the‬ ‭time‬ ‭of‬ ‭the‬ ‭patient’s‬ ‭visit.‬ ‭During‬ ‭the‬ ‭first‬ ‭6‬ ‭cycles‬ ‭of‬ ‭treatment‬ ‭with‬ ‭split‬ ‭doses‬ ‭of‬
‭gemcitabine‬ ‭plus‬ ‭cisplatin,‬ ‭complete‬ ‭blood‬ ‭count‬ ‭and‬ ‭biochemistry‬ ‭(liver,‬ ‭renal‬ ‭and‬ ‭electrolytes)‬ ‭on‬ ‭D1‬ ‭and‬
‭D8are‬ ‭mandatory‬ ‭for‬ ‭patient‬‭safety‬‭assurance‬‭and‬‭treatment‬‭continuation‬‭.‬‭Biochemistry‬‭tests‬‭include‬‭albumin,‬
‭alkaline‬ ‭phosphatase,‬ ‭lactate‬ ‭dehydrogenase‬ ‭(LDH),‬ ‭calcium,‬ ‭magnesium,‬ ‭phosphorus,‬ ‭sodium,‬ ‭potassium,‬
‭creatinine,‬‭creatine‬‭kinase,‬‭direct‬‭bilirubin,‬‭indirect‬‭bilirubin,‬‭total‬‭bilirubin,‬‭total‬‭protein,‬‭urea,‬‭uric‬‭acid,‬‭amylase,‬
‭lipase,‬ ‭and‬ ‭glucose‬ ‭tests.‬ ‭Liver‬ ‭test‬ ‭panel‬ ‭functions‬ ‭include‬ ‭alanine‬ ‭transaminase‬ ‭(ALT),‬ ‭aspartate‬‭transaminase‬
‭(AST),‬‭alkaline‬‭phosphatase‬‭(ALP),‬‭and‬‭gamma-glutamyl‬‭transpeptidase‬‭(GGT)‬‭tests.‬‭Tests‬‭for‬‭pancreatic‬‭enzymes‬
‭include‬ ‭lipase,‬ ‭protease‬ ‭(optional),‬ ‭amylase,‬ ‭and‬ ‭trypsinogen‬ ‭(optional)‬ ‭tests.‬‭If‬‭screening‬‭clinical‬‭chemistry‬‭and‬
‭haematology‬ ‭assessments‬ ‭are‬ ‭performed‬ ‭within‬ ‭3‬‭days‬‭prior‬‭to‬‭day‬‭1‬‭(first‬‭infusion‬‭day),‬‭they‬‭do‬‭not‬‭need‬‭to‬‭be‬
‭repeated at day 1.‬
‭Faecal‬ ‭samples:‬ ‭Specimens‬ ‭will‬ ‭be‬ ‭collected‬ ‭at‬ ‭baseline‬ ‭(before‬ ‭start‬ ‭of‬ ‭treatment),‬ ‭Cycle‬ ‭4‬ ‭Day‬ ‭1‬ ‭and‬ ‭after‬
‭progression;‬ ‭the‬ ‭sample‬ ‭must‬ ‭be‬ ‭processed‬ ‭and‬ ‭retained‬ ‭in‬ ‭the‬ ‭local‬ ‭laboratory‬ ‭until‬ ‭Sponsor‬ ‭indications‬ ‭for‬
‭shipment.‬
‭Thyroid Function:‬‭TSH and free T4.‬
‭HBV/HCV test:‬‭Serology including HIV, hepatitis B‬‭(HBsAg and anti-HBc), and hepatitis C virus (HCV).‬
‭Pregnancy‬ ‭test‬ ‭(serum/urine):‬ ‭For‬ ‭women‬ ‭of‬ ‭childbearing‬ ‭potential‬ ‭only.‬ ‭A‬ ‭urine‬ ‭or‬ ‭serum‬ ‭pregnancy‬ ‭test‬ ‭is‬
‭acceptable.‬‭Women‬‭of‬‭childbearing‬‭potential‬‭are‬‭required‬‭to‬‭have‬‭a‬‭pregnancy‬‭test‬‭within‬‭7‬‭days‬‭prior‬‭to‬‭the‬‭first‬
‭dose‬‭of‬‭the‬‭study‬‭drug,‬‭and‬‭every‬‭4‬‭weeks‬‭thereafter.‬‭Pregnancy‬‭tests‬‭may‬‭occur‬‭on‬‭day‬‭1,‬‭but‬‭the‬‭results‬‭must‬‭be‬
‭available and reviewed by the treating physician or investigator prior to commencing an infusion.‬
‭Urinalysis:‬‭Protein,‬‭glucose,‬‭blood,‬‭Urine‬‭dipstick/other‬‭semiquantitative‬‭method,‬‭for‬‭urine‬‭protein:‬‭if‬‭≥‬‭2+,‬‭collect‬
‭24-hour.‬
‭ECG:‬‭12-lead ECG. Any clinically significant abnormalities‬‭detected require triplicate ECG results.‬
‭FEVI:‬‭MUGA‬‭Scan‬‭or‬‭ECHO,‬‭the‬‭technique‬‭used‬‭at‬‭screening‬‭will‬‭be‬‭consistently‬‭used‬‭throughout‬‭the‬‭study,‬‭in‬
‭the following assessments.‬
‭Tumor‬‭assessments:‬‭CT‬‭scan‬‭or‬‭MRI‬‭is‬‭to‬‭be‬‭performed‬‭at‬‭baseline,‬‭on‬‭week‬‭9,‬‭on‬‭week‬‭18‬‭and‬‭q12w‬‭±‬‭1w‬‭until‬
‭the‬ ‭confirmation‬ ‭of‬ ‭objective‬ ‭disease‬ ‭progression‬‭or‬‭death‬‭(whichever‬‭comes‬‭first).‬‭The‬‭same‬‭imaging‬‭technique‬
‭used‬ ‭to‬ ‭characterize‬ ‭each‬ ‭identified‬ ‭and‬ ‭reported‬ ‭lesion‬ ‭at‬ ‭screening‬ ‭will‬ ‭be‬ ‭employed‬ ‭in‬ ‭the‬ ‭following‬ ‭tumor‬
‭assessments.‬ ‭This‬ ‭schedule‬ ‭must‬ ‭be‬ ‭followed‬ ‭regardless‬ ‭of‬ ‭any‬ ‭delays‬ ‭in‬ ‭dosing,‬ ‭in‬ ‭case‬ ‭of‬ ‭suspected‬
‭pseudo-progression;‬ ‭treatment‬ ‭should‬ ‭be‬ ‭continued‬ ‭until‬ ‭progression‬ ‭of‬ ‭disease‬ ‭is‬ ‭confirmed‬ ‭from‬ ‭the‬ ‭imaging‬
‭results.‬‭RECIST‬‭assessments‬‭will‬‭be‬‭performed‬‭on‬‭images‬‭from‬‭CT‬‭scans‬‭(preferred)‬‭or‬‭MRI,‬‭each‬‭preferably‬‭with‬
‭IV‬‭contrast‬‭of‬‭the‬‭neck,‬‭chest,‬‭abdomen‬‭(including‬‭liver‬‭and‬‭adrenal‬‭glands),‬‭and‬‭pelvis.‬‭Additional‬‭anatomy‬‭should‬
‭be‬ ‭imaged‬ ‭based‬ ‭on‬ ‭signs‬ ‭and‬ ‭symptoms‬‭of‬‭individual‬‭patients‬‭at‬‭baseline‬‭and‬‭follow-up.‬ ‭Baseline‬‭assessments‬
‭should‬‭be‬‭performed‬‭no‬‭more‬‭than‬‭28‬‭days‬‭before‬‭the‬‭date‬‭of‬‭inclusion‬‭and,‬‭ideally,‬‭should‬‭be‬‭performed‬‭as‬‭close‬‭as‬
‭possible‬‭to‬‭and‬‭prior‬‭to‬‭the‬‭start‬‭of‬‭treatment.‬‭CR‬‭and‬‭PR‬‭must‬‭be‬‭confirmed‬‭with‬‭repeated‬‭imaging‬‭performed‬‭at‬
‭least‬‭4‬‭weeks‬‭after‬‭initial‬‭documentation‬‭of‬‭response.‬‭Assessment‬‭of‬‭response‬‭will‬‭be‬‭performed‬‭using‬‭RECIST‬‭1.1.‬
‭If‬‭radiologic‬‭imaging‬‭shows‬‭disease‬‭progression,‬‭the‬‭confirmatory‬‭scans‬‭should‬‭be‬‭performed‬‭preferably‬‭at‬‭the‬‭next‬
‭scheduled‬ ‭imaging‬ ‭visit‬ ‭and‬ ‭no‬ ‭less‬ ‭than‬ ‭4‬ ‭weeks‬ ‭after‬ ‭the‬ ‭prior‬‭assessment‬‭of‬‭PD‬‭(in‬‭the‬‭absence‬‭of‬‭clinically‬
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‭significant‬ ‭deterioration).‬ ‭If‬ ‭an‬ ‭unscheduled‬‭assessment‬‭was‬‭performed‬‭and‬‭the‬‭patient‬‭has‬‭not‬‭progressed,‬‭every‬
‭attempt should be made to perform the subsequent assessment at the next scheduled visit.‬
‭Treatment‬‭dosing‬‭compliance:‬‭Study‬‭drug‬‭compliance‬‭will‬‭be‬‭assessed‬‭by‬‭the‬‭Investigator‬‭and/or‬‭study‬‭personnel‬
‭at‬ ‭each‬ ‭patient’s‬ ‭visit,‬ ‭and‬ ‭it‬ ‭will‬ ‭be‬ ‭captured‬ ‭in‬ ‭the‬ ‭patient’s‬ ‭records‬ ‭as‬ ‭part‬ ‭of‬ ‭source‬ ‭documentation‬ ‭at‬ ‭each‬
‭patient’s visit. Corresponding drug administration information will be reported also in the eCRF.‬
‭Chemotherapy‬‭dispensing/administration:‬‭Results‬‭for‬‭LTFs,‬‭electrolytes,‬‭and‬‭creatinine‬‭must‬‭be‬‭available‬‭before‬
‭commencing‬ ‭an‬ ‭infusion‬ ‭(within‬ ‭3‬ ‭days)‬ ‭and‬ ‭reviewed‬ ‭by‬ ‭the‬ ‭treating‬‭physician‬‭or‬‭investigator‬‭prior‬‭to‬‭dosing.‬
‭Specific‬ ‭details‬ ‭on‬ ‭haematological‬ ‭and‬ ‭renal‬ ‭function‬ ‭parameters‬ ‭for‬ ‭treatment‬ ‭interruption‬ ‭and‬ ‭resuming‬ ‭are‬
‭detailed in the gemcitabine and cisplatin administration section.‬
‭Atezolizumab‬ ‭dispensing/administration:‬ ‭Every‬ ‭3‬ ‭weeks‬ ‭until‬ ‭PD‬ ‭or‬ ‭unacceptable‬ ‭toxicity.‬ ‭Continuation‬ ‭of‬
‭atezolizumab‬ ‭treatment‬ ‭could‬ ‭be‬ ‭considered‬ ‭for‬ ‭patients‬ ‭who‬ ‭have‬ ‭been‬ ‭reported‬ ‭with‬ ‭PD‬ ‭on‬ ‭the‬ ‭week‬ ‭9‬
‭radiological evaluation but, according to the PI’s criteria, might be considered as with clinical benefit.‬
‭Adverse‬ ‭events:‬ ‭Adverse‬‭events‬‭should‬‭be‬‭documented‬‭and‬‭recorded‬‭at‬‭each‬‭visit‬‭using‬‭NCI-CTCAE‬‭v5.0.‬‭AEs‬
‭(serious‬‭and‬‭non-serious)‬‭should‬‭be‬‭recorded‬‭in‬‭the‬‭eCRF‬‭and‬‭patient‬‭records,‬‭from‬‭the‬‭time‬‭the‬‭patient‬‭has‬‭taken‬‭at‬
‭least‬‭1‬‭dose‬‭of‬‭study‬‭treatment‬‭through‬‭and‬‭including‬‭90‬‭calendar‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭IMP.‬‭If‬‭a‬‭patent‬‭begins‬
‭a‬‭new‬‭anticancer‬‭therapy,‬‭the‬‭AE‬‭reporting‬‭period‬‭for‬‭non-serious‬‭AEs‬‭ends‬‭at‬‭the‬‭time‬‭the‬‭new‬‭treatment‬‭is‬‭started.‬
‭For‬ ‭SAEs,‬ ‭the‬ ‭active‬ ‭reporting‬‭period‬‭to‬‭Sponsor‬‭or‬‭it‬‭designated,‬‭begins‬‭from‬‭the‬‭time‬‭that‬‭the‬‭patient‬‭provides‬
‭informed‬ ‭consent,‬ ‭which‬ ‭is‬ ‭obtained‬ ‭prior‬ ‭to‬ ‭the‬ ‭patient’s‬ ‭participation‬ ‭in‬ ‭this‬ ‭study,‬ ‭through‬ ‭and‬ ‭including‬ ‭90‬
‭calendar days after the last administration of the investigational products.‬
‭Concomitant‬‭medications:‬‭Concomitant‬‭medication‬‭will‬‭be‬‭recorded‬‭from‬‭28‬‭days‬‭prior‬‭to‬‭start‬‭of‬‭study‬‭treatment‬
‭and‬‭up‬‭to‬‭90‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭study‬‭treatment.‬‭All‬‭concomitant‬‭medications‬‭should‬‭be‬‭recorded‬‭in‬‭the‬‭CRF‬
‭including‬‭supportive‬‭care‬‭drugs‬‭(i.e.,‬‭antiemetics‬‭treatment‬‭and‬‭prophylaxis),‬‭the‬‭drugs‬‭used‬‭to‬‭treat‬‭adverse‬‭events‬
‭or chronic diseases, and non-drug supportive interventions (e.g. transfusions).‬
‭Biomarker‬ ‭study:‬ ‭Archival‬ ‭Tumor‬ ‭block‬ ‭at‬ ‭baseline‬ ‭and‬‭processed‬‭blood‬‭samples‬‭at‬‭baseline,‬‭day‬‭1‬‭of‬‭cycle‬‭7‬
‭(D1),‬ ‭and‬ ‭at‬ ‭EOT/progression.‬ ‭Blood‬ ‭samples‬ ‭should‬ ‭be‬ ‭obtained‬ ‭in‬ ‭all‬ ‭patients‬ ‭at‬ ‭the‬ ‭time‬ ‭of‬ ‭EOT‬ ‭(even‬ ‭by‬
‭toxicity‬‭without‬‭progressing)‬‭and‬‭samples‬‭are‬‭to‬‭be‬‭stored‬‭at‬‭site‬‭at‬‭-80‬‭ºC‬‭and‬‭are‬‭to‬‭be‬‭sent‬‭at‬‭the‬‭end‬‭of‬‭study‬‭(1‬
‭dry ice shipment per site).‬
‭New‬ ‭systemic‬ ‭cancer‬ ‭treatment:‬‭Information‬‭on‬‭subsequent‬‭treatments‬‭should‬‭include‬‭the‬‭list‬‭of‬‭post-treatment‬
‭therapies,‬ ‭drugs‬ ‭administered,‬ ‭and‬ ‭the‬ ‭date‬ ‭of‬‭initiation‬‭and‬‭discontinuation‬‭of‬‭each‬‭drug,‬‭and‬‭the‬‭corresponding‬
‭disease progression date (if applicable). All the data will be recorded in the medical record and in the eCRF.‬
‭Survival‬ ‭assessment‬ ‭(EOS):‬ ‭After‬ ‭progression,‬ ‭the‬ ‭patient‬ ‭will‬ ‭be‬ ‭followed‬ ‭for‬ ‭survival‬ ‭until‬ ‭death,‬ ‭loss‬ ‭of‬
‭follow-up,‬ ‭total‬ ‭patient‬ ‭consent‬ ‭withdrawal‬ ‭(refusing‬ ‭to‬ ‭any‬ ‭trial‬ ‭procedure),‬ ‭or‬ ‭end‬ ‭of‬ ‭study.‬‭Patient‬‭long‬‭term‬
‭follow-up‬‭to‬‭determine‬‭status‬‭(alive,‬‭death,‬‭loss‬‭of‬‭follow‬‭up,‬‭etc.)‬‭may‬‭be‬‭performed‬‭by‬‭phone,‬‭if‬‭the‬‭patient‬‭is‬‭not‬
‭coming‬‭to‬‭the‬‭clinic‬‭due‬‭to‬‭other‬‭reasons.‬‭The‬‭investigator‬‭must‬‭document‬‭in‬‭writing‬‭the‬‭results‬‭of‬‭the‬‭phone‬‭call‬‭in‬
‭the patient records and in the eCRF.‬
‭8.4.‬
‭Determinations‬
‭in‬
‭the‬
‭selection‬
‭phase‬
‭(screening‬
‭and‬
‭baseline‬
‭determinations)‬
‭Within 28 days prior to inclusion:‬
‭●‬ ‭Informed consent‬
‭●‬ ‭Medical History (Medical and oncology specific)‬
‭●‬ ‭Archival tumor block‬
‭●‬ ‭HBV/HCV test‬
‭●‬ ‭ECG‬
‭●‬ ‭FEVI‬
‭●‬ ‭Tumor assessment‬
‭●‬ ‭Thyroid function‬
‭●‬ ‭Urinalysis‬
‭Within‬‭3‬‭days‬‭prior‬‭to‬‭inclusion‬‭(not‬‭needed‬‭to‬‭be‬‭repeated‬‭if‬‭it‬‭is‬‭performed‬‭within‬‭3‬‭days‬‭to‬
‭treatment initiation)‬
‭●‬ ‭Physical Exam‬
‭●‬ ‭ECOG‬
‭●‬ ‭Contraception check‬
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‭●‬ ‭Vital signs (BP, PR)‬
‭●‬ ‭Coagulation‬
‭●‬ ‭Hematology‬
‭●‬ ‭Blood chemistry‬
‭●‬ ‭Pregnancy test (serum/urine)‬
‭●‬ ‭Blood collection (biomarkers)‬
‭●‬ ‭Faecal sample collection (biomarkers)‬
‭●‬ ‭Adverse events‬
‭●‬ ‭Concomitant medications‬
‭8.5.‬
‭Determinations and procedures during the treatment period (up to cycle 6)‬
‭8.5.1.‬ ‭Day 1 (considering 3 week cycles)‬
‭●‬ ‭Physical Exam‬
‭●‬ ‭ECOG‬
‭●‬ ‭Contraception check‬
‭●‬ ‭Vital signs (BP, PR)‬
‭●‬ ‭Coagulation‬
‭●‬ ‭Hematology‬
‭●‬ ‭Blood chemistry‬
‭●‬ ‭Thyroid function‬
‭●‬ ‭Pregnancy test (serum/urine)‬
‭●‬ ‭Urinalysis‬
‭●‬ ‭Adverse events‬
‭●‬ ‭Concomitant medications‬
‭●‬ ‭Treatment dosing compliance‬
‭●‬ ‭Atezolizumab administration‬
‭●‬ ‭Split doses of gemcitabine and cisplatin administration‬
‭8.5.2.‬ ‭Day 8 (considering 3 week cycles)‬
‭●‬ ‭Physical Exam‬
‭●‬ ‭ECOG‬
‭●‬ ‭Vital signs‬
‭●‬ ‭Hematology‬
‭●‬ ‭Blood chemistry‬
‭●‬ ‭Adverse events‬
‭●‬ ‭Treatment dosing compliance‬
‭●‬ ‭Concomitant medication‬
‭●‬ ‭Split doses of gemcitabine and cisplatin administration‬
‭8.5.3.‬ ‭Other determinations during treatment‬
‭●‬ ‭Tumor‬‭assessment:‬‭On‬‭week‬‭9,‬‭week‬‭18‬‭(prior‬‭starting‬‭atezolizumab‬‭monotherapy‬
‭and‬ ‭every‬‭12‬‭weeks‬‭+/-7‬‭days‬‭thereafter‬‭until‬‭the‬‭confirmation‬‭of‬‭objective‬‭disease‬
‭progression or death (whichever comes first).‬
‭●‬ ‭Safety‬ ‭determinations:‬‭Hematology‬‭and‬‭Blood‬‭chemistry‬‭(including‬‭renal‬‭function‬
‭assessment‬ ‭with‬ ‭urea‬ ‭and‬‭creatinine)‬‭should‬‭be‬‭evaluated‬‭weekly‬‭during‬‭the‬‭first‬‭6‬
‭cycles of treatment as per recommendations for gemcitabine treatment.‬
‭●‬ ‭When clinically indicated:‬‭ECG, and FEVI.‬
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‭8.5.4.‬ ‭Determinations‬ ‭and‬ ‭procedures‬ ‭on‬ ‭day‬ ‭1‬ ‭of‬ ‭cycle‬ ‭7‬ ‭(D1-C7)‬ ‭and‬
‭subsequent cycles (D1-Cn)‬
‭●‬ ‭Physical Exam‬
‭●‬ ‭ECOG‬
‭●‬ ‭Contraception check‬
‭●‬ ‭Vital signs (BP, PR)‬
‭●‬ ‭Coagulation‬
‭●‬ ‭Hematology‬
‭●‬ ‭Blood chemistry‬
‭●‬ ‭Thyroid function‬
‭●‬ ‭Pregnancy test (serum/urine)‬
‭●‬ ‭Urinalysis‬
‭●‬ ‭Treatment compliance dosing‬
‭●‬ ‭Atezolizumab administration‬
‭●‬ ‭Concomitant medication‬
‭●‬ ‭Adverse event‬
‭When clinically indicated:‬‭urinalysis, ECG, and FEVI.‬
‭Additionally at D1-C7:‬
‭●‬ ‭Blood collection (biomarkers) only D1 C7.‬
‭●‬ ‭Tumor‬ ‭assessment:‬ ‭CT‬ ‭Scan‬ ‭or‬ ‭MRI‬ ‭prior‬ ‭to‬ ‭D1C7‬ ‭(on‬ ‭week‬ ‭18‬ ‭from‬ ‭treatment‬
‭starting).‬
‭When applicable‬
‭●‬ ‭Tumor‬‭assessment:‬‭CT‬‭Scan‬‭or‬‭MRI‬‭is‬‭to‬‭be‬‭performed‬‭on‬‭week‬‭9,‬‭week‬‭18‬‭and‬‭every‬
‭12‬‭weeks‬‭until‬‭the‬‭confirmation‬‭of‬‭objective‬‭disease‬‭progression‬‭or‬‭death‬‭(whichever‬
‭comes first).‬
‭●‬ ‭When clinically indicated:‬‭ECG, and FEVI.‬
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‭8.6.‬
‭Determinations at safety visit‬
‭●‬ ‭Physical Exam‬
‭●‬ ‭ECOG‬
‭●‬ ‭Contraception check‬
‭●‬ ‭Vital signs (BP, PR)‬
‭●‬ ‭Coagulation‬
‭●‬ ‭Hematology‬
‭●‬ ‭Blood chemistry‬
‭●‬ ‭Thyroid function‬
‭●‬ ‭Pregnancy test (serum/urine)‬
‭●‬ ‭Urinalysis‬
‭●‬ ‭ECG‬
‭●‬ ‭FEVI‬
‭●‬ ‭Adverse events‬
‭●‬ ‭Concomitant medications‬
‭8.7.‬
‭Follow-up determinations‬
‭8.7.1. Follow up after end of treatment (prior PD)‬
‭Every 12 weeks:‬
‭●‬ ‭Tumor‬ ‭assessment:‬ ‭CT‬ ‭Scan‬‭or‬‭MRI‬‭is‬‭to‬‭be‬‭performed‬‭on‬‭week‬‭9,‬‭week‬‭18‬‭and‬
‭every‬ ‭12‬ ‭weeks‬ ‭until‬ ‭the‬ ‭confirmation‬ ‭of‬ ‭objective‬ ‭disease‬ ‭progression‬ ‭or‬ ‭death‬
‭(whichever comes first).‬
‭●‬ ‭New systemic cancer treatment.‬
‭●‬ ‭By the time of disease progression,‬‭Blood collection‬‭(biomarkers)‬
‭8.7.2. Follow up after end of treatment (after PD)‬
‭Every 6 months:‬
‭●‬ ‭New systemic cancer treatment‬
‭●‬ ‭Survival assessment‬
‭9.‬
‭SAFETY EVALUATION‬
‭ICH‬ ‭GCP‬ ‭requires‬ ‭that‬ ‭both‬ ‭investigators‬ ‭and‬ ‭sponsors‬ ‭follow‬ ‭specific‬ ‭procedures‬ ‭when‬
‭reporting‬ ‭adverse‬ ‭events/reactions‬ ‭in‬ ‭clinical‬ ‭trials.‬ ‭These‬ ‭procedures‬ ‭are‬ ‭described‬‭in‬‭this‬
‭section of the protocol.‬
‭Any‬‭event‬‭involving‬‭adverse‬‭drug‬‭reactions‬‭(ADR),‬‭illnesses‬‭with‬‭onset‬‭during‬‭the‬‭study‬‭or‬
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‭exacerbations of pre-existing illnesses should be recorded.‬
‭In‬ ‭addition,‬ ‭clinically‬ ‭significant‬ ‭changes‬ ‭in‬ ‭physical‬ ‭examination‬ ‭findings‬ ‭and‬ ‭abnormal‬
‭objective‬ ‭test‬ ‭findings‬ ‭(e.g.,‬ ‭x-ray,‬ ‭ECG)‬ ‭should‬ ‭also‬ ‭be‬ ‭recorded‬ ‭as‬ ‭AE.‬ ‭The‬ ‭criteria‬ ‭for‬
‭determining‬‭whether‬‭an‬‭abnormal‬‭objective‬‭test‬‭finding‬‭should‬‭be‬‭reported‬‭as‬‭an‬‭AE‬‭are‬‭as‬
‭follows:‬
‭●‬ ‭test result is associated with clinically significant symptoms, and/or‬
‭●‬ ‭test‬ ‭result‬ ‭leads‬ ‭to‬ ‭a‬ ‭change‬ ‭in‬ ‭study‬ ‭dosing‬ ‭or‬ ‭discontinuation‬ ‭from‬ ‭the‬ ‭study,‬
‭significant additional concomitant drug treatment or other therapy, and/or‬
‭●‬ ‭test result leads to any of the outcomes included in the definition of a SAE, and/or test‬
‭result is considered to be an AE by the investigator.‬
‭9.1.‬
‭Definitions‬
‭The definitions from ICH GCP apply in this trial protocol.‬
‭9.1.1.‬ ‭Adverse event (AE)‬
‭An‬ ‭adverse‬ ‭event‬ ‭is‬ ‭any‬‭untoward‬‭medical‬‭occurrence‬‭in‬‭a‬‭patient‬‭or‬‭clinical‬‭investigation‬
‭subject which does not necessarily have a causal relationship with the study treatment.‬
‭Examples of AEs include but are not limited to:‬
‭●‬ ‭Abnormal test findings;‬
‭●‬ ‭Clinically significant symptoms and signs;‬
‭●‬ ‭Changes in physical examination findings;‬
‭●‬ ‭Hypersensitivity;‬
‭●‬ ‭Drug abuse;‬
‭●‬ ‭Drug dependency.‬
‭Additionally, they may include signs or symptoms resulting from:‬
‭●‬ ‭Drug overdose;‬
‭●‬ ‭Drug withdrawal;‬
‭●‬ ‭Drug misuse;‬
‭●‬ ‭Drug interactions;‬
‭●‬ ‭Extravasation;‬
‭●‬ ‭Exposure during pregnancy (EDP);‬
‭●‬ ‭Exposure via breastfeeding;‬
‭●‬ ‭Medication error;‬
‭●‬ ‭Occupational exposure;‬
‭●‬ ‭Worsening‬‭of‬‭signs‬‭and‬‭symptoms‬‭of‬‭the‬‭malignancy‬‭under‬‭study‬‭should‬‭be‬‭reported‬
‭as‬ ‭AEs‬ ‭in‬ ‭the‬ ‭appropriate‬ ‭section‬ ‭of‬ ‭the‬ ‭CRF.‬ ‭Disease‬ ‭progression‬ ‭assessed‬ ‭by‬
‭measurement‬ ‭of‬ ‭malignant‬ ‭lesions‬ ‭on‬ ‭radiographs‬ ‭or‬ ‭other‬ ‭methods‬ ‭should‬ ‭not‬ ‭be‬
‭reported as AEs.‬
‭9.1.2.‬ ‭Atezolizumab Adverse Event of Special Interest‬
‭Adverse‬‭events‬‭of‬‭special‬‭interest‬‭are‬‭required‬‭to‬‭be‬‭reported‬‭by‬‭the‬‭investigator‬‭to‬‭the‬‭Sponsor‬
‭immediately‬ ‭(i.e.,‬ ‭no‬ ‭more‬ ‭than‬ ‭24‬ ‭hours‬ ‭after‬ ‭learning‬ ‭of‬ ‭the‬ ‭event;‬ ‭see‬ ‭Section‬ ‭9.2‬ ‭for‬
‭reporting instructions).‬
‭Adverse events of special interest for this study are as follows:‬
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‭●‬ ‭Cases‬‭of‬‭potential‬‭drug-induced‬‭liver‬‭injury‬‭that‬‭include‬‭an‬‭elevated‬‭ALT‬‭or‬‭AST‬‭in‬
‭combination‬‭with‬‭either‬‭an‬‭elevated‬‭bilirubin‬‭or‬‭clinical‬‭jaundice,‬‭as‬‭defined‬‭by‬‭Hy's‬
‭Law.‬
‭●‬ ‭Suspected transmission of an infectious agent by the study treatment, as defined below‬
‭●‬ ‭Any‬ ‭organism,‬ ‭virus,‬ ‭or‬ ‭infectious‬ ‭particle‬ ‭(e.g.,‬ ‭prion‬ ‭protein‬ ‭transmitting‬
‭transmissible‬ ‭spongiform‬ ‭encephalopathy),‬ ‭pathogenic‬ ‭or‬ ‭non-pathogenic,‬ ‭is‬
‭considered‬ ‭an‬ ‭infectious‬ ‭agent.‬ ‭A‬ ‭transmission‬ ‭of‬ ‭an‬ ‭infectious‬ ‭agent‬ ‭may‬ ‭be‬
‭suspected‬‭from‬‭clinical‬‭symptoms‬‭or‬‭laboratory‬‭findings‬‭that‬‭indicate‬‭an‬‭infection‬‭in‬‭a‬
‭patient‬‭exposed‬‭to‬‭a‬‭medicinal‬‭product.‬‭This‬‭term‬‭applies‬‭only‬‭when‬‭a‬‭contamination‬
‭of study treatment is suspected.‬
‭●‬ ‭Systemic lupus erythematosus‬
‭●‬ ‭Events‬ ‭suggestive‬ ‭of‬ ‭hypersensitivity,‬ ‭infusion-related‬ ‭reactions,‬ ‭cytokine-release‬
‭syndrome, HLH, and MAS‬
‭●‬ ‭Nephritis‬
‭●‬ ‭Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)‬
‭●‬ ‭Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)‬
‭●‬ ‭Vasculitis‬
‭●‬ ‭Autoimmune hemolytic anemia‬
‭●‬ ‭Severe‬‭cutaneous‬‭reactions‬‭(e.g.,‬‭Stevens-Johnson‬‭syndrome,‬‭dermatitis‬‭bullous,‬‭toxic‬
‭epidermal necrolysis)‬
‭9.1.3.‬ ‭Laboratory Abnormalities‬
‭All‬ ‭laboratory‬ ‭data‬ ‭required‬ ‭by‬ ‭this‬ ‭protocol‬ ‭and‬ ‭any‬ ‭other‬ ‭clinical‬ ‭investigations‬ ‭will‬ ‭be‬
‭reviewed.‬ ‭Any‬ ‭abnormal‬ ‭value‬ ‭that‬ ‭leads‬ ‭to‬ ‭a‬ ‭change‬ ‭in‬ ‭subject‬ ‭management‬ ‭(eg,‬ ‭dose‬
‭reduction‬ ‭or‬ ‭delay‬ ‭or‬ ‭requirement‬ ‭for‬ ‭additional‬ ‭medication‬ ‭or‬ ‭monitoring)‬ ‭or‬ ‭that‬ ‭is‬
‭considered‬‭to‬‭be‬‭of‬‭clinical‬‭significance‬‭by‬‭the‬‭Investigator‬‭will‬‭be‬‭reported‬‭as‬‭an‬‭AE‬‭or‬‭SAE‬
‭as‬ ‭appropriate,‬ ‭unless‬ ‭this‬ ‭value‬ ‭is‬ ‭consistent‬ ‭with‬ ‭the‬ ‭subject’s‬‭present‬‭disease‬‭state‬‭or‬‭is‬
‭consistent with values obtained prior to entry into the study.‬
‭9.1.4.‬ ‭Medication errors‬
‭Medication‬ ‭errors‬ ‭may‬ ‭result,‬ ‭in‬ ‭this‬ ‭study,‬‭from‬‭the‬‭administration‬‭or‬‭consumption‬‭of‬‭the‬
‭wrong product, the wrong patient at the wrong time, or at the wrong dosage strength.‬
‭Such‬‭medication‬‭errors‬‭occurring‬‭to‬‭a‬‭study‬‭participant‬‭are‬‭to‬‭be‬‭captured‬‭on‬‭the‬‭eCRF,‬‭and‬
‭reported‬‭through‬‭the‬‭SAE‬‭form‬‭when‬‭appropriate.‬‭In‬‭the‬‭event‬‭of‬‭medication‬‭dosing‬‭error,‬‭the‬
‭sponsor should be notified immediately.‬
‭Medication‬ ‭errors‬ ‭are‬ ‭reportable‬ ‭irrespective‬ ‭of‬ ‭the‬ ‭presence‬ ‭of‬ ‭an‬ ‭associated‬ ‭AE/SAE,‬
‭including:‬
‭●‬ ‭Medication errors involving patient exposure to the investigational product;‬
‭●‬ ‭Potential‬‭medication‬‭errors‬‭or‬‭uses‬‭outside‬‭of‬‭what‬‭is‬‭foreseen‬‭in‬‭the‬‭protocol‬‭that‬‭do‬
‭or do not involve the participating patient.‬
‭Whether‬ ‭or‬ ‭not‬ ‭the‬ ‭medication‬ ‭error‬ ‭is‬ ‭accompanied‬ ‭by‬ ‭an‬ ‭AE,‬ ‭as‬ ‭determined‬ ‭by‬ ‭the‬
‭investigator,‬‭the‬‭medication‬‭error‬‭is‬‭captured‬‭on‬‭the‬‭medication‬‭error‬‭version‬‭of‬‭the‬‭AE‬‭page‬
‭and, if applicable, any associated AEs are captured on an AE CRF page.‬
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‭The guidance on reporting of medication errors also applies to the reporting of overdose.‬
‭9.1.4.1. Atezolizumab overdose‬
‭The‬‭standard‬‭fixed‬‭dose‬‭of‬‭Atezolizumab‬‭is‬‭1200‬‭mg‬‭is‬‭equivalent‬‭to‬‭15‬‭mg/kg‬‭in‬‭a‬‭typical‬
‭patient.‬‭No‬‭dose-limiting‬‭toxicities‬‭were‬‭observed‬‭at‬‭the‬‭20‬‭mg/kg‬‭dose‬‭level‬‭and‬‭the‬‭incidence‬
‭and‬ ‭intensity‬ ‭of‬‭AEs‬‭reported‬‭have‬‭not‬‭been‬‭shown‬‭to‬‭be‬‭dependent‬‭on‬‭dose.‬‭A‬‭maximum‬
‭tolerated dose has not been established.‬
‭Atezolizumab‬‭is‬‭supplied‬‭in‬‭vials‬‭containing‬‭the‬‭fixed‬‭1200‬‭mg‬‭dose‬‭of‬‭drug‬‭substance,‬‭which‬
‭minimizes‬‭the‬‭chance‬‭of‬‭overdose.‬‭Because‬‭the‬‭dose‬‭per‬‭patient‬‭is‬‭not‬‭based‬‭on‬‭weight‬‭or‬‭body‬
‭surface‬‭area,‬‭and‬‭no‬‭dose‬‭calculation‬‭is‬‭required,‬‭the‬‭risk‬‭of‬‭overdose‬‭due‬‭to‬‭medication‬‭errors‬
‭is minimal.‬
‭The data available to date suggest that the potential for harm from overdose is very low.‬
‭9.1.4.2. Gemcitabine overdose‬
‭There‬‭is‬‭no‬‭known‬‭antidote‬‭for‬‭overdose‬‭of‬‭gemcitabine.‬‭Doses‬‭as‬‭high‬‭as‬‭5700‬‭mg/m2‬‭have‬
‭been‬ ‭administered‬ ‭by‬ ‭intravenous‬ ‭infusion‬ ‭over‬ ‭30-minutes‬ ‭every‬ ‭2‬ ‭weeks‬ ‭with‬ ‭clinically‬
‭acceptable‬‭toxicity.‬‭In‬‭the‬‭event‬‭of‬‭suspected‬‭overdose,‬‭the‬‭patient‬‭should‬‭be‬‭monitored‬‭with‬
‭appropriate blood counts and receive supportive therapy, as necessary.‬
‭9.1.4.3. Cisplatin overdose‬
‭An‬ ‭acute‬ ‭overdose‬ ‭of‬ ‭cisplatin‬ ‭may‬ ‭result‬ ‭in‬ ‭renal‬ ‭failure,‬ ‭liver‬ ‭failure,‬ ‭deafness,‬ ‭ocular‬
‭toxicity‬‭(including‬‭detachment‬‭of‬‭the‬‭retina),‬‭significant‬‭myelosuppression,‬‭untreatable‬‭nausea‬
‭and vomiting and/or neuritis. An overdose may be fatal.‬
‭There‬‭is‬‭no‬‭specific‬‭antidote‬‭in‬‭the‬‭event‬‭of‬‭an‬‭over‬‭dosage‬‭of‬‭cisplatin.‬‭Even‬‭if‬‭haemodialysis‬
‭is‬‭initiated‬‭4‬‭hours‬‭after‬‭the‬‭overdose‬‭it‬‭has‬‭little‬‭effect‬‭on‬‭the‬‭elimination‬‭of‬‭cisplatin‬‭from‬‭the‬
‭body following a strong and rapid fixation of cisplatin to proteins.‬
‭Treatment in the event of an overdose consists of general support measures.‬
‭9.1.5.‬ ‭Adverse reaction (AR)‬
‭All‬‭untoward‬‭and‬‭unintended‬‭responses‬‭to‬‭an‬‭investigational‬‭medicinal‬‭product‬‭related‬‭to‬‭any‬
‭dose administered.‬
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‭9.1.6.‬ ‭Serious Adverse Event (SAE)‬
‭Any untoward medical occurrence or effect that at any dose:‬
‭1.‬ ‭Results in death (is fatal),‬
‭2.‬ ‭Is life-threatening,‬
‭3.‬ ‭Requires or prolongs inpatient hospitalization,‬
‭4.‬ ‭Results in persistent or significant disability or incapacity,‬
‭5.‬ ‭Is a congenital anomaly or birth defect, or‬
‭6.‬ ‭Is medically significant.‬
‭Progression‬ ‭of‬ ‭the‬ ‭malignancy‬ ‭under‬ ‭study‬ ‭(including‬‭signs‬‭and‬‭symptoms‬‭of‬‭progression)‬
‭should‬ ‭not‬ ‭be‬ ‭reported‬ ‭as‬ ‭an‬ ‭SAE‬ ‭unless‬ ‭the‬ ‭outcome‬ ‭is‬ ‭fatal‬ ‭within‬ ‭the‬ ‭safety‬‭reporting‬
‭period.‬ ‭Hospitalization‬ ‭due‬ ‭to‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭disease‬ ‭progression‬ ‭should‬ ‭not‬ ‭be‬
‭reported as an SAE.‬
‭Medical‬‭and‬‭scientific‬‭judgement‬‭should‬‭be‬‭exercised‬‭in‬‭deciding‬‭whether‬‭urgent‬‭reporting‬‭is‬
‭appropriate‬‭in‬‭other‬‭situations‬‭such‬‭as‬‭important‬‭medical‬‭events‬‭that‬‭may‬‭not‬‭be‬‭immediately‬
‭life-threatening‬ ‭or‬ ‭result‬ ‭in‬ ‭hospitalization‬ ‭but‬ ‭may‬ ‭jeopardize‬ ‭the‬ ‭patient‬ ‭or‬ ‭may‬ ‭require‬
‭intervention to prevent one of the outcomes listed in the above definition.‬
‭Any‬‭suspected‬‭transmission‬‭of‬‭an‬‭infectious‬‭agent‬‭through‬‭the‬‭medication‬‭is‬‭also‬‭considered‬‭a‬
‭SAE.‬
‭The‬‭terms‬‭"severe"‬‭and‬‭"serious"‬‭are‬‭not‬‭synonymous.‬ ‭Severity‬‭refers‬‭to‬‭the‬‭intensity‬‭of‬‭an‬
‭adverse‬‭event‬‭(e.g.,‬‭rated‬‭as‬‭mild,‬‭moderate,‬‭or‬‭severe,‬‭or‬‭according‬‭to‬‭NCI‬‭CTCAE;‬‭the‬‭event‬
‭itself‬‭may‬‭be‬‭of‬‭relatively‬‭minor‬‭medical‬‭significance‬‭(such‬‭as‬‭severe‬‭headache‬‭without‬‭any‬
‭further findings).‬
‭Severity‬‭and‬‭seriousness‬‭need‬‭to‬‭be‬‭independently‬‭assessed‬‭for‬‭each‬‭adverse‬‭event‬‭recorded‬‭on‬
‭the eCRF.‬
‭Serious‬ ‭adverse‬ ‭events‬ ‭are‬ ‭required‬ ‭to‬ ‭be‬ ‭reported‬ ‭by‬ ‭the‬ ‭investigator‬ ‭to‬ ‭the‬ ‭Sponsor‬
‭immediately‬ ‭(i.e.,‬ ‭no‬ ‭more‬ ‭than‬ ‭24‬ ‭hours‬ ‭after‬ ‭learning‬ ‭of‬ ‭the‬ ‭event;‬ ‭see‬ ‭Section‬ ‭9.2‬ ‭for‬
‭reporting instructions).‬
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‭9.1.7.‬ ‭Protocol-Specified Serious Adverse Events‬
‭There‬ ‭are‬ ‭no‬ ‭protocol-specified‬ ‭SAEs‬ ‭in‬ ‭this‬ ‭study.‬ ‭All‬ ‭SAEs‬ ‭will‬ ‭be‬ ‭reported‬ ‭by‬ ‭the‬
‭investigator‬‭as‬‭described‬‭in‬‭the‬‭previous‬‭sections,‬‭and‬‭will‬‭be‬‭handled‬‭as‬‭SAEs‬‭in‬‭the‬‭safety‬
‭database.‬
‭9.1.8.‬ ‭Life Threatening Event‬
‭It‬‭is‬‭any‬‭event‬‭in‬‭which‬‭the‬‭subject‬‭was‬‭at‬‭risk‬‭of‬‭death‬‭at‬‭the‬‭time‬‭of‬‭the‬‭event;‬‭it‬‭does‬‭not‬
‭refer to an event which hypothetically might have caused death if it were more severe.‬
‭9.1.9.‬ ‭Hospitalization / Prolongation of Hospitalization‬
‭Any‬‭event‬‭requiring‬‭hospitalization‬‭(or‬‭prolongation‬‭of‬‭hospitalization)‬‭that‬‭occurs‬‭or‬‭worsens‬
‭during‬‭a‬‭patient’s‬‭participation‬‭in‬‭a‬‭clinical‬‭study‬‭must‬‭be‬‭reported‬‭as‬‭a‬‭serious‬‭adverse‬‭event.‬
‭Prolongation‬ ‭of‬ ‭hospitalization‬ ‭is‬ ‭defined‬ ‭as‬ ‭any‬ ‭extension‬ ‭of‬ ‭an‬ ‭inpatient‬ ‭hospitalization‬
‭beyond‬‭the‬‭stay‬‭anticipated/required‬‭for‬‭the‬‭initial‬‭admission,‬‭as‬‭determined‬‭by‬‭the‬‭investigator‬
‭or treating physician.‬
‭Hospitalizations that do not meet the criteria for serious adverse event reporting are:‬
‭1.‬ ‭Reasons‬ ‭described‬ ‭in‬ ‭protocol‬ ‭(e.g.,‬ ‭drug‬ ‭administration,‬ ‭protocol-required‬
‭investigations).‬ ‭Hospitalizations‬ ‭or‬ ‭prolonged‬ ‭hospitalization‬ ‭for‬ ‭a‬ ‭complication‬ ‭of‬
‭therapy administration or procedures will be reported as a Serious Adverse Event.‬
‭2.‬ ‭Hospitalization‬‭or‬‭prolonged‬‭hospitalization‬‭for‬‭technical,‬‭practical‬‭or‬‭social‬‭reasons,‬
‭in the absence of an adverse event.‬
‭3.‬ ‭Pre-planned‬ ‭hospitalizations‬ ‭(i.e.,‬ ‭planned‬ ‭before‬ ‭study‬ ‭entry).‬ ‭Any‬ ‭surgery‬ ‭or‬
‭procedure planned before study entry must be documented on the case report form.‬
‭9.1.10.‬ ‭Unexpected adverse event (not listed)‬
‭An‬‭unexpected‬‭AA,‬‭whose‬‭nature‬‭or‬‭severity‬‭does‬‭not‬‭correspond‬‭to‬‭the‬‭product‬‭information.‬
‭The reference documents to establish the expectedness will be:‬
‭●‬ ‭Atezolizumab, last version of Investigator Brochure available for the Sponsor‬
‭●‬ ‭Gemcitabine, last version of the SmPC.‬
‭●‬ ‭Cisplatin, last version of the SmPC.‬
‭9.1.11.‬ ‭Adverse Event Associated With the Use of the Drug (Adverse Reaction)‬
‭The‬ ‭investigator’s‬ ‭assessment‬ ‭of‬ ‭causality‬ ‭must‬ ‭be‬ ‭provided‬ ‭for‬ ‭all‬ ‭AEs‬ ‭(serious‬ ‭and‬
‭non-serious);‬‭the‬‭investigator‬‭must‬‭record‬‭the‬‭causal‬‭relationship‬‭in‬‭the‬‭CRF,‬‭as‬‭appropriate,‬
‭and‬‭report‬‭such‬‭an‬‭assessment‬‭in‬‭accordance‬‭with‬‭the‬‭serious‬‭adverse‬‭reporting‬‭requirements‬‭if‬
‭applicable.‬‭An‬‭investigator’s‬‭causality‬‭assessment‬‭is‬‭the‬‭determination‬‭of‬‭whether‬‭there‬‭exists‬
‭a‬ ‭reasonable‬ ‭possibility‬ ‭that‬ ‭the‬ ‭investigational‬ ‭product‬ ‭caused‬ ‭or‬ ‭contributed‬ ‭to‬ ‭an‬ ‭AE;‬
‭generally‬ ‭the‬ ‭facts‬ ‭(evidence)‬ ‭or‬ ‭arguments‬ ‭to‬ ‭suggest‬ ‭a‬ ‭causal‬ ‭relationship‬ ‭should‬ ‭be‬
‭provided.‬‭If‬‭the‬‭investigator‬‭does‬‭not‬‭know‬‭whether‬‭or‬‭not‬‭the‬‭investigational‬‭product‬‭caused‬
‭the‬‭event,‬‭then‬‭the‬‭event‬‭will‬‭be‬‭handled‬‭as‬‭“related‬‭to‬‭investigational‬‭product”‬‭for‬‭reporting‬
‭purposes,‬ ‭as‬ ‭defined‬ ‭by‬ ‭the‬ ‭sponsor‬ ‭(see‬ ‭the‬ ‭section‬ ‭on‬ ‭Reporting‬ ‭Requirements).‬ ‭If‬ ‭the‬
‭investigator's‬‭causality‬‭assessment‬‭is‬‭“unknown‬‭but‬‭not‬‭related‬‭to‬‭investigational‬‭product”,‬‭this‬
‭should be clearly documented on study records.‬
‭In‬ ‭addition,‬ ‭if‬ ‭the‬ ‭investigator‬ ‭determines‬‭an‬‭SAE‬‭is‬‭associated‬‭with‬‭study‬‭procedures,‬‭the‬
‭investigator‬ ‭must‬ ‭record‬ ‭this‬ ‭causal‬ ‭relationship‬ ‭in‬ ‭the‬ ‭source‬ ‭documents‬ ‭and‬ ‭CRF,‬ ‭as‬
‭appropriate,‬ ‭and‬ ‭report‬ ‭such‬ ‭an‬ ‭assessment‬ ‭in‬ ‭accordance‬ ‭with‬ ‭the‬ ‭SAE‬ ‭reporting‬
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‭requirements, if applicable.‬
‭For‬‭combination‬‭treatments,‬‭causality‬‭assessment‬‭will‬‭be‬‭performed‬‭for‬‭each‬‭of‬‭the‬‭individual‬
‭drugs included in the combination.‬
‭An‬‭adverse‬‭event‬‭is‬‭considered‬‭associated‬‭with‬‭the‬‭use‬‭of‬‭the‬‭drug‬‭(Adverse‬‭Reaction)‬‭if‬‭the‬
‭attribution is possible, probable, or very likely by the definitions listed below.‬
‭9.1.12.‬ ‭Attribution Definitions‬
‭Not Related‬
‭An adverse event that is not related to the use of the drug.‬
‭Doubtful‬
‭An‬‭adverse‬‭event‬‭for‬‭which‬‭an‬‭alternative‬‭explanation‬‭is‬‭more‬‭likely,‬‭e.g.,‬‭concomitant‬‭drug(s),‬
‭concomitant‬ ‭disease(s),‬ ‭or‬ ‭the‬ ‭relationship‬ ‭in‬ ‭time‬ ‭suggests‬ ‭that‬ ‭a‬ ‭causal‬ ‭relationship‬ ‭is‬
‭unlikely.‬
‭Possible‬
‭An‬‭adverse‬‭event‬‭that‬‭might‬‭be‬‭due‬‭to‬‭the‬‭use‬‭of‬‭the‬‭drug.‬‭An‬‭alternative‬‭explanation,‬‭e.g.,‬
‭concomitant‬ ‭drug(s),‬ ‭concomitant‬ ‭disease(s),‬ ‭is‬ ‭inconclusive.‬ ‭The‬ ‭relationship‬ ‭in‬ ‭time‬ ‭is‬
‭reasonable; therefore, the causal relationship cannot be excluded.‬
‭Probable‬
‭An‬ ‭adverse‬ ‭event‬ ‭that‬ ‭might‬ ‭be‬ ‭due‬ ‭to‬ ‭the‬ ‭use‬ ‭of‬ ‭the‬ ‭drug.‬ ‭The‬ ‭relationship‬ ‭in‬ ‭time‬ ‭is‬
‭suggestive‬ ‭(e.g.,‬ ‭confirmed‬ ‭by‬ ‭de-challenge).‬ ‭An‬‭alternative‬‭explanation‬‭is‬‭less‬‭likely,‬‭e.g.,‬
‭concomitant drug(s), concomitant disease(s).‬
‭Very Likely‬
‭An‬ ‭adverse‬ ‭event‬ ‭that‬ ‭is‬ ‭listed‬ ‭as‬ ‭a‬ ‭possible‬ ‭adverse‬ ‭reaction‬ ‭and‬ ‭cannot‬ ‭be‬ ‭reasonably‬
‭explained‬‭by‬‭an‬‭alternative‬‭explanation,‬‭e.g.,‬‭concomitant‬‭drug(s),‬‭concomitant‬‭disease(s).‬‭The‬
‭relationship in time is very suggestive (e.g., it is confirmed by dechallenge and rechallenge).‬
‭9.1.3.‬ ‭Intensity (Severity) Criteria‬
‭The‬‭intensity‬‭of‬‭AEs‬‭will‬‭be‬‭classified‬‭using‬‭the‬‭Common‬‭Terminology‬‭Criteria‬‭for‬‭AEs‬‭of‬‭the‬
‭National‬ ‭Cancer‬ ‭Institute,‬ ‭version‬ ‭5.0‬ ‭(NCI-CTCAE)‬ ‭and‬ ‭will‬ ‭be‬ ‭recorded‬ ‭in‬ ‭detail‬ ‭as‬
‭instructed‬ ‭in‬ ‭the‬ ‭eCRF.‬ ‭If‬ ‭an‬ ‭AE‬ ‭occurs‬ ‭that‬ ‭is‬ ‭not‬ ‭listed‬ ‭in‬ ‭the‬ ‭NCI-CTCAE‬ ‭V5.0‬
‭classification system, the 5-point scale detailed below will be used instead:‬
‭-‬
‭Mild: General malaise, without interruption of normal daily activity.‬
‭-‬
‭Moderate: Sufficient general malaise to reduce or affect normal daily activity.‬
‭-‬
‭Severe: Incapacity for work or the development of normal daily activity.‬
‭-‬
‭Life threatening or disabling: Represents an immediate threat to life.‬
‭-‬
‭Death: AE-related.‬
‭Grade‬
‭Grade‬
‭Severity‬
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‭1‬
‭Mild;‬ ‭asymptomatic‬ ‭or‬ ‭mild‬ ‭symptoms;‬ ‭clinical‬ ‭or‬ ‭diagnostic‬ ‭observations‬
‭only; or intervention not indicated‬
‭2‬
‭Moderate;‬ ‭minimal,‬ ‭local,‬ ‭or‬ ‭non-invasive‬ ‭intervention‬‭indicated;‬‭or‬‭limiting‬
‭age-appropriate instrumental activities of daily living‬‭a‬
‭3‬
‭Severe‬ ‭or‬ ‭medically‬ ‭significant,‬ ‭but‬ ‭not‬ ‭immediately‬ ‭life-threatening;‬
‭hospitalization‬ ‭or‬ ‭prolongation‬ ‭of‬ ‭hospitalization‬ ‭indicated;‬ ‭disabling;‬ ‭or‬
‭limiting self-care activities of daily living‬‭b, c‬
‭4‬
‭Life-threatening consequences or urgent intervention indicated‬‭d‬
‭5‬
‭Death related to adverse event‬‭d‬
‭NCI CTCAE‬‭ ‬‭=‬‭ ‬‭National Cancer Institute Common Terminology‬‭Criteria for Adverse Events.‬
‭Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:‬
‭http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm‬
‭a‬ ‭Instrumental activities of daily living refer to‬‭preparing meals, shopping for groceries or‬
‭clothes, using the telephone, managing money, etc.‬
‭b‬ ‭Examples of self-care activities of daily living‬‭include bathing, dressing and undressing,‬
‭feeding oneself, using the toilet, and taking medications, as performed by patients who are‬
‭not bedridden.‬
‭c‬ ‭If an event is assessed as a "significant medical‬‭event," it must be reported as a serious‬
‭adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious‬
‭adverse event in Section 5.2.2.‬
‭d‬ ‭Grade 4 and 5 events must be reported as serious‬‭adverse events (see Section 9.2  for‬
‭reporting instructions), per the definition of serious adverse event in Section 9.1.‬
‭9.1.14.‬ ‭Exposure during Pregnancy‬
‭If,‬‭following‬‭initiation‬‭of‬‭the‬‭investigational‬‭product,‬‭it‬‭is‬‭subsequently‬‭discovered‬‭that‬‭a‬‭study‬
‭participant‬ ‭is‬ ‭pregnant‬ ‭or‬ ‭may‬ ‭have‬ ‭been‬ ‭pregnant‬ ‭at‬ ‭the‬ ‭time‬ ‭of‬ ‭investigational‬ ‭product‬
‭exposure,‬‭within‬‭5‬‭months‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭atezolizumab‬‭,‬‭or‬‭within‬‭6‬‭months‬‭after‬‭the‬‭last‬
‭dose‬ ‭of‬ ‭atezolizumab,‬ ‭the‬ ‭investigational‬ ‭product‬ ‭will‬ ‭be‬ ‭permanently‬ ‭discontinued‬ ‭in‬ ‭an‬
‭appropriate manner (e.g., dose tapering if necessary for participant).‬
‭Any‬ ‭pregnancy‬ ‭that‬ ‭occurs‬ ‭in‬ ‭a‬ ‭female‬ ‭partner‬ ‭of‬ ‭a‬‭male‬‭study‬‭participant‬‭should‬‭also‬‭be‬
‭reported‬‭to‬‭the‬‭sponsor‬‭within‬‭24‬‭hours‬‭of‬‭becoming‬‭aware.‬‭Male‬‭patients‬‭will‬‭be‬‭instructed‬
‭through‬ ‭the‬ ‭Informed‬ ‭Consent‬ ‭Form‬ ‭to‬ ‭immediately‬ ‭inform‬ ‭the‬ ‭investigator‬ ‭if‬ ‭his‬ ‭partner‬
‭becomes‬‭pregnant‬‭during‬‭the‬‭chemotherapy‬‭treatment‬‭period‬‭or‬‭within‬‭6‬‭months‬‭after‬‭the‬‭last‬
‭dose‬‭of‬‭chemotherapy.‬‭In‬‭order‬‭for‬‭Sponsor‬‭or‬‭designee‬‭to‬‭collect‬‭any‬‭pregnancy‬‭surveillance‬
‭information‬‭from‬‭the‬‭female‬‭partner,‬‭the‬‭female‬‭partner‬‭must‬‭sign‬‭an‬‭informed‬‭consent‬‭form‬
‭for disclosure of this information.‬
‭In‬‭both‬‭cases,‬‭the‬‭investigator‬‭must‬‭immediately‬‭notify‬‭the‬‭Sponsor‬‭Pharmacovigilance‬‭Office‬
‭by sending the Pregnancy form (see ISF).‬
‭Follow-up‬‭information‬‭regarding‬‭the‬‭course‬‭of‬‭the‬‭pregnancy,‬‭including‬‭perinatal‬‭and‬‭neonatal‬
‭outcome‬‭and,‬‭where‬‭applicable,‬‭offspring‬‭information,‬‭study‬‭discontinuation‬‭must‬‭be‬‭reported‬
‭following the before procedure described during at least 1 year after child-bearing.‬
‭Any‬‭serious‬‭adverse‬‭events‬‭associated‬‭with‬‭the‬‭pregnancy‬‭(e.g.,‬‭an‬‭event‬‭in‬‭the‬‭fetus,‬‭an‬‭event‬
‭in‬‭the‬‭mother‬‭during‬‭or‬‭after‬‭the‬‭pregnancy,‬‭or‬‭a‬‭congenital‬‭anomaly/birth‬‭defect‬‭in‬‭the‬‭child)‬
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‭or abortion should be reported as a SAE.‬
‭9.1.15.‬ ‭Occupational Exposure‬
‭An‬ ‭occupational‬ ‭exposure‬ ‭occurs‬ ‭when,‬ ‭during‬ ‭the‬ ‭performance‬ ‭of‬ ‭job‬ ‭duties,‬ ‭a‬ ‭person‬
‭(whether‬ ‭a‬ ‭healthcare‬ ‭professional‬ ‭or‬ ‭otherwise)‬ ‭gets‬ ‭in‬ ‭unplanned‬ ‭direct‬ ‭contact‬‭with‬‭the‬
‭product, which may or may not lead to the occurrence of an AE.‬
‭An‬ ‭occupational‬ ‭exposure‬ ‭is‬ ‭reported‬ ‭to‬ ‭the‬ ‭drug‬ ‭safety‬ ‭unit‬ ‭within‬ ‭24‬ ‭hours‬ ‭of‬ ‭the‬
‭investigator’s‬ ‭awareness,‬ ‭using‬ ‭the‬ ‭SAE‬ ‭report‬ ‭form,‬ ‭regardless‬ ‭of‬ ‭whether‬ ‭there‬ ‭is‬ ‭an‬
‭associated‬‭AE/SAE.‬‭Since‬‭the‬‭information‬‭does‬‭not‬‭pertain‬‭to‬‭a‬‭patient‬‭enrolled‬‭in‬‭the‬‭study,‬
‭the‬‭information‬‭is‬‭not‬‭reported‬‭on‬‭a‬‭CRF;‬‭however,‬‭a‬‭copy‬‭of‬‭the‬‭completed‬‭SAE‬‭report‬‭form‬
‭is maintained in the investigator site file.‬
‭9.1.16.‬ ‭Expedited reporting‬
‭The‬ ‭sponsor‬ ‭assumes‬ ‭responsibility‬ ‭for‬ ‭appropriate‬ ‭reporting‬ ‭of‬ ‭adverse‬ ‭events‬ ‭to‬ ‭the‬
‭regulatory‬‭authorities.‬‭The‬‭sponsor‬‭will‬‭also‬‭report‬‭all‬‭serious‬‭adverse‬‭events‬‭that‬‭are‬‭unlisted‬
‭(unexpected)‬‭and‬‭be‬‭associated‬‭with‬‭the‬‭use‬‭of‬‭the‬‭study‬‭drug.‬‭The‬‭sponsor‬‭must‬‭report‬‭these‬
‭events to investigators and competent authorities in accordance with current regulations.‬
‭9.2.‬
‭Collection and reporting of Adverse Events information‬
‭The sponsor will collect AEs up to 30 days after administration of the last dose of study drug.‬
‭All‬‭adverse‬‭events‬‭must‬‭be‬‭recorded‬‭using‬‭medical‬‭terminology‬‭in‬‭the‬‭source‬‭document‬‭and‬
‭the‬‭eCRF.‬‭Investigators‬‭must‬‭assess‬‭the‬‭severity‬‭(grade)‬‭of‬‭the‬‭event‬‭following‬‭NCI-CTCAE‬‭V‬
‭5.0‬ ‭Criteria‬ ‭and‬ ‭assign‬ ‭a‬ ‭relationship‬ ‭to‬ ‭study‬ ‭therapy‬ ‭and‬ ‭pursue‬ ‭and‬ ‭obtain‬ ‭information‬
‭adequate‬ ‭both‬ ‭to‬ ‭determine‬ ‭the‬ ‭outcome‬ ‭and‬ ‭to‬ ‭assess‬ ‭whether‬ ‭it‬ ‭meets‬ ‭the‬ ‭criteria‬ ‭for‬
‭classification‬‭as‬‭a‬‭SAE‬‭requiring‬‭immediate‬‭notification.‬‭The‬‭investigator‬‭must‬‭provide‬‭any‬
‭information as requested by the sponsor in addition to that on the eCRF.‬
‭Any‬‭serious‬‭adverse‬‭event‬‭which‬‭occurs‬‭from‬‭patient‬‭informed‬‭consent‬‭signature,‬‭during‬‭the‬
‭clinical‬‭study‬‭or‬‭within‬‭90‬‭days‬‭of‬‭receiving‬‭the‬‭last‬‭dose‬‭of‬‭study‬‭medication,‬‭whether‬‭or‬‭not‬
‭related to the study drug, must be reported by the investigator.‬
‭If‬‭a‬‭patient‬‭begins‬‭a‬‭new‬‭anticancer‬‭therapy,‬‭the‬‭AE‬‭reporting‬‭period‬‭for‬‭non-serious‬‭AEs‬‭ends‬
‭at‬‭the‬‭time‬‭the‬‭new‬‭treatment‬‭is‬‭started.‬‭Death‬‭must‬‭be‬‭reported‬‭if‬‭it‬‭occurs‬‭during‬‭the‬‭SAE‬
‭reporting‬‭period‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭investigational‬‭product,‬‭irrespective‬‭of‬‭any‬‭intervening‬
‭treatment.‬
‭In‬‭addition,‬‭any‬‭SAEs‬‭which‬‭occur‬‭as‬‭a‬‭result‬‭of‬‭protocol‬‭specific‬‭diagnostic‬‭procedures‬‭or‬
‭interventions‬‭must‬‭also‬‭be‬‭reported.‬ ‭Beyond‬‭this‬‭period‬‭of‬‭time,‬‭only‬‭those‬‭SAEs‬‭suspected‬‭to‬
‭be related to the study drug will be reported.‬
‭All‬ ‭SAEs‬ ‭suspected‬ ‭to‬ ‭be‬ ‭related‬ ‭to‬ ‭study‬ ‭treatment‬ ‭should‬ ‭be‬ ‭followed‬ ‭after‬ ‭the‬
‭treatment/study‬ ‭withdrawal‬ ‭until‬‭the‬‭event‬‭or‬‭its‬‭symptoms‬‭have‬‭resolved‬‭or‬‭stabilized‬‭at‬‭a‬
‭grade acceptable to the Investigator, Chief investigator and/or Sponsor.‬
‭Site‬‭staff‬‭should‬‭notify‬‭the‬‭sponsor,‬‭all‬‭the‬‭pregnancies‬‭of‬‭female‬‭subjects‬‭and‬‭female‬‭partners‬
‭of‬‭male‬‭subjects‬‭that‬‭occurred‬‭during‬‭the‬‭clinical‬‭trial‬‭within‬‭24‬‭hours‬‭from‬‭becoming‬‭aware.‬
‭Site‬‭staff‬‭should‬‭also‬‭communicate‬‭the‬‭outcome‬‭of‬‭the‬‭pregnancy‬‭within‬‭24‬‭hours‬‭since‬‭the‬
‭awareness.‬
‭The‬‭cause‬‭of‬‭death‬‭of‬‭a‬‭deceased‬‭patient‬‭in‬‭a‬‭clinical‬‭trial,‬‭whether‬‭the‬‭case‬‭of‬‭an‬‭expected‬
‭event‬‭or‬‭associated‬‭with‬‭the‬‭investigational‬‭agent,‬‭is‬‭considered‬‭an‬‭SAE‬‭and‬‭therefore‬‭must‬‭be‬
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‭communicated‬‭using‬‭the‬‭SAE‬‭form.‬‭The‬‭autopsy‬‭report‬‭should‬‭be‬‭sent‬‭to‬‭Sponsor‬‭identified‬
‭only with the patient inclusion number.‬
‭All serious adverse events, AESIs and pregnancy cases must be reported by fax within 24‬
‭h to MFAR Clinical Research, S.L. by fax (+ 34 93 253 11 68) or e-mail to‬
‭investigacion@mfar.net‬
‭The‬ ‭SAE‬ ‭report‬ ‭should‬ ‭comprise‬ ‭a‬ ‭full‬ ‭written‬ ‭summary,‬ ‭detailing‬ ‭relevant‬‭aspects‬‭of‬‭the‬
‭adverse‬‭events‬‭in‬‭question.‬‭Where‬‭applicable,‬‭information‬‭from‬‭relevant‬‭hospital‬‭case‬‭records‬
‭and‬‭autopsy‬‭reports‬‭should‬‭be‬‭included.‬‭Follow-up‬‭information‬‭should‬‭be‬‭forwarded‬‭to‬‭MFAR‬
‭Clinical‬‭Research,‬‭S.L.‬‭by‬‭fax‬‭(+‬‭34‬‭93‬‭253‬‭11‬‭68)‬‭or‬‭e-mail‬‭to‬‭investigacion@mfar.net‬
‭within 24 hours.‬
‭All‬‭SAEs‬‭suspected‬‭to‬‭be‬‭related‬‭to‬‭study‬‭drug‬‭must‬‭be‬‭followed‬‭up‬‭after‬‭the‬‭time‬‭of‬‭therapy‬
‭discontinuation‬‭until‬‭the‬‭event‬‭or‬‭its‬‭consequences‬‭resolve‬‭or‬‭stabilize‬‭at‬‭an‬‭acceptable‬‭level‬
‭for the investigator, the Trial Chief Investigator and/or Sponsor.‬
‭Non-Serious Adverse Event Reporting Requirements‬
‭All‬‭AEs‬‭will‬‭be‬‭reported‬‭on‬‭the‬‭AE‬‭page(s)‬‭of‬‭the‬‭CRF.‬‭It‬‭should‬‭be‬‭noted‬‭that‬‭the‬‭form‬‭for‬
‭collection‬ ‭of‬ ‭SAE‬ ‭information‬ ‭is‬ ‭not‬ ‭the‬ ‭same‬ ‭as‬ ‭the‬ ‭AE‬ ‭CRF.‬ ‭Where‬ ‭the‬ ‭same‬ ‭data‬‭are‬
‭collected,‬‭the‬‭forms‬‭must‬‭be‬‭completed‬‭in‬‭a‬‭consistent‬‭manner.‬‭For‬‭example,‬‭the‬‭same‬‭AE‬‭term‬
‭should‬‭be‬‭used‬‭on‬‭both‬‭forms.‬‭AEs‬‭should‬‭be‬‭reported‬‭using‬‭concise‬‭medical‬‭terminology‬‭on‬
‭the CRFs as well as on the form for collection of SAE information.‬
‭Sponsor’s Reporting Requirements to Regulatory Authorities‬
‭Adverse‬ ‭event‬ ‭reporting,‬ ‭including‬ ‭suspected‬ ‭unexpected‬‭serious‬‭adverse‬‭reactions,‬‭will‬‭be‬
‭carried out in accordance with applicable local regulations.‬
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‭10.‬
‭STATISTICAL CONSIDERATIONS‬
‭Detailed‬‭methodology‬‭for‬‭summary‬‭and‬‭statistical‬‭analyses‬‭of‬‭the‬‭data‬‭collected‬‭in‬‭this‬‭study‬
‭will‬ ‭be‬ ‭documented‬ ‭in‬ ‭a‬ ‭statistical‬ ‭analysis‬ ‭plan‬ ‭(SAP),‬ ‭which‬ ‭will‬ ‭be‬ ‭maintained‬ ‭by‬ ‭the‬
‭Sponsor.‬
‭This‬ ‭document‬ ‭may‬ ‭modify‬ ‭the‬ ‭plans‬ ‭outlined‬ ‭in‬ ‭the‬ ‭protocol;‬ ‭however,‬ ‭any‬ ‭major‬
‭modifications‬‭of‬‭the‬‭primary‬‭endpoint‬‭and/or‬‭its‬‭analysis‬‭will‬‭also‬‭be‬‭reflected‬‭in‬‭a‬‭protocol‬
‭amendment.‬
‭10.1.‬ ‭Sample size calculation‬
‭Fleming's‬‭phase‬‭II‬‭procedure‬‭(‬‭Fleming‬‭TR,‬‭1982‬‭)‬‭will‬‭be‬‭used.‬‭The‬‭null‬‭hypothesis‬‭that‬‭the‬
‭smallest‬‭response‬‭probability‬‭is‬‭0.3‬‭will‬‭be‬‭tested‬‭against‬‭a‬‭one-sided‬‭alternative.‬‭In‬‭the‬‭first‬
‭stage,‬‭46‬‭patients‬‭will‬‭be‬‭accrued.‬‭An‬‭intermediate‬‭analysis‬‭will‬‭be‬‭performed‬‭once‬‭these‬‭first‬
‭46‬‭patients‬‭reach‬‭6‬‭months‬‭after‬‭study‬‭treatment‬‭initiation.‬‭If‬‭there‬‭are‬‭16‬‭or‬‭fewer‬‭responses‬‭in‬
‭these‬ ‭46‬ ‭patients,‬ ‭the‬ ‭study‬ ‭will‬ ‭be‬ ‭stopped.‬ ‭This‬ ‭intermediate‬‭analysis‬‭is‬‭established‬‭as‬‭a‬
‭cut-off‬‭point‬‭to‬‭stop‬‭the‬‭study‬‭if‬‭the‬‭benefit‬‭for‬‭the‬‭patient‬‭in‬‭terms‬‭of‬‭objective‬‭response‬‭does‬
‭not‬‭justify‬‭its‬‭continuation‬‭with‬‭sufficient‬‭clarity.‬‭If‬‭there‬‭is‬‭no‬‭preliminary‬‭evidence‬‭in‬‭the‬‭first‬
‭46‬‭patients,‬‭which‬‭allows‬‭enough‬‭statistical‬‭power‬‭to‬‭reject‬‭the‬‭null‬‭hypothesis,‬‭the‬‭recruitment‬
‭will‬‭stop‬‭as‬‭it‬‭is‬‭considered‬‭that‬‭the‬‭efficacy‬‭of‬‭the‬‭treatment‬‭is‬‭not‬‭sufficient‬‭to‬‭justify‬‭the‬
‭inclusion‬‭of‬‭more‬‭patients.‬‭Otherwise,‬‭20‬‭additional‬‭patients‬‭will‬‭be‬‭accrued‬‭for‬‭a‬‭total‬‭of‬‭66.‬
‭The‬‭null‬‭hypothesis‬‭will‬‭be‬‭rejected‬‭if‬‭25‬‭or‬‭more‬‭responses‬‭are‬‭observed‬‭in‬‭66‬‭patients.‬‭This‬
‭design yields a type I error rate of 0.05 and power of 0.9 when the true response rate is 0.5.‬
‭Variables‬
‭Descriptions‬
‭α‬
‭Probability of type I error: 0.05‬
‭β‬
‭Probability of type II error: 0.1‬
‭p‬‭0‬
‭Response Probability of Poor Drug (P0) ---> 0.30‬
‭P1‬
‭Response Probability of Good Drug (P1) ---> 0.50‬
‭Nmax‬
‭Maximum number of patients to be recruited: 66‬
‭Numstage‬
‭Number of stages in Phase II clinical trial: 2‬
‭n‬‭i‬
‭Number of patients to be recruited in stage i= 46‬
‭R1‬
‭Upper Limit For 1st Stage Rejection of Drug (r1)= 16‬
‭R‬
‭Upper Limit for 2nd Stage Rejection of Drug (r)= 25‬
‭10.2.‬ ‭Study endpoints‬
‭10.2.1.‬ ‭Primary endpoint‬
‭Overall Response Rate (ORR):‬‭Percentage/proportion‬‭of patients with confirmed complete‬
‭response (CR) or partial response (PR) as their overall best response throughout the study‬
‭period.‬
‭10.2.2. Secondary endpoints‬
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‭Efficacy endpoints:‬
‭●‬ ‭Duration of response‬‭(DoR):‬‭Time from first confirmed‬‭response (CR or PR) to the‬
‭date of the documented PD as determined using RECIST 1.1 criteria or death due to‬
‭any cause, whichever occurs first.‬
‭●‬ ‭Time to response‬‭(TtR):‬‭Time from first dosing date‬‭to the date of the documented‬
‭ORR as determined using RECIST 1.1 criteria.‬
‭●‬ ‭Clinical benefit‬‭:‬‭Percentage/proportion of patients‬‭with confirmed complete response‬
‭(CR) or partial response (PR), or stable disease (SD) as their overall best response‬
‭throughout the study period.‬
‭●‬ ‭Overall Survival‬‭(OS)‬
‭○‬ ‭Time‬‭from‬‭first‬‭dosing‬‭date‬‭to‬‭the‬‭date‬‭of‬‭death.‬‭A‬‭subject‬‭who‬‭has‬‭not‬‭died‬
‭will be censored at the last known date alive.‬
‭○‬ ‭Proportion‬‭of‬‭patients‬‭alive‬‭at‬‭the‬‭end‬‭of‬‭the‬‭atezolizumab‬‭plus‬‭split‬‭dose‬‭of‬
‭gemcitabine and cisplatin combination stage.‬
‭○‬ ‭Proportion of patients alive at the end of follow-up.‬
‭●‬ ‭Progression-Free Survival‬‭(PFS)‬
‭○‬ ‭Time‬‭from‬‭first‬‭dosing‬‭date‬‭to‬‭the‬‭date‬‭of‬‭confirmed‬‭PD.‬‭A‬‭subject‬‭who‬‭has‬
‭not died will be censored at the last known date alive.‬
‭○‬ ‭Proportion of patients free of PD at 6 months since start of treatment.‬
‭○‬ ‭Proportion of patients free of PD at the end of follow-up.‬
‭Safety endpoints‬
‭●‬ ‭Adverse‬‭events‬‭(AE)‬‭assessment:‬‭Type,‬‭frequency,‬‭severity‬‭and‬‭outcome‬‭of‬‭adverse‬
‭events .‬
‭●‬ ‭Treatment-related AEs:‬‭Type, frequency, severity and‬‭outcome.‬
‭Exploratory endpoints‬
‭●‬ ‭Biomarkers and/or genes expression and participant outcomes.‬
‭10.3.‬ ‭Efficacy assessment‬
‭10.3.1.‬ ‭Efficacy variables‬
‭Overall‬‭Response‬‭Rate‬‭(ORR)‬‭at‬‭6‬‭months‬‭from‬‭first‬‭dose:‬‭includes‬‭patients‬‭with‬‭confirmed‬
‭persistent‬‭partial‬‭(PR)‬‭and‬‭complete‬‭response‬‭(CR)‬‭as‬‭best‬‭response‬‭according‬‭to‬‭RECIST‬‭v‬
‭1.1, at 6 months from adaptive the study treatment initiation.‬
‭Overall‬‭Response‬‭Rate‬‭(ORR)‬‭from‬‭first‬‭dose:‬‭includes‬‭patients‬‭with‬‭confirmed‬‭persistent‬
‭partial‬‭(PR)‬‭and‬‭complete‬‭response‬‭(CR)‬‭as‬‭best‬‭response‬‭according‬‭to‬‭RECIST‬‭1.1,‬‭at‬‭the‬‭end‬
‭of their participation in the study.‬
‭Time‬ ‭to‬ ‭response:‬ ‭Time‬ ‭to‬ ‭response‬ ‭(TTR)‬ ‭is‬ ‭defined‬‭as‬‭the‬‭time‬‭from‬‭the‬‭start‬‭of‬‭study‬
‭treatment‬ ‭to‬ ‭the‬ ‭first‬ ‭objective‬ ‭tumor‬ ‭response‬ ‭(tumor‬ ‭shrinkage‬ ‭of‬ ‭≥30%)‬ ‭observed‬ ‭for‬
‭patients who achieved a CR or PR.‬
‭Duration‬ ‭of‬ ‭response‬ ‭(DOR):‬ ‭DOR‬ ‭is‬ ‭calculated‬ ‭as‬ ‭the‬ ‭time‬ ‭from‬ ‭the‬ ‭date‬ ‭of‬ ‭first‬
‭documented‬‭CR‬‭or‬‭PR,‬‭as‬‭per‬‭RECIST‬‭1.1,‬‭to‬‭the‬‭first‬‭documented‬‭progression‬‭or‬‭death‬‭due‬‭to‬
‭underlying cancer.‬
‭Overall‬‭Survival‬‭(OS):‬‭Median‬‭Overall‬‭Survival‬‭(mOS)‬‭is‬‭calculated‬‭as‬‭the‬‭time‬‭from‬‭the‬
‭date of inclusion to date of death due to any cause.‬
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‭Progression-free‬‭Survival‬‭(PFS):‬‭Median‬‭Progression‬‭free‬‭survival‬‭(mPFS)‬‭is‬‭defined‬‭as‬‭the‬
‭time‬‭from‬‭the‬‭date‬‭of‬‭inclusion‬‭to‬‭the‬‭date‬‭of‬‭the‬‭first‬‭documented‬‭disease‬‭progression‬‭or‬‭death‬
‭due‬‭to‬‭any‬‭cause,‬‭whichever‬‭occurs‬‭first.‬‭PFS‬‭will‬‭be‬‭determined‬‭based‬‭on‬‭tumour‬‭assessment‬
‭(RECIST‬‭version‬‭1.1‬‭criteria).‬‭The‬‭local‬‭Investigator's‬‭assessments‬‭will‬‭be‬‭used‬‭for‬‭analyses.‬
‭Patients‬‭who‬‭are‬‭alive‬‭and‬‭have‬‭not‬‭progressed‬‭at‬‭the‬‭last‬‭follow-up‬‭will‬‭be‬‭censored‬‭at‬‭the‬
‭date‬‭of‬‭the‬‭last‬‭available‬‭image‬‭determination‬‭(CT‬‭scan‬‭or‬‭MRI).‬‭Patients‬‭with‬‭no‬‭additional‬
‭image‬ ‭test‬ ‭other‬ ‭than‬ ‭that‬ ‭at‬ ‭baseline‬ ‭will‬ ‭be‬ ‭censored‬ ‭to‬ ‭the‬‭day‬‭after‬‭inclusion.‬‭Patients‬
‭initiating‬‭new‬‭anticancer‬‭therapy‬‭(without‬‭progression‬‭to‬‭the‬‭study‬‭treatment)‬‭will‬‭be‬‭censored‬
‭to the date of new anticancer therapy initiation.‬
‭Clinical‬ ‭Benefit‬ ‭(CB)‬ ‭Rate:‬ ‭Clinical‬ ‭Benefit‬ ‭Rate‬ ‭(CBR)‬ ‭is‬ ‭defined‬ ‭as‬ ‭the‬‭percentage‬‭of‬
‭patients‬‭who‬‭achieved‬‭complete‬‭response,‬‭partial‬‭response‬‭and‬‭stable‬‭disease.‬‭Stable‬‭disease‬
‭should be maintained for at least 6 months to be considered as a CBR event.‬
‭10.4.‬ ‭Safety assessment‬
‭The‬‭safety‬‭population‬‭(SP)‬‭consists‬‭of‬‭all‬‭enrolled‬‭subjects‬‭who‬‭received‬‭at‬‭least‬‭one‬‭dose‬‭of‬
‭study‬‭treatment.‬‭Patients‬‭will‬‭be‬‭monitored‬‭for‬‭safety‬‭during‬‭all‬‭the‬‭stages‬‭of‬‭the‬‭study.‬‭All‬
‭safety and tolerability assessments will be done at pre-dosing time, unless otherwise specified.‬
‭Safety‬‭parameters‬‭are‬‭AE,‬‭SAE,‬‭AESI,‬‭pregnancy,‬‭medication‬‭error,‬‭and‬‭overdose.‬‭Additional‬
‭safety information could be derived from ECG, lab test, pregnancy test, or vital sign exam.‬
‭The‬‭assessment‬‭of‬‭adverse‬‭events‬‭will‬‭include‬‭the‬‭type‬‭of‬‭event‬‭(including‬‭symptoms,‬‭physical‬
‭exam‬‭findings‬‭and‬‭laboratory‬‭abnormalities),‬‭the‬‭incidence,‬‭severity,‬‭timing,‬‭seriousness,‬‭and‬
‭relatedness‬‭regarding‬‭the‬‭treatment‬‭under‬‭study.‬‭Adverse‬‭events‬‭will‬‭be‬‭recorded‬‭and‬‭reported‬
‭in‬‭the‬‭corresponding‬‭section‬‭of‬‭the‬‭case‬‭report‬‭form.‬‭The‬‭grade‬‭of‬‭adverse‬‭events‬‭will‬‭be‬‭coded‬
‭according‬ ‭to‬ ‭the‬ ‭National‬ ‭Cancer‬ ‭Institute’s‬ ‭Common‬ ‭Toxicity‬ ‭criteria‬ ‭(NCI-CTCAE‬ ‭v5.0‬
‭scoring system). The worst toxicity score will be recorded.‬
‭10.5.‬ ‭Definition of study populations‬
‭Data will be analysed in the following populations:‬
‭1.‬ ‭Intent-To-Treat (ITT):‬‭All patients that have been‬‭enrolled in the trial.‬
‭2.‬ ‭Evaluable‬‭population‬‭per‬‭protocol‬‭(PP):‬‭All‬‭patients‬‭fulfilling‬‭all‬‭eligibility‬‭criteria‬
‭without‬‭any‬‭protocol‬‭deviation‬‭that‬‭makes‬‭the‬‭patient‬‭invalid‬‭for‬‭the‬‭primary‬‭endpoint‬
‭evaluation.‬
‭3.‬ ‭Safety population (SP):‬‭All patients receiving at‬‭least one dose of the study treatments.‬
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‭10.6.‬ ‭Data quality control‬
‭A‬‭Data‬‭Management‬‭Plan‬‭(DMP)‬‭will‬‭be‬‭elaborated‬‭for‬‭this‬‭trial‬‭in‬‭order‬‭to‬‭outline‬‭the‬‭data‬
‭management‬ ‭procedures‬‭and‬‭the‬‭related‬‭responsibilities‬‭of‬‭trial‬‭staff.‬‭The‬‭DMP‬‭will‬‭clearly‬
‭specify‬ ‭the‬ ‭data‬‭quality‬‭control‬‭tasks‬‭to‬‭be‬‭performed‬‭and‬‭the‬‭corresponding‬‭responsibility,‬
‭timelines, etc., according to international guidelines in the subject and GCPs.‬
‭Following‬‭data‬‭entry‬‭of‬‭the‬‭investigator‬‭staff‬‭into‬‭the‬‭data‬‭capture‬‭system‬‭(eCRF),‬‭the‬‭data‬
‭entered‬ ‭will‬ ‭be‬ ‭reconciled‬ ‭against‬ ‭the‬ ‭original‬ ‭case‬ ‭report‬ ‭form,‬ ‭review‬ ‭form/clinic‬
‭notes/laboratory‬‭reports‬‭by‬‭CRA‬‭during‬‭monitoring‬‭visits,‬‭according‬‭to‬‭the‬‭monitoring‬‭plan.‬
‭Any‬‭identified‬‭issues‬‭should‬‭be‬‭clarified‬‭with‬‭the‬‭Investigator‬‭staff.‬‭Any‬‭necessary‬‭corrections‬
‭should be made in the corresponding field of the eCRF.‬
‭The‬‭monitoring‬‭plan‬‭will‬‭establish‬‭that‬‭source‬‭data‬‭verification‬‭(SDV)‬‭is‬‭expected‬‭for‬‭a‬‭subset‬
‭of‬ ‭variables,‬ ‭according‬ ‭to‬ ‭study‬ ‭status,‬‭starting‬‭on‬‭the‬‭approval‬‭of‬‭this‬‭DMP‬‭and‬‭the‬‭SDV‬
‭strategy agreed.‬
‭Remote‬ ‭QC‬ ‭activities‬ ‭will‬ ‭be‬ ‭outlined‬ ‭in‬ ‭the‬ ‭Monitoring‬ ‭Plan‬ ‭for‬ ‭relevant‬ ‭variables‬ ‭as‬
‭eligibility, primary endpoints, safety endpoints and relevant secondary endpoints.‬
‭Performance‬‭of‬‭these‬‭checks‬‭is‬‭expected‬‭on‬‭all‬‭the‬‭patients‬‭included‬‭(this‬‭estimate‬‭may‬‭vary‬
‭according to the quality of the data reported by the research team).‬
‭Any‬‭finding‬‭will‬‭be‬‭reflected‬‭in‬‭the‬‭monitoring‬‭report‬‭and‬‭will‬‭be‬‭conveniently‬‭managed‬‭with‬
‭sites‬‭(including‬‭Principal‬‭Investigator)‬‭and‬‭informed‬‭to‬‭the‬‭Coordinating‬‭Investigator,‬‭as‬‭the‬
‭representative‬ ‭of‬ ‭the‬ ‭Sponsor‬ ‭in‬ ‭this‬ ‭study,‬ ‭and‬ ‭when‬ ‭applicable,‬ ‭notified‬ ‭to‬ ‭competent‬
‭authorities according to local regulations.‬
‭10.7.‬ ‭Statistical analysis‬
‭For‬ ‭each‬ ‭categorical‬ ‭variable,‬ ‭the‬ ‭results‬ ‭will‬ ‭be‬ ‭summarised‬ ‭by‬ ‭frequencies‬ ‭and‬
‭percentages/proportions along with 95 % confidence intervals (95% CIs) when applicable.‬
‭For‬‭each‬‭continuous‬‭variable,‬‭the‬‭results‬‭will‬‭be‬‭summarised‬‭by‬‭descriptive‬‭statistics‬‭such‬‭as‬
‭median,‬‭range,‬‭and‬‭range‬‭or‬‭by‬‭means,‬‭standard‬‭deviations,‬‭and‬‭(95%‬‭CIs).‬‭For‬‭time‬‭to‬‭event‬
‭endpoints,‬‭Kaplan-Meier‬‭estimates‬‭at‬‭selected‬‭time‬‭points‬‭and‬‭corresponding‬‭curves‬‭will‬‭be‬
‭presented.‬‭Time‬‭to‬‭event‬‭is‬‭derived‬‭relative‬‭to‬‭the‬‭first‬‭study‬‭treatment‬‭administration‬‭and‬‭will‬
‭be expressed in weeks and/or months.‬
‭Vital‬‭signs,‬‭ECG‬‭parameters,‬‭clinical‬‭laboratory‬‭data‬‭(haematology,‬‭serum‬‭biochemistry,‬‭and‬
‭urinalysis)‬‭will‬‭be‬‭presented‬‭in‬‭tabular‬‭form.‬‭Laboratory‬‭values‬‭will‬‭be‬‭expressed‬‭as‬‭absolute‬
‭values‬ ‭and‬ ‭in‬ ‭grades‬ ‭(ordinal‬ ‭categorical‬ ‭variables),‬ ‭when‬ ‭feasible.‬ ‭In‬ ‭case‬ ‭of‬ ‭laboratory‬
‭findings‬ ‭reported‬ ‭as‬ ‭adverse‬‭events,‬‭values‬‭will‬‭be‬‭presented‬‭and/or‬‭classified‬‭according‬‭to‬
‭NCI CTCAE v 5.0.‬
‭All‬‭adverse‬‭events,‬‭including‬‭treatment-emergent‬‭AE‬‭(AEs‬‭starting‬‭after‬‭the‬‭administration‬‭of‬
‭study‬‭treatment‬‭and‬‭up‬‭to‬‭study‬‭completion)‬‭will‬‭be‬‭summarised‬‭by‬‭system‬‭organ‬‭class‬‭and‬
‭preferred‬‭term.‬‭Grading‬‭will‬‭be‬‭presented‬‭by‬‭type‬‭and‬‭in‬‭tables‬‭showing‬‭the‬‭frequency‬‭and‬
‭percentage‬‭of‬‭the‬‭within-patient‬‭worst‬‭grades.‬‭In‬‭addition,‬‭grade‬‭≥‬‭3‬‭AEs‬‭will‬‭be‬‭summarised‬
‭separately. Further analyses could be performed.‬
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‭Analysis‬‭will‬‭be‬‭based‬‭on‬‭observed‬‭data,‬‭and‬‭missing‬‭data‬‭for‬‭drop-outs‬‭are‬‭not‬‭replaced‬‭by‬
‭methods like LOCF (last option carried forward).‬
‭Full analysis details will be outlined in the statistical analysis plan (SAP).‬
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‭11.‬
‭LEGAL AND ETHICS CONSIDERATION‬
‭11.1.‬
‭Ethical conduct of the study‬
‭The‬ ‭study‬ ‭will‬ ‭be‬ ‭conducted‬ ‭in‬ ‭accordance‬‭with‬‭the‬‭principles‬‭of‬‭the‬‭Helsinki‬‭Declaration‬
‭Adopted‬‭by‬‭the‬‭18th‬‭World‬‭Medical‬‭Assembly,‬‭Helsinki,‬‭Finland,‬‭June‬‭1964‬‭updated‬‭to‬‭its‬
‭latest‬ ‭version‬ ‭Fortaleza,‬ ‭Brazil,‬ ‭October‬ ‭2013.‬ ‭With‬ ‭the‬ ‭Good‬ ‭Clinical‬ ‭Practice‬ ‭(GCP)‬
‭standards‬ ‭issued‬ ‭by‬ ‭the‬ ‭Working‬ ‭Party‬ ‭on‬ ‭Medicinal‬ ‭Product‬ ‭Efficacy‬ ‭of‬ ‭the‬ ‭European‬
‭Economic Community (1990) (CPMP / ICH / 135/95).‬
‭And the laws and regulations in force in Spain:‬
‭●‬ ‭The‬‭Oviedo‬‭Convention‬‭of‬‭April‬‭4,‬‭1997‬‭on‬‭human‬‭rights‬‭and‬‭biomedicine,‬‭ratified‬‭in‬
‭the BOE in October 1999.‬
‭●‬ ‭The‬‭rules‬‭for‬‭the‬‭adequate‬‭protection‬‭of‬‭personal‬‭data,‬‭in‬‭accordance‬‭with‬‭Law‬‭3/2018‬
‭Protection of Personal Data and guarantee of digital rights.‬
‭●‬ ‭The‬ ‭rights‬ ‭and‬ ‭obligations‬ ‭regarding‬ ‭information‬ ‭and‬ ‭clinical‬ ‭documentation,‬ ‭as‬
‭provided in Law 41/2002, of November 14, basic regulation of patient autonomy.‬
‭●‬ ‭Royal‬ ‭Decree‬ ‭1090/2015,‬ ‭of‬ ‭4‬ ‭December,‬ ‭regulating‬ ‭clinical‬ ‭trials‬ ‭with‬ ‭medicinal‬
‭products,‬ ‭Ethics‬ ‭Committees‬ ‭for‬ ‭Investigation‬ ‭with‬ ‭medicinal‬ ‭products‬ ‭and‬ ‭the‬
‭Spanish Clinical Studies Registry.‬
‭●‬ ‭Law 14/2007, of July 3, on Biomedical Research.‬
‭11.2.‬
‭Independent Ethical Committee (IEC) Review‬
‭Prior‬ ‭to‬ ‭the‬ ‭commencement‬ ‭of‬ ‭the‬ ‭trial‬ ‭at‬ ‭a‬ ‭given‬ ‭site,‬ ‭this‬ ‭clinical‬ ‭trial‬ ‭protocol‬ ‭will‬‭be‬
‭submitted‬‭together‬‭with‬‭its‬‭associated‬‭documents‬‭to‬‭the‬‭Central‬‭IEC‬‭for‬‭its‬‭approval,‬‭which‬
‭will be filed in the Investigator Site File. A copy will be filed in the Sponsor Trial Master File.‬
‭The‬‭IEC‬‭will‬‭be‬‭asked‬‭to‬‭document‬‭the‬‭date‬‭of‬‭the‬‭meeting‬‭at‬‭which‬‭the‬‭favourable‬‭opinion‬‭or‬
‭approval‬ ‭was‬ ‭given,‬ ‭with‬ ‭the‬ ‭members‬ ‭and‬ ‭voting‬ ‭members‬ ‭present.‬ ‭Written‬ ‭evidence‬ ‭of‬
‭favourable‬‭opinion‬‭or‬‭approval‬‭that‬‭clearly‬‭identifies‬‭the‬‭trial,‬‭the‬‭clinical‬‭trial‬‭protocol‬‭and‬‭the‬
‭version, the Subject Information and Informed Consent Form, should be provided.‬
‭Amendments‬‭to‬‭this‬‭clinical‬‭trial‬‭protocol‬‭will‬‭also‬‭be‬‭submitted‬‭to‬‭the‬‭concerned‬‭IEC,‬‭before‬
‭implementation‬‭of‬‭substantial‬‭changes.‬‭Relevant‬‭safety‬‭information‬‭will‬‭be‬‭submitted‬‭to‬‭the‬
‭IEC during the course of the trial, in accordance with national regulations and requirements.‬
‭Initial‬‭IEC‬‭positive‬‭vote,‬‭and‬‭all‬‭materials‬‭approved‬‭by‬‭the‬‭IEC‬‭for‬‭this‬‭study‬‭including‬‭the‬
‭patient‬ ‭consent‬ ‭form‬ ‭and‬‭recruitment‬‭materials‬‭must‬‭be‬‭maintained‬‭by‬‭the‬‭Investigator‬‭and‬
‭made available for inspection.‬
‭11.3.‬
‭Authorities‬
‭The‬‭study‬‭protocol‬‭and/or‬‭related‬‭documents‬‭will‬‭be‬‭submitted‬‭to‬‭regulatory‬‭authorities‬‭before‬
‭commencement‬ ‭of‬ ‭the‬ ‭clinical‬‭trial,‬‭as‬‭national‬‭authorities‬‭in‬‭the‬‭country‬‭where‬‭the‬‭trial‬‭is‬
‭taking place.‬
‭11.4.‬
‭Informed consent‬
‭The‬‭patient‬‭should‬‭sign‬‭an‬‭informed‬‭consent‬‭that‬‭will‬‭include‬‭the‬‭information‬‭for‬‭the‬‭clinical‬
‭trial and associated translational research.‬
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‭The‬ ‭clinician‬ ‭will‬ ‭have‬ ‭to‬ ‭explain‬ ‭the‬ ‭nature,‬ ‭objectives‬ ‭and‬‭possible‬‭consequences‬‭of‬‭the‬
‭clinical‬‭trial‬‭in‬‭a‬‭manner‬‭that‬‭is‬‭understandable‬‭by‬‭the‬‭patient.‬‭The‬‭patient‬‭must‬‭give‬‭his/her‬
‭consent before being admitted into the study and before biological samples are taken.‬
‭The‬‭study‬‭subject‬‭will‬‭provide‬‭his/her‬‭consent,‬‭signing‬‭by‬‭duplicate‬‭the‬‭appropriate‬‭model.‬‭For‬
‭this‬‭purpose,‬‭each‬‭model‬‭must‬‭carry‬‭the‬‭signature‬‭of‬‭investigator‬‭and‬‭patient.‬‭The‬‭investigator‬
‭will retain one copy of the original of each patient signed consent form.‬
‭The‬‭investigator‬‭will‬‭not‬‭start‬‭any‬‭investigation‬‭related‬‭with‬‭the‬‭study‬‭until‬‭the‬‭written‬‭consent‬
‭has been obtained.‬
‭The‬‭informed‬‭consent‬‭form‬‭used‬‭in‬‭this‬‭study,‬‭and‬‭any‬‭changes‬‭made‬‭during‬‭the‬‭course‬‭of‬‭the‬
‭study, must be prospectively approved by the Ethics Committee.‬
‭11.5.‬
‭Confidentiality‬
‭In‬‭order‬‭to‬‭guarantee‬‭the‬‭confidentiality‬‭of‬‭the‬‭clinical‬‭trial‬‭data‬‭according‬‭to‬‭the‬‭provisions‬‭of‬
‭The‬ ‭rules‬ ‭for‬ ‭the‬ ‭adequate‬ ‭protection‬ ‭of‬ ‭personal‬ ‭data,‬ ‭in‬ ‭accordance‬ ‭with‬ ‭Law‬ ‭3/2018‬
‭Protection‬‭of‬‭Personal‬‭Data‬‭and‬‭guarantee‬‭of‬‭digital‬‭rights,‬‭only‬‭the‬‭personnel‬‭designated‬‭by‬
‭the‬‭Sponsor‬‭will‬‭have‬‭access‬‭to‬‭the‬‭patient‬‭data‬‭for‬‭monitoring/auditing‬‭purposes,‬‭Investigators‬
‭and his/her staff, the Ethic Committee and the pertinent Competent Authorities.‬
‭The‬‭investigator‬‭should‬‭facilitate‬‭access‬‭to‬‭the‬‭source‬‭documents‬‭and‬‭data‬‭for‬‭monitoring‬‭and‬
‭auditing purposes.‬
‭The‬‭content‬‭of‬‭the‬‭case‬‭report‬‭forms‬‭(CRF),‬‭as‬‭well‬‭as‬‭the‬‭documents‬‭generated‬‭during‬‭the‬
‭study‬‭will‬‭be‬‭protected‬‭from‬‭non-permitted‬‭uses‬‭by‬‭persons‬‭not‬‭involved‬‭in‬‭the‬‭investigation,‬
‭and‬‭will‬‭therefore‬‭be‬‭considered‬‭strictly‬‭confidential‬‭and‬‭not‬‭revealed‬‭to‬‭third‬‭parties,‬‭except‬
‭those specified in the previous paragraphs.‬
‭11.6.‬
‭Insurance Policy‬
‭The‬ ‭insurance‬ ‭or‬ ‭indemnity‬ ‭in‬ ‭accordance‬ ‭with‬ ‭pertinent‬ ‭regulatory‬ ‭requirements‬ ‭will‬ ‭be‬
‭provided.‬‭All‬‭patients‬‭in‬‭this‬‭study‬‭are‬‭insured‬‭through‬‭the‬‭corresponding‬‭insurance‬‭policy‬‭that‬
‭satisfies the conditions stipulated by the RD 1090/2015 in Spain.‬
‭11.7.‬
‭End of study definition‬
‭The‬‭end‬‭of‬‭study‬‭is‬‭defined‬‭as‬‭the‬‭Last‬‭Patient‬‭Last‬‭Visit‬‭(LPLV)‬‭and‬‭will‬‭be‬‭considered‬‭at‬‭24‬
‭months‬‭after‬‭last‬‭patient‬‭first‬‭visit‬‭(LPFV),‬‭Sponsor‬‭will‬‭ask‬‭survival‬‭status‬‭of‬‭all‬‭patients‬‭at‬
‭the‬‭final‬‭clinical‬‭trial‬‭database‬‭closing,‬‭in‬‭order‬‭to‬‭maximise‬‭the‬‭median‬‭follow‬‭up‬‭of‬‭patients‬
‭for overall survival data.‬
‭11.8.‬
‭Early study termination‬
‭The‬ ‭clinical‬ ‭trial‬ ‭may‬ ‭be‬ ‭terminated‬ ‭prematurely‬ ‭or‬ ‭suspended‬ ‭at‬ ‭the‬ ‭request‬ ‭of‬ ‭Health‬
‭Authorities‬ ‭or‬ ‭if‬ ‭new‬ ‭safety‬ ‭or‬ ‭efficacy‬ ‭information‬ ‭leads‬ ‭to‬ ‭an‬ ‭unfavourable‬ ‭risk‬ ‭benefit‬
‭judgment‬‭for‬‭any‬‭IMP.‬‭The‬‭Sponsor‬‭may‬‭discontinue‬‭the‬‭trial‬‭if‬‭it‬‭becomes‬‭unjustifiable‬‭for‬
‭medical‬‭or‬‭ethical‬‭reasons,‬‭poor‬‭enrolment,‬‭or‬‭the‬‭discontinuation‬‭of‬‭clinical‬‭development‬‭of‬
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‭the IMP or withdrawal of the IMP from the market for safety reasons.‬
‭Health‬ ‭Authorities‬ ‭and‬ ‭Independent‬ ‭Ethics‬ ‭Committees‬ ‭(IECs)‬ ‭will‬ ‭be‬ ‭informed‬ ‭about‬‭the‬
‭discontinuation of the trial in accordance with applicable regulations.‬
‭In‬ ‭case‬ ‭of‬ ‭early‬‭termination‬‭of‬‭the‬‭study,‬‭all‬‭the‬‭study‬‭material‬‭(study‬‭drugs,‬‭etc.)‬‭must‬‭be‬
‭returned to the Sponsor.‬
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‭12.‬
‭STUDY PROCEDURES‬
‭12.1.‬ ‭Responsibilities according to Good Clinical Practice‬
‭Responsibilities‬ ‭of‬ ‭the‬ ‭principal‬ ‭investigator‬ ‭of‬ ‭each‬ ‭participating‬ ‭center‬ ‭includes‬ ‭what‬ ‭is‬
‭detailed in section 4 of the‬‭Guideline for good clinical‬‭practice E6 (R2)‬‭.‬
‭12.2.‬ ‭Instructions for e-CRF completion‬
‭The‬‭data‬‭will‬‭be‬‭recorded‬‭using‬‭the‬‭Electronic‬‭Data‬‭Capture‬‭software‬‭property‬‭of‬‭MFAR‬‭S.L.‬
‭The‬‭MFAR‬‭e-CRF‬‭environment‬‭will‬‭be‬‭used‬‭for‬‭data‬‭collection‬‭in‬‭this‬‭study.‬‭The‬‭database‬‭can‬
‭be‬ ‭accessed‬ ‭through‬ ‭the‬ ‭following‬ ‭link:‬ ‭www.mfar.es/access‬‭.‬ ‭Access‬ ‭to‬ ‭data‬ ‭is‬‭secure‬‭and‬
‭restricted‬‭for‬‭authorised‬‭users.‬‭Each‬‭user‬‭requires‬‭a‬‭username‬‭and‬‭password‬‭for‬‭exclusively‬
‭personal use, as per good clinical practice.‬
‭All‬ ‭the‬ ‭EDC‬ ‭users‬ ‭are‬ ‭uniquely‬‭identified‬‭by‬‭name,‬‭all‬‭the‬‭access‬‭to‬‭the‬‭software‬‭is‬‭made‬
‭through a secure, encrypted connection and all the activities are logged and audited.‬
‭All‬‭the‬‭EDC‬‭forms‬‭are‬‭designed‬‭according‬‭to‬‭the‬‭eCRF‬‭defined‬‭by‬‭the‬‭study‬‭protocol,‬‭and‬‭are‬
‭validated‬ ‭according‬ ‭to‬ ‭the‬ ‭DVP‬ ‭(Data‬ ‭Validation‬ ‭Plan).‬ ‭There‬ ‭will‬‭be‬‭eCRFs‬‭for‬‭different‬
‭visits,‬‭and‬‭whether‬‭these‬‭are‬‭mandatory‬‭(m)‬‭and‬‭non-mandatory‬‭eCRFs‬‭(such‬‭as‬‭laboratory‬
‭testing and the corresponding validation of variables, rules and extraction).‬
‭Data‬ ‭on‬ ‭Adverse‬ ‭Event‬ ‭(AE),‬ ‭Adverse‬ ‭Reactions‬ ‭(AR),‬ ‭Serious‬ ‭Adverse‬ ‭Events‬ ‭(SAEs),‬
‭Serious‬ ‭Adverse‬ ‭Reactions‬ ‭(SARs)‬ ‭and‬ ‭Suspected‬ ‭Unexpected‬ ‭SARs‬ ‭(SUSARs)‬ ‭will‬ ‭be‬
‭undertaken‬‭by‬‭Sites‬‭in‬‭the‬‭eCRF‬‭and‬‭are‬‭transferred‬‭to‬‭the‬‭study‬‭database‬‭along‬‭with‬‭the‬‭rest‬‭of‬
‭variables.‬
‭Electronic‬‭Case‬‭Report‬‭Form‬‭(eCRF)‬‭includes‬‭the‬‭CTCAE‬‭version‬‭5.0‬‭terms‬‭as‬‭a‬‭pulldown‬‭list‬
‭in‬‭order‬‭to‬‭categorise‬‭the‬‭events,‬‭additionally‬‭when‬‭the‬‭variable‬‭“SAE”‬‭is‬‭marked‬‭as‬‭“yes”,‬‭an‬
‭automatic‬‭email‬‭is‬‭sent‬‭to‬‭the‬‭MFAR‬‭Staff‬‭in‬‭order‬‭to‬‭be‬‭aware‬‭of‬‭the‬‭paper‬‭based‬‭SAE‬‭form‬‭is‬
‭expected‬‭to‬‭be‬‭received,‬‭for‬‭regulatory‬‭reporting‬‭purposes.‬‭As‬‭data‬‭cleaning‬‭procedure,‬‭SAE‬
‭received‬‭in‬‭paper‬‭based‬‭form‬‭are‬‭conciliate‬‭with‬‭the‬‭adverse‬‭events‬‭data‬‭collected‬‭in‬‭the‬‭eCRF‬
‭and‬‭is‬‭ensured‬‭that‬‭all‬‭the‬‭events‬‭reported‬‭by‬‭means‬‭of‬‭SAE‬‭form‬‭are‬‭also‬‭collected‬‭in‬‭the‬
‭eCRF,‬‭that‬‭is‬‭the‬‭final‬‭destination‬‭of‬‭any‬‭adverse‬‭event‬‭(whether‬‭be‬‭AE,‬‭AR,‬‭SAE,‬‭SAR‬‭or‬
‭SUSAR).‬
‭12.3.‬ ‭Drug supply‬
‭AUREA‬ ‭is‬ ‭an‬ ‭Investigator‬ ‭Initiated‬ ‭Study,‬ ‭Atezolizumab‬ ‭will‬ ‭be‬ ‭supplied‬ ‭by‬ ‭the‬‭Sponsor‬
‭through‬‭Roche,‬‭the‬‭Sponsor‬‭will‬‭supply‬‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬‭months‬‭of‬‭treatment‬‭for‬
‭each‬‭patient.‬‭The‬‭treatment‬‭for‬‭patients‬‭not‬‭progressing‬‭at‬‭24‬‭months‬‭will‬‭be‬‭according‬‭to‬‭PI‬
‭criteria,‬‭following‬‭his/her‬‭local‬‭normal‬‭practise.‬‭If‬‭as‬‭per‬‭Treating‬‭Physician‬‭criteria,‬‭the‬‭best‬
‭option‬ ‭for‬ ‭the‬ ‭patient‬ ‭would‬ ‭be‬ ‭to‬ ‭continue‬ ‭with‬ ‭Atezolizumab,‬ ‭the‬ ‭administration‬ ‭may‬
‭continue‬‭but‬‭following‬‭Site’s‬‭supply‬‭channels‬‭(other‬‭than‬‭those‬‭provided‬‭by‬‭Sponsor),‬‭after‬
‭managing local administrative approvals‬
‭Gemcitabine and Cisplatin will be provided by the sites as per standard care criteria.‬
‭12.3.1. Packaging and labelling‬
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‭Packaging‬ ‭and‬ ‭labeling‬ ‭of‬ ‭study‬ ‭treatment‬ ‭will‬ ‭be‬ ‭in‬ ‭accordance‬ ‭with‬ ‭applicable‬ ‭local‬
‭regulatory requirements and applicable Good Manufacturing Practice (GMP) guidelines.‬
‭12.4.‬ ‭Final report and Publications‬
‭As‬‭stated‬‭in‬‭article‬‭42‬‭of‬‭RD‬‭1090/2015‬‭of‬‭clinical‬‭trials,‬‭the‬‭Sponsor‬‭is‬‭obliged‬‭to‬‭publish‬
‭both‬‭positive‬‭and‬‭negative‬‭results‬‭of‬‭the‬‭authorized‬‭clinical‬‭trials‬‭in‬‭scientific‬‭journals‬‭and‬‭with‬
‭mention to the Ethical Committee of Clinical Research that approved the study.‬
‭The‬‭clinical‬‭publication‬‭will‬‭be‬‭carried‬‭out‬‭by‬‭the‬‭Coordinating‬‭Investigator‬‭in‬‭collaboration‬
‭and‬ ‭Principal‬ ‭Investigators.‬ ‭Coordinating‬ ‭Investigator‬ ‭and‬ ‭Principal‬ ‭Investigators‬ ‭who‬
‭contributed‬ ‭with‬ ‭at‬ ‭least‬ ‭3%‬ ‭of‬ ‭the‬ ‭patients‬ ‭will‬ ‭be‬‭the‬‭authors.‬‭The‬‭order‬‭of‬‭authors‬‭will‬
‭strictly depend on the number of patients included by the Investigators.‬
‭The‬‭anonymity‬‭of‬‭the‬‭source‬‭subjects‬‭of‬‭the‬‭data‬‭and‬‭biological‬‭samples‬‭will‬‭be‬‭maintained‬‭at‬
‭all times.‬
‭The‬ ‭results‬ ‭or‬ ‭conclusions‬ ‭of‬ ‭the‬ ‭study‬ ‭will‬ ‭be‬ ‭communicated‬ ‭primarily‬ ‭in‬ ‭scientific‬
‭publications before being released to the non-health public.‬
‭No efficacy study outcome will be reported prematurely or sensationalistically.‬
‭Participating‬ ‭investigators‬ ‭should‬‭not‬‭publish‬‭any‬‭patient‬‭data‬‭that‬‭is‬‭directly‬‭related‬‭to‬‭the‬
‭study objectives until the trial report is published.‬
‭The‬ ‭trial‬ ‭will‬ ‭be‬ ‭registered‬ ‭in‬ ‭the‬ ‭Spanish‬ ‭Registry‬ ‭of‬ ‭Clinical‬ ‭Studies‬ ‭(REEC)‬ ‭and‬
‭www.clinicaltrials.gov‬‭.‬
‭12.5.‬ ‭Monitoring‬
‭The‬‭study‬‭will‬‭be‬‭monitored‬‭through‬‭local‬‭visits,‬‭telephone‬‭calls‬‭and‬‭periodic‬‭inspection‬‭of‬
‭CRFs.‬ ‭During‬ ‭the‬ ‭study,‬ ‭according‬ ‭to‬ ‭monitoring‬ ‭plan,‬ ‭a‬ ‭monitor‬ ‭from‬ ‭MFAR‬ ‭Clinical‬
‭Research‬ ‭or‬ ‭a‬ ‭representative‬ ‭will‬ ‭have‬ ‭regular‬‭contact‬‭with‬‭the‬‭investigational‬‭site,‬‭for‬‭the‬
‭following:‬
‭●‬ ‭Provide information and support to the investigator(s)‬
‭●‬ ‭Confirm that facilities remain acceptable‬
‭●‬ ‭Confirm‬ ‭that‬ ‭the‬ ‭investigational‬ ‭team‬ ‭is‬ ‭adhering‬ ‭to‬ ‭the‬ ‭protocol,‬ ‭data‬ ‭are‬ ‭being‬
‭accurately‬ ‭recorded‬ ‭in‬ ‭the‬ ‭case‬ ‭report‬ ‭forms,‬ ‭and‬ ‭that‬ ‭investigational‬ ‭product‬
‭accountability checks are being performed‬
‭●‬ ‭Perform‬‭source‬‭data‬‭verification.‬‭This‬‭includes‬‭a‬‭comparison‬‭of‬‭the‬‭data‬‭in‬‭the‬‭case‬
‭report‬‭forms‬‭with‬‭the‬‭patient’s‬‭medical‬‭records‬‭at‬‭the‬‭hospital‬‭or‬‭practice,‬‭and‬‭other‬
‭records‬‭relevant‬‭to‬‭the‬‭study.‬‭This‬‭will‬‭require‬‭direct‬‭access‬‭to‬‭all‬‭original‬‭records‬‭for‬
‭each patient (e.g., clinic charts).‬
‭●‬ ‭Record‬ ‭and‬ ‭report‬ ‭any‬ ‭protocol‬ ‭deviations‬ ‭not‬ ‭previously‬ ‭sent‬ ‭to‬ ‭MFAR‬ ‭Clinical‬
‭Research.‬
‭●‬ ‭Confirm‬‭that‬‭AEs‬‭and‬‭SAEs‬‭have‬‭been‬‭properly‬‭documented‬‭on‬‭eCRFs,‬‭all‬‭SAEs‬‭have‬
‭been‬ ‭forwarded‬ ‭to‬ ‭MFAR‬‭Clinical‬‭Research,‬‭and‬‭all‬‭the‬‭SAEs‬‭that‬‭met‬‭criteria‬‭for‬
‭reporting have been forwarded to the IEC‬
‭The‬‭monitor‬‭will‬‭be‬‭available‬‭between‬‭visits‬‭if‬‭the‬‭investigator(s)‬‭or‬‭other‬‭staff‬‭members‬‭need‬
‭information or advice.‬
‭12.6.‬ ‭Clinical Study Report‬
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‭According‬‭to‬‭local‬‭regulation,‬‭the‬‭summary‬‭of‬‭results‬‭of‬‭the‬‭trial‬‭will‬‭be‬‭sent‬‭to‬‭the‬‭AEMPS‬
‭and‬‭the‬‭CEIm‬‭no‬‭later‬‭than‬‭one‬‭year‬‭after‬‭the‬‭date‬‭of‬‭the‬‭end‬‭of‬‭the‬‭trial‬‭globally.‬‭The‬‭summary‬
‭of results will follow the European format required for EudraCT.‬
‭12.7.‬ ‭Protocol Amendments‬
‭Supplements‬‭and‬‭changes‬‭to‬‭the‬‭protocol‬‭can‬‭be‬‭performed‬‭exclusively‬‭by‬‭the‬‭Sponsor,‬‭who‬
‭must‬ ‭submit‬ ‭them‬ ‭to‬ ‭the‬ ‭Ethics‬ ‭Committee‬ ‭and‬ ‭the‬ ‭local‬ ‭Regulatory‬ ‭Authority‬ ‭protocol‬
‭amendments.‬
‭Relevant‬ ‭safety‬ ‭information‬ ‭will‬ ‭be‬ ‭submitted‬ ‭to‬‭the‬‭IEC‬‭during‬‭the‬‭course‬‭of‬‭the‬‭trial,‬‭in‬
‭accordance with national regulations and requirements.‬
‭Initial‬‭IEC‬‭positive‬‭vote,‬‭and‬‭all‬‭materials‬‭approved‬‭by‬‭the‬‭IEC‬‭for‬‭this‬‭study‬‭including‬‭the‬
‭patient‬ ‭consent‬ ‭form‬ ‭and‬‭recruitment‬‭materials‬‭must‬‭be‬‭maintained‬‭by‬‭the‬‭Investigator‬‭and‬
‭made available for inspection.‬
‭12.8.‬ ‭Data Handling‬
‭The‬‭data‬‭will‬‭be‬‭recorded‬‭using‬‭the‬‭Electronic‬‭Data‬‭Capture‬‭software‬‭property‬‭of‬‭MFAR‬‭S.L.,‬
‭which‬ ‭is‬ ‭developed‬ ‭and‬ ‭maintained‬ ‭with‬ ‭strict‬ ‭observance‬ ‭of‬ ‭the‬ ‭regulatory‬ ‭standards‬ ‭for‬
‭Clinical EDC systems, with special observance of the guidelines specified at:‬
‭●‬
‭CPMP/ICH/135/95. ICH E6. Note for Guidance on Good Clinical Practice.‬
‭●‬
‭Good‬ ‭Clinical‬ ‭Data‬ ‭Management‬ ‭Practice,‬ ‭Version‬ ‭4,‬ ‭Society‬ ‭for‬ ‭Clinical‬ ‭Data‬
‭Management (SCDM), October 2005.‬
‭●‬
‭EMEA.‬‭Reflection‬‭on‬‭expectations‬‭for‬‭electronic‬‭source‬‭documents‬‭used‬‭in‬‭clinical‬
‭trials. London, 17 October 2007.‬
‭●‬
‭Directive‬ ‭9‬ ‭Guidance‬ ‭for‬ ‭Industry.‬ ‭Part‬ ‭11,‬ ‭Electronic‬ ‭Records;‬ ‭Electronic‬
‭Signatures – Scope and Application (August 2003).‬
‭●‬
‭FDA.‬‭Guidance‬‭for‬‭Industry.‬‭Computerised‬‭Systems‬‭Used‬‭in‬‭Clinical‬‭Investigations‬
‭(May 2007).‬
‭●‬
‭FDA.‬‭Guidance‬‭for‬‭Industry.‬‭Part‬‭11,‬‭Electronic‬‭Records;‬‭Electronic‬‭Signatures‬‭–‬
‭Scope and Application (August 2003)‬
‭●‬
‭Organic‬‭Law‬‭3/2018,‬‭of‬‭December‬‭5,‬‭Protection‬‭of‬‭Personal‬‭Data‬‭and‬‭guarantee‬‭of‬
‭digital rights‬
‭The‬‭EDC‬‭database‬‭is‬‭hosted‬‭at‬‭a‬‭data‬‭server‬‭located‬‭at‬‭the‬‭Data‬‭Centre‬‭maintained‬‭by‬‭Claranet‬
‭SAU‬‭located‬‭at‬‭“‬‭Calle‬‭Juan‬‭Gris,‬‭10-18,‬‭08014‬‭Barcelona‬‭”‬‭.‬‭The‬‭physical‬‭access‬‭to‬‭the‬‭Data‬
‭Centre‬ ‭is‬ ‭restricted‬ ‭to‬ ‭authorised‬ ‭Claranet‬ ‭personnel,‬ ‭and‬ ‭logical‬ ‭access‬ ‭to‬‭the‬‭database‬‭is‬
‭restricted to named MFAR personnel.‬
‭All‬ ‭the‬ ‭EDC‬ ‭users‬ ‭are‬ ‭uniquely‬‭identified‬‭by‬‭name,‬‭all‬‭the‬‭access‬‭to‬‭the‬‭software‬‭is‬‭made‬
‭through a secure, encrypted connection and all the activities are logged and audited.‬
‭All‬‭the‬‭EDC‬‭forms‬‭are‬‭designed‬‭according‬‭to‬‭the‬‭eCRF‬‭defined‬‭by‬‭the‬‭study‬‭protocol,‬‭and‬‭are‬
‭validated according to the DVP (Data Validation Plan).‬
‭12.9.‬ ‭Documentation‬
‭The‬ ‭Investigator/Institution‬ ‭should‬ ‭maintain‬ ‭trial‬ ‭documents‬ ‭according‬ ‭to‬ ‭ICH‬ ‭Topic‬ ‭E6‬
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‭Section‬‭8‬‭,‬‭and‬‭as‬‭required‬‭by‬‭pertinent‬‭regulatory‬‭requirements.‬‭According‬‭to‬‭RD‬‭1090/2015‬
‭on Clinical trial, the archive period for all essential documents is 25 years.‬
‭Essential‬‭documents‬‭should‬‭be‬‭stored‬‭according‬‭to‬‭ICH‬‭GCP‬‭guidelines‬‭for‬‭a‬‭longer‬‭period‬‭of‬
‭time,‬‭if‬‭required‬‭by‬‭pertinent‬‭regulations.‬‭The‬‭original‬‭patient‬‭data‬‭(clinical‬‭record)‬‭must‬‭be‬
‭kept archived for the time stipulated by the study centre regulations.‬
‭All‬ ‭original‬ ‭subject‬ ‭files‬ ‭(medical‬ ‭records)‬ ‭must‬ ‭be‬ ‭stored‬ ‭at‬ ‭the‬ ‭site‬ ‭(hospital,‬ ‭research‬
‭institution,‬‭or‬‭practice)‬‭for‬‭the‬‭longest‬‭possible‬‭time‬‭permitted‬‭by‬‭the‬‭applicable‬‭regulations,‬
‭and/or‬‭as‬‭per‬‭ICH‬‭GCP‬‭guidelines,‬‭whichever‬‭is‬‭longer‬‭(In‬‭Spain‬‭25‬‭years).‬‭In‬‭any‬‭case,‬‭the‬
‭Investigator‬ ‭should‬ ‭ensure‬ ‭that‬ ‭no‬ ‭destruction‬ ‭of‬‭medical‬‭records‬‭is‬‭performed‬‭without‬‭the‬
‭written approval of the Sponsor.‬
‭12.10.‬ ‭Audits and inspections‬
‭Authorised‬ ‭representatives‬ ‭of‬ ‭Sponsor,‬ ‭a‬ ‭regulatory‬ ‭authority,‬ ‭an‬ ‭Independent‬ ‭Ethics‬
‭Committee‬ ‭may‬ ‭visit‬ ‭the‬ ‭site‬ ‭to‬ ‭perform‬ ‭audits‬ ‭or‬ ‭inspections,‬ ‭including‬ ‭source‬ ‭data‬
‭verification.‬ ‭The‬ ‭purpose‬ ‭of‬ ‭a‬ ‭Sponsor‬ ‭audit‬ ‭or‬ ‭inspection‬ ‭is‬ ‭to‬ ‭systematically‬ ‭and‬
‭independently‬‭examine‬‭all‬‭study-related‬‭activities‬‭and‬‭documents‬‭to‬‭determine‬‭whether‬‭these‬
‭activities‬‭were‬‭conducted,‬‭and‬‭data‬‭were‬‭recorded,‬‭analysed,‬‭and‬‭accurately‬‭reported‬‭according‬
‭to‬ ‭the‬ ‭protocol,‬ ‭Good‬ ‭Clinical‬ ‭Practice‬ ‭guidelines‬ ‭of‬ ‭the‬ ‭International‬ ‭Conference‬ ‭on‬
‭Harmonisation,‬‭and‬‭any‬‭applicable‬‭regulatory‬‭requirements.‬‭The‬‭investigator‬‭should‬‭contact‬
‭the‬ ‭Sponsor‬ ‭through‬ ‭MFAR‬ ‭immediately‬ ‭if‬ ‭contacted‬ ‭by‬ ‭a‬ ‭regulatory‬ ‭agency‬ ‭about‬ ‭an‬
‭inspection.‬
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‭13.‬
‭TRANSLATIONAL SUBSTUDIES‬
‭A‬‭key‬‭objective‬‭of‬‭the‬‭biomarker‬‭analyses‬‭that‬‭will‬‭be‬‭performed‬‭in‬‭this‬‭study‬‭is‬‭to‬‭investigate‬
‭candidate‬‭biomarkers‬‭that‬‭may‬‭have‬‭predictive‬‭value‬‭in‬‭identifying‬‭those‬‭patients‬‭who‬‭may‬
‭benefit‬‭from‬‭treatment‬‭with‬‭the‬‭combination‬‭of‬‭atezolizumab‬‭1‬‭and‬‭split‬‭dose‬‭GC.‬‭In‬‭addition,‬
‭analyses‬ ‭of‬ ‭blood‬ ‭biomarkers‬ ‭obtained‬ ‭before,‬ ‭during‬ ‭and‬ ‭after‬ ‭treatment‬ ‭will‬ ‭provide‬ ‭an‬
‭opportunity‬ ‭to‬ ‭investigate‬ ‭pharmacodynamic‬ ‭effects.‬ ‭Samples‬ ‭collected‬ ‭at‬ ‭the‬ ‭End‬ ‭of‬
‭Treatment/Withdrawal‬‭visit‬‭enable‬‭investigation‬‭of‬‭potential‬‭mechanisms‬‭of‬‭resistance‬‭to‬‭the‬
‭drug combination.‬
‭The following biological samples are required:‬
‭●‬ ‭Tumor‬ ‭sample,‬ ‭archive‬ ‭tumor‬ ‭sample‬ ‭in‬ ‭order‬ ‭to‬ ‭evaluate‬ ‭changes‬ ‭in‬ ‭signaling‬
‭molecules in response to study treatment in tumour tissue.‬
‭●‬ ‭Processed‬‭blood‬‭samples‬‭obtained‬‭before‬‭treatment,‬‭at‬‭D1C7‬‭of‬‭treatment,‬‭and‬‭at‬‭the‬
‭end‬‭of‬‭treatment/progression,‬‭in‬‭order‬‭to‬‭evaluate‬‭changes‬‭in‬‭signaling‬‭molecules‬‭in‬
‭response to study treatment in blood.‬
‭●‬ ‭Faecal samples for microbiome analyses.‬
‭13.1.‬ ‭Archived Tumor Biospecimens‬
‭Somatic‬‭alterations‬‭in‬‭tumours‬‭including‬‭proteomics,‬‭transcriptomics‬‭and‬‭metabolics‬‭will‬‭be‬
‭analyzed. No germinal line determinations will be performed.‬
‭Tumor‬‭biological‬‭specimens‬‭from‬‭archived‬‭tissue‬‭samples‬‭will‬‭be‬‭used‬‭to‬‭analyze‬‭candidate‬
‭DNA,‬‭RNA,‬‭or‬‭protein‬‭markers,‬‭or‬‭relevant‬‭signature‬‭of‬‭markers‬‭for‬‭their‬‭ability‬‭to‬‭identify‬
‭those patients who are most likely to benefit from treatment with the study drugs.‬
‭Tumor‬‭tissue‬‭biomarker‬‭analyses,‬‭including‬‭determination‬‭of‬‭PD-L1‬‭status,‬‭will‬‭be‬‭performed‬
‭retrospectively‬‭in‬‭a‬‭central‬‭laboratory.‬‭PD-L1‬‭status‬‭will‬‭be‬‭assessed‬‭using‬‭a‬‭validated‬‭PD-L1‬
‭IHC‬ ‭test‬ ‭kit‬ ‭manufactured‬ ‭under‬ ‭GMP‬ ‭specifications,‬ ‭in‬ ‭conjunction‬ ‭with‬ ‭a‬ ‭pre-specified‬
‭scoring‬ ‭algorithm‬ ‭and‬ ‭cutoff‬ ‭defining‬ ‭PD-L1‬ ‭positive‬ ‭versus‬ ‭negative‬ ‭status‬ ‭that‬ ‭will‬ ‭be‬
‭established prior to initiation of scoring of PD-L1.‬
‭Additional‬‭tumor‬‭tissue‬‭biomarkers‬‭that‬‭may‬‭be‬‭analyzed‬‭include,‬‭but‬‭may‬‭not‬‭necessarily‬‭be‬
‭limited‬ ‭to,‬ ‭gene‬ ‭expression‬ ‭profiles‬ ‭and/or‬ ‭quantitation‬ ‭of‬ ‭tumor-infiltrating‬ ‭CD8+‬ ‭T‬
‭lymphocytes by IHC and/or tissue FoxP3, PD-1, or PD-L2.‬
‭13.2.‬ ‭Peripheral Blood‬
‭Specimens‬‭will‬‭be‬‭processed‬‭and‬‭retained‬‭in‬‭local‬‭laboratories‬‭until‬‭Sponsor‬‭indications‬‭for‬
‭shipments.‬‭It‬‭will‬‭include‬‭whole‬‭blood,‬‭serum‬‭and‬‭plasma‬‭samples‬‭that‬‭will‬‭be‬‭retained‬‭in‬‭the‬
‭central laboratory for exploratory assessments.‬
‭Samples‬‭may‬‭be‬‭used‬‭to‬‭identify‬‭or‬‭characterize‬‭cells,‬‭DNA,‬‭RNA,‬‭or‬‭protein‬‭markers‬‭known‬
‭or‬‭suspected‬‭to‬‭be‬‭of‬‭relevance‬‭to‬‭the‬‭mechanisms‬‭of‬‭action,‬‭or‬‭the‬‭development‬‭of‬‭resistance‬
‭to‬ ‭study‬ ‭treatment.‬ ‭These‬ ‭include‬ ‭biomarkers‬ ‭that‬ ‭may‬ ‭aid‬ ‭in‬ ‭the‬ ‭identification‬ ‭of‬ ‭those‬
‭patients‬‭who‬‭might‬‭preferentially‬‭benefit‬‭from‬‭treatment‬‭with‬‭IMP‬‭1‬‭in‬‭combination‬‭with‬‭IMP‬
‭2,‬‭which‬‭may‬‭include‬‭but‬‭are‬‭not‬‭limited‬‭to‬‭biomarkers‬‭related‬‭to‬‭anti-tumor‬‭immune‬‭response‬
‭or target modulation, such as (not necessarily be limited to) soluble IL-8 or IFNγ.‬
‭Information‬ ‭regarding‬ ‭sample‬ ‭collection,‬ ‭management‬ ‭and‬ ‭shipments‬ ‭are‬ ‭provided‬ ‭in‬ ‭the‬
‭translational research manual.‬
‭13.3.‬ ‭F‬‭aecal samples‬
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‭Specimens‬‭will‬‭be‬‭processed‬‭and‬‭retained‬‭in‬‭local‬‭laboratories‬‭until‬‭Sponsor‬‭indications‬‭for‬
‭shipments.‬‭It‬‭will‬‭include‬‭a‬‭total‬‭of‬‭3‬‭samples:‬‭basal‬‭faecal‬‭sample‬‭collected‬‭prior‬‭treatment‬
‭initiation,‬‭faecal‬‭sample‬‭at‬‭Cycle‬‭4‬‭Day‬‭1‬‭and‬‭after‬‭progression.‬‭ ‬‭Information‬‭regarding‬‭sample‬
‭collection, management and shipments are provided in the translational research manual.‬
‭AUREA -  SOGUG-2020-IEC(VEJ)-1 - Protocol version 2.0 08MAR2022‬
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‭14.‬
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‭https://www.ema.europa.eu/en/medicines/human/EPAR/tecentriq‬
‭Thompson‬ ‭RH,‬ ‭Kuntz‬ ‭SM,‬ ‭Leibovich‬ ‭BC,‬ ‭et‬ ‭al.‬ ‭Tumor‬ ‭B7-H1‬ ‭is‬ ‭associated‬ ‭with‬ ‭poor‬
‭prognosis‬ ‭in‬ ‭renal‬ ‭cell‬ ‭carcinoma‬ ‭patients‬ ‭with‬ ‭long-term‬ ‭follow-up.‬ ‭Cancer‬ ‭Res.‬
‭2006;66:3381-5.‬
‭van‬‭Leenders‬‭GJLH.‬‭PD-L1‬‭testing‬‭in‬‭urothelial‬‭carcinoma:‬‭are‬‭we‬‭there‬‭yet?‬‭Transl‬‭Androl‬
‭Urol. 2019;8:S466-8.‬
‭Von‬ ‭der‬ ‭Maase‬ ‭H,‬ ‭Hansen‬ ‭SW,‬ ‭Roberts‬ ‭PI,‬ ‭et‬ ‭al.‬ ‭Gemcitabine‬ ‭and‬ ‭cisplatin‬ ‭versus‬
‭methotrexate,‬ ‭vinblastine,‬ ‭doxorubicin,‬ ‭and‬ ‭cisplatin‬ ‭in‬ ‭advanced‬ ‭or‬ ‭metastatic‬ ‭bladder‬
‭cancer:‬ ‭results‬ ‭of‬ ‭a‬ ‭large,‬ ‭randomized,‬ ‭multinational,‬ ‭phase‬ ‭III‬ ‭study.‬ ‭J‬ ‭Clin‬ ‭Oncol.‬
‭2000;18:3068-77.‬
‭Witjes‬ ‭AJ,‬‭Lebret‬‭T,‬‭Compérat‬‭EM,‬‭Cowan‬‭NC,‬‭De‬‭Santis‬‭M,‬‭Bruins‬‭HM,‬‭et‬‭al.‬‭Updated‬
‭2016‬ ‭EAU‬ ‭Guidelines‬ ‭on‬ ‭Muscle-invasive‬ ‭and‬ ‭Metastatic‬ ‭Bladder‬ ‭Cancer.‬ ‭Eur‬ ‭Urol.‬
‭2017;71:462-75.‬
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‭APPENDICES‬
‭Appendix 1. Management of Atezolizumab-specific Adverse Events‬
‭A)‬ ‭Management Guidelines for Pulmonary Events, Including Pneumonitis‬
‭Event‬
‭Management‬
‭Pulmonary event, Grade 1‬
‭●‬
‭Continue atezolizumab and monitor closely.‬
‭●‬
‭Re-evaluate on serial imaging.‬
‭●‬
‭Consider patient referral to pulmonary specialist.‬
‭●‬
‭For‬
‭Grade‬
‭1‬
‭pneumonitis,‬
‭consider‬
‭withholding‬
‭atezolizumab.‬
‭Pulmonary event, Grade 2‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Refer‬ ‭patient‬ ‭to‬ ‭pulmonary‬ ‭and‬ ‭infectious‬ ‭disease‬
‭specialists and consider bronchoscopy or BAL.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone or equivalent.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭●‬
‭For‬‭recurrent‬‭events‬‭or‬‭events‬‭with‬‭no‬‭improvement‬‭after‬
‭48–72‬ ‭hours‬ ‭of‬ ‭corticosteroids,‬ ‭treat‬ ‭as‬ ‭a‬ ‭Grade‬ ‭3‬ ‭or‬ ‭4‬
‭event.‬
‭Pulmonary event, Grade 3‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭●‬
‭Bronchoscopy or BAL is recommended.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day IV methylprednisolone.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over 1 month.‬
‭BAL = bronchoscopic alveolar lavage.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬‭length‬‭of‬‭the‬‭extended‬‭period‬‭of‬‭time‬‭must‬‭be‬‭based‬‭on‬‭the‬‭assessment‬‭of‬‭benefit-risk‬‭by‬‭the‬
‭investigator‬ ‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬
‭by the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬ ‭corticosteroids‬ ‭have‬ ‭been‬ ‭initiated,‬ ‭they‬ ‭must‬ ‭be‬ ‭tapered‬ ‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭should‬‭be‬‭based‬‭on‬‭investigator’s‬‭assessment‬‭of‬‭benefit-risk‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate).Medical Monitor is available to advise as needed.‬
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‭B)‬ ‭Management Guidelines for Hepatic Events‬
‭Event‬
‭Management‬
‭Hepatic event,‬
‭Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Monitor‬‭LFTs‬‭until‬‭values‬‭resolve‬‭to‬‭within‬‭normal‬‭limits‬
‭or to baseline values.‬
‭Hepatic event,‬
‭Grade 2‬
‭All events:‬
‭●‬
‭Monitor‬ ‭LFTs‬ ‭more‬ ‭frequently‬ ‭until‬ ‭return‬ ‭to‬ ‭baseline‬
‭values.‬
‭Events of  5 days’ duration:‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset. a‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab. b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Hepatic event,‬
‭Grade 3 or 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭●‬
‭Consider‬ ‭patient‬ ‭referral‬ ‭to‬ ‭gastrointestinal‬ ‭specialist‬‭for‬
‭evaluation‬‭and‬‭liver‬‭biopsy‬‭to‬‭establish‬‭etiology‬‭of‬‭hepatic‬
‭injury.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over 1 month.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>‬‭12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬‭length‬‭of‬‭the‬‭extended‬‭period‬‭of‬‭time‬‭must‬‭be‬‭based‬‭on‬‭the‬‭assessment‬‭of‬‭benefit-risk‬‭by‬‭the‬
‭investigator‬ ‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬
‭by the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬‭atezolizumab‬
‭should‬‭be‬‭based‬‭on‬‭investigator’s‬‭assessment‬‭of‬‭benefit-risk‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate). Medical Monitor is available to advise as needed.‬
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‭C)‬ ‭Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis)‬
‭Event‬
‭Management‬
‭Diarrhea or colitis,‬
‭Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Initiate symptomatic treatment.‬
‭●‬
‭Endoscopy is recommended if symptoms persist for 7 days.‬
‭●‬
‭Monitor closely.‬
‭Diarrhea or colitis,‬
‭Grade 2‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Initiate symptomatic treatment.‬
‭●‬
‭Patient referral to GI specialist is recommended.‬
‭●‬
‭For‬ ‭recurrent‬ ‭events‬ ‭or‬ ‭events‬ ‭that‬ ‭persist‬ ‭>‬ ‭5‬ ‭days,‬
‭initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Diarrhea or colitis,‬
‭Grade 3‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Refer‬ ‭patient‬ ‭to‬ ‭GI‬ ‭specialist‬ ‭for‬ ‭evaluation‬ ‭and‬
‭confirmatory biopsy.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Diarrhea or colitis,‬
‭Grade 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭●‬
‭Refer‬ ‭patient‬ ‭to‬ ‭GI‬ ‭specialist‬ ‭for‬ ‭evaluation‬ ‭and‬
‭confirmation biopsy.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over 1 month.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>‬‭12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭based‬ ‭on‬‭assessment‬‭of‬‭benefit-risk‬‭by‬‭the‬
‭investigator‬ ‭and‬ ‭in‬ ‭alignment‬ ‭with‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬‭by‬
‭the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
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‭should‬‭be‬‭based‬‭on‬‭investigator’s‬‭assessment‬‭of‬‭benefit-risk‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate). Medical Monitor is available to advise as needed.‬
‭D)‬ ‭Management Guidelines for Endocrine Events‬
‭Event‬
‭Management‬
‭Asymptomatic‬
‭hypothyroidism‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Initiate treatment with thyroid replacement hormone.‬
‭●‬
‭Monitor TSH closely.‬
‭Symptomatic‬
‭hypothyroidism‬
‭●‬
‭Withhold atezolizumab.‬
‭●‬
‭Initiate treatment with thyroid replacement hormone.‬
‭●‬
‭Monitor TSH closely.‬
‭●‬
‭Consider patient referral to endocrinologist.‬
‭●‬
‭Resume‬ ‭atezolizumab‬ ‭when‬‭symptoms‬‭are‬‭controlled‬‭and‬
‭thyroid function is improving.‬
‭Asymptomatic‬
‭hyperthyroidism‬
‭TSH‬‭≥‬‭0.1 mU/L and < 0.5 mU/L:‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Monitor TSH every 4 weeks.‬
‭●‬
‭Consider patient referral to endocrinologist.‬
‭TSH < 0.1 mU/L:‬
‭●‬
‭Follow guidelines for symptomatic hyperthyroidism.‬
‭●‬
‭Consider patient referral to endocrinologist.‬
‭Symptomatic‬
‭hyperthyroidism‬
‭●‬
‭Withhold atezolizumab.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭anti-thyroid‬ ‭drug‬ ‭such‬ ‭as‬
‭methimazole or carbimazole as needed.‬
‭●‬
‭Consider patient referral to endocrinologist.‬
‭●‬
‭Resume‬ ‭atezolizumab‬ ‭when‬‭symptoms‬‭are‬‭controlled‬‭and‬
‭thyroid function is improving.‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical‬ ‭Monitor‬ ‭for‬ ‭life-threatening‬ ‭immune-mediated‬
‭hyperthyroidism.‬
‭Symptomatic adrenal‬
‭insufficiency,‬
‭Grade 2 - 4‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Refer patient to endocrinologist.‬
‭●‬
‭Perform appropriate imaging.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better‬‭and‬‭patient‬‭is‬‭stable‬
‭on replacement therapy, resume atezolizumab.‬‭b‬
‭●‬
‭If‬‭event‬‭does‬‭not‬‭resolve‬‭to‬‭Grade‬‭1‬‭or‬‭better‬‭or‬‭patient‬‭is‬
‭not‬ ‭stable‬ ‭on‬ ‭replacement‬ ‭therapy‬ ‭while‬ ‭withholding‬
‭atezolizumab,‬ ‭permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬
‭contact Medical Monitor.‬‭c‬
‭Hyperglycemia,‬
‭Grade 1 or 2‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Investigate‬ ‭for‬ ‭diabetes.‬ ‭If‬ ‭patient‬ ‭has‬ ‭Type‬ ‭1‬ ‭diabetes,‬
‭treat‬ ‭as‬ ‭a‬ ‭Grade‬ ‭3‬ ‭event.‬ ‭If‬‭patient‬‭does‬‭not‬‭have‬‭Type‬‭1‬
‭diabetes, treat as per institutional guidelines.‬
‭●‬
‭Monitor for glucose control.‬
‭Hyperglycemia,‬
‭Grade 3 or 4‬
‭●‬
‭Withhold atezolizumab.‬
‭●‬
‭Initiate treatment with insulin.‬
‭●‬
‭Evaluate‬ ‭for‬ ‭diabetic‬ ‭ketoacidosis‬ ‭and‬ ‭manage‬ ‭as‬ ‭per‬
‭institutional guidelines.‬
‭●‬
‭Monitor for glucose control.‬
‭●‬
‭Resume‬‭atezolizumab‬‭when‬‭symptoms‬‭resolve‬‭and‬‭glucose‬
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‭levels are stable.‬
‭Hypophysitis‬
‭(pan-hypopituitarism),‬
‭Grade 2 or 3‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset. a‬
‭●‬
‭Refer patient to endocrinologist.‬
‭●‬
‭Perform brain MRI (pituitary protocol).‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭Initiate hormone replacement if clinically indicated.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab. b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭●‬
‭For recurrent hypophysitis, treat as a Grade 4 event.‬
‭Hypophysitis‬
‭(pan-hypopituitarism),‬
‭Grade 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor. c‬
‭●‬
‭Refer patient to endocrinologist.‬
‭●‬
‭Perform brain MRI (pituitary protocol).‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭Initiate hormone replacement if clinically indicated.‬
‭IV= intravenous;‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬‭length‬‭of‬‭the‬‭extended‬‭period‬‭of‬‭time‬‭must‬‭be‬‭based‬‭on‬‭the‬‭assessment‬‭of‬‭benefit-risk‬‭by‬‭the‬
‭investigator‬ ‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬
‭by the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭should‬‭be‬‭based‬‭on‬‭investigator’s‬‭assessment‬‭of‬‭benefit-risk‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate). Medical Monitor is available to advise as needed.‬
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‭E)‬ ‭Management Guidelines for Ocular Events‬
‭Event‬
‭Management‬
‭Ocular event,‬
‭Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Patient‬
‭referral‬
‭to‬
‭ophthalmologist‬
‭is‬
‭strongly‬
‭recommended.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭topical‬ ‭corticosteroid‬ ‭eye‬ ‭drops‬
‭and topical immunosuppressive therapy.‬
‭●‬
‭If symptoms persist, treat as a Grade 2 event.‬
‭Ocular event,‬
‭Grade 2‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.a‬
‭●‬
‭Patient‬
‭referral‬
‭to‬
‭ophthalmologist‬
‭is‬
‭strongly‬
‭recommended.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭topical‬ ‭corticosteroid‬ ‭eye‬ ‭drops‬
‭and topical immunosuppressive therapy.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Ocular event,‬
‭Grade 3 or 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor. c Refer patient to ophthalmologist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over 1 month.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭based‬ ‭on‬‭assessment‬‭of‬‭benefit-risk‬‭by‬‭the‬
‭investigator‬ ‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬
‭by the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭should‬‭be‬‭based‬‭on‬‭investigator’s‬‭assessment‬‭of‬‭benefit-risk‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate). Medical Monitor is available to advise as needed.‬
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‭F)‬ ‭Management Guidelines for Immune-Mediated Myocarditis‬
‭Event‬
‭Management‬
‭Immune-mediated‬
‭myocarditis, Grade 2,‬
‭3 or 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor. c‬
‭●‬
‭Refer patient to cardiologist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭as‬ ‭per‬ ‭institutional‬ ‭guidelines‬ ‭and‬
‭consider‬ ‭antiarrhythmic‬ ‭drugs,‬ ‭temporary‬ ‭pacemaker,‬
‭ECMO, or VAD as appropriate.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over ≥ 1 month.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭based‬ ‭on‬‭assessment‬‭of‬‭benefit-risk‬‭by‬‭the‬
‭investigator‬ ‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬
‭by the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭should‬‭be‬‭based‬‭on‬‭investigator’s‬‭assessment‬‭of‬‭benefit-risk‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate). Medical Monitor is available to advise as needed.‬
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‭G)‬ ‭Management‬ ‭Guidelines‬ ‭for‬ ‭Infusion-Related‬ ‭Reactions‬ ‭and‬ ‭Cytokine-Release‬
‭Syndrome‬
‭Event‬
‭Management‬
‭Grade 1‬‭a‬
‭Fever‬‭b‬‭with or‬
‭without‬
‭constitutional‬
‭symptoms‬
‭●‬
‭Immediately interrupt infusion.‬
‭●‬
‭Upon‬ ‭symptom‬ ‭resolution,‬ ‭wait‬ ‭for‬ ‭30‬ ‭minutes‬ ‭and‬ ‭then‬
‭restart‬ ‭infusion‬ ‭at‬‭half‬‭the‬‭rate‬‭being‬‭given‬‭at‬‭the‬‭time‬‭of‬
‭event onset.‬
‭●‬
‭If‬ ‭the‬ ‭infusion‬ ‭is‬ ‭tolerated‬ ‭at‬ ‭the‬ ‭reduced‬ ‭rate‬ ‭for‬ ‭30‬
‭minutes,‬‭the‬‭infusion‬‭rate‬‭may‬‭be‬‭increased‬‭to‬‭the‬‭original‬
‭rate.‬
‭●‬
‭If symptoms recur, discontinue infusion of this dose.‬
‭●‬
‭Administer‬
‭symptomatic‬
‭treatment,‬
‭c‬
‭including‬
‭maintenance of IV fluids for hydration.‬
‭●‬
‭In‬ ‭case‬ ‭of‬ ‭rapid‬ ‭decline‬ ‭or‬ ‭prolonged‬‭CRS‬‭(2‬‭days)‬‭or‬‭in‬
‭patients‬ ‭with‬ ‭significant‬ ‭symptoms‬ ‭and/or‬ ‭comorbidities,‬
‭consider managing as per Grade 2.‬
‭●‬
‭For‬ ‭subsequent‬ ‭infusions,‬ ‭consider‬‭administration‬‭of‬‭oral‬
‭premedication‬ ‭with‬ ‭antihistamines,‬ ‭anti-pyretics,‬ ‭and/or‬
‭analgesics, and monitor closely for IRRs and/or CRS.‬
‭Grade 2‬‭a‬
‭Fever‬‭b‬‭with‬
‭hypotension not‬
‭requiring‬
‭vasopressors‬
‭and/or‬
‭Hypoxia requiring‬
‭low-flow oxygen d‬
‭by nasal cannula or‬
‭blow-by‬
‭●‬
‭Immediately interrupt infusion.‬
‭●‬
‭Upon‬ ‭symptom‬ ‭resolution,‬ ‭wait‬ ‭for‬ ‭30‬ ‭minutes‬ ‭and‬ ‭then‬
‭restart‬ ‭infusion‬ ‭at‬‭half‬‭the‬‭rate‬‭being‬‭given‬‭at‬‭the‬‭time‬‭of‬
‭event onset.‬
‭●‬
‭If symptoms recur, discontinue infusion of this dose.‬
‭●‬
‭Administer symptomatic treatment.‬‭c‬
‭●‬
‭For hypotension, administer IV fluid bolus as needed.‬
‭●‬
‭Monitor‬ ‭cardiopulmonary‬ ‭and‬ ‭other‬ ‭organ‬ ‭function‬
‭closely‬ ‭(in‬ ‭the‬ ‭ICU,‬ ‭if‬ ‭appropriate).‬ ‭Administer‬‭IV‬‭fluids‬
‭as‬
‭clinically‬
‭indicated,‬
‭and‬
‭manage‬
‭constitutional‬
‭symptoms‬ ‭and‬ ‭organ‬ ‭toxicities‬ ‭as‬ ‭per‬ ‭institutional‬
‭practice.‬
‭●‬
‭Rule‬ ‭out‬ ‭other‬ ‭inflammatory‬ ‭conditions‬ ‭that‬ ‭can‬ ‭mimic‬
‭CRS‬ ‭(e.g.,‬ ‭sepsis).‬ ‭If‬ ‭no‬ ‭improvement‬ ‭within‬ ‭24‬ ‭hours,‬
‭initiate‬‭workup‬‭and‬‭assess‬‭for‬‭signs‬‭and‬‭symptoms‬‭of‬‭HLH‬
‭or MAS.‬
‭●‬
‭Consider‬ ‭IV‬ ‭corticosteroids‬ ‭(e.g.,‬ ‭methylprednisolone‬ ‭2‬
‭mg/kg/day or dexamethasone 10 mg every 6 hours).‬
‭●‬
‭Consider anti-cytokine therapy.‬‭e‬
‭●‬
‭Consider‬ ‭hospitalization‬ ‭until‬ ‭complete‬ ‭resolution‬ ‭of‬
‭symptoms.‬‭If‬‭no‬‭improvement‬‭within‬‭24‬‭hours,‬‭manage‬‭as‬
‭per‬‭Grade‬‭3,‬‭that‬‭is,‬‭hospitalize‬‭patient‬‭(monitoring‬‭in‬‭the‬
‭ICU‬
‭is‬
‭recommended),‬
‭permanently‬
‭discontinue‬
‭atezolizumab, and contact Medical Monitor.‬
‭●‬
‭If‬‭symptoms‬‭resolve‬‭to‬‭Grade‬‭1‬‭or‬‭better‬‭for‬‭3‬‭consecutive‬
‭days,‬ ‭the‬‭next‬‭dose‬‭of‬‭atezolizumab‬‭may‬‭be‬‭administered.‬
‭For‬ ‭subsequent‬ ‭infusions,‬ ‭consider‬‭administration‬‭of‬‭oral‬
‭premedication‬ ‭with‬ ‭antihistamines,‬ ‭anti-pyretics,‬ ‭and/or‬
‭analgesics and monitor closely for IRRs and/or CRS.‬
‭●‬
‭If‬ ‭symptoms‬ ‭do‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭for‬ ‭3‬
‭consecutive days, contact Medical Monitor.‬
‭Grade 3‬‭a‬
‭Fever‬‭b‬‭with‬
‭hypotension‬
‭requiring a‬
‭vasopressor (with‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭f‬
‭●‬
‭Administer symptomatic treatment.‬‭c‬
‭●‬
‭For‬
‭hypotension,‬
‭administer‬
‭IV‬
‭fluid‬
‭bolus‬
‭and‬
‭vasopressor as needed.‬
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‭or without‬
‭vasopressin)‬
‭and/or‬
‭Hypoxia requiring‬
‭high-flow oxygen d‬
‭by nasal cannula,‬
‭face mask,‬
‭non-rebreather‬
‭mask, or venturi‬
‭mask‬
‭●‬
‭Monitor‬ ‭cardiopulmonary‬ ‭and‬ ‭other‬ ‭organ‬ ‭function‬
‭closely;‬
‭monitoring‬
‭in‬
‭the‬ ‭ICU‬ ‭is‬ ‭recommended.‬
‭Administer‬ ‭IV‬ ‭fluids‬ ‭as‬ ‭clinically‬ ‭indicated,‬ ‭and‬ ‭manage‬
‭constitutional‬ ‭symptoms‬ ‭and‬ ‭organ‬ ‭toxicities‬ ‭as‬ ‭per‬
‭institutional practice.‬
‭●‬
‭Rule‬ ‭out‬ ‭other‬ ‭inflammatory‬ ‭conditions‬ ‭that‬ ‭can‬ ‭mimic‬
‭CRS‬ ‭(e.g.,‬ ‭sepsis).‬ ‭If‬ ‭no‬ ‭improvement‬ ‭within‬ ‭24‬ ‭hours,‬
‭initiate‬‭workup‬‭and‬‭assess‬‭for‬‭signs‬‭and‬‭symptoms‬‭of‬‭HLH‬
‭or MAS.‬
‭●‬
‭Administer‬ ‭IV‬ ‭corticosteroids‬ ‭(e.g.,‬ ‭methylprednisolone‬‭2‬
‭mg/kg/day or dexamethasone 10 mg every 6 hours).‬
‭●‬
‭Consider anti-cytokine therapy.‬‭e‬
‭●‬
‭Hospitalize‬‭patient‬‭until‬‭complete‬‭resolution‬‭of‬‭symptoms.‬
‭If‬‭no‬‭improvement‬‭within‬‭24‬‭hours,‬‭manage‬‭as‬‭per‬‭Grade‬
‭4,‬‭that‬‭is,‬‭admit‬‭patient‬‭to‬‭ICU‬‭and‬‭initiate‬‭hemodynamic‬
‭monitoring,‬ ‭mechanical‬ ‭ventilation,‬ ‭and/or‬ ‭IV‬ ‭fluids‬ ‭and‬
‭vasopressors‬‭as‬‭needed;‬‭for‬‭patients‬‭who‬‭are‬‭refractory‬‭to‬
‭anti-cytokine‬ ‭therapy,‬ ‭experimental‬ ‭treatments‬ ‭may‬ ‭be‬
‭considered‬ ‭at‬ ‭the‬ ‭discretion‬ ‭of‬ ‭the‬ ‭investigator‬ ‭and‬ ‭in‬
‭consultation with the Medical Monitor.‬
‭Grade 4‬‭a‬
‭Fever‬‭b‬‭with‬
‭hypotension‬
‭requiring multiple‬
‭vasopressors‬
‭(excluding‬
‭vasopressin)‬
‭and/or‬
‭Hypoxia requiring‬
‭oxygen by positive‬
‭pressure (e.g.,‬
‭CPAP, BiPAP,‬
‭intubation and‬
‭mechanical‬
‭ventilation)‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭f‬
‭●‬
‭Administer symptomatic treatment.‬‭c‬
‭●‬
‭Admit‬
‭patient‬ ‭to‬ ‭ICU‬ ‭and‬ ‭initiate‬ ‭hemodynamic‬
‭monitoring,‬ ‭mechanical‬ ‭ventilation,‬ ‭and/or‬ ‭IV‬ ‭fluids‬ ‭and‬
‭vasopressors‬ ‭as‬ ‭needed.‬ ‭Monitor‬ ‭other‬ ‭organ‬ ‭function‬
‭closely.‬ ‭Manage‬ ‭constitutional‬ ‭symptoms‬ ‭and‬ ‭organ‬
‭toxicities as per institutional practice.‬
‭●‬
‭Rule‬ ‭out‬ ‭other‬ ‭inflammatory‬ ‭conditions‬ ‭that‬ ‭can‬ ‭mimic‬
‭CRS‬ ‭(e.g.,‬ ‭sepsis).‬ ‭If‬ ‭no‬ ‭improvement‬ ‭within‬ ‭24‬ ‭hours,‬
‭initiate‬‭workup‬‭and‬‭assess‬‭for‬‭signs‬‭and‬‭symptoms‬‭of‬‭HLH‬
‭or MAS.‬
‭●‬
‭Administer‬ ‭IV‬ ‭corticosteroids‬ ‭(e.g.,‬ ‭methylprednisolone‬‭2‬
‭mg/kg/day or dexamethasone 10 mg every 6 hours).‬
‭●‬
‭Consider‬ ‭anti-cytokine‬ ‭therapy.‬ ‭e‬ ‭For‬ ‭patients‬ ‭who‬ ‭are‬
‭refractory‬
‭to‬
‭anti-cytokine‬
‭therapy,‬
‭experimental‬
‭treatments‬ ‭g‬ ‭may‬ ‭be‬ ‭considered‬ ‭at‬ ‭the‬ ‭discretion‬ ‭of‬ ‭the‬
‭investigator and in consultation with the Medical Monitor.‬
‭●‬
‭Hospitalize patient until complete resolution of symptoms.‬
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‭ASTCT‬‭=‬‭American‬‭Society‬‭for‬‭Transplantation‬‭and‬‭Cellular‬‭Therapy;‬‭BiPAP‬‭=‬‭bi-level‬‭positive‬‭airway‬
‭pressure;‬ ‭CAR‬ ‭=‬ ‭chimeric‬ ‭antigen‬ ‭receptor;‬ ‭CPAP‬ ‭=‬ ‭continuous‬ ‭positive‬ ‭airway‬ ‭pressure;‬ ‭CRS‬ ‭=‬
‭cytokine-release‬ ‭syndrome;‬ ‭CTCAE‬ ‭=‬ ‭Common‬ ‭Terminology‬ ‭Criteria‬ ‭for‬ ‭Adverse‬ ‭Events;‬ ‭eCRF‬ ‭=‬
‭electronic‬‭Case‬‭Report‬‭Form;‬‭HLH‬‭=‬‭hemophagocytic‬‭lymphohistiocytosis;‬‭ICU‬‭=‬‭intensive‬‭care‬‭unit;‬
‭IRR‬ ‭=‬ ‭infusion-related‬ ‭reaction;‬ ‭MAS‬ ‭=‬ ‭macrophage‬ ‭activation‬‭syndrome;‬‭NCCN‬‭=‬‭National‬‭Cancer‬
‭Comprehensive Network; NCI  National Cancer Institute.‬
‭Note:‬‭The‬‭management‬‭guidelines‬‭have‬‭been‬‭adapted‬‭from‬‭NCCN‬‭guidelines‬‭for‬‭management‬‭of‬‭CAR‬
‭T-cell-related toxicities (Version 2.2019).‬
‭a‬ ‭Grading‬ ‭system‬ ‭for‬ ‭management‬ ‭guidelines‬ ‭is‬ ‭based‬ ‭on‬ ‭ASTCT‬ ‭consensus‬ ‭grading‬ ‭for‬ ‭CRS.‬ ‭NCI‬
‭CTCAE‬‭(version‬‭as‬‭specified‬‭in‬‭the‬‭protocol)‬‭should‬‭be‬‭used‬‭when‬‭reporting‬‭severity‬‭of‬‭IRRs,‬‭CRS,‬‭or‬
‭organ‬‭toxicities‬‭associated‬‭with‬‭CRS‬‭on‬‭the‬‭Adverse‬‭Event‬‭eCRF.‬‭Organ‬‭toxicities‬‭associated‬‭with‬‭CRS‬
‭should not influence overall CRS grading.‬
‭b‬ ‭Fever‬‭is‬‭defined‬‭as‬‭temperature‬ ‭38C‬‭not‬‭attributable‬‭to‬‭any‬‭other‬‭cause.‬‭In‬‭patients‬‭who‬‭develop‬‭CRS‬
‭and‬‭then‬‭receive‬‭anti-pyretic,‬‭anti-cytokine,‬‭or‬‭corticosteroid‬‭therapy,‬‭fever‬‭is‬‭no‬‭longer‬‭required‬‭when‬
‭subsequently‬ ‭determining‬ ‭event‬ ‭severity‬ ‭(grade).‬ ‭In‬ ‭this‬ ‭case,‬ ‭the‬ ‭grade‬ ‭is‬ ‭driven‬ ‭by‬ ‭the‬‭presence‬‭of‬
‭hypotension and/or hypoxia.‬
‭c‬ ‭Symptomatic‬ ‭treatment‬ ‭may‬ ‭include‬ ‭oral‬ ‭or‬ ‭IV‬ ‭antihistamines,‬ ‭anti-pyretics,‬ ‭analgesics,‬
‭bronchodilators,‬ ‭and/or‬ ‭oxygen.‬ ‭For‬‭bronchospasm,‬‭urticaria,‬‭or‬‭dyspnea,‬‭additional‬‭treatment‬‭may‬‭be‬
‭administered as per institutional practice.‬
‭d‬ ‭Low‬‭flow‬‭is‬‭defined‬‭as‬‭oxygen‬‭delivered‬‭at‬ ‭6‬‭L/min,‬‭and‬‭high‬‭flow‬‭is‬‭defined‬‭as‬‭oxygen‬‭delivered‬‭at‬
‭6 L/min.‬
‭e‬ ‭There‬‭are‬‭case‬‭reports‬‭where‬‭anti-cytokine‬‭therapy‬‭has‬‭been‬‭used‬‭for‬‭treatment‬‭of‬‭CRS‬‭with‬‭immune‬
‭checkpoint‬ ‭inhibitors/ICI‬‭(‬‭Rotz‬‭et‬‭al.‬‭2017‬‭;‬‭Adashek‬‭and‬‭Feldman‬‭2019‬‭),‬‭but‬‭data‬‭are‬‭limited,‬‭and‬‭the‬
‭role of such treatment in the setting of antibody-associated CRS has not been established.‬
‭f‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬ ‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬‭rechallenge‬‭patients‬‭with‬‭atezolizumab‬‭should‬‭be‬‭based‬‭on‬
‭investigator’s‬ ‭assessment‬ ‭of‬ ‭benefit-risk‬ ‭and‬ ‭documented‬ ‭by‬ ‭the‬ ‭investigator‬ ‭(or‬ ‭an‬ ‭appropriate‬
‭delegate).‬ ‭Medical‬ ‭Monitor‬‭is‬‭available‬‭to‬‭advise‬‭as‬‭needed.‬‭For‬‭subsequent‬‭infusions,‬‭administer‬‭oral‬
‭premedication‬‭with‬‭antihistamines,‬‭anti-pyretics,‬‭and/or‬‭analgesics,‬‭and‬‭monitor‬‭closely‬‭for‬‭IRRs‬‭and/or‬
‭CRS.‬‭Premedication‬‭with‬‭corticosteroids‬‭and‬‭extending‬‭the‬‭infusion‬‭time‬‭may‬‭also‬‭be‬‭considered‬‭after‬
‭assessing the benefit-risk ratio.‬
‭g‬‭Refer to‬‭Riegler et al. (2019)‬‭for information on‬‭experimental treatments for CRS.‬
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‭H)‬ ‭Management Guidelines for Pancreatic Events, Including Pancreatitis‬
‭Event‬
‭Management‬
‭Amylase and/or lipase‬
‭elevation, Grade 2‬
‭Amylase and/or lipase > 1.5 - 2.0 ULN:‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Monitor amylase and lipase weekly.‬
‭●‬
‭For‬ ‭prolonged‬ ‭elevation‬ ‭(e.g.,‬ ‭>‬ ‭3‬ ‭weeks),‬ ‭consider‬
‭treatment‬
‭●‬
‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭10‬ ‭mg/day‬ ‭oral‬
‭prednisone.‬
‭Asymptomatic with amylase and/or lipase > 2.0 - 5.0 x ULN:‬
‭●‬
‭Treat as a Grade 3 event.‬
‭Amylase and/or lipase‬
‭elevation, Grade 3 or 4‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Refer patient to GI specialist.‬
‭●‬
‭Monitor amylase and lipase every other day.‬
‭●‬
‭If‬
‭no‬
‭improvement,‬
‭consider‬
‭treatment‬
‭with‬
‭corticosteroids‬
‭equivalent‬
‭to‬
‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭●‬
‭For‬
‭recurrent‬
‭events,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Immune-mediated‬
‭pancreatitis, Grade 2 or 3‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Refer patient to GI specialist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭●‬
‭For‬
‭recurrent‬
‭events,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Immune-mediated‬
‭pancreatitis, Grade 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭●‬
‭Refer patient to GI specialist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over‬‭≥‬‭1 month.‬
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‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬‭length‬‭of‬‭the‬‭extended‬‭period‬‭of‬‭time‬‭must‬‭be‬‭based‬‭on‬‭the‬‭assessment‬‭of‬‭benefit-risk‬‭by‬‭the‬
‭investigator‬ ‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬
‭by the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭should‬‭be‬‭based‬‭on‬‭investigator’s‬‭assessment‬‭of‬‭benefit-risk‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate). Medical Monitor is available to advise as needed.‬
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‭I)‬ ‭Management Guidelines for Dermatologic Events‬
‭Event‬
‭Management‬
‭Dermatologic‬
‭event, Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Consider‬ ‭treatment‬ ‭with‬ ‭topical‬ ‭corticosteroids‬ ‭and/or‬
‭other symptomatic therapy (e.g., antihistamines).‬
‭Dermatologic‬
‭event, Grade 2‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Consider‬ ‭patient‬ ‭referral‬ ‭to‬ ‭dermatologist‬ ‭for‬ ‭evaluation‬
‭and, if indicated, biops.‬
‭●‬
‭Initiate treatment with topical corticosteroids.‬
‭●‬
‭Consider‬
‭treatment‬
‭with‬
‭higher-potency‬
‭topical‬
‭corticosteroids if event does not improve.‬
‭●‬
‭If‬ ‭unresponsive‬ ‭to‬ ‭topical‬ ‭corticosteroids,‬ ‭consider‬ ‭oral‬
‭prednisone 0.5 mg/kg/day.‬
‭Dermatologic‬
‭event, Grade 3‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Refer‬ ‭patient‬ ‭to‬ ‭dermatologist‬ ‭for‬ ‭evaluation‬ ‭and,‬ ‭if‬
‭indicated, biopsy.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭10‬
‭mg/day‬ ‭oral‬‭prednisone,‬‭increasing‬‭dose‬‭to‬‭1-2‬‭mg/kg/day‬
‭if event does not improve within 48-72 hours.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Dermatologic‬
‭event, Grade 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭Stevens-Johnson syndrome‬
‭or toxic epidermal‬
‭necrolysis, (any grade)‬
‭Additional‬ ‭guidance‬ ‭for‬ ‭Stevens-Johnson‬ ‭syndrome‬ ‭or‬ ‭toxic‬
‭epidermal necrolysis:‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭suspected‬ ‭Stevens-Johnson‬
‭syndrome or toxic epidermal necrolysis.‬
‭●‬
‭Confirm‬ ‭diagnosis‬ ‭by‬ ‭referring‬ ‭patient‬ ‭to‬ ‭a‬ ‭specialist‬
‭(dermatologist,‬ ‭ophthalmologist‬ ‭or‬ ‭urologist‬ ‭as‬ ‭relevant)‬
‭for evaluation and, if indicated, biopsy.‬
‭●‬
‭Follow‬
‭the‬
‭applicable‬ ‭treatment‬ ‭and‬ ‭management‬
‭guidelines above.‬
‭●‬
‭If‬‭Stevens-Johnson‬‭syndrome‬‭or‬‭toxic‬‭epidermal‬‭necrolysis‬
‭is confirmed, permanently discontinue atezolizumab.‬
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‭a‬‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬ ‭12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬‭for‬‭corticosteroids‬‭(if‬
‭initiated)‬‭to‬‭be‬‭reduced‬‭to‬‭the‬‭equivalent‬‭of‬ ‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬‭acceptable‬‭length‬‭of‬‭the‬‭extended‬‭period‬‭of‬
‭time‬ ‭must‬ ‭be‬ ‭based‬ ‭on‬ ‭assessment‬‭of‬‭benefit-risk‬‭by‬‭the‬‭investigator‬‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬
‭duration of treatment and documented by the investigator. Medical Monitor is available to advise as needed.‬
‭b‬‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬ ‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬ ‭10‬‭mg/day‬‭oral‬‭prednisone‬
‭before atezolizumab can be resumed.‬
‭c‬‭Resumption‬‭of‬‭atezolizumab‬‭may‬‭be‬‭considered‬‭in‬‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬‭recovered‬‭from‬‭the‬
‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬ ‭should‬ ‭be‬ ‭based‬ ‭on‬ ‭investigator’s‬
‭assessment‬‭of‬‭benefit-risk‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬‭appropriate‬‭delegate).‬‭Medical‬‭Monitor‬‭is‬‭available‬‭to‬
‭advise as needed..‬
‭●‬ ‭For‬ ‭suspected‬ ‭SCARs‬ ‭the‬ ‭patients‬ ‭should‬ ‭be‬ ‭referred‬ ‭to‬ ‭a‬ ‭dermatologist‬ ‭for‬ ‭further‬ ‭diagnosis‬ ‭and‬
‭management‬
‭● Atezolizumab should be withheld for patients with suspected SJS or TEN‬
‭● Atezolizumab should be permanently withdrawn for any grade confirmed SJS or TEN‬
‭●‬ ‭Caution‬ ‭should‬ ‭be‬ ‭used‬ ‭when‬ ‭considering‬ ‭the‬ ‭use‬ ‭of‬‭atezolizumab‬‭in‬‭a‬‭patient‬‭who‬‭has‬‭previously‬
‭experienced‬ ‭a‬ ‭severe‬ ‭or‬ ‭life-threatening‬ ‭skin‬ ‭adverse‬ ‭reaction‬ ‭on‬ ‭prior‬ ‭treatment‬ ‭with‬ ‭other‬
‭immune-stimulatory anticancer agents.‬
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‭J)‬ ‭Management Guidelines for Neurologic Disorders‬
‭Event‬
‭Management‬
‭Immune-mediated‬
‭neuropathy, Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Investigate etiology‬
‭Immune-mediated‬
‭neuropathy, Grade 2‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Investigate etiology and refer patient to neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Immune-mediated‬
‭neuropathy, Grade 3 or 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭●‬
‭Refer patient to neurologist‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭Myasthenia gravis and‬
‭Guillain-Barré syndrome‬
‭(any grade)‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭●‬
‭Refer patient to neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭●‬
‭Consider‬ ‭initiation‬ ‭of‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral or IV prednisone.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬‭length‬‭of‬‭the‬‭extended‬‭period‬‭of‬‭time‬‭must‬‭be‬‭based‬‭on‬‭the‬‭assessment‬‭of‬‭benefit-risk‬‭by‬‭the‬
‭investigator‬ ‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬
‭by the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭based‬‭on‬‭investigator’s‬‭assessment‬‭of‬‭benefit-risk‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬‭appropriate‬
‭delegate). Medical Monitor is available to advise as needed.‬
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‭K)‬ ‭Management Guidelines for Immune-Mediated Meningoencephalitis‬
‭Event‬
‭Management‬
‭Immune-mediated‬
‭meningoencephalitis, all‬
‭grades‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭a‬
‭●‬
‭Refer‬ ‭patient‬ ‭to‬ ‭neurologist.‬
‭Initiate‬ ‭treatment‬ ‭with‬
‭corticosteroids‬
‭equivalent‬
‭to‬
‭1-2‬
‭mg/kg/day‬
‭IV‬
‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬ ‭mg/kg/day‬ ‭oral‬
‭prednisone or equivalent upon improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over‬‭≥‬‭1 month‬
‭a‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭should‬‭be‬‭based‬‭on‬‭investigator’s‬‭assessment‬‭of‬‭benefit-risk‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate). Medical Monitor is available to advise as needed.‬
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‭L)‬ ‭Management Guidelines for Renal Events‬
‭Event‬
‭Management‬
‭Renal event, Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Monitor‬ ‭kidney‬ ‭function,‬ ‭including‬ ‭creatinine‬ ‭and‬ ‭urine‬
‭protein,‬‭closely‬‭until‬‭values‬‭resolve‬‭to‬‭within‬‭normal‬‭limits‬
‭or to baseline values.‬
‭Renal event, Grade 2‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Refer patient to renal specialist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Renal event, Grade 3 or 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬
‭●‬
‭Refer patient to renal specialist and consider renal biopsy.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭taper‬
‭corticosteroids over‬‭≥‬‭1 month.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭based‬ ‭on‬‭assessment‬‭of‬‭benefit-risk‬‭by‬‭the‬
‭investigator‬ ‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬
‭by the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭should‬‭be‬‭based‬‭on‬‭investigator’s‬‭assessment‬‭of‬‭benefit-risk‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate). Medical Monitor is available to advise as needed.‬
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‭M)‬‭Management Guidelines for Immune-Mediated Myositis‬
‭Event‬
‭Management‬
‭Immune-mediated myositis,‬
‭Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Refer patient to rheumatologist or neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭Immune-mediated myositis,‬
‭Grade 2‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset a and contact Medical Monitor.‬
‭●‬
‭Refer patient to rheumatologist or neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭●‬
‭Consider‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬‭to‬‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬‭corticosteroids‬‭are‬‭initiated‬‭and‬‭event‬‭does‬‭not‬‭improve‬
‭within‬ ‭48‬ ‭hours‬ ‭after‬ ‭initiating‬ ‭corticosteroids,‬ ‭consider‬
‭adding an immunosuppressive agent.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Immune-mediated myositis,‬
‭Grade 3‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset a and contact Medical Monitor.‬
‭●‬
‭Refer patient to rheumatologist or neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭●‬
‭Respiratory support may be required in more severe cases.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬‭methylprednisolone,‬‭or‬‭higher-dose‬‭bolus‬‭if‬
‭patient‬
‭is‬ ‭severely‬ ‭compromised‬ ‭(e.g.,‬ ‭cardiac‬ ‭or‬
‭respiratory‬ ‭symptoms,‬ ‭dysphagia,‬ ‭or‬ ‭weakness‬ ‭that‬
‭severely‬ ‭limits‬ ‭mobility);‬ ‭convert‬ ‭to‬ ‭1-2‬ ‭mg/kg/day‬ ‭oral‬
‭prednisone or equivalent upon improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬ ‭b‬ ‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬
‭better‬ ‭while‬ ‭withholding‬ ‭atezolizumab,‬ ‭permanently‬
‭discontinue atezolizumab and contact Medical Monitor.‬‭c‬
‭●‬
‭For recurrent events, treat as a Grade 4 event.‬
‭Immune-mediated myositis,‬
‭Grade 4‬
‭(CTCAE v5.0 guidelines‬
‭only)‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭●‬
‭Refer patient to rheumatologist or neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭●‬
‭Respiratory‬‭support‬‭may‬‭be‬‭required‬‭in‬‭more‬‭severe‬‭cases.‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬‭methylprednisolone,‬‭or‬‭higher-dose‬‭bolus‬‭if‬
‭patient‬
‭is‬ ‭severely‬ ‭compromised‬ ‭(e.g.,‬ ‭cardiac‬ ‭or‬
‭respiratory‬ ‭symptoms,‬ ‭dysphagia,‬ ‭or‬ ‭weakness‬ ‭that‬
‭severely‬ ‭limits‬ ‭mobility);‬ ‭convert‬ ‭to‬ ‭12‬ ‭mg/kg/day‬ ‭oral‬
‭prednisone or equivalent upon improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over‬‭≥‬‭1 month.‬
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‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬‭length‬‭of‬‭the‬‭extended‬‭period‬‭of‬‭time‬‭must‬‭be‬‭based‬‭on‬‭the‬‭assessment‬‭of‬‭benefit-risk‬‭by‬‭the‬
‭investigator‬ ‭and‬‭in‬‭alignment‬‭with‬‭the‬‭protocol‬‭requirement‬‭for‬‭duration‬‭of‬‭treatment‬‭and‬‭documented‬
‭by the investigator. Medical Monitor is available to advise as needed.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬ ‭from‬ ‭the‬ ‭immune-mediated‬ ‭event.‬ ‭The‬ ‭decision‬ ‭to‬ ‭rechallenge‬ ‭patients‬ ‭with‬ ‭atezolizumab‬
‭should‬‭be‬‭based‬‭on‬‭investigator’s‬‭assessment‬‭of‬‭benefit-risk‬‭and‬‭documented‬‭by‬‭the‬‭investigator‬‭(or‬‭an‬
‭appropriate delegate). Medical Monitor is available to advise as needed.‬
‭AUREA -  SOGUG-2020-IEC(VEJ)-1 - Protocol version 2.0 08MAR2022‬
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‭Clinical Trial Protocol‬
‭Protocol Number:‬
‭SOGUG-2020-IEC(VEJ)-1‬
‭Title:‬
‭Phase‬ ‭II,‬ ‭multicenter,‬ ‭non-randomized,‬ ‭single-arm,‬ ‭open-label‬ ‭trial‬ ‭of‬
‭atezolizumab‬‭in‬‭combination‬‭of‬‭split-doses‬‭of‬‭gemcitabine‬‭plus‬‭cisplatin‬‭in‬
‭patients with locally advanced or metastatic urothelial carcinoma‬
‭Short title:‬
‭Study‬‭of‬‭atezolizumab‬‭combined‬‭with‬‭split-dose‬‭gemcitabine‬‭plus‬‭cisplatin‬
‭in urothelial carcinoma‬
‭Acronym:‬
‭AUREA‬
‭Nº EudraCT:‬
‭2020-001326-65‬
‭Sponsor:‬
‭Spanish Oncology Genitourinary Group (SOGUG)‬
‭Velázquez, 7, 3a. planta, 28001‬
‭Madrid, Spain‬
‭Coordinating:‬
‭Investigator:‬
‭Guillermo de Velasco, M.D., PhD.‬
‭Medical Oncology Department‬
‭Hospital Universitario 12 de Octubre,‬
‭Av Córdoba s/n 28041,‬
‭Madrid, Spain‬
‭VERSION 1.1 - 6.NOV.2020‬
‭Confidentiality Statement‬
‭The‬ ‭information‬ ‭contained‬ ‭in‬‭this‬‭document‬‭is‬‭the‬‭property‬‭of‬‭the‬‭sponsor‬‭and‬‭therefore‬‭is‬
‭provided‬‭confidentially‬‭for‬‭review‬‭by‬‭you,‬‭your‬‭investigative‬‭team,‬‭the‬‭Investigational‬‭Ethics‬
‭Committee,‬‭and‬‭the‬‭competent‬‭authorities.‬‭This‬‭information‬‭must‬‭not‬‭be‬‭revealed‬‭to‬‭any‬‭other‬
‭party‬‭without‬‭previous‬‭authorization‬‭in‬‭writing‬‭by‬‭the‬‭sponsor,‬‭except‬‭as‬‭needed‬‭to‬‭obtain‬‭the‬
‭informed consent of the subjects who may be given the medicinal product.‬
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‭Page‬‭213‬‭of‬‭315‬


‭SPONSOR’S PROTOCOL SIGNATURE PAGE‬
‭I‬‭approve‬‭the‬‭design‬‭of‬‭the‬‭clinical‬‭trial‬‭and‬‭I‬‭understand‬‭and‬‭will‬‭conduct‬‭the‬‭trial‬‭according‬
‭to‬‭the‬‭clinical‬‭trial‬‭protocol,‬‭any‬‭approved‬‭protocol‬‭amendments,‬‭International‬‭Conference‬‭on‬
‭Harmonization‬‭Good‬‭Clinical‬‭Practice,‬‭and‬‭all‬‭applicable‬‭Health‬‭Authority‬‭requirements‬‭and‬
‭national laws.‬
‭Dr. José Ángel Arranz Arija‬
‭SOGUG Chairman‬
‭Signature‬
‭Signature date‬
‭(DD-mm-YYYY)‬
‭Dr. Guillermo de Velasco‬
‭Coordinating Investigator‬
‭Signature‬
‭Signature date‬
‭(DD-mm-YYYY)‬
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‭Page‬‭214‬‭of‬‭315‬


‭PRINCIPAL INVESTIGATOR’S PROTOCOL SIGNATURE PAGE‬
‭I have read this protocol and agree to conduct this clinical trial in accordance with all the‬
‭provisions of the Protocol, any approved protocol amendments, International Conference on‬
‭Harmonization‬ ‭Good‬ ‭Clinical‬ ‭Practice,‬ ‭Helsinki‬ ‭Declaration‬ ‭and‬ ‭all‬ ‭applicable‬ ‭Health‬
‭Authority  requirements and national laws‬
‭Site‬‭: _______________________________________________‬
‭Name:‬‭__________________________________________‬
‭Date:‬‭_________________________________________‬
‭Principal Investigator Signature:‬‭__________________________________‬
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‭INDEX‬
‭SPONSOR’S PROTOCOL SIGNATURE PAGE‬
‭1‬
‭PRINCIPAL INVESTIGATOR’S PROTOCOL SIGNATURE PAGE‬
‭3‬
‭1. SUMMARY‬
‭10‬
‭1.1. Type of application‬
‭10‬
‭1.2. Study Title‬
‭10‬
‭1.3. Protocol Number and Version‬
‭10‬
‭1.4. Nº EudraCT‬
‭10‬
‭1.5. Sponsor Data‬
‭10‬
‭1.6. Coordinating Investigator‬
‭10‬
‭1.7. Principal Investigators‬
‭10‬
‭1.8. Study Sites‬
‭10‬
‭1.9. Monitoring Organization‬
‭10‬
‭1.10. Disease under study‬
‭10‬
‭1.11. Study Phase‬
‭10‬
‭1.12. Study Treatments‬
‭10‬
‭1.13. Objectives‬
‭11‬
‭1.14. Endpoints‬
‭12‬
‭1.15. Sample Size‬
‭12‬
‭1.16. Eligibility and withdrawal criteria‬
‭12‬
‭1.17. Planned trial period‬
‭16‬
‭2. GENERAL INFORMATION‬
‭21‬
‭2.1. Study Identification‬
‭21‬
‭2.2. Monitoring Organization‬
‭21‬
‭2.3. Sponsor information‬
‭21‬
‭2.4. Coordinating investigator‬
‭21‬
‭2.5. Investigators and study centres‬
‭21‬
‭3. INVESTIGATIONAL MEDICINAL PRODUCT (IMP) DESCRIPTION‬
‭22‬
‭3.1. Study medication‬
‭22‬
‭4. RATIONALE AND OBJECTIVES‬
‭23‬
‭4.1. Rationale‬
‭23‬
‭4.1.1. Current state of the art‬
‭23‬
‭4.1.2. Split-Dose Cisplatin‬
‭23‬
‭4.1.3. PD-L1 and the role of atezolizumab in mUC‬
‭24‬
‭4.2. Hypothesis‬
‭24‬
‭4.3. Rationale for dose selection‬
‭25‬
‭4.4. Study Objectives‬
‭26‬
‭4.4.1. Primary Objectives‬
‭26‬
‭4.4.2. Secondary Objectives‬
‭26‬
‭4.4.3. Exploratory objectives‬
‭26‬
‭5. STUDY DESIGN‬
‭26‬
‭5.1. Study design‬
‭27‬
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‭5.2. Patient selection‬
‭28‬
‭5.3. Screening period and screening failure‬
‭28‬
‭5.4. Patient registration/enrollment‬
‭29‬
‭5.5. Treatment description, doses and schedules‬
‭29‬
‭5.6. Duration of study, recruitment, treatment and follow-up‬
‭30‬
‭5.7. Determinations during the study‬
‭30‬
‭5.7.1. Screening phase‬
‭30‬
‭5.7.2. Treatment phase‬
‭30‬
‭5.7.3. Safety visit (after the end of treatment by any reason)‬
‭31‬
‭5.7.4. Follow up until progression‬
‭31‬
‭5.7.5. Follow up after progression‬
‭31‬
‭5.8. End of study (EoS)‬
‭31‬
‭5.9. Outcome assessments‬
‭31‬
‭5.9.1. Response evaluation according RECIST 1.1‬
‭31‬
‭5.9.2. Safety assessments‬
‭32‬
‭6. STUDY POPULATION‬
‭33‬
‭6.1. Inclusion criteria‬
‭33‬
‭6.2. Exclusion criteria‬
‭34‬
‭6.3. Criteria for withdrawal from the treatment and study‬
‭37‬
‭6.3.1. Permanent Interruption of study treatments‬
‭37‬
‭6.3.2. Withdrawal from the study‬
‭38‬
‭7. TREATMENT DESCRIPTION‬
‭39‬
‭7.1. Study medication‬
‭39‬
‭7.1.1. Atezolizumab‬
‭39‬
‭7.1.2.   Gemcitabine and Cisplatin‬
‭39‬
‭7.2. Treatment accountability and compliance‬
‭39‬
‭7.2.1. Atezolizumab accountability and compliance‬
‭39‬
‭7.2.2. Gemcitabine and Cisplatin accountability and compliance‬
‭40‬
‭7.3. Preparation and Dispensing‬
‭40‬
‭7.3.1. Atezolizumab preparation and dispensing‬
‭40‬
‭7.3.2. Gemcitabine plus cisplatin preparation and dispensing‬
‭40‬
‭7.4. Investigational Medical Products Administration‬
‭40‬
‭7.4.1. Atezolizumab administration‬
‭40‬
‭7.4.1.1. Intrapatient Atezolizumab Dose Reduction‬
‭41‬
‭7.4.2. Gemcitabine and cisplatin administration‬
‭41‬
‭7.4.2.1. Gemcitabine administration‬
‭41‬
‭7.4.2.2. Cisplatin administration‬
‭42‬
‭7.4.2.3. Intrapatient Gemcitabine and Cisplatin Dose Reduction‬
‭42‬
‭7.5. Special Precautions for Investigational Medical Products‬
‭43‬
‭7.5.1. Special Precautions for Atezolizumab‬
‭43‬
‭7.5.1.1. Hepatic impairment‬
‭43‬
‭7.5.1.2. Renal impairment‬
‭44‬
‭7.5.1.3. Reproductive and Developmental Toxicity‬
‭44‬
‭7.5.1.4. Immune-mediated adverse reactions‬
‭44‬
‭7.5.2. Special Precautions for Gemcitabine‬
‭48‬
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‭7.5.3. Special Precautions for Cisplatin‬
‭48‬
‭7.6. Investigational Product Storage‬
‭48‬
‭7.6.1. Atezolizumab storage‬
‭49‬
‭7.6.2. Gemcitabine and cisplatin storage‬
‭50‬
‭7.7. Investigational Product Accountability‬
‭50‬
‭7.8. Destruction of Investigational Product Supplies‬
‭50‬
‭7.9. Concomitant Treatments‬
‭50‬
‭7.9.1. Inhibitors and Inducers of CYP Enzymes‬
‭51‬
‭7.9.2. Concomitant Surgery‬
‭51‬
‭7.9.3. Concomitant Radiotherapy‬
‭51‬
‭7.9.4. Other Prohibited Concomitant Medications and Therapies‬
‭51‬
‭7.10. Rescue Medications and Supportive Care‬
‭52‬
‭7.10.1. Supportive Care Guidelines‬
‭52‬
‭8. STUDY PROCEDURES AND EVALUATIONS‬
‭54‬
‭8.1. Definition of efficacy variables‬
‭54‬
‭8.2. Safety and tolerability‬
‭55‬
‭8.3. Study determinations‬
‭55‬
‭8.4. Determinations in the selection phase (screening and baseline determinations)‬
‭58‬
‭8.5. Determinations and procedures during the treatment period (up to cycle 6)‬
‭59‬
‭8.5.1. Day 1 (considering 3 week cycles)‬
‭59‬
‭8.5.2. Day 8 (considering 3 week cycles)‬
‭59‬
‭8.5.3. Other determinations during treatment‬
‭60‬
‭8.5.4. Determinations and procedures on day 1 of cycle 7 (D1-C7) and subsequent‬
‭cycles (D1-Cn)‬
‭60‬
‭8.6. Determinations at safety visit‬
‭61‬
‭8.7. Follow-up determinations‬
‭61‬
‭8.7.1. Follow up after end of treatment (prior DP)‬
‭61‬
‭8.7.2. Follow up after end of treatment (after PD)‬
‭61‬
‭9. SAFETY EVALUATION‬
‭62‬
‭9.1. Definitions‬
‭62‬
‭9.1.1. Adverse event (AE)‬
‭62‬
‭9.1.2. Atezolizumab Adverse Event of Special Interest‬
‭63‬
‭9.1.3. Laboratory Abnormalities‬
‭63‬
‭9.1.4. Medication errors‬
‭63‬
‭9.1.4.1. Atezolizumab overdose‬
‭64‬
‭9.1.4.2. Gemcitabine overdose‬
‭64‬
‭9.1.4.3. Cisplatin overdose‬
‭64‬
‭9.1.5. Adverse reaction (AR)‬
‭65‬
‭9.1.6. Serious Adverse Event (SAE)‬
‭65‬
‭9.1.7. Protocol-Specified Serious Adverse Events‬
‭66‬
‭9.1.8. Life Threatening Event‬
‭66‬
‭9.1.9. Hospitalization / Prolongation of Hospitalization‬
‭66‬
‭9.1.10. Unexpected adverse event (not listed)‬
‭66‬
‭9.1.11. Adverse Event Associated With the Use of the Drug (Adverse Reaction)‬
‭66‬
‭9.1.12. Attribution Definitions‬
‭67‬
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‭9.1.3. Intensity (Severity) Criteria‬
‭67‬
‭9.1.14. Exposure during Pregnancy‬
‭68‬
‭9.1.15. Occupational Exposure‬
‭69‬
‭9.1.16. Expedited reporting‬
‭69‬
‭9.2. Collection and reporting of Adverse Events information‬
‭69‬
‭10. STATISTICAL CONSIDERATIONS‬
‭71‬
‭10.1. Sample size calculation‬
‭71‬
‭10.2. Study endpoints‬
‭71‬
‭10.2.1. Primary endpoint‬
‭71‬
‭10.2.2. Secondary endpoints‬
‭71‬
‭10.3. Efficacy assessment‬
‭72‬
‭10.3.1. Efficacy variables‬
‭72‬
‭10.4. Safety assessment‬
‭73‬
‭10.5. Definition of study populations‬
‭73‬
‭10.6. Data quality control‬
‭73‬
‭10.7. Statistical analysis‬
‭74‬
‭11. LEGAL AND ETHICS CONSIDERATION‬
‭75‬
‭11.1. Ethical conduct of the study‬
‭75‬
‭11.2. Independent Ethical Committee (IEC) Review‬
‭75‬
‭11.3. Authorities‬
‭75‬
‭11.4. Informed consent‬
‭76‬
‭11.5. Confidentiality‬
‭76‬
‭11.6. Insurance Policy‬
‭76‬
‭11.7. End of study definition‬
‭76‬
‭11.8. Early study termination‬
‭77‬
‭12. STUDY PROCEDURES‬
‭78‬
‭12.1. Responsibilities according to Good Clinical Practice‬
‭78‬
‭12.2. Instructions for e-CRF completion‬
‭78‬
‭12.3. Drug supply‬
‭78‬
‭12.3.1. Packaging and labelling‬
‭79‬
‭12.4. Final report and Publications‬
‭79‬
‭12.5. Monitoring‬
‭79‬
‭12.6. Clinical Study Report‬
‭80‬
‭12.7. Protocol Amendments‬
‭80‬
‭12.8. Data Handling‬
‭80‬
‭12.9. Documentation‬
‭81‬
‭12.10. Audits and inspections‬
‭81‬
‭13. TRANSLATIONAL SUBSTUDIES‬
‭82‬
‭13.1. Archived Tumor Biospecimens‬
‭82‬
‭13.2. Peripheral Blood‬
‭82‬
‭13.3. Faecal samples‬
‭84‬
‭14. REFERENCES‬
‭85‬
‭APPENDICES‬
‭88‬
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‭Appendix 1. Management of Atezolizumab-specific Adverse Events‬
‭89‬
‭Management Guidelines for Pulmonary Events, Including Pneumonitis‬
‭89‬
‭Management Guidelines for Hepatic Events‬
‭90‬
‭Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis)‬
‭92‬
‭Management Guidelines for Hepatic Events‬
‭93‬
‭Management Guidelines for Endocrine Events‬
‭94‬
‭Management Guidelines for Ocular Events‬
‭96‬
‭Management Guidelines for Immune-Mediated Myocarditis‬
‭97‬
‭Management Guidelines for Infusion-Related Reactions and Cytokine-Release‬
‭Syndrome‬
‭98‬
‭Management Guidelines for Pancreatic Events, Including Pancreatitis‬
‭101‬
‭Management Guidelines for Dermatologic Events‬
‭103‬
‭Management Guidelines for Neurologic Disorders‬
‭104‬
‭Management Guidelines for Immune-Mediated Meningoencephalitis‬
‭105‬
‭Management Guidelines for Renal Events‬
‭106‬
‭Management Guidelines for Immune-Mediated Myositis‬
‭107‬
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‭1.‬
‭SUMMARY‬
‭1.1.‬
‭Type of application‬
‭Clinical trial with approved medications with a potential better regimen.‬
‭1.2.‬
‭Study Title‬
‭Phase‬ ‭II,‬ ‭multicenter,‬ ‭non-randomized,‬ ‭single-arm,‬ ‭open-label‬ ‭trial‬ ‭of‬ ‭atezolizumab‬ ‭in‬
‭combination‬‭of‬‭split-doses‬‭of‬‭gemcitabine‬‭plus‬‭cisplatin‬‭in‬‭patients‬‭with‬‭locally‬‭advanced‬‭or‬
‭metastatic urothelial carcinoma‬
‭1.3.‬
‭Protocol Number and Version‬
‭SOGUG-2020-IEC(VEJ)-1 -  VERSION 1.1 6.NOV.2020‬
‭1.4.‬
‭Nº EudraCT‬
‭2020-001326-65‬
‭1.5.‬
‭Sponsor Data‬
‭Spanish Oncology Genitourinary Group (SOGUG)‬
‭C/ Velazquez 7, 3a. planta‬
‭28001, Madrid, Spain‬
‭secretaria@sogug.es‬
‭1.6.‬
‭Coordinating Investigator‬
‭Guillermo de Velasco, M.D., PhD.‬
‭Medical Oncology Department‬
‭Hospital Universitario 12 de Octubre‬
‭1.7.‬
‭Principal Investigators‬
‭The‬ ‭list‬ ‭of‬ ‭sites‬ ‭and‬ ‭the‬ ‭corresponding‬ ‭Principal‬ ‭Investigators‬ ‭is‬ ‭provided‬ ‭in‬ ‭the‬ ‭attached‬
‭document.‬
‭1.8.‬
‭Study Sites‬
‭It is expected the participation of 12 Sites in Spain.‬
‭1.9.‬
‭Monitoring Organization‬
‭MFAR Clinical Research‬
‭C/ Sinfonía 28, 2-1, 28001, Madrid, Spain‬
‭investigacion@mfar.net‬
‭1.10.‬ ‭Disease under study‬
‭Locally advanced and metastatic urothelial carcinoma (mUC)‬
‭1.11.‬
‭Study Phase‬
‭Phase II clinical trial; Investigator Initiated Study (IIS)‬
‭1.12.‬ ‭Study Treatments‬
‭All‬‭study‬‭treatments‬‭are‬‭intended‬‭for‬‭administration‬‭as‬‭described‬‭below‬‭(regarding‬‭maximum‬
‭treatment‬‭duration‬‭as‬‭per‬‭protocol),‬‭until‬‭PD,‬‭unacceptable‬‭toxicity,‬‭investigator’s‬‭decision‬‭or‬
‭patient’s consent withdrawal (whichever occurs first).‬
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‭●‬ ‭Atezolizumab‬‭at‬‭a‬‭fixed‬‭dose‬‭of‬‭1200‬‭mg/m‬‭2‬‭by‬‭intravenous‬‭(IV)‬‭infusion‬‭on‬‭D1‬‭of‬
‭each‬ ‭cycle‬ ‭up‬ ‭to‬ ‭disease‬ ‭progression,‬ ‭unacceptable‬ ‭toxicity‬ ‭or‬ ‭absence‬ ‭of‬ ‭clinical‬
‭benefit.‬ ‭AUREA‬ ‭is‬ ‭an‬ ‭Investigator‬ ‭Initiated‬ ‭Study,‬ ‭the‬ ‭Sponsor‬ ‭will‬ ‭supply‬
‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬‭months‬‭of‬‭treatment‬‭for‬‭each‬‭patient.‬‭For‬‭those‬‭patients‬‭in‬
‭which‬‭the‬‭PI‬‭considers‬‭that‬‭the‬‭best‬‭option‬‭for‬‭the‬‭patient‬‭is‬‭continuing‬‭atezolizumab‬
‭for‬ ‭more‬ ‭than‬ ‭24‬ ‭months,‬ ‭available‬‭commercial‬‭Site‬‭supplies‬‭should‬‭be‬‭used,‬‭after‬
‭managed local administrative regulation.‬
‭●‬ ‭Gemcitabine‬‭1000‬‭mg/m‬‭2‬ ‭IV‬‭on‬‭D1‬‭and‬‭1000‬‭mg/m‬‭2‬ ‭IV‬‭on‬‭D8‬‭of‬‭each‬‭21-day‬‭cycle‬
‭plus‬‭Cisplatin‬‭70‬‭mg/m‬‭2‬ ‭by‬‭IV‬‭on‬‭split-dose‬‭schedule‬‭of‬‭35‬‭mg/m‬‭2‬‭on‬‭day‬‭1‬‭(D1)‬‭and‬
‭35 mg/m‬‭2‬‭on day 8 (D8)‬‭for up to 6 cycles.‬
‭1.13.‬ ‭Objectives‬
‭Primary Objective:‬
‭To‬‭evaluate‬‭the‬‭preliminary‬‭efficacy‬‭of‬‭atezolizumab‬‭plus‬‭split-dose‬‭gemcitabine‬‭and‬‭cisplatin‬
‭(GC)‬ ‭for‬ ‭the‬ ‭first-line‬ ‭setting,‬ ‭in‬ ‭patients‬ ‭with‬ ‭histologically‬ ‭confirmed‬ ‭advanced‬ ‭(locally‬
‭advanced‬‭and‬‭metastatic)‬‭urothelial‬‭cancer‬‭in‬‭terms‬‭of‬‭overall‬‭response‬‭rate‬‭(ORR)‬‭assessed‬‭by‬
‭the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.‬
‭Secondary Objectives‬
‭Efficacy:‬
‭●‬ ‭To‬ ‭evaluate‬ ‭the‬ ‭duration‬ ‭of‬ ‭response‬ ‭(DoR)‬ ‭associated‬ ‭with‬ ‭the‬ ‭study‬ ‭treatment,‬
‭understood‬‭as‬‭the‬‭time‬‭from‬‭first‬‭confirmed‬‭response‬‭(CR‬‭or‬‭PR)‬‭to‬‭the‬‭date‬‭of‬‭the‬
‭documented‬‭progressive‬‭disease‬‭as‬‭determined‬‭using‬‭RECIST‬‭1.1‬‭criteria‬‭or‬‭death‬‭due‬
‭to any cause, whichever occurs first.‬
‭●‬ ‭To‬ ‭determine‬ ‭the‬ ‭overall‬ ‭survival‬ ‭(OS)‬ ‭of‬ ‭patients‬ ‭with‬ ‭locally-advanced‬ ‭or‬ ‭mUC‬
‭treated‬‭with‬‭the‬‭intended‬‭treatment‬‭regimen,‬‭understood‬‭as‬‭the‬‭time‬‭from‬‭first‬‭dosing‬
‭date‬‭to‬‭the‬‭date‬‭of‬‭death.‬‭A‬‭subject‬‭who‬‭has‬‭not‬‭died‬‭will‬‭be‬‭censored‬‭at‬‭the‬‭lastat‬‭last‬
‭known date alive.‬
‭●‬ ‭To‬‭evaluate‬‭the‬‭time‬‭to‬‭response‬‭(TtR)‬‭associated‬‭with‬‭the‬‭study‬‭treatment,‬‭understood‬
‭as‬‭the‬‭time‬‭from‬‭the‬‭first‬‭dose‬‭of‬‭the‬‭study‬‭treatment‬‭to‬‭theand‬‭confirmed‬‭response‬
‭(CR or PR) based on RECIST 1.1 criteria.‬
‭●‬ ‭To evaluate the‬‭clinical benefit rate (CBR)‬‭, defined‬‭as the percentage of patients who‬
‭have achieved complete response, partial response and stable disease. Stable disease‬
‭should be maintained for at least 6 months to be considered as CBR event.‬
‭●‬ ‭To‬‭determine‬‭the‬‭progression-free‬‭survival‬‭(PFS)‬‭of‬‭patients‬‭with‬‭locally-advanced‬‭or‬
‭mUC‬ ‭treated‬ ‭with‬ ‭the‬ ‭intended‬ ‭treatment‬ ‭regimen,‬ ‭defined‬ ‭as‬ ‭the‬ ‭time‬ ‭from‬ ‭first‬
‭dosing‬‭date‬‭until‬‭disease‬‭progression‬‭or‬‭death‬‭from‬‭any‬‭cause.‬‭Patients‬‭who‬‭have‬‭not‬
‭progressed and start a new line of treatment will be censored.‬
‭Safety:‬
‭●‬ ‭To‬ ‭evaluate‬ ‭safety‬ ‭of‬ ‭the‬ ‭intended‬ ‭treatment‬ ‭regimen‬ ‭based‬ ‭on‬ ‭the‬ ‭frequency‬ ‭and‬
‭severity of adverse events assessed by NCI CTCAE v5.0.‬
‭Exploratory objectives‬
‭●‬ ‭To‬ ‭explore‬ ‭potential‬ ‭correlation‬ ‭of‬ ‭efficacy‬ ‭with‬ ‭relevant‬ ‭potential‬ ‭prognostic‬
‭factors/stratification factors‬
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‭●‬ ‭To‬‭evaluate‬‭the‬‭relationship‬‭between‬‭the‬‭expression‬‭of‬‭PD-L1‬‭and‬‭microbiome‬‭with‬
‭ORR and PFS during experimental treatment.‬
‭1.14.‬ ‭Endpoints‬
‭Primary endpoint:‬
‭●‬ ‭Overall Response Rate (ORR)‬
‭Secondary endpoints‬
‭●‬ ‭Duration of response‬‭(DoR)‬
‭●‬ ‭Overall Survival‬‭(OS)‬
‭●‬ ‭Time to response‬‭(TtR)‬
‭●‬ ‭Clinical benefit‬‭(CB)‬
‭●‬ ‭Progression-Free Survival‬‭(PFS)‬
‭Safety endpoints‬
‭●‬ ‭Adverse events‬‭(AE)‬
‭●‬ ‭Treatment-related AEs‬‭(TRAEs)‬
‭Exploratory endpoints‬
‭●‬ ‭Biomarkers expression‬
‭1.15.‬ ‭Sample Size‬
‭A minimum of 66 patients will be included in the trial.‬
‭1.16.‬ ‭Eligibility and withdrawal criteria‬
‭Inclusion criteria‬
‭1.‬ ‭Male or female subjects ≥ 18 years old.‬
‭2.‬ ‭Written‬‭informed‬‭consent‬‭approved‬‭by‬‭the‬‭Independent‬‭Ethics‬‭Committee‬‭(IEC),‬‭prior‬
‭to the performance of any trial activities.‬
‭3.‬ ‭Patients‬ ‭with‬ ‭histologically‬ ‭documented,‬ ‭locally‬ ‭advanced‬ ‭(T4B,‬ ‭any‬ ‭N;‬ ‭or‬ ‭any‬‭T,‬
‭N2-3) or metastatic urothelial carcinoma (M1, Stage IV)*.‬
‭*Also‬‭termed‬‭transitional‬‭cell‬‭carcinoma‬‭(TCC)‬‭or‬‭urothelial‬‭cell‬‭carcinoma‬‭[UCC]‬‭of‬
‭the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra).‬
‭4.‬ ‭Patients‬‭should‬‭not‬‭be‬‭eligible‬‭(unfit)‬‭for‬‭full‬‭dose‬‭of‬‭cisplatin,‬‭in‬‭the‬‭investigator’s‬
‭judgement, based on:‬
‭a.‬ ‭Age older than 70 years.‬
‭b.‬ ‭ECOG‬ ‭Performance‬ ‭status‬ ‭(PS)‬ ‭2‬ ‭or‬ ‭Karnofsky‬ ‭PS‬ ‭of‬ ‭60‬ ‭-‬ ‭70%‬ ‭(only‬‭15‬
‭patients will be included with ECOG 2).‬
‭c.‬ ‭Measured‬ ‭creatinine‬ ‭clearance‬ ‭(ClCr)‬ ‭>‬ ‭30‬ ‭and‬ ‭<‬ ‭60‬ ‭mL/min‬ ‭by‬ ‭the‬
‭Cockcroft-Gault‬ ‭formula‬ ‭(Cockcroft‬ ‭and‬ ‭Gault‬ ‭1976)‬ ‭or‬ ‭by‬ ‭24-hour‬ ‭urine‬
‭collection for the determination of creatinine clearance:‬
‭Males:‬
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‭Creatinine CL (mL/min)  =‬
‭Weight (kg) × (140 – Age)‬
‭72 x serum creatinine (mg/dL)‬
‭Females:‬
‭Creatinine CL (mL/min)  =‬
‭Weight (kg) × (140 – Age)‬‭×0.85‬
‭72 x serum creatinine (mg/dL)‬
‭d.‬ ‭Any‬‭other‬‭reason‬‭the‬‭physician‬‭considers‬‭but‬‭should‬‭specify‬‭in‬‭the‬‭CRF‬‭and‬
‭discussed with the PI.‬
‭5.‬ ‭At‬ ‭least‬ ‭one‬ ‭measurable‬ ‭lesion‬ ‭through‬ ‭radiographic‬‭tumor‬‭evaluation‬‭(CT‬‭scan‬‭or‬
‭magnetic‬ ‭resonance‬ ‭imaging/MRI)‬ ‭as‬ ‭defined‬‭by‬‭RECIST‬‭version‬‭1.1,‬‭that‬‭has‬‭not‬
‭been previously irradiated within 4 weeks prior to the study enrolment.‬
‭6.‬ ‭Patients‬ ‭with‬ ‭an‬ ‭archival‬ ‭or‬ ‭de‬ ‭novo‬ ‭tumor‬ ‭biopsy‬ ‭(representative‬ ‭formalin-fixed‬
‭paraffin-embedded/FFPE‬‭paraffin‬‭block‬‭obtained‬‭within‬‭6‬‭months‬‭prior‬‭to‬‭inclusion)‬
‭with‬ ‭an‬ ‭associated‬‭pathology‬‭report,‬‭for‬‭testing‬‭of‬‭PD-L1‬‭expression‬‭prior‬‭to‬‭study‬
‭enrollment. Samples in unstained slides could be acceptable (at least 15 slides).‬
‭7.‬ ‭Patients with adequate normal organ and marrow function as defined below:‬
‭a.‬ ‭Haemoglobin ≥ 9.0 g/dL.‬
‭b.‬ ‭Absolute neutrophil count (ANC)‬‭>‬‭1500 per mm‬‭3‬‭.‬
‭c.‬ ‭Platelet count ≥ 100,000 per mm‬‭3‬‭.‬
‭d.‬ ‭Serum‬‭bilirubin‬‭≤‬‭1.5‬‭X‬‭institutional‬‭upper‬‭limit‬‭of‬‭normal‬‭(ULN)‬‭unless‬‭liver‬
‭metastases‬ ‭are‬ ‭present,‬ ‭in‬ ‭which‬ ‭case‬ ‭it‬‭must‬‭be‬‭≤‬‭2X‬‭ULN.‬‭This‬‭will‬‭not‬
‭apply‬‭to‬‭patients‬‭with‬‭confirmed‬‭Gilbert’s‬‭syndrome‬‭(persistent‬‭or‬‭recurrent‬
‭hyperbilirubinemia‬ ‭that‬ ‭is‬ ‭predominantly‬ ‭unconjugated‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬
‭haemolysis‬ ‭or‬ ‭hepatic‬ ‭pathology);‬ ‭however,‬ ‭they‬ ‭will‬ ‭be‬ ‭allowed‬ ‭only‬ ‭in‬
‭consultation with their physician.‬
‭e.‬ ‭Serum‬‭transaminases‬‭(ALT,‬‭AST‬‭and‬‭GGT)‬‭≤‬‭2.5X‬‭institutional‬‭upper‬‭limit‬‭of‬
‭normal‬ ‭unless‬ ‭liver‬ ‭metastases‬ ‭are‬ ‭present,‬ ‭in‬ ‭which‬ ‭case‬‭it‬‭must‬‭be‬‭≤‬‭3X‬
‭ULN.‬
‭8.‬ ‭No major active bleeding.‬
‭9.‬ ‭Female‬ ‭subjects‬ ‭of‬ ‭childbearing‬ ‭potential‬ ‭(not‬ ‭surgically‬ ‭sterile‬ ‭or‬ ‭at‬ ‭least‬‭2‬‭years‬
‭postmenopausal)‬‭must‬‭provide‬‭a‬‭negative‬‭urine‬‭pregnancy‬‭test‬‭at‬‭screening,‬‭and‬‭use‬‭a‬
‭medically‬ ‭accepted‬ ‭double‬ ‭barrier‬ ‭method‬ ‭of‬ ‭contraception‬ ‭(i.e.‬ ‭condom‬ ‭with‬
‭spermicide‬‭+‬‭IUD‬‭or‬‭cervical‬‭caps).‬‭In‬‭addition,‬‭they‬‭must‬‭agree‬‭to‬‭continue‬‭the‬‭use‬‭of‬
‭this‬ ‭double‬ ‭barrier‬ ‭method‬ ‭for‬ ‭the‬ ‭duration‬ ‭of‬ ‭the‬ ‭study‬ ‭and‬ ‭for‬ ‭6‬ ‭months‬ ‭after‬
‭participation in the study.‬
‭10.‬‭Males‬‭should‬‭agree‬‭to‬‭abstain‬‭from‬‭sexual‬‭intercourse‬‭with‬‭a‬‭female‬‭partner‬‭or‬‭agree‬
‭to‬ ‭use‬ ‭a‬ ‭double‬ ‭barrier‬ ‭method‬ ‭of‬ ‭contraception‬ ‭(i.e.‬ ‭condom‬ ‭with‬ ‭spermicide,‬ ‭in‬
‭addition‬‭to‬‭having‬‭their‬‭female‬‭partner‬‭use‬‭some‬‭contraceptive‬‭measures‬‭such‬‭as‬‭oral‬
‭contraceptive‬ ‭drugs,‬ ‭intrauterine‬ ‭device‬ ‭(IUD)‬ ‭hormonal‬ ‭contraception,‬ ‭or‬ ‭cervical‬
‭caps), for the duration of the study and for 6 months after participation in the study‬
‭11.‬ ‭Willingness‬‭and‬‭ability‬‭of‬‭patients‬‭to‬‭comply‬‭with‬‭the‬‭protocol‬‭for‬‭the‬‭duration‬‭of‬‭the‬
‭study‬‭including‬‭undergoing‬‭treatment‬‭as‬‭well‬‭as‬‭availability‬‭for‬‭scheduled‬‭visits‬‭and‬
‭examinations including follow up.‬
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‭Exclusion criteria‬
‭1.‬ ‭Prior‬‭treatment‬‭with‬‭any‬‭immune‬‭checkpoint‬‭inhibitor‬‭therapy‬‭(e.g.,‬‭CTLA4,‬‭PD-1,‬‭or‬
‭PD-L1 targeting agent).*‬
‭*‬‭Note‬‭:‬ ‭Prior‬ ‭adjuvant‬ ‭or‬ ‭neoadjuvant‬ ‭treatment‬ ‭with‬ ‭targeted‬ ‭therapy/checkpoint‬
‭inhibitors‬‭is‬‭allowed,‬‭as‬‭long‬‭as‬‭the‬‭last‬‭dose‬‭was‬‭administered‬‭at‬‭least‬‭12‬‭months‬‭prior‬
‭to the patient inclusion in this trial.‬
‭2.‬ ‭Presence‬‭of‬‭active‬‭second‬‭malignancy‬‭and/or‬‭prior‬‭malignancy‬‭in‬‭the‬‭last‬‭2‬‭years‬‭is‬
‭allowed except for the following:‬
‭a.‬ ‭adequately treated basal cell or squamous cell skin cancer,‬
‭b.‬ ‭adequately‬‭treated‬‭Stage‬‭I‬‭or‬‭II‬‭cancer‬‭from‬‭which‬‭the‬‭patient‬‭is‬‭currently‬‭in‬
‭complete remission per investigators' clinical judgment.‬
‭3.‬ ‭Patient receiving radiation therapy within 4 weeks before inclusion.‬
‭4.‬ ‭Active‬ ‭or‬ ‭prior‬ ‭documented‬ ‭autoimmune‬ ‭disease‬ ‭within‬ ‭the‬ ‭past‬ ‭2‬ ‭years‬ ‭NOTE:‬
‭Subjects‬‭with‬‭vitiligo,‬‭Grave's‬‭disease,‬‭or‬‭psoriasis‬‭not‬‭requiring‬‭systemic‬‭treatment‬
‭(within the past 2 years) are not excluded.‬
‭5.‬ ‭Active‬ ‭or‬ ‭prior‬‭documented‬‭inflammatory‬‭bowel‬‭disease‬‭(e.g..,‬‭Crohn's‬‭disease‬‭and‬
‭ulcerative colitis).‬
‭6.‬ ‭History of allogeneic organ transplant.‬
‭7.‬ ‭Subjects‬ ‭having‬ ‭a‬ ‭diagnosis‬ ‭of‬‭immunodeficiency‬‭or‬‭are‬‭receiving‬‭systemic‬‭steroid‬
‭therapy‬‭or‬‭any‬‭other‬‭form‬‭of‬‭immunosuppressive‬‭therapy‬‭within‬‭28‬‭days‬‭prior‬‭to‬‭the‬
‭first dose of trial treatment.‬
‭8.‬ ‭Current‬ ‭or‬ ‭prior‬ ‭use‬ ‭of‬ ‭immunosuppressive‬ ‭medication‬ ‭within‬ ‭7‬ ‭days‬ ‭prior‬ ‭to‬
‭enrolment, except the following:‬
‭a.‬ ‭Intranasal,‬ ‭inhaled,‬ ‭topical‬ ‭steroids,‬ ‭or‬ ‭local‬ ‭steroid‬ ‭injections‬ ‭(eg,‬
‭intra-articular injection);‬
‭i.‬
‭Systemic‬ ‭corticosteroids‬ ‭at‬ ‭physiologic‬ ‭doses‬ ‭≤10‬ ‭mg/day‬ ‭of‬
‭prednisone or equivalent;‬
‭ii.‬
‭Steroids‬‭as‬‭premedication‬‭for‬‭hypersensitivity‬‭reactions‬‭(eg,‬‭CT‬‭scan‬
‭premedication).‬
‭9.‬ ‭The‬‭subject‬‭has‬‭uncontrolled,‬‭significant‬‭intercurrent‬‭or‬‭recent‬‭illness‬‭(within‬‭6‬‭months‬
‭prior to inclusion) including, but not limited to, the following conditions:‬
‭a.‬ ‭Cardiovascular disorders:‬
‭i.‬
‭Class‬‭3‬‭or‬‭4‬‭congestive‬‭heart‬‭failure‬‭as‬‭defined‬‭by‬‭the‬‭New‬‭York‬‭Heart‬
‭Association,‬
‭unstable‬
‭angina‬
‭pectoris,‬
‭and‬
‭serious‬
‭cardiac‬
‭arrhythmias.‬
‭ii.‬
‭Uncontrolled‬‭hypertension‬‭defined‬‭as‬‭sustained‬‭blood‬‭press‬‭>‬‭150‬‭mm‬
‭hg‬‭systolic‬‭or‬‭>‬‭100‬‭mm‬‭hg‬‭diastolic‬‭despite‬‭optimal‬‭antihypertensive‬
‭treatment.‬
‭iii.‬
‭Stroke‬ ‭(including‬ ‭transient‬ ‭ischemic‬ ‭attack‬ ‭[TIA]),‬ ‭myocardial‬
‭infarction,‬‭other‬‭ischemic‬‭event,‬‭or‬‭thromboembolic‬‭event‬‭(e.g.,‬‭deep‬
‭venous‬‭thrombosis‬‭[DVT]‬‭and‬‭pulmonary‬‭embolism)‬‭within‬‭6‬‭months‬
‭before‬‭inclusion.‬‭Subjects‬‭with‬‭a‬‭more‬‭recent‬‭diagnosis‬‭of‬‭DVT‬‭are‬
‭allowed‬‭if‬‭stable,‬‭asymptomatic,‬‭and‬‭treated‬‭with‬‭LMWH‬‭for‬‭at‬‭least‬
‭6 weeks before study treatment.‬
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‭b.‬ ‭Gastrointestinal‬ ‭disorders‬ ‭(e.g.,‬ ‭malabsorption‬ ‭syndrome‬ ‭or‬ ‭gastric‬ ‭outlet‬
‭obstruction)‬ ‭including‬ ‭those‬ ‭associated‬ ‭with‬ ‭a‬ ‭high‬ ‭risk‬ ‭of‬ ‭perforation‬ ‭or‬
‭fistula formulation:‬
‭i.‬
‭Tumours‬ ‭invading‬ ‭the‬ ‭GI‬ ‭tract,‬ ‭active‬ ‭peptic‬ ‭ulcer‬ ‭disease,‬
‭inflammatory‬
‭bowel‬
‭disease,‬
‭ulcerative‬
‭colitis,‬ ‭diverticulitis,‬
‭cholecystitis,‬
‭symptomatic‬
‭cholangitis‬
‭or‬
‭appendicitis,‬
‭acute‬
‭pancreatitis‬‭or‬‭acute‬‭obstruction‬‭of‬‭the‬‭pancreatic‬‭or‬‭biliary‬‭duct,‬‭or‬
‭gastric outlet obstruction.‬
‭ii.‬
‭Abdominal‬
‭fistula,‬
‭GI‬
‭perforation,‬
‭bowel‬
‭obstruction,‬
‭or‬
‭intra-abdominal‬ ‭abscess‬ ‭within‬ ‭6‬ ‭months‬ ‭before‬ ‭inclusion.‬ ‭Note:‬
‭complete‬ ‭healing‬ ‭of‬ ‭an‬ ‭intra-abdominal‬ ‭abscess‬ ‭must‬‭be‬‭confirmed‬
‭prior to start of the treatment.‬
‭c.‬ ‭Clinically‬‭significant‬‭hematemesis‬‭or‬‭hemoptysis‬‭of‬‭>‬‭0.5‬‭teaspoon‬‭(>‬‭2.5‬‭ml)‬
‭of‬‭red‬‭blood‬‭or‬‭history‬‭of‬‭other‬‭significant‬‭bleeding‬‭within‬‭3‬‭months‬‭before‬
‭treatment.‬
‭d.‬ ‭Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.‬
‭e.‬ ‭Lesions invading major pulmonary blood vessels.‬
‭f.‬
‭Other clinically significant disorders such as:‬
‭i.‬
‭Active‬ ‭infection‬‭requiring‬‭systemic‬‭treatment,‬‭infection‬‭with‬‭human‬
‭immunodeficiency‬
‭virus‬
‭or‬
‭acquired‬
‭immunodeficiency‬
‭syndrome-related illness, or chronic hepatitis B or C infection.‬
‭ii.‬
‭Serious non-healing wound/ulcer/bone fracture.‬
‭iii.‬
‭Malabsorption syndrome.‬
‭iv.‬
‭Moderate to severe hepatic impairment (child-pugh B or C).‬
‭v.‬
‭Requirement for hemodialysis or peritoneal dialysis.‬
‭vi.‬
‭Uncontrolled diabetes mellitus.‬
‭10.‬‭Major‬‭surgery‬‭(e.g.,‬‭GI‬‭surgery‬‭and‬‭removal‬‭or‬‭biopsy‬‭of‬‭brain‬‭metastasis)‬‭within‬‭8‬
‭weeks‬ ‭before‬ ‭inclusion.‬ ‭Complete‬ ‭wound‬ ‭healing‬ ‭from‬ ‭major‬ ‭surgery‬ ‭must‬ ‭have‬
‭occurred‬ ‭4‬ ‭weeks‬ ‭before‬ ‭study‬ ‭treatment‬ ‭and‬ ‭from‬ ‭minor‬ ‭surgery‬ ‭(e.g.,‬ ‭simple‬
‭excision,‬ ‭tooth‬ ‭extraction)‬ ‭at‬ ‭least‬ ‭10‬ ‭days‬ ‭before‬ ‭study‬ ‭treatment.‬ ‭Subjects‬ ‭with‬
‭clinically relevant ongoing complications from prior surgery are not eligible.‬
‭11.‬ ‭Known‬ ‭human‬ ‭immunodeficiency‬ ‭virus‬ ‭(HIV)‬ ‭or‬ ‭acquired‬ ‭immunodeficiency‬
‭syndrome (AIDS)-related illness.‬
‭12.‬‭Any‬‭test‬‭for‬‭hepatitis‬‭B‬‭virus‬‭(HBV)‬‭or‬‭hepatitis‬‭C‬‭virus‬‭(HCV)‬‭indicating‬‭acute‬‭or‬
‭chronic infection.‬
‭13.‬‭Women who are pregnant or are breastfeeding.‬
‭14.‬‭Male‬‭patients‬‭must‬‭be‬‭surgically‬‭sterile‬‭or‬‭must‬‭agree‬‭to‬‭use‬‭effective‬‭contraception‬
‭during the period of therapy.‬
‭15.‬‭Any‬ ‭of‬ ‭the‬ ‭following‬ ‭within‬ ‭6‬ ‭months‬ ‭prior‬ ‭to‬ ‭study‬‭entry:‬‭myocardial‬‭infarction,‬
‭uncontrolled‬ ‭angina,‬ ‭uncontrolled‬ ‭hypertension,‬ ‭coronary/peripheral‬ ‭artery‬ ‭bypass‬
‭graft,‬ ‭symptomatic‬ ‭congestive‬ ‭heart‬ ‭failure,‬ ‭cerebrovascular‬ ‭accident‬ ‭or‬ ‭transient‬
‭ischemic attack.‬
‭16.‬‭Previously‬‭identified‬‭allergy‬‭or‬‭hypersensitivity‬‭to‬‭components‬‭of‬‭the‬‭study‬‭treatment‬
‭formulations.‬
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‭1.17.‬ ‭Planned trial period‬
‭●‬ ‭Enrolment/recruitment period: 12 months‬
‭●‬ ‭First patient first visit (FPFV): TBD‬
‭●‬ ‭Last patient last visit (LPLV): FPFV + 24 months‬
‭●‬ ‭Treatment period: Up to 24 months of LPFV‬
‭●‬ ‭Follow-up period: 24 months‬
‭●‬ ‭Planned end of study date: FPFV + up to 36 months‬
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‭GLOSSARY OF ABBREVIATIONS‬
‭Abbreviation or‬
‭Specialist Term‬
‭Explanation‬
‭ADR‬
‭Adverse drug reaction‬
‭AE‬
‭Adverse event‬
‭aUC‬
‭Advanced urothelial cancer‬
‭BMI‬
‭Body Mass Index‬
‭BP‬
‭Blood Pressure‬
‭CIs‬
‭Confidence intervals‬
‭CK‬
‭Creatine‬ ‭kinase‬ ‭(CK),‬ ‭also‬ ‭known‬ ‭as‬ ‭creatine‬ ‭phosphokinase‬ ‭(CPK)‬ ‭or‬
‭phosphocreatine kinase‬
‭CB‬
‭Clinical benefit‬
‭CR‬
‭Complete Response‬
‭CRA‬
‭Clinical Research Associate‬
‭CTCAE‬
‭Common Terminology Criteria for Adverse Events‬
‭CT Scan‬
‭Computed Tomography Scan‬
‭DMP‬
‭Data Management Plan‬
‭CYP‬
‭Cytochromes P450 enzymes‬
‭DoR‬
‭Duration of response‬
‭DVP‬
‭Data Validation Plan‬
‭ECHO‬
‭Echocardiogram‬
‭ECG‬
‭Electrocardiogram‬
‭ECOG‬
‭Eastern Cooperative Oncology Group‬
‭eCRF‬
‭Electronic Case Report Form‬
‭EDC‬
‭Electronic Data Capture‬
‭ECG‬
‭Electrocardiogram‬
‭EMA‬
‭European Medicines Agency‬
‭ESMO‬
‭European Society of Medical Oncology‬
‭FBE‬
‭Full blood examination‬
‭FDA‬
‭US Food and Drug Administration‬
‭FFPE‬
‭Formalin-fixed paraffin-embedded‬
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‭FPFV‬
‭First patient first visit‬
‭FU‬
‭Follow-up‬
‭GC‬
‭Gemcitabine plus cisplatin‬
‭GCP‬
‭Good Clinical Practice‬
‭G-CSF‬
‭Granulocyte colony-stimulating factor‬
‭GH‬
‭Growth hormone‬
‭Hb‬
‭Haemoglobin‬
‭IB‬
‭Investigator Brochure‬
‭ICF‬
‭Informed Consent Form‬
‭ICH‬
‭International Conference on Harmonization‬
‭ICI‬
‭Immune Checkpoint Inhibitors‬
‭IEC‬
‭Independent Ethics Committee‬
‭IgG1‬
‭Immunoglobulin G1‬
‭IIS‬
‭Investigator Initiated Study‬
‭IMP‬
‭Investigational Medicinal Product‬
‭ISF‬
‭Investigator Site File‬
‭ITT‬
‭Intention To Treat‬
‭IUD‬
‭Intrauterine device‬
‭LPLV‬
‭Last visit Last patient‬
‭MedDRA‬
‭Medical Dictionary for Regulatory Activities‬
‭MRI‬
‭Magnetic Resonance Imaging‬
‭mUC‬
‭Metastatic urothelial cancer‬
‭MUGA‬
‭Multigated Acquisition Scan‬
‭MVAC‬
‭Dose-dense methotrexate, vinblastine, doxorubicin and cisplatin‬
‭NCI‬
‭National Cancer Institute (USA)‬
‭ORR‬
‭Overall response rate‬
‭OS‬
‭Overall Survival‬
‭PD‬
‭Progression disease‬
‭PE‬
‭Physical Examination‬
‭PFS‬
‭Progression Free Survival‬
‭PI‬
‭Principal Investigator‬
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‭PP‬
‭Per Protocol‬
‭PR‬
‭Partial Response‬
‭PS‬
‭Performance Status‬
‭QD‬
‭Quaque die, every day “once daily”‬
‭QxW‬
‭Every X weeks‬
‭RECIST‬
‭Response Evaluation Criteria In Solid Tumours‬
‭REEC‬
‭Registro Español de Estudios Clínicos (Spanish Registry of Clinical Studies)‬
‭Rx‬
‭Radiography‬
‭SAE‬
‭Serious adverse event‬
‭SAP‬
‭Statistical Analysis Plan‬
‭SAR‬
‭Serious adverse reaction‬
‭SC‬
‭Subcutaneous‬
‭SD‬
‭Stable disease‬
‭SDV‬
‭Source Data Verification‬
‭SmPC‬
‭Summary of Product Characteristics‬
‭SP‬
‭Safety Population‬
‭SUSAR‬
‭Suspected unexpected serious adverse reaction‬
‭PD-1‬
‭Programmed death-1‬
‭PD-L1‬
‭Programmed death ligand-1‬
‭TR‬
‭Translational Research‬
‭UC‬
‭Urothelial cancer‬
‭ULN‬
‭Upper Limit of Normality‬
‭VS‬
‭Vital Signs‬
‭WBC‬
‭White Blood Count‬
‭wGC‬
‭weekly Gemcitabine plus cisplatin‬
‭WHO‬
‭World Health Organization‬
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‭2.‬
‭GENERAL INFORMATION‬
‭2.1.‬
‭Study Identification‬
‭Short‬ ‭title‬‭:‬ ‭Study‬ ‭of‬ ‭atezolizumab‬ ‭and‬ ‭split-dose‬ ‭cisplatin/gemcitabine‬ ‭and‬ ‭in‬ ‭urothelial‬
‭carcinoma‬
‭Protocol number:‬‭SOGUG-2020-IEC (VEJ-1)‬
‭EudraCT No.‬‭: 2020-001326-65‬
‭2.2.‬
‭Monitoring Organization‬
‭MFAR Clinical Research‬
‭C/ Sinfonía 28, 2-1, 28001, Madrid, Spain‬
‭investigacion@mfar.net‬
‭2.3.‬
‭Sponsor information‬
‭Spanish Oncology Genitourinary Group (SOGUG)‬
‭C/ Velazquez 7, 3a planta,‬
‭28001, Madrid, Spain‬
‭secretaria@sogug.es‬
‭2.4.‬
‭Coordinating investigator‬
‭Guillermo de Velasco M.D., PhD.‬
‭Hospital Universitario 12 de Octubre‬
‭Av Córdoba s/n‬
‭28041, Madrid, Spain.‬
‭2.5.‬
‭Investigators and study centres‬
‭It‬‭is‬‭expected‬‭the‬‭participation‬‭of‬‭12‬‭Sites‬‭in‬‭Spain.‬‭The‬‭list‬‭of‬‭Sites‬‭and‬‭the‬‭corresponding‬
‭Principal Investigators is provided in a separated document.‬
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‭3.‬
‭INVESTIGATIONAL MEDICINAL PRODUCT (IMP) DESCRIPTION‬
‭3.1.‬
‭Study medication‬
‭Atezolizumab:‬
‭Pharmacotherapeutic‬ ‭group:‬ ‭Antineoplastic‬ ‭agents,‬ ‭monoclonal‬ ‭antibodies.‬ ‭ATC‬ ‭code:‬
‭L01XC‬
‭Presentation:‬‭60‬‭mg/mL‬‭glass‬‭vials‬‭of‬‭20-mL,‬‭nominal‬‭atezolizumab‬‭amount‬‭per‬‭vial,‬‭1200‬
‭mg. Commercial medication labeled for clinical trial.‬
‭Pharmaceutical‬ ‭form:‬ ‭Concentrate‬ ‭for‬ ‭solution‬ ‭for‬ ‭infusion.‬ ‭Clear,‬ ‭colourless‬ ‭to‬ ‭slightly‬
‭yellowish liquid.‬
‭Supply:‬‭Roche‬‭Pharma‬‭will‬‭supply‬‭atezolizumab‬‭to‬‭the‬‭Sponsor‬‭that‬‭will‬‭supply‬‭this‬‭product‬
‭to the sites pharmacy.‬
‭Gemcitabine‬
‭Pharmacotherapeutic‬‭group:‬‭Antineoplastic‬‭agents‬‭-‬‭Alkylating‬‭agents‬‭-‬‭Antimetabolites‬‭-‬
‭Pyrimidine analogues, ATC code: L01BC05‬
‭Presentation:‬‭;‬ ‭Glass‬ ‭vial:‬ ‭*200‬ ‭mg/5.3‬ ‭mL‬ ‭or‬ ‭200‬ ‭mg/2‬ ‭mL;‬ ‭1000‬ ‭mg/10‬ ‭mL‬ ‭or‬ ‭1000‬
‭mg/26.3mL;‬ ‭1500‬ ‭mg/15‬ ‭mL‬ ‭and‬ ‭*2000‬ ‭mg/52.6‬ ‭mL‬ ‭or‬ ‭2000‬ ‭mg/20‬ ‭mL.‬ ‭Commercial‬
‭medication not-labeled for clinical trial.‬
‭Pharmaceutical‬‭form:‬ ‭*‬‭Concentrate‬ ‭for‬ ‭solution‬ ‭for‬ ‭infusion‬ ‭according‬ ‭to‬ ‭different‬
‭commercial presentations authorized in Spain.‬
‭Supply:‬‭By participating sites under standard treatment‬‭criteria‬
‭Cisplatin‬
‭Pharmacotherapeutic‬‭group:‬‭Antineoplastic‬‭agents‬‭-‬‭Other‬‭antineoplastic‬‭agents,‬‭ATC‬‭code:‬
‭L01XA01‬
‭Presentation:‬‭1‬‭mg/mL‬‭glass‬‭vials‬‭of‬‭10-mL,‬‭50-mL‬‭and‬‭100-mL.‬‭Commercial‬‭medication‬
‭not-labeled for clinical trial.‬
‭Pharmaceutical form:‬‭Concentrate for solution for‬‭infusion.‬
‭Supply:‬‭By participating sites under standard treatment‬‭criteria.‬
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‭4.‬
‭RATIONALE AND OBJECTIVES‬
‭4.1.‬
‭Rationale‬
‭4.1.1.‬ ‭Current state of the art‬
‭Cisplatin-based‬‭chemotherapy‬‭(70 mg/m‬‭2‬‭)‬‭has‬‭been‬‭the‬‭standard‬‭of‬‭care‬‭for‬‭first-line‬‭treatment‬
‭for‬‭surgically‬‭unresectable‬‭and‬‭metastatic‬‭patients‬‭fit‬‭enough‬‭to‬‭tolerate‬‭cisplatin‬‭for‬‭more‬‭than‬
‭30‬ ‭years‬ ‭(‬‭Saxman‬ ‭SB,‬ ‭et‬ ‭al.‬ ‭1997;‬ ‭Von‬ ‭der‬ ‭Maase,‬ ‭et‬ ‭al.‬ ‭2000;‬ ‭Bellmunt‬ ‭J,‬‭et‬‭al.‬‭2016‬‭).‬
‭However,‬‭a‬‭standard‬‭dose‬‭schedule‬‭is‬‭not‬‭feasible‬‭for‬‭a‬‭significant‬‭number‬‭of‬‭patients‬‭(about‬
‭50%).‬‭Age-related‬‭physiological‬‭changes‬‭and‬‭comorbidities‬‭are‬‭common‬‭in‬‭the‬‭uro-oncology‬
‭field‬ ‭and,‬ ‭as‬ ‭expected,‬ ‭affect‬ ‭treatment‬ ‭choices‬ ‭and‬ ‭outcomes.‬‭Renal‬‭function‬‭impairment,‬
‭cardiovascular‬ ‭disease,‬ ‭neuropathy,‬ ‭hearing‬ ‭loss‬ ‭are‬ ‭commonly‬ ‭reported‬ ‭in‬ ‭patients‬ ‭with‬
‭bladder‬‭cancer‬‭(‬‭Bellmunt‬‭J,‬‭et‬‭al.‬‭2016‬‭;‬‭Katz‬‭H,‬‭et‬‭al.‬‭2017‬‭);‬‭but‬‭its‬‭toxicity‬‭(‬‭van‬‭Leenders‬
‭GJLH, 2019‬‭).‬
‭According‬‭to‬‭the‬‭most‬‭recent‬‭update‬‭on‬‭cumulative‬‭evidence‬‭and‬‭as‬‭summarized‬‭in‬‭the‬‭most‬
‭recent‬‭ESMO‬‭Bladder‬‭Cancer‬‭Treatment‬‭Recommendations‬‭published‬‭on‬‭16‬‭December‬‭2019,‬
‭a‬‭number‬‭of‬‭cisplatin-containing‬‭regimens‬‭are‬‭acceptable‬‭although‬‭gemcitabine‬‭and‬‭cisplatin‬
‭[I,‬‭A]‬‭is‬‭the‬‭most‬‭widely‬ ‭accepted‬‭(‬‭Von‬‭der‬‭Maase,‬‭et‬‭al.‬‭2000‬‭).‬ ‭Dose-dense‬‭methotrexate,‬
‭vinblastine,‬ ‭doxorubicin‬ ‭and‬ ‭cisplatin‬ ‭(MVAC)‬ ‭[I,‬ ‭B],‬ ‭MVAC‬ ‭with‬ ‭granulocyte‬
‭colony-stimulating‬‭factor‬‭(G-CSF)‬‭[I,‬‭B],‬‭and‬‭gemcitabine,‬‭cisplatin‬‭and‬‭paclitaxel‬‭[I,‬‭C]‬‭are‬
‭alternatives‬‭which‬‭have‬‭established‬‭themselves‬‭as‬‭options‬‭over‬‭time‬‭(‬‭Loehrer‬‭PJ,‬‭et‬‭al.‬‭1992;‬
‭Sternberg‬ ‭CN,‬‭et‬‭al‬‭2006;‬‭Bellmunt‬‭J,‬‭et‬‭al.‬‭2012;‬‭Grande‬‭E,‬‭et‬‭al.‬‭2019‬‭).‬‭Although‬‭these‬
‭specific‬‭regimens‬‭may‬‭lack‬‭proven‬‭advantage‬‭or‬‭non-inferiority‬‭compared‬‭with‬‭gemcitabine‬
‭and cisplatin, they can be considered as options in selected patients.‬
‭4.1.2.‬ ‭Split-Dose Cisplatin‬
‭For‬‭those‬‭patients‬‭with‬‭mUC‬‭cisplatin-ineligible‬‭or‬‭who‬‭have‬‭progressed‬‭on‬‭a‬‭platinum-based‬
‭regimen‬‭treatment‬‭options‬‭are‬‭limited‬‭(‬‭Koshkin‬‭VS,‬‭et‬‭al.‬‭2018‬‭)‬‭and‬‭are‬‭usually‬‭palliated‬‭with‬
‭carboplatin-based‬ ‭regimen,‬ ‭single-agent‬‭taxane‬‭or‬‭gemcitabine,‬‭or‬‭split-dose‬‭cisplatin-based‬
‭regimens‬‭may‬‭be‬‭employed.‬‭In‬‭fact,‬‭some‬‭studies‬‭have‬‭presented‬‭data‬‭on‬‭up‬‭to‬‭50%‬‭of‬‭patients‬
‭eligible‬‭for‬‭cisplatin‬‭might‬‭be‬‭treated‬‭with‬‭carboplatin-based‬‭chemotherapy‬‭based‬‭on‬‭physician‬
‭criteria (ie. IMvigor 130;‬‭Grande E, et al. 2019‬‭).‬
‭The‬ ‭difficult-to-treat‬ ‭concept‬ ‭of‬ ‭this‬ ‭disease‬ ‭entails‬ ‭the‬ ‭undoubtedly‬ ‭high‬ ‭age‬ ‭of‬ ‭most‬ ‭of‬
‭around 80% of patients with UC (‬‭Gore JL, et al. 2010‬‭).‬
‭Administration‬‭of‬‭cisplatin‬‭35 mg/m2‬‭on‬‭day‬‭1 + 8‬‭or‬‭1 + 2‬‭(i.e.,‬‭split‬‭schedule)‬‭is‬‭a‬‭commonly‬
‭used‬ ‭alternative.‬ ‭Several‬ ‭studies‬‭have‬‭reported‬‭that‬‭split‬‭dose‬‭GC‬‭has‬‭comparable‬‭response‬
‭rates‬‭in‬‭metastatic‬‭disease‬‭to‬‭other‬‭platinum‬‭containing‬‭regimens‬‭(‬‭Morales-Barrera‬‭R,‬‭et‬‭al.‬
‭2012‬‭),‬ ‭but‬ ‭has‬ ‭a‬ ‭favourable‬ ‭toxicity‬‭profile‬‭and‬‭considerably‬‭less‬‭time‬‭burden‬‭on‬‭day‬‭care‬
‭facilities‬ ‭(‬‭Sellers‬‭LE,‬‭et‬‭al.‬‭2016‬‭).‬‭These‬‭led‬‭us‬‭to‬‭consider‬‭that‬‭split‬‭dose‬‭GC‬‭should‬‭be‬‭a‬
‭feasible alternative to the longer more toxic regimens, particularly in metastatic disease.‬
‭4.1.3.‬ ‭PD-L1 and the role of atezolizumab in mUC‬
‭Expression‬‭of‬‭programmed‬‭death‬‭ligand-1‬‭(PD-L1)‬‭is‬‭prevalent‬‭among‬‭many‬‭human‬‭tumors‬
‭(‬‭Dong‬‭et‬‭al.‬‭2002‬‭),‬‭and‬‭its‬‭overexpression‬‭is‬‭associated‬‭with‬‭poor‬‭prognosis‬‭for‬‭patients‬‭with‬
‭certain‬‭cancers‬‭(‬‭Thompson‬‭et‬‭al.‬‭2006;‬‭Hamanishi‬‭et‬‭al.‬‭2007;‬‭Okazaki‬‭T‬‭and‬‭Honjo‬‭T,‬‭2007;‬
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‭Hino‬ ‭et‬ ‭al.‬ ‭2010,‬ ‭Mu‬ ‭et‬ ‭al.‬ ‭2011‬‭).‬ ‭Therefore,‬ ‭interruption‬ ‭of‬ ‭the‬ ‭PD-L1/PD‬ ‭1‬ ‭pathway‬
‭represents an attractive strategy to reinvigorate tumor-specific T cell immunity.‬
‭Since‬ ‭May‬ ‭2016,‬ ‭five‬ ‭different‬ ‭agents‬ ‭targeting‬ ‭the‬ ‭PD-1/PD-L1‬ ‭pathway‬ ‭(atezolizumab,‬
‭pembrolizumab,‬ ‭nivolumab,‬ ‭avelumab,‬ ‭durvalumab)‬ ‭have‬ ‭received‬ ‭FDA‬ ‭approval‬ ‭for‬ ‭the‬
‭treatment‬‭of‬‭aUC‬‭in‬‭the‬‭platinum-refractory‬‭setting,‬‭while‬‭pembrolizumab‬‭and‬‭atezolizumab‬
‭are‬‭FDA-approved‬‭for‬‭cisplatin-ineligible‬‭patients‬‭in‬‭the‬‭first-line‬‭setting‬‭(‬‭Koshkin‬‭VS‬‭2018‬‭).‬
‭For‬ ‭platinum‬ ‭or‬ ‭chemotherapy-ineligible‬ ‭patients‬‭with‬‭mUC,‬‭immune‬‭checkpoint‬‭inhibitors‬
‭(ICI)‬‭such‬‭as‬‭inhibitors‬‭of‬‭programmed‬‭death-1/programmed‬‭death-ligand‬‭1‬‭(PD-1/PD-L1)‬‭are‬
‭approved‬ ‭regardless‬ ‭of‬ ‭PD-L1‬ ‭expression,‬ ‭including‬ ‭pembrolizumab‬ ‭and‬ ‭atezolizumab‬
‭(‬‭Einstein and Sonpavde, 2019‬‭).‬
‭Atezolizumab‬‭is‬‭a‬‭humanized‬‭immunoglobulin‬‭(IgG1)‬‭monoclonal‬‭antibody‬‭that‬‭is‬‭produced‬
‭in‬ ‭Chinese‬ ‭hamster‬ ‭ovary‬ ‭(CHO)‬ ‭cells.‬ ‭Atezolizumab‬ ‭targets‬ ‭programmed‬ ‭death-ligand‬ ‭1‬
‭(PD-L1)‬‭on‬‭tumor-infiltrating‬‭immune‬‭cells‬‭(ICs)‬‭or‬‭tumor‬‭cells‬‭(TCs)‬‭and‬‭prevents‬‭interaction‬
‭with‬‭the‬‭programmed‬‭death-1‬‭(PD-1)‬‭receptor‬‭and‬‭B7.1‬‭(CD80),‬‭both‬‭of‬‭which‬‭function‬‭as‬
‭inhibitory‬‭receptors‬‭expressed‬‭on‬‭T‬‭cells‬‭and‬‭other‬‭immune‬‭cells.‬‭The‬‭PD-1‬‭and‬‭PD-L1:B7.1‬
‭interactions‬ ‭may‬ ‭enhance‬ ‭the‬ ‭magnitude‬ ‭and‬ ‭quality‬ ‭of‬ ‭the‬ ‭tumor-specific‬ ‭T‬‭cell‬‭response‬
‭through‬ ‭increased‬ ‭T‬ ‭cell‬ ‭priming,‬ ‭expansion,‬ ‭and/or‬ ‭effector‬ ‭function.‬ ‭Atezolizumab‬ ‭was‬
‭engineered‬‭to‬‭eliminate‬‭Fc-effector‬‭function‬‭via‬‭a‬‭single‬‭amino‬‭acid‬‭substitution‬‭at‬‭position‬
‭298‬‭on‬‭the‬‭heavy‬‭chain,‬‭which‬‭results‬‭in‬‭a‬‭non-glycosylated‬‭antibody‬‭that‬‭has‬‭minimal‬‭binding‬
‭to‬‭Fc‬‭receptors‬‭and,‬‭consequently,‬‭eliminates‬‭detectable‬‭Fc‬‭effector‬‭function.‬‭By‬‭eliminating‬
‭Fc-effector‬ ‭function‬ ‭and‬ ‭antibody-dependent‬ ‭cell-mediated‬ ‭cytotoxicity,‬ ‭antibody-mediated‬
‭clearance of activated effector T cells is also eliminated.‬
‭Atezolizumab‬‭has‬‭demonstrated‬‭efficacy‬‭and‬‭a‬‭tolerable‬‭safety‬‭profile‬‭in‬‭a‬‭range‬‭of‬‭cancers,‬
‭including‬ ‭locally‬ ‭advanced‬ ‭or‬ ‭mUC‬ ‭(‬‭Herbst‬ ‭RS,‬ ‭et‬ ‭al.‬ ‭2014;‬ ‭Powles‬ ‭T,‬ ‭et‬ ‭al.‬ ‭2014,‬
‭Fehrenbacher‬ ‭L‬ ‭et‬ ‭al.‬ ‭2016;‬ ‭McDermott‬ ‭DF,‬ ‭et‬ ‭al.‬ ‭2016;‬ ‭Rosenberg‬ ‭JE,‬ ‭et‬ ‭al.‬ ‭2016‬‭).‬
‭Cumulative‬ ‭data‬ ‭on‬ ‭efficacy‬ ‭at‬ ‭the‬ ‭time‬ ‭of‬ ‭this‬ ‭study‬ ‭design‬ ‭(March‬ ‭2020)‬ ‭suggest‬ ‭that‬
‭atezolizumab‬‭as‬‭a‬‭single-agent‬‭for‬‭first-line‬‭in‬‭patients‬‭with‬‭mUC‬‭entails‬‭clinical‬‭benefit‬‭in‬
‭terms of objective responses, durable responses, and OS.‬
‭Clinical‬‭data‬‭from‬‭the‬‭first-line‬‭cisplatin-ineligible‬‭IMvigor210‬‭cohort—the‬‭first‬‭report‬‭of‬‭an‬
‭anti–PD-L1/PD-1‬ ‭checkpoint‬ ‭inhibitor‬ ‭in‬ ‭this‬ ‭setting—‬ ‭atezolizumab‬ ‭conferred‬ ‭significant‬
‭clinical‬‭benefit‬‭(‬‭Rosenberg‬‭JE,‬‭et‬‭al.‬‭2016‬‭),‬‭leading‬‭to‬‭accelerated‬‭regulatory‬‭approval,‬‭and‬
‭several‬ ‭biomarkers‬ ‭associated‬ ‭with‬ ‭response‬ ‭were‬ ‭identified.‬ ‭Furthermore,‬ ‭encouraging‬
‭durable‬ ‭response‬ ‭rates,‬ ‭survival‬ ‭and‬ ‭tolerability‬ ‭(‬‭Balar‬ ‭AV,‬ ‭et‬ ‭al.‬ ‭2017‬‭)‬ ‭have‬ ‭been‬ ‭also‬
‭reported.‬
‭Interim‬‭results‬‭(2018)‬‭from‬‭the‬‭ongoing‬‭IMvigor‬‭130‬‭trial‬‭(atezolizumab‬‭vs‬‭atezolizumab‬‭plus‬
‭platinum-based‬‭chemotherapy‬‭in‬‭locally‬‭advanced/mUC‬‭not‬‭previously‬‭treated)‬‭has‬‭shown‬‭a‬
‭reduction‬ ‭on‬ ‭survival‬‭for‬‭those‬‭patients‬‭treated‬‭with‬‭atezolizumab‬‭alone‬‭when‬‭compared‬‭to‬
‭those‬‭who‬‭received‬‭platinum-based‬‭chemotherapy‬‭(carbo-‬‭or‬‭cis-‬‭at‬‭physician‬‭discretion),‬‭not‬
‭previously‬‭treated‬‭and‬‭with‬‭tumors‬‭showing‬‭a‬‭low-PD-L1‬‭expression‬‭(<5%‬‭of‬‭immune‬‭cells‬
‭with positive staining) (‬‭EMA Tecentriq Assessment‬‭Report‬‭).‬
‭4.2.‬
‭Hypothesis‬
‭The‬ ‭results‬ ‭of‬ ‭trials‬ ‭combining‬ ‭checkpoint‬ ‭inhibitors‬‭or‬‭platinum-based‬‭chemotherapy‬‭plus‬
‭PD-1/PD-L1‬ ‭inhibitors‬ ‭are‬ ‭eagerly‬ ‭awaited.‬ ‭The‬ ‭combination‬ ‭of‬ ‭split‬ ‭cisplatin‬ ‭with‬
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‭atezolizumab‬‭is‬‭a‬‭feasible‬‭treatment‬‭that‬‭may‬‭provide‬‭better‬‭outcomes‬‭than‬‭carboplatin/based‬
‭combinations.‬
‭In‬‭the‬‭IMvigor130,‬‭52%‬‭of‬‭patients‬‭considered‬‭cisplatin‬‭eligible‬‭at‬‭the‬‭entry‬‭of‬‭the‬‭study‬‭were‬
‭treated‬‭with‬‭carboplatin.‬‭Subanalysis‬‭presented‬‭at‬‭ESMO‬‭2019‬‭(‬‭Grande‬‭E,‬‭et‬‭al.‬‭2019‬‭)‬‭has‬
‭also‬ ‭shown‬ ‭a‬ ‭longer‬‭median‬‭OS‬‭are‬‭achieved‬‭with‬‭cisplatin-based‬‭chemotherapy‬‭combined‬
‭with‬‭atezolizumab‬‭(21.7‬‭months)‬‭when‬‭compared‬‭to‬‭the‬‭carboplatin-based‬‭chemotherapy‬‭plus‬
‭atezolizumab‬ ‭(14.2‬ ‭months),‬ ‭with‬ ‭similar‬ ‭findings‬ ‭when‬ ‭it‬ ‭comes‬‭to‬‭PFS‬‭8.8‬‭months‬‭with‬
‭cisplatin/gemcitabine/atezolizumab vs 7.1 months carboplatin/gemcitabine/atezolizumab.‬
‭A‬ ‭reasonable‬ ‭strategy‬ ‭may‬ ‭be‬ ‭the‬ ‭use‬ ‭of‬ ‭split‬ ‭cisplatin‬ ‭with‬ ‭atezolizumab‬ ‭to‬ ‭increase‬ ‭the‬
‭number of patients receiving cisplatin.‬
‭4.3.‬
‭Rationale for dose selection‬
‭As‬‭per‬‭Atezolizumab‬‭Investigator’s‬‭Brochure‬‭(IB)‬‭at‬‭the‬‭time‬‭of‬‭this‬‭study‬‭design‬‭(‬‭version‬‭15,‬
‭July‬‭2019‬‭),‬‭the‬‭standard‬‭fixed‬‭dose‬‭of‬‭1200‬‭mg,‬‭equivalent‬‭to‬‭15mg/kg‬‭in‬‭a‬‭typical‬‭patient.‬‭No‬
‭dose-limiting‬ ‭toxicities‬ ‭were‬ ‭observed‬ ‭at‬ ‭the‬ ‭20‬ ‭mg/kg‬ ‭dose‬ ‭level‬ ‭and‬ ‭the‬ ‭incidence‬ ‭and‬
‭intensity‬‭of‬‭AEs‬‭reported‬‭have‬‭not‬‭been‬‭shown‬‭to‬‭be‬‭dependent‬‭on‬‭dose.‬‭A‬‭maximum‬‭tolerated‬
‭dose‬‭has‬‭not‬‭been‬‭established.‬‭Atezolizumab‬‭is‬‭supplied‬‭in‬‭vials‬‭containing‬‭the‬‭fixed‬‭1200‬‭mg‬
‭dose‬‭of‬‭drug‬‭substance,‬‭which‬‭minimizes‬‭the‬‭chance‬‭of‬‭overdose.‬‭Because‬‭the‬‭dose‬‭per‬‭patient‬
‭is‬‭not‬‭based‬‭on‬‭weight‬‭or‬‭body‬‭surface‬‭area,‬‭and‬‭no‬‭dose‬‭calculation‬‭is‬‭required,‬‭the‬‭risk‬‭of‬
‭overdose‬ ‭due‬ ‭to‬ ‭medication‬ ‭errors‬ ‭is‬ ‭minimal.‬ ‭The‬ ‭data‬ ‭available‬ ‭to‬ ‭date‬ ‭suggest‬‭that‬‭the‬
‭potential for harm from overdose is very low.‬
‭Weekly‬ ‭gemcitabine‬ ‭with‬ ‭GC‬ ‭every‬ ‭3-4‬ ‭weeks‬ ‭is‬ ‭considered‬ ‭conventional‬ ‭first-line‬
‭chemotherapy‬‭for‬‭aUC.‬‭Weekly‬‭split-dose‬‭cisplatin‬‭with‬‭wGC‬‭might‬‭be‬‭less‬‭toxic‬‭and‬‭have‬
‭similar‬ ‭activity.‬ ‭Considering‬ ‭the‬ ‭probable‬ ‭lower‬ ‭nephrotoxicity‬ ‭of‬ ‭fractionated‬ ‭cisplatin,‬
‭prospective‬ ‭evaluation‬ ‭of‬ ‭wGC‬ ‭might‬ ‭be‬ ‭warranted‬‭across‬‭cisplatin-eligible‬‭and‬‭-ineligible‬
‭patients‬‭to‬‭develop‬‭a‬‭single‬‭chemotherapy‬‭template‬‭for‬‭the‬‭development‬‭of‬‭combinations‬‭with‬
‭biological agents in a broad population of patients (‬‭Maughan BL, et al. 2013‬‭).‬
‭In‬‭conclusion,‬‭the‬‭proposed‬‭scientific‬‭rationale‬‭and‬‭the‬‭preliminary‬‭benefit-risk‬‭profile‬‭of‬‭the‬
‭study‬ ‭treatments‬ ‭observed‬ ‭in‬ ‭previous‬ ‭trials‬ ‭support‬ ‭the‬ ‭further‬ ‭investigation‬ ‭of‬ ‭the‬
‭combination in the patient population and dosification regimen chosen for this study.‬
‭4.4.‬
‭Study Objectives‬
‭4.4.1. Primary Objectives‬
‭To‬‭evaluate‬‭the‬‭preliminary‬‭efficacy‬‭of‬‭atezolizumab‬‭plus‬‭split-dose‬‭gemcitabine‬‭and‬‭cisplatin‬
‭(GC)‬ ‭for‬ ‭the‬ ‭first-line‬ ‭setting,‬ ‭in‬ ‭patients‬ ‭with‬ ‭histologically‬ ‭confirmed‬ ‭advanced‬ ‭(locally‬
‭advanced‬‭and‬‭metastatic)‬‭urothelial‬‭cancer‬‭in‬‭terms‬‭of‬‭overall‬‭response‬‭rate‬‭(ORR)‬‭assessed‬‭by‬
‭the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.‬
‭4.4.2. Secondary Objectives‬
‭Efficacy:‬
‭●‬ ‭To‬ ‭evaluate‬ ‭the‬ ‭duration‬ ‭of‬ ‭response‬ ‭(DoR)‬ ‭associated‬ ‭with‬ ‭the‬ ‭study‬ ‭treatment,‬
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‭understood‬‭as‬‭the‬‭time‬‭from‬‭first‬‭confirmed‬‭response‬‭(CR‬‭or‬‭PR)‬‭to‬‭the‬‭date‬‭of‬‭the‬
‭documented‬‭progressive‬‭disease‬‭as‬‭determined‬‭using‬‭RECIST‬‭1.1‬‭criteria‬‭or‬‭death‬‭due‬
‭to any cause, whichever occurs first.‬
‭●‬ ‭To‬ ‭determine‬ ‭the‬ ‭overall‬ ‭survival‬ ‭(OS)‬ ‭of‬ ‭patients‬ ‭with‬ ‭locally-advanced‬ ‭or‬ ‭mUC‬
‭treated‬‭with‬‭the‬‭intended‬‭treatment‬‭regimen,‬‭understood‬‭as‬‭the‬‭time‬‭from‬‭first‬‭dosing‬
‭date‬‭to‬‭the‬‭date‬‭of‬‭death.‬‭A‬‭subject‬‭who‬‭has‬‭not‬‭died‬‭will‬‭be‬‭censored‬‭at‬‭the‬‭last‬‭known‬
‭date alive.‬
‭●‬ ‭To‬‭evaluate‬‭the‬‭time‬‭to‬‭response‬‭(TtR)‬‭associated‬‭with‬‭the‬‭study‬‭treatment,‬‭understood‬
‭as‬‭the‬‭time‬‭from‬‭the‬‭first‬‭dose‬‭of‬‭the‬‭study‬‭treatment‬‭to‬‭the‬‭and‬‭confirmed‬‭response‬
‭(CR or PR) based on RECIST 1.1 criteria.‬
‭●‬ ‭To evaluate the‬‭clinical benefit rate (CBR)‬‭, defined‬‭as the percentage of patients who‬
‭have achieved complete response, partial response and stable disease. Stable disease‬
‭should be maintained for at least 6 months to be considered as a CBR event.‬
‭●‬ ‭To‬‭determine‬‭the‬‭progression-free‬‭survival‬‭(PFS)‬‭of‬‭patients‬‭with‬‭locally-advanced‬‭or‬
‭mUC‬ ‭treated‬ ‭with‬ ‭the‬ ‭intended‬ ‭treatment‬ ‭regimen,‬ ‭defined‬ ‭as‬ ‭the‬ ‭time‬ ‭from‬ ‭first‬
‭dosing‬‭date‬‭until‬‭disease‬‭progression‬‭or‬‭death‬‭from‬‭any‬‭cause.‬‭Patients‬‭who‬‭have‬‭not‬
‭progressed and start a new line of treatment will be censored.‬
‭Safety:‬
‭●‬ ‭To‬ ‭evaluate‬ ‭safety‬ ‭of‬ ‭the‬ ‭intended‬ ‭treatment‬ ‭regimen‬ ‭based‬ ‭on‬ ‭the‬ ‭frequency‬ ‭and‬
‭severity of adverse events assessed by NCI CTCAE v5.0.‬
‭4.‬‭4‬‭.3.‬ ‭Exploratory‬‭objectives‬
‭●‬ ‭To‬ ‭explore‬ ‭potential‬ ‭correlation‬ ‭of‬ ‭efficacy‬ ‭with‬ ‭relevant‬ ‭potential‬ ‭prognostic‬
‭factors/stratification factors‬
‭●‬ ‭To‬‭evaluate‬‭the‬‭relationship‬‭between‬‭the‬‭expression‬‭of‬‭PD-L1‬‭and‬‭microbiome‬‭with‬
‭ORR and PFS during experimental treatment.‬
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‭5.‬ ‭STUDY DESIGN‬
‭5.1.‬
‭Study design‬
‭The‬ ‭AUREA‬ ‭study‬ ‭is‬ ‭a‬ ‭multicenter,‬ ‭open‬ ‭labelled,‬‭single‬‭arm,‬‭Phase‬‭II‬‭clinical‬‭trial‬‭of‬‭of‬
‭atezolizumab‬‭in‬‭combination‬‭of‬‭split-dose‬‭cisplatin‬‭plus‬‭gemcitabine‬‭in‬‭patients‬‭with‬‭locally‬
‭advanced‬‭or‬‭metastatic‬‭urothelial‬‭carcinoma‬‭(additional‬‭details‬‭on‬‭the‬‭eligibility‬‭criteria‬‭of‬‭the‬
‭study are found in section 6 of this protocol).‬
‭The‬‭design‬‭includes‬‭screening‬‭phase,‬‭combined‬‭treatment‬‭initial‬‭phase,‬‭monotherapy‬‭treatment‬
‭phase,‬ ‭follow-up‬ ‭phase‬ ‭and‬ ‭translational‬ ‭research‬ ‭with‬ ‭biopsies,‬ ‭blood‬ ‭samples‬ ‭and‬ ‭faecal‬
‭samples.‬
‭The‬ ‭dose‬ ‭scheme‬ ‭includes‬ ‭the‬ ‭initial‬ ‭dose‬ ‭of‬ ‭atezolizumab‬ ‭(1200‬ ‭mg)‬ ‭intravenously‬
‭administered‬ ‭every‬ ‭21‬ ‭days‬ ‭(one‬ ‭cycle)‬‭up‬‭to‬‭disease‬‭progression,‬‭unacceptable‬‭toxicity‬‭or‬
‭absence‬ ‭of‬ ‭clinical‬ ‭benefit.‬ ‭Dose‬ ‭adjustment‬ ‭or‬ ‭dose‬ ‭reductions‬ ‭of‬ ‭atezolizumab‬ ‭are‬ ‭not‬
‭expected.‬‭Additional‬‭information‬‭on‬‭the‬‭treatment,‬‭modifications,‬‭and‬‭dose‬‭delays‬‭is‬‭available‬
‭in‬ ‭section‬ ‭7‬ ‭of‬ ‭this‬ ‭protocol.‬ ‭AUREA‬ ‭is‬ ‭an‬ ‭Investigator‬ ‭Initiated‬ ‭Study,‬ ‭the‬ ‭Sponsor‬ ‭will‬
‭supply‬‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬‭months‬‭of‬‭treatment‬‭for‬‭each‬‭patient.‬‭For‬‭those‬‭patients‬‭in‬
‭which‬‭the‬‭PI‬‭considers‬‭that‬‭the‬‭best‬‭option‬‭for‬‭the‬‭patient‬‭is‬‭continuing‬‭atezolizumab‬‭for‬‭more‬
‭than‬ ‭24‬ ‭months,‬ ‭available‬ ‭commercial‬ ‭Site‬ ‭supplies‬ ‭should‬ ‭be‬ ‭used,‬ ‭after‬ ‭managed‬ ‭local‬
‭administrative regulation.‬
‭Study‬ ‭treatment‬ ‭will‬ ‭begin‬ ‭as‬ ‭soon‬ ‭as‬ ‭possible‬ ‭after‬ ‭signing‬ ‭the‬ ‭informed‬‭consent‬‭(as‬‭per‬
‭section 5.2‬‭of this protocol) and inclusion will be‬‭completed as per‬‭section 5.3‬‭of this protocol.‬
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‭Figure 1. Study design‬
‭5.2.‬
‭Patient selection‬
‭Once‬‭all‬‭regulatory‬‭and‬‭sponsor‬‭requirements‬‭are‬‭completed‬‭confirming‬‭that‬‭the‬‭study‬‭is‬‭fully‬
‭active‬‭in‬‭the‬‭corresponding‬‭site,‬‭informed‬‭consents‬‭can‬‭be‬‭offered‬‭to‬‭potential‬‭patients,‬‭and‬
‭patient selection can start in this site.‬
‭5.3.‬
‭Screening period and screening failure‬
‭Informed‬ ‭consent‬ ‭will‬ ‭be‬ ‭obtained‬ ‭prior‬ ‭to‬ ‭the‬ ‭start‬ ‭of‬ ‭the‬ ‭specified‬ ‭screening‬ ‭window.‬
‭Procedures‬‭conducted‬‭as‬‭part‬‭of‬‭the‬‭subject’s‬‭routine‬‭clinical‬‭management‬‭(e.g..,‬‭blood‬‭count‬
‭determinations‬‭and‬‭imaging‬‭studies)‬‭prior‬‭to‬‭signing‬‭of‬‭ICF‬‭may‬‭be‬‭used‬‭for‬‭screening‬‭or‬‭for‬
‭defining baseline data, provided these procedures are conducted as specified in the protocol.‬
‭Other‬‭procedures‬‭(such‬‭as‬‭the‬‭faecal‬‭sample‬‭collection)‬‭must‬‭be‬‭developed‬‭once‬‭the‬‭patient‬‭has‬
‭provided the signed consent for participation.‬
‭Once‬ ‭ICFs‬ ‭are‬ ‭signed,‬ ‭a‬ ‭trial‬ ‭screening‬ ‭number‬ ‭will‬ ‭be‬ ‭assigned‬ ‭to‬ ‭each‬ ‭patient‬ ‭after‬
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‭registering‬ ‭at‬ ‭Electronic‬‭Data‬‭Capture‬‭(EDC)‬‭platform.‬‭Each‬‭site‬‭will‬‭receive‬‭access‬‭to‬‭the‬
‭EDC‬‭platform‬‭to‬‭register‬‭each‬‭screened‬‭case‬‭because‬‭as‬‭per‬‭GCP‬‭guidelines,‬‭it‬‭is‬‭mandatory‬‭to‬
‭register every patient who signs a consent form.‬
‭Furthermore,‬ ‭within‬ ‭the‬ ‭Investigator‬ ‭Site‬ ‭File‬ ‭(ISF),‬ ‭a‬ ‭Patient‬ ‭Identification‬ ‭List‬ ‭will‬ ‭be‬
‭included‬‭in‬‭order‬‭to‬‭identify‬‭patients‬‭according‬‭to‬‭local‬‭normal‬‭practice.‬‭This‬‭document‬‭will‬
‭allow‬ ‭for‬ ‭immediate‬ ‭and‬ ‭unequivocal‬ ‭identification‬ ‭of‬‭patients‬‭participating‬‭in‬‭this‬‭clinical‬
‭trial.‬
‭This‬‭document‬‭will‬‭always‬‭be‬‭stored‬‭under‬‭Investigator‬‭staff‬‭custody‬‭at‬‭the‬‭site.‬‭The‬‭screening‬
‭number‬ ‭will‬ ‭identify‬ ‭patients‬ ‭throughout‬ ‭the‬ ‭screening‬ ‭period‬ ‭while‬ ‭procedures‬ ‭needed‬ ‭to‬
‭confirm‬‭the‬‭subjects’‬‭suitability‬‭for‬‭the‬‭trial‬‭protocol,‬‭such‬‭as‬‭clinical‬‭laboratory‬‭tests,‬‭imaging,‬
‭and others are performed.‬
‭Screening‬‭determinations‬‭should‬‭be‬‭performed‬‭as‬‭per‬‭indications‬‭specified‬‭in‬‭Table‬‭4‬‭include‬
‭ICF‬‭signature,‬‭eligibility‬‭assessments,‬‭tumour‬‭characteristics,‬‭ECG,‬‭clinical‬‭evaluation‬‭(AE,‬
‭PE,‬‭ECOG,‬‭VS,‬‭BMI,‬‭and‬‭symptom‬‭control),‬‭laboratory‬‭determinations‬‭(FBE,‬‭Biochemistry,‬
‭electrolytes,‬ ‭liver‬ ‭panel‬ ‭TF),‬ ‭Pancreatic‬ ‭enzymes,‬ ‭serology,‬ ‭urinalysis,‬ ‭pregnancy‬ ‭test,‬
‭concomitant‬ ‭medication,‬ ‭biological‬ ‭samples‬ ‭(tumour‬ ‭sample,‬‭biomarkers),‬‭CT‬‭Scan‬‭/‬‭MRI.‬
‭Availability‬ ‭of‬ ‭archival‬ ‭tumor‬ ‭blocks‬ ‭should‬ ‭be‬ ‭verified.‬ ‭Additional‬ ‭information‬ ‭about‬
‭screening procedures can be found in‬‭Section 8.4‬‭of‬‭this protocol.‬
‭5.4.‬
‭Patient registration/enrollment‬
‭After‬ ‭confirming‬ ‭that‬ ‭a‬ ‭patient‬ ‭fulfils‬ ‭all‬ ‭eligibility‬ ‭criteria‬ ‭of‬ ‭the‬ ‭study‬ ‭(‬‭Section‬ ‭6‬‭,‬‭study‬
‭population‬‭),‬ ‭site‬ ‭staff‬ ‭will‬ ‭initiate‬ ‭the‬ ‭electronic‬ ‭case‬ ‭report‬ ‭form‬ ‭(eCRF)‬ ‭registration‬
‭procedure.‬ ‭Once‬ ‭registration‬ ‭has‬ ‭been‬ ‭completed,‬ ‭the‬ ‭site‬ ‭staff‬ ‭will‬ ‭receive‬‭the‬‭“Inclusion‬
‭confirmation‬‭communication”,‬‭and‬‭study‬‭treatment‬‭can‬‭be‬‭initiated‬‭as‬‭per‬‭Section‬‭7‬‭(treatment‬
‭description‬‭).‬
‭5.5.‬
‭Treatment description, doses and schedules‬
‭During‬ ‭treatment,‬ ‭patients‬ ‭should‬ ‭be‬ ‭visited‬ ‭at‬ ‭baseline‬ ‭for‬ ‭administration‬ ‭of‬ ‭the‬ ‭study‬
‭treatment‬‭(Day‬‭1‬‭of‬‭each‬‭cycle)‬‭as‬‭follows:‬‭Atezolizumab‬‭1200‬‭mg,‬‭gemcitabine‬‭1000‬‭mg/m‬‭2‬
‭and‬ ‭cisplatin‬ ‭35‬ ‭mg/m‬‭2‬‭.‬ ‭A‬ ‭second‬ ‭visit‬ ‭on‬ ‭day‬ ‭8‬ ‭(D8)‬ ‭should‬ ‭be‬ ‭compiled‬ ‭in‬ ‭order‬ ‭to‬
‭administer the second dose of gemcitabine 1000 mg/m‬‭2‬‭and cisplatin 35 mg/m‬‭2‬‭cisplatin.‬
‭Atezolizumab‬ ‭will‬ ‭be‬ ‭administered‬ ‭first‬ ‭as‬ ‭a‬ ‭IV‬ ‭infusion‬ ‭according‬ ‭to‬ ‭what‬ ‭is‬ ‭detailed‬‭in‬
‭section‬ ‭7.4‬ ‭of‬ ‭this‬ ‭protocol,‬ ‭followed‬ ‭by‬ ‭the‬ ‭cisplatin‬ ‭infusion‬ ‭and‬ ‭then‬ ‭the‬ ‭gemcitabine‬
‭infusion.‬‭The‬‭GC‬‭infusion‬‭will‬‭start‬‭at‬‭least‬‭30‬‭minutes‬‭after‬‭completion‬‭of‬‭the‬‭atezolizumab‬
‭infusion.‬ ‭At‬ ‭the‬ ‭investigator’s‬ ‭discretion,‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭administered‬‭over‬‭a‬‭longer‬
‭infusion time (60 minutes) if the participant developed a prior infusion reaction.‬
‭This‬‭regimen‬‭will‬‭be‬‭repeated‬‭every‬‭three‬‭weeks‬‭(q3w)‬‭for‬‭up‬‭to‬‭6‬‭cycles.‬‭Once‬‭cycle‬‭6‬‭is‬
‭done,‬ ‭Atezolizumab‬ ‭1200‬ ‭mg/m‬‭2‬ ‭will‬‭be‬‭administered‬‭as‬‭monotherapy‬‭every‬‭3‬‭weeks‬‭until‬
‭disease‬ ‭progression,‬ ‭discontinuation‬ ‭due‬ ‭to‬ ‭unacceptable‬‭toxicity,‬‭withdrawal‬‭of‬‭consent‬‭or‬
‭absence‬‭of‬‭clinical‬‭benefit.‬‭AUREA‬‭is‬‭an‬‭Investigator‬‭Initiated‬‭Study,‬‭the‬‭Sponsor‬‭will‬‭supply‬
‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬‭months‬‭of‬‭treatment‬‭for‬‭each‬‭patient.‬‭For‬‭those‬‭patients‬‭in‬‭which‬
‭the‬‭PI‬‭considers‬‭that‬‭the‬‭best‬‭option‬‭for‬‭the‬‭patient‬‭is‬‭continuing‬‭atezolizumab‬‭for‬‭more‬‭than‬‭24‬
‭months,‬‭available‬‭commercial‬‭Site‬‭supplies‬‭should‬‭be‬‭used,‬‭after‬‭managed‬‭local‬‭administrative‬
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‭regulation.‬
‭All‬ ‭chemotherapy‬ ‭agents’‬ ‭preparation,‬ ‭premedication,‬ ‭administration,‬ ‭monitoring,‬ ‭and‬
‭management‬‭of‬‭complications‬‭are‬‭to‬‭follow‬‭local‬‭prescription‬‭guidelines‬‭and‬‭regulations.‬‭The‬
‭dose of chemotherapy may be capped per local standards.‬
‭All‬ ‭participants‬ ‭will‬ ‭be‬ ‭monitored‬ ‭continuously‬ ‭for‬ ‭adverse‬ ‭events‬ ‭(AEs)‬ ‭while‬ ‭on‬ ‭study‬
‭treatment.‬‭Treatment‬‭modifications‬‭(eg,‬‭dose‬‭delay,‬‭reduction,‬‭retreatment,‬‭or‬‭discontinuation)‬
‭will‬‭be‬‭based‬‭on‬‭specific‬‭laboratory‬‭and‬‭adverse‬‭event‬‭criteria,‬‭as‬‭described‬‭in‬‭Section‬‭7.45.2‬
‭and‬‭Section 7.55.3‬‭.‬
‭Table 1. AUREA’s trial treatment schedule‬
‭Drug‬
‭Drug‬
‭Frequency‬
‭Administration‬
‭Treatment period‬
‭Use‬
‭Atezolizumab‬
‭1200 mg‬
‭Q3W‬
‭IV infusion‬
‭Day 1 of each cycle‬
‭Experimental‬
‭Gemcitabine‬
‭1000‬
‭mg/m‬‭2‬‭/day‬
‭Q3W‬
‭IV infusion‬
‭Day 1 and Day 8 of‬
‭each cycle up to 6‬
‭cycles‬
‭Experimental‬
‭Cisplatin‬
‭35 mg/m‬‭2‬‭/day‬
‭Q3W‬
‭IV infusion‬
‭Day 1 and Day 8 of‬
‭each cycle up to 6‬
‭cycles‬
‭Experimental‬
‭5.6.‬
‭Duration of study, recruitment, treatment and follow-up‬
‭●‬ ‭Enrolment/recruitment period: 12 months‬
‭●‬ ‭First patient first visit (FPFV): TBD‬
‭●‬ ‭Last patient last visit (LPLV): FPFV + 24 months‬
‭●‬ ‭Treatment period: Up to 24 months from LPFV‬
‭●‬ ‭Follow-up period: 24 months‬
‭●‬ ‭Planned end of study date: FPFV + up to 36 months‬
‭5.7.‬
‭Determinations during the study‬
‭Determination‬ ‭during‬ ‭the‬ ‭study‬ ‭will‬ ‭be‬ ‭performed‬ ‭as‬ ‭per‬ ‭Table‬ ‭4‬ ‭and‬ ‭Section‬ ‭8.3‬ ‭of‬‭this‬
‭protocol.‬
‭5.7.1.‬ ‭Screening phase‬
‭The‬ ‭baseline‬ ‭assessments‬ ‭and‬ ‭procedures‬ ‭should‬ ‭be‬ ‭performed‬ ‭within‬ ‭28‬ ‭days‬ ‭before‬
‭inclusion, and when applicable, as close as possible to the start of study treatment.‬
‭5.7.2.‬ ‭Treatment phase‬
‭Before‬ ‭each‬ ‭treatment‬ ‭administration‬ ‭chemotherapy/atezolizumab‬‭administration‬‭laboratory,‬
‭medical‬ ‭consulting‬ ‭and‬ ‭other‬ ‭determinations‬ ‭will‬ ‭be‬ ‭performed‬ ‭according‬ ‭to‬ ‭Table‬ ‭4‬ ‭and‬
‭Section 8.5‬‭to ensure that treatment can be safely‬‭administered.‬
‭A‬ ‭CT‬ ‭Scan‬ ‭or‬‭MRI‬‭will‬‭be‬‭performed‬‭at‬‭baseline,‬‭on‬‭week‬‭9,‬‭week‬‭18‬‭and‬‭then‬‭every‬‭12‬
‭weeks‬‭(q12w)‬‭±‬‭1w‬‭until‬‭objective‬‭disease‬‭progression‬‭as‬‭per‬‭PI’s‬‭criteria‬‭or‬‭death‬‭(whichever‬
‭comes‬‭first).‬‭Blood‬‭samples‬‭for‬‭biomarkers‬‭studies‬‭should‬‭be‬‭collected‬‭before‬‭administration‬
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‭of cycles 4 and 7 and at the time of PD (end of treatment if applicable).‬
‭For‬ ‭patients‬ ‭with‬ ‭progression‬ ‭reported‬ ‭as‬ ‭per‬ ‭RECIST‬ ‭criteria‬ ‭at‬ ‭week‬ ‭9,‬ ‭continuity‬ ‭of‬
‭treatment‬‭with‬‭atezolizumab‬‭should‬‭be‬‭evaluated‬‭by‬‭the‬‭PI‬‭of‬‭each‬‭site‬‭as‬‭per‬‭clinical‬‭benefit‬
‭criteria.‬
‭5.7.3.‬ ‭Safety visit (after the end of treatment by any reason)‬
‭Safety‬‭follow-up‬‭visits‬‭will‬‭be‬‭scheduled‬‭up‬‭to‬‭30‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭study‬‭treatment‬
‭(end of treatment).‬
‭5.7.4.‬ ‭Follow up until progression‬
‭After‬‭the‬‭end‬‭of‬‭the‬‭combined‬‭treatment‬‭with‬‭atezolizumab‬‭and‬‭split‬‭dose‬‭of‬‭gemcitabine‬‭and‬
‭cisplatin,‬‭if‬‭the‬‭patient‬‭has‬‭finished‬‭treatment‬‭without‬‭progression‬‭and‬‭does‬‭not‬‭start‬‭a‬‭new‬
‭treatment‬‭line,‬‭will‬‭be‬‭visited‬‭every‬‭12‬‭weeks.‬‭At‬‭the‬‭time‬‭of‬‭progression‬‭blood‬‭samples‬‭should‬
‭be collected for biomarkers studies.‬
‭5.7.5.‬ ‭Follow up after progression‬
‭Overall,‬‭after‬‭progression,‬‭patients‬‭will‬‭continue‬‭the‬‭long-term‬‭follow‬‭up‬‭every‬‭6‬‭months‬‭until‬
‭death‬‭or‬‭end‬‭of‬‭study.‬‭Sponsor‬‭will‬‭ask‬‭the‬‭survival‬‭status‬‭of‬‭all‬‭patients‬‭at‬‭the‬‭final‬‭clinical‬
‭trial‬ ‭database‬ ‭closing,‬ ‭in‬ ‭order‬ ‭to‬ ‭maximise‬ ‭the‬ ‭median‬ ‭follow‬ ‭up‬ ‭of‬ ‭patients‬ ‭for‬ ‭overall‬
‭survival data.‬
‭In‬‭cases‬‭where‬‭atezolizumab‬‭treatment‬‭has‬‭been‬‭maintained‬‭because‬‭of‬‭clinical‬‭benefit,‬‭follow‬
‭up‬‭will‬‭comply‬‭with‬‭the‬‭“Follow‬‭up‬‭until‬‭progression”‬‭conditions,‬‭with‬‭visits‬‭every‬‭12‬‭weeks‬
‭along with radiological evaluation/assessment of the disease.‬
‭5.8.‬
‭End of study (EoS)‬
‭The‬‭end‬‭of‬‭study‬‭is‬‭defined‬‭as‬‭the‬‭Last‬‭Patient‬‭Last‬‭Visit‬‭(LPLV)‬‭and‬‭will‬‭be‬‭considered‬‭at‬‭24‬
‭months‬‭after‬‭last‬‭patient‬‭first‬‭visit‬‭(LPFV),‬‭Sponsor‬‭will‬‭ask‬‭survival‬‭status‬‭of‬‭all‬‭patients‬‭at‬
‭the‬‭final‬‭clinical‬‭trial‬‭database‬‭closing,‬‭in‬‭order‬‭to‬‭maximise‬‭the‬‭median‬‭follow‬‭up‬‭of‬‭patients‬
‭for overall survival data.‬
‭5.9.‬
‭Outcome assessments‬
‭5.9.1. Response evaluation according RECIST 1.1‬
‭All‬‭patients‬‭will‬‭have‬‭their‬‭best‬‭response‬‭according‬‭to‬‭RECIST‬‭criteria‬‭1.1‬‭from‬‭the‬‭start‬‭of‬
‭study treatment until the end of treatment classified as outlined below:‬
‭●‬ ‭Complete‬‭or‬‭partial‬‭responses‬‭may‬‭be‬‭claimed‬‭only‬‭if‬‭the‬‭criteria‬‭for‬‭each‬‭are‬‭met‬‭at‬‭a‬
‭subsequent time point at least 4 weeks later.‬
‭●‬ ‭Complete‬ ‭Response‬ ‭(CR):‬ ‭disappearance‬ ‭of‬ ‭all‬ ‭target‬ ‭and‬ ‭non-target‬ ‭lesions‬ ‭and‬
‭normalization‬ ‭of‬ ‭tumour‬ ‭markers.‬ ‭Pathological‬ ‭lymph‬ ‭nodes‬ ‭must‬ ‭have‬ ‭short‬ ‭axis‬
‭measures‬ ‭<‬ ‭10‬ ‭mm‬ ‭(‬‭Note‬‭:‬ ‭continue‬ ‭to‬ ‭record‬ ‭the‬ ‭measurement‬‭even‬‭if‬‭<‬‭10‬‭mm‬‭and‬
‭considered‬ ‭CR).‬ ‭Tumour‬ ‭markers‬ ‭must‬ ‭have‬ ‭normalized.‬ ‭Residual‬ ‭lesions‬ ‭(other‬ ‭than‬
‭nodes‬‭<‬‭10‬‭mm)‬‭thought‬‭to‬‭be‬‭non-malignant‬‭should‬‭be‬‭further‬‭investigated‬‭(by‬‭cytology‬
‭or PET scans) before CR can be accepted.‬
‭●‬ ‭Partial‬‭Response‬‭(PR):‬‭at‬‭least‬‭a‬‭30%‬‭decrease‬‭in‬‭the‬‭sum‬‭of‬‭measures‬‭(longest‬‭diameter‬
‭for‬‭tumour‬‭lesions‬‭and‬‭short‬‭axis‬‭measure‬‭for‬‭nodes)‬‭of‬‭target‬‭lesions,‬‭taking‬‭as‬‭reference‬
‭the baseline sum of diameters. Non target lesions must be non-PD.‬
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‭●‬ ‭Stable‬‭Disease‬‭(SD):‬‭Neither‬‭sufficient‬‭shrinkage‬‭to‬‭qualify‬‭for‬‭PR‬‭nor‬‭sufficient‬‭increase‬
‭to qualify for PD taking as reference the smallest sum of diameters on study.‬
‭●‬ ‭Progressive‬‭Disease‬‭(PD):‬‭at‬‭least‬‭a‬‭20%‬‭increase‬‭in‬‭the‬‭sum‬‭of‬‭diameters‬‭of‬‭measured‬
‭lesions‬‭taking‬‭as‬‭references‬‭the‬‭smallest‬‭sum‬‭of‬‭diameters‬‭recorded‬‭on‬‭study‬‭(including‬
‭baseline)‬ ‭AND‬ ‭an‬ ‭absolute‬ ‭increase‬ ‭of‬ ‭≥‬ ‭5‬ ‭mm.‬‭Appearance‬‭of‬‭new‬‭lesions‬‭will‬‭also‬
‭constitute‬ ‭PD‬ ‭(including‬ ‭lesions‬ ‭in‬ ‭previously‬ ‭unassessed‬ ‭areas).‬ ‭In‬ ‭exceptional‬
‭circumstances,‬ ‭unequivocal‬ ‭progression‬ ‭of‬ ‭non-target‬ ‭disease‬ ‭may‬ ‭be‬ ‭accepted‬ ‭as‬
‭evidence‬ ‭of‬ ‭disease‬ ‭progression,‬ ‭where‬ ‭the‬ ‭overall‬ ‭tumour‬ ‭burden‬ ‭has‬ ‭increased‬
‭sufficiently‬‭to‬‭merit‬‭discontinuation‬‭of‬‭treatment,‬‭for‬‭example‬‭where‬‭the‬‭tumour‬‭burden‬
‭appears‬‭to‬‭have‬‭increased‬‭by‬‭at‬‭least‬‭73%‬‭in‬‭volume‬‭(which‬‭is‬‭the‬‭increase‬‭in‬‭volume‬
‭when‬‭all‬‭dimensions‬‭of‬‭a‬‭single‬‭lesion‬‭increase‬‭by‬‭20%).‬‭Modest‬‭increases‬‭in‬‭the‬‭size‬‭of‬
‭one‬ ‭or‬ ‭more‬ ‭non-target‬ ‭lesions‬ ‭are‬ ‭NOT‬ ‭considered‬ ‭unequivocal‬ ‭progression.‬ ‭If‬ ‭the‬
‭evidence‬‭of‬‭PD‬‭is‬‭equivocal‬‭(target‬‭or‬‭non-target),‬‭treatment‬‭may‬‭continue‬‭until‬‭the‬‭next‬
‭assessment, but on further documentation, the earlier date must be used.‬
‭5.9.2.‬ ‭Safety assessments‬
‭Safety‬ ‭parameters‬ ‭are‬ ‭AE,‬ ‭SAE,‬ ‭AESI,‬ ‭pregnancy,‬ ‭medication‬ ‭error,‬ ‭overdose.‬ ‭Additional‬
‭safety‬‭information‬‭could‬‭be‬‭derived‬‭from‬‭ECG,‬‭lab‬‭test,‬‭pregnancy‬‭test,‬‭or‬‭vital‬‭sign‬‭exam.‬
‭The‬‭assessment‬‭of‬‭adverse‬‭events‬‭will‬‭include‬‭the‬‭type‬‭of‬‭event‬‭(including‬‭symptoms,‬‭physical‬
‭exam‬‭findings‬‭and‬‭laboratory‬‭abnormalities),‬‭the‬‭incidence,‬‭severity,‬‭timing,‬‭seriousness,‬‭and‬
‭relatedness‬‭regarding‬‭the‬‭treatment‬‭under‬‭study.‬‭Adverse‬‭events‬‭will‬‭be‬‭recorded‬‭and‬‭reported‬
‭in‬‭the‬‭corresponding‬‭section‬‭of‬‭the‬‭case‬‭report‬‭form.‬‭The‬‭grade‬‭of‬‭adverse‬‭events‬‭will‬‭be‬‭coded‬
‭according‬ ‭to‬ ‭the‬ ‭National‬ ‭Cancer‬ ‭Institute’s‬ ‭Common‬ ‭Toxicity‬ ‭criteria‬ ‭(NCI-CTCAE‬ ‭v5.0‬
‭scoring‬ ‭system).‬ ‭The‬ ‭worst‬ ‭toxicity‬ ‭score‬ ‭will‬ ‭be‬ ‭recorded.‬ ‭In‬‭case‬‭of‬‭SAE‬‭and‬‭AESI‬‭the‬
‭investigator‬‭should‬‭immediately‬‭fill‬‭in‬‭the‬‭dedicated‬‭SAE‬‭form‬‭and‬‭send‬‭it‬‭by‬‭as‬‭detailed‬‭in‬
‭Section 9.2‬
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‭6.‬
‭STUDY POPULATION‬
‭6.1.‬
‭Inclusion criteria‬
‭1.‬ ‭Male or female subjects ≥ 18 years old.‬
‭2.‬ ‭Written‬‭informed‬‭consent‬‭approved‬‭by‬‭the‬‭Independent‬‭Ethics‬‭Committee‬‭(IEC),‬‭prior‬
‭to the performance of any trial activities.‬
‭3.‬ ‭Patients‬ ‭with‬ ‭histologically‬ ‭documented,‬ ‭locally‬ ‭advanced‬ ‭(T4B,‬ ‭any‬ ‭N;‬ ‭or‬ ‭any‬‭T,‬
‭N2-3) or metastatic urothelial carcinoma (M1, Stage IV)*.‬
‭*Also‬‭termed‬‭transitional‬‭cell‬‭carcinoma‬‭(TCC)‬‭or‬‭urothelial‬‭cell‬‭carcinoma‬‭[UCC]‬‭of‬
‭the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra).‬
‭4.‬ ‭Patients‬‭should‬‭not‬‭be‬‭eligible‬‭(unfit)‬‭for‬‭full‬‭dose‬‭of‬‭cisplatin,‬‭in‬‭the‬‭investigator’s‬
‭judgement, based on:‬
‭a.‬ ‭Age older than 70 years‬
‭a.‬ ‭ECOG‬ ‭Performance‬ ‭status‬ ‭(PS)‬ ‭2‬ ‭or‬ ‭Karnofsky‬ ‭PS‬‭of‬‭60‬‭-‬‭70%‬ ‭(only‬‭15‬
‭patients will be included with ECOG 2)‬
‭b.‬ ‭Measured‬ ‭creatinine‬ ‭clearance‬ ‭(ClCr)‬ ‭>‬ ‭30‬ ‭and‬ ‭<‬ ‭60‬ ‭mL/min‬ ‭by‬ ‭the‬
‭Cockcroft-Gault‬ ‭formula‬ ‭(Cockcroft‬ ‭and‬ ‭Gault‬ ‭1976)‬ ‭or‬ ‭by‬ ‭24-hour‬ ‭urine‬
‭collection for the determination of creatinine clearance:‬
‭Males:‬
‭Creatinine CL (mL/min)  =‬
‭Weight (kg) × (140 – Age)‬
‭72 x serum creatinine (mg/dL)‬
‭Females:‬
‭Creatinine CL (mL/min)  =‬
‭Weight (kg) × (140 – Age)‬‭×0.85‬
‭72 x serum creatinine (mg/dL)‬
‭c.‬ ‭Any‬‭other‬‭reason‬‭the‬‭physician‬‭considers‬‭but‬‭should‬‭specify‬‭in‬‭the‬‭CRF‬‭and‬
‭discussed with the PI.‬
‭5.‬ ‭At‬ ‭least‬ ‭one‬ ‭measurable‬ ‭lesion‬ ‭through‬ ‭radiographic‬‭tumor‬‭evaluation‬‭(CT‬‭scan‬‭or‬
‭magnetic‬ ‭resonance‬ ‭imaging)‬‭as‬‭defined‬‭by‬‭RECIST‬‭version‬‭1.1,‬‭that‬‭has‬‭not‬‭been‬
‭previously irradiated within 4 weeks prior to the study enrolment.‬
‭6.‬ ‭Patients‬ ‭with‬ ‭an‬ ‭archival‬ ‭or‬ ‭de‬ ‭novo‬ ‭tumor‬ ‭biopsy‬ ‭(representative‬ ‭formalin-fixed‬
‭paraffin-embedded/FFPE‬‭paraffin‬‭block‬‭obtained‬‭within‬‭6‬‭months‬‭prior‬‭to‬‭inclusion)‬
‭with‬ ‭an‬ ‭associated‬‭pathology‬‭report,‬‭for‬‭testing‬‭of‬‭PD-L1‬‭expression‬‭prior‬‭to‬‭study‬
‭enrollment. Samples in unstained slides could be acceptable (at least 15 slides).‬
‭7.‬ ‭Patients with adequate normal organ and marrow function as defined below:‬
‭a.‬ ‭Haemoglobin (Hb) ≥ 9.0 g/dL.‬
‭b.‬ ‭Absolute neutrophil count (ANC)‬‭>‬‭1500 per mm‬‭3‬‭.‬
‭c.‬ ‭Platelet count ≥ 100,000 per mm‬‭3‬‭.‬
‭d.‬ ‭Serum‬‭bilirubin‬‭≤‬‭1.5‬‭X‬‭institutional‬‭upper‬‭limit‬‭of‬‭normal‬‭(ULN)‬‭unless‬‭liver‬
‭metastases‬ ‭are‬ ‭present,‬ ‭in‬ ‭which‬ ‭case‬ ‭it‬‭must‬‭be‬‭≤‬‭2X‬‭ULN.‬‭This‬‭will‬‭not‬
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‭apply‬‭to‬‭patients‬‭with‬‭confirmed‬‭Gilbert’s‬‭syndrome‬‭(persistent‬‭or‬‭recurrent‬
‭hyperbilirubinemia‬ ‭that‬ ‭is‬ ‭predominantly‬ ‭unconjugated‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬
‭haemolysis‬ ‭or‬ ‭hepatic‬ ‭pathology);‬ ‭however,‬ ‭they‬ ‭will‬ ‭be‬ ‭allowed‬ ‭only‬ ‭in‬
‭consultation with their physician.‬
‭e.‬ ‭Serum‬‭transaminases‬‭(ALT,‬‭AST‬‭and‬‭GGT)‬‭≤‬‭2.5X‬‭institutional‬‭upper‬‭limit‬‭of‬
‭normal‬ ‭unless‬ ‭liver‬ ‭metastases‬ ‭are‬ ‭present,‬ ‭in‬ ‭which‬ ‭case‬‭it‬‭must‬‭be‬‭≤‬‭3X‬
‭ULN.‬
‭8.‬ ‭No major active bleeding.‬
‭9.‬ ‭Female‬ ‭subjects‬ ‭of‬ ‭childbearing‬ ‭potential‬ ‭(not‬ ‭surgically‬ ‭sterile‬ ‭or‬ ‭at‬ ‭least‬‭2‬‭years‬
‭postmenopausal)‬‭must‬‭provide‬‭a‬‭negative‬‭urine‬‭pregnancy‬‭test‬‭at‬‭screening,‬‭and‬‭use‬‭a‬
‭medically‬ ‭accepted‬ ‭double‬ ‭barrier‬ ‭method‬ ‭of‬ ‭contraception‬ ‭(i.e.‬ ‭condom‬ ‭with‬
‭spermicide‬‭+‬‭IUD‬‭or‬‭cervical‬‭caps).‬‭In‬‭addition,‬‭they‬‭must‬‭agree‬‭to‬‭continue‬‭the‬‭use‬‭of‬
‭this‬ ‭double‬ ‭barrier‬ ‭method‬ ‭for‬ ‭the‬ ‭duration‬ ‭of‬ ‭the‬ ‭study‬ ‭and‬ ‭for‬ ‭6‬ ‭months‬ ‭after‬
‭participation in the study.‬
‭10.‬‭Males‬‭should‬‭agree‬‭to‬‭abstain‬‭from‬‭sexual‬‭intercourse‬‭with‬‭a‬‭female‬‭partner‬‭or‬‭agree‬
‭to‬ ‭use‬ ‭a‬ ‭double‬ ‭barrier‬ ‭method‬ ‭of‬ ‭contraception‬ ‭(i.e.‬ ‭condom‬ ‭with‬ ‭spermicide,‬ ‭in‬
‭addition‬‭to‬‭having‬‭their‬‭female‬‭partner‬‭use‬‭some‬‭contraceptive‬‭measures‬‭such‬‭as‬‭oral‬
‭contraceptive‬ ‭drugs,‬ ‭intrauterine‬ ‭device‬ ‭(IUD)‬ ‭hormonal‬ ‭contraception,‬ ‭or‬ ‭cervical‬
‭caps), for the duration of the study and for 6 months after participation in the study‬
‭11.‬ ‭Willingness‬‭and‬‭ability‬‭of‬‭patients‬‭to‬‭comply‬‭with‬‭the‬‭protocol‬‭for‬‭the‬‭duration‬‭of‬‭the‬
‭study‬‭including‬‭undergoing‬‭treatment‬‭as‬‭well‬‭as‬‭availability‬‭for‬‭scheduled‬‭visits‬‭and‬
‭examinations including follow up.‬
‭6.2.‬
‭Exclusion criteria‬
‭1.‬ ‭Prior‬‭treatment‬‭with‬‭any‬‭immune‬‭checkpoint‬‭inhibitor‬‭therapy‬‭(e.g.,‬‭CTLA4,‬‭PD-1,‬‭or‬
‭PD-L1 targeting agent).*‬
‭*‬‭Note‬‭:‬ ‭Prior‬ ‭adjuvant‬ ‭or‬ ‭neoadjuvant‬ ‭treatment‬ ‭with‬ ‭targeted‬ ‭therapy/checkpoint‬
‭inhibitors‬‭is‬‭allowed,‬‭as‬‭long‬‭as‬‭the‬‭last‬‭dose‬‭was‬‭administered‬‭at‬‭least‬‭12‬‭months‬‭prior‬
‭to the patient inclusion in this trial.‬
‭2.‬ ‭Presence‬‭of‬‭active‬‭second‬‭malignancy‬‭and/or‬‭prior‬‭malignancy‬‭in‬‭the‬‭last‬‭2‬‭years‬‭is‬
‭allowed except for the following:‬
‭a.‬ ‭adequately treated basal cell or squamous cell skin cancer,‬
‭b.‬ ‭adequately‬‭treated‬‭Stage‬‭I‬‭or‬‭II‬‭cancer‬‭from‬‭which‬‭the‬‭patient‬‭is‬‭currently‬‭in‬
‭complete remission per investigators' clinical judgment.‬
‭3.‬ ‭Patient receiving radiation therapy within 4 weeks before inclusion.‬
‭4.‬ ‭Active‬ ‭or‬ ‭prior‬ ‭documented‬ ‭autoimmune‬ ‭disease‬ ‭within‬ ‭the‬ ‭past‬ ‭2‬ ‭years‬ ‭NOTE:‬
‭Subjects‬‭with‬‭vitiligo,‬‭Grave's‬‭disease,‬‭or‬‭psoriasis‬‭not‬‭requiring‬‭systemic‬‭treatment‬
‭(within the past 2 years) are not excluded.‬
‭5.‬ ‭Active‬ ‭or‬ ‭prior‬ ‭documented‬ ‭inflammatory‬ ‭bowel‬ ‭disease‬‭(e.g.,‬‭Crohn's‬‭disease‬‭and‬
‭ulcerative colitis).‬
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‭6.‬ ‭History of allogeneic organ transplant.‬
‭7.‬ ‭Subjects‬ ‭having‬ ‭a‬ ‭diagnosis‬ ‭of‬‭immunodeficiency‬‭or‬‭are‬‭receiving‬‭systemic‬‭steroid‬
‭therapy‬‭or‬‭any‬‭other‬‭form‬‭of‬‭immunosuppressive‬‭therapy‬‭within‬‭28‬‭days‬‭prior‬‭to‬‭the‬
‭first dose of trial treatment.‬
‭8.‬ ‭Current‬ ‭or‬ ‭prior‬ ‭use‬ ‭of‬ ‭immunosuppressive‬ ‭medication‬ ‭within‬ ‭7‬ ‭days‬ ‭prior‬ ‭to‬
‭enrolment, except the following:‬
‭a.‬ ‭Intranasal,‬ ‭inhaled,‬ ‭topical‬ ‭steroids,‬ ‭or‬ ‭local‬ ‭steroid‬ ‭injections‬ ‭(eg,‬
‭intra-articular injection);‬
‭i.‬
‭Systemic‬ ‭corticosteroids‬ ‭at‬ ‭physiologic‬ ‭doses‬ ‭≤10‬ ‭mg/day‬ ‭of‬
‭prednisone or equivalent;‬
‭ii.‬
‭Steroids‬‭as‬‭premedication‬‭for‬‭hypersensitivity‬‭reactions‬‭(eg,‬‭CT‬‭scan‬
‭premedication).‬
‭9.‬ ‭The‬‭subject‬‭has‬‭uncontrolled,‬‭significant‬‭intercurrent‬‭or‬‭recent‬‭illness‬‭(within‬‭6‬‭months‬
‭prior to inclusion) including, but not limited to, the following conditions:‬
‭a.‬ ‭Cardiovascular disorders:‬
‭i.‬
‭Class‬‭3‬‭or‬‭4‬‭congestive‬‭heart‬‭failure‬‭as‬‭defined‬‭by‬‭the‬‭New‬‭York‬‭Heart‬
‭Association,‬
‭unstable‬
‭angina‬
‭pectoris,‬
‭and‬
‭serious‬
‭cardiac‬
‭arrhythmias.‬
‭ii.‬
‭Uncontrolled‬‭hypertension‬‭defined‬‭as‬‭sustained‬‭blood‬‭press‬‭>‬‭150‬‭mm‬
‭hg‬‭systolic‬‭or‬‭>‬‭100‬‭mm‬‭hg‬‭diastolic‬‭despite‬‭optimal‬‭antihypertensive‬
‭treatment.‬
‭iii.‬
‭Stroke‬ ‭(including‬ ‭transient‬ ‭ischemic‬ ‭attack‬ ‭[TIA]),‬ ‭myocardial‬
‭infarction,‬‭other‬‭ischemic‬‭event,‬‭or‬‭thromboembolic‬‭event‬‭(e.g.,‬‭deep‬
‭venous‬‭thrombosis‬‭[DVT]‬‭and‬‭pulmonary‬‭embolism)‬‭within‬‭6‬‭months‬
‭before‬‭inclusion.‬‭Subjects‬‭with‬‭a‬‭more‬‭recent‬‭diagnosis‬‭of‬‭DVT‬‭are‬
‭allowed‬‭if‬‭stable,‬‭asymptomatic,‬‭and‬‭treated‬‭with‬‭LMWH‬‭for‬‭at‬‭least‬
‭6 weeks before study treatment.‬
‭b.‬ ‭Gastrointestinal‬ ‭disorders‬ ‭(e.g.,‬ ‭malabsorption‬ ‭syndrome‬ ‭or‬ ‭gastric‬ ‭outlet‬
‭obstruction)‬ ‭including‬ ‭those‬ ‭associated‬ ‭with‬ ‭a‬ ‭high‬ ‭risk‬ ‭of‬ ‭perforation‬ ‭or‬
‭fistula formulation:‬
‭i.‬
‭Tumours‬ ‭invading‬ ‭the‬ ‭GI‬ ‭tract,‬ ‭active‬ ‭peptic‬ ‭ulcer‬ ‭disease,‬
‭inflammatory‬
‭bowel‬
‭disease,‬
‭ulcerative‬
‭colitis,‬ ‭diverticulitis,‬
‭cholecystitis,‬
‭symptomatic‬
‭cholangitis‬
‭or‬
‭appendicitis,‬
‭acute‬
‭pancreatitis‬‭or‬‭acute‬‭obstruction‬‭of‬‭the‬‭pancreatic‬‭or‬‭biliary‬‭duct,‬‭or‬
‭gastric outlet obstruction.‬
‭ii.‬
‭Abdominal‬
‭fistula,‬
‭GI‬
‭perforation,‬
‭bowel‬
‭obstruction,‬
‭or‬
‭intra-abdominal‬ ‭abscess‬ ‭within‬ ‭6‬ ‭months‬ ‭before‬ ‭inclusion.‬ ‭Note:‬
‭complete‬ ‭healing‬ ‭of‬ ‭an‬ ‭intra-abdominal‬ ‭abscess‬ ‭must‬‭be‬‭confirmed‬
‭prior to start of the treatment.‬
‭c.‬ ‭Clinically‬‭significant‬‭hematemesis‬‭or‬‭hemoptysis‬‭of‬‭>‬‭0.5‬‭teaspoon‬‭(>‬‭2.5‬‭ml)‬
‭of‬‭red‬‭blood‬‭or‬‭history‬‭of‬‭other‬‭significant‬‭bleeding‬‭within‬‭3‬‭months‬‭before‬
‭treatment.‬
‭d.‬ ‭Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.‬
‭e.‬ ‭Lesions invading major pulmonary blood vessels.‬
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‭f.‬
‭Other clinically significant disorders such as:‬
‭i.‬
‭Active‬ ‭infection‬‭requiring‬‭systemic‬‭treatment,‬‭infection‬‭with‬‭human‬
‭immunodeficiency‬
‭virus‬
‭or‬
‭acquired‬
‭immunodeficiency‬
‭syndrome-related illness, or chronic hepatitis B or C infection.‬
‭ii.‬
‭Serious non-healing wound/ulcer/bone fracture.‬
‭iii.‬
‭Malabsorption syndrome.‬
‭iv.‬
‭Moderate to severe hepatic impairment (child-pugh B or C).‬
‭v.‬
‭Requirement for hemodialysis or peritoneal dialysis.‬
‭vi.‬
‭Uncontrolled diabetes mellitus.‬
‭10.‬‭Major‬‭surgery‬‭(e.g.,‬‭GI‬‭surgery‬‭and‬‭removal‬‭or‬‭biopsy‬‭of‬‭brain‬‭metastasis)‬‭within‬‭8‬
‭weeks‬ ‭before‬ ‭inclusion.‬ ‭Complete‬ ‭wound‬ ‭healing‬ ‭from‬ ‭major‬ ‭surgery‬ ‭must‬ ‭have‬
‭occurred‬ ‭4‬ ‭weeks‬ ‭before‬ ‭study‬ ‭treatment‬ ‭and‬ ‭from‬ ‭minor‬ ‭surgery‬ ‭(e.g.,‬ ‭simple‬
‭excision,‬ ‭tooth‬ ‭extraction)‬ ‭at‬ ‭least‬ ‭10‬ ‭days‬ ‭before‬ ‭study‬ ‭treatment.‬ ‭Subjects‬ ‭with‬
‭clinically relevant ongoing complications from prior surgery are not eligible.‬
‭11.‬ ‭Known‬ ‭human‬ ‭immunodeficiency‬ ‭virus‬ ‭(HIV)‬ ‭or‬ ‭acquired‬ ‭immunodeficiency‬
‭syndrome (AIDS)-related illness.‬
‭12.‬‭Any‬‭test‬‭for‬‭hepatitis‬‭B‬‭virus‬‭(HBV)‬‭or‬‭hepatitis‬‭C‬‭virus‬‭(HCV)‬‭indicating‬‭acute‬‭or‬
‭chronic infection.‬
‭13.‬‭Women who are pregnant or are breastfeeding.‬
‭14.‬‭Male‬‭patients‬‭must‬‭be‬‭surgically‬‭sterile‬‭or‬‭must‬‭agree‬‭to‬‭use‬‭effective‬‭contraception‬
‭during the period of therapy.‬
‭15.‬‭Any‬ ‭of‬ ‭the‬ ‭following‬ ‭within‬ ‭6‬ ‭months‬ ‭prior‬ ‭to‬ ‭study‬‭entry:‬‭myocardial‬‭infarction,‬
‭uncontrolled‬ ‭angina,‬ ‭uncontrolled‬ ‭hypertension,‬ ‭coronary/peripheral‬ ‭artery‬ ‭bypass‬
‭graft,‬ ‭symptomatic‬ ‭congestive‬ ‭heart‬ ‭failure,‬ ‭cerebrovascular‬ ‭accident‬ ‭or‬ ‭transient‬
‭ischemic attack.‬
‭16.‬‭Previously‬‭identified‬‭allergy‬‭or‬‭hypersensitivity‬‭to‬‭components‬‭of‬‭the‬‭study‬‭treatment‬
‭formulations.‬
‭6.3.‬
‭Criteria for withdrawal from the treatment and study‬
‭6.3.1. Permanent Interruption of study treatments‬
‭Any‬ ‭reason‬ ‭for‬ ‭discontinuing‬ ‭investigational‬ ‭products‬ ‭must‬ ‭be‬ ‭clearly‬ ‭recorded‬ ‭on‬ ‭the‬
‭electronic case report forms (eCRF).‬
‭Patients‬‭will‬‭receive‬‭the‬‭product‬‭under‬‭investigation‬‭as‬‭per‬‭schedule‬‭described‬‭in‬‭section‬‭5.5‬‭of‬
‭this protocol or until any of the following occurs:‬
‭●‬ ‭Objective‬‭disease‬‭progression‬‭.‬‭However,‬‭patients‬‭with‬‭disease‬‭progression‬‭at‬
‭week‬‭9‬‭who‬‭are‬‭continuing‬‭to‬‭derive‬‭clinical‬‭benefit‬‭from‬‭the‬‭study‬‭treatment‬‭will‬‭be‬
‭eligible‬ ‭to‬ ‭continue‬ ‭with‬ ‭single-agent‬ ‭atezolizumab,‬ ‭provided‬ ‭that‬ ‭the‬ ‭treating‬
‭physician has determined that the benefit/risk for doing so is favorable;‬
‭●‬ ‭Global deterioration of health status requiring discontinuation‬‭;‬
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‭●‬ ‭Unacceptable‬‭toxicity.‬‭If‬‭the‬‭unacceptable‬‭toxicity‬‭is‬‭attributed‬‭to‬‭one‬‭of‬‭the‬
‭two‬‭study‬‭treatments,‬‭the‬‭investigator‬‭(in‬‭discussion‬‭with‬‭the‬‭sponsor)‬‭may‬‭continue‬
‭treatment with the other study treatment;‬
‭●‬ ‭Investigator’s decision;‬
‭●‬ ‭Pregnancy;‬
‭●‬ ‭Protocol‬‭violation,‬‭only‬‭when‬‭non-compliance‬‭might‬‭significantly‬‭impact‬‭in‬
‭patients‬ ‭safety‬ ‭and/or‬ ‭trial‬ ‭results‬ ‭validity,‬ ‭as‬ ‭per‬ ‭case‬ ‭by‬ ‭case‬ ‭Sponsor‬
‭assessment/criteria;‬
‭●‬ ‭Lost to follow-up;‬
‭●‬ ‭Patient refused further treatment (follow-up permitted by patient);‬
‭●‬ ‭Study terminated by sponsor;‬
‭●‬ ‭Death.‬
‭For‬‭all‬‭participants,‬‭global‬‭deterioration‬‭of‬‭health‬‭status‬‭requiring‬‭discontinuation‬‭of‬
‭treatment‬‭without‬‭objective‬‭evidence‬‭of‬‭disease‬‭progression‬‭at‬‭that‬‭time‬‭should‬‭be‬‭reported‬‭as‬
‭‘symptomatic deterioration’ in the source data and in the eCRF.‬
‭A‬‭temporary‬‭interruption‬‭in‬‭study‬‭medication‬‭due‬‭to‬‭an‬‭AE‬‭is‬‭not‬‭considered‬‭to‬‭be‬‭permanent‬
‭discontinuation from investigational product.‬
‭Tumor‬‭assessments‬‭for‬‭participants,‬‭who‬‭discontinue‬‭study‬‭treatment‬‭without‬‭radiographic‬
‭progression, should continue as per protocol until radiographic progression is determined.‬
‭Chemotherapy‬ ‭dose‬ ‭reduction‬ ‭is‬ ‭allowed‬‭in‬‭study.‬‭Any‬‭participant‬‭with‬‭two‬‭prior‬‭dose‬
‭reductions‬‭to‬‭one‬‭agent‬‭who‬‭experiences‬‭a‬‭toxicity‬‭that‬‭would‬‭cause‬‭a‬‭third‬‭dose‬‭reduction‬
‭must‬ ‭be‬ ‭discontinued‬ ‭from‬ ‭that‬ ‭agent.‬ ‭A‬ ‭participant‬ ‭who‬ ‭is‬ ‭discontinued‬ ‭from‬ ‭the‬
‭chemotherapy treatment will remain on the study and receive atezolizumab.‬
‭If‬ ‭a‬ ‭participant‬ ‭meets‬ ‭criteria‬ ‭for‬ ‭discontinuation‬ ‭and‬ ‭the‬ ‭investigator‬ ‭is‬ ‭unable‬‭to‬
‭determine‬‭whether‬‭the‬‭event‬‭is‬‭related‬‭to‬‭atezolizumab‬‭or‬‭chemotherapy,‬‭the‬‭participant‬‭should‬
‭discontinue all treatments.‬
‭The‬‭assessment‬‭for‬‭discontinuation‬‭of‬‭atezolizumab‬‭should‬‭be‬‭made‬‭separately‬‭from‬
‭the‬‭assessment‬‭made‬‭for‬‭discontinuation‬‭of‬‭chemotherapy.‬‭If‬‭criteria‬‭for‬‭discontinuation‬‭for‬
‭atezolizumab‬‭are‬‭met‬‭before‬‭the‬‭first‬‭6‬‭atezolizumab‬‭+‬‭split-doses‬‭of‬‭gemcitabine‬‭and‬‭cisplatin‬
‭chemotherapy‬ ‭cycles‬ ‭have‬ ‭been‬ ‭completed,‬ ‭the‬ ‭split-dose‬ ‭GC‬ ‭chemotherapy‬‭may‬‭continue‬
‭until 6 cycles have been completed.‬
‭6.3.2. Withdrawal from the study‬
‭Subjects‬ ‭will‬ ‭be‬ ‭encouraged‬ ‭to‬ ‭complete‬ ‭the‬ ‭study;‬‭however,‬‭they‬‭may‬‭voluntarily‬
‭withdraw at any time.‬
‭The‬ ‭investigator‬ ‭may‬ ‭also,‬ ‭at‬ ‭his/her‬ ‭discretion,‬ ‭withdraw‬ ‭the‬ ‭subject‬ ‭from‬
‭participating in this study at any time, or the sponsor may discontinue the study.‬
‭Reasons for early withdrawal from the study should be documented in the eCRF as:‬
‭●‬ ‭Study closed/terminated by sponsor;‬
‭●‬ ‭Lost to follow-up;‬
‭●‬ ‭Investigator’s decision;‬
‭●‬ ‭Subject withdrew consent (refused further follow-up);‬
‭●‬ ‭Major‬‭protocol‬‭non-compliance.‬‭Protocol‬‭violation,‬‭only‬‭when‬‭non-compliance‬‭might‬
‭significantly‬‭impact‬‭in‬‭patients‬‭safety‬‭and/or‬‭trial‬‭results‬‭validity,‬‭as‬‭per‬‭case‬‭by‬‭case‬
‭Sponsor assessment/criteria;‬
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‭●‬ ‭Death.‬
‭If‬‭a‬‭patient‬‭does‬‭not‬‭return‬‭for‬‭a‬‭scheduled‬‭visit,‬‭every‬‭effort‬‭should‬‭be‬‭made‬‭to‬‭contact‬‭the‬
‭patient.‬‭All‬‭attempts‬‭to‬‭contact‬‭the‬‭patient‬‭and‬‭information‬‭received‬‭during‬‭contact‬‭attempts‬
‭must‬‭be‬‭documented‬‭in‬‭the‬‭patient’s‬‭medical‬‭record.‬‭In‬‭any‬‭circumstances,‬‭every‬‭effort‬‭should‬
‭be‬‭made‬‭to‬‭document‬‭patient‬‭outcomes,‬‭if‬‭possible.‬‭The‬‭investigator‬‭should‬‭inquire‬‭about‬‭the‬
‭reason‬ ‭for‬ ‭withdrawal,‬ ‭request‬ ‭the‬ ‭patient‬ ‭to‬ ‭return‬ ‭all‬ ‭unused‬ ‭investigational‬ ‭product(s),‬
‭request‬‭that‬‭the‬‭patient‬‭return‬‭for‬‭a‬‭final‬‭visit,‬‭if‬‭applicable,‬‭and‬‭follow‬‭up‬‭with‬‭the‬‭patient‬
‭regarding any unresolved AEs.‬
‭If‬‭the‬‭patient‬‭withdraws‬‭from‬‭the‬‭study,‬‭and‬‭also‬‭withdraws‬‭consent‬‭for‬‭disclosure‬‭of‬‭future‬
‭information,‬ ‭no‬ ‭further‬ ‭evaluations‬ ‭should‬ ‭be‬ ‭performed,‬ ‭and‬‭no‬‭additional‬‭data‬‭should‬‭be‬
‭collected.‬ ‭The‬ ‭sponsor‬ ‭may‬ ‭retain‬ ‭and‬ ‭continue‬ ‭to‬ ‭use‬ ‭any‬ ‭data‬ ‭collected‬ ‭before‬ ‭such‬
‭withdrawal of consent.‬
‭Date‬‭of‬‭withdrawal‬‭from‬‭the‬‭study,‬‭with‬‭reason‬‭for‬‭withdrawal,‬‭will‬‭be‬‭recorded‬‭on‬‭the‬‭eCRF.‬
‭In‬‭the‬‭case‬‭of‬‭death,‬‭a‬‭death‬‭certificate‬‭should‬‭be‬‭obtained‬‭if‬‭possible,‬‭with‬‭the‬‭cause‬‭of‬‭death‬
‭evaluated and documented.‬
‭Note: Patients withdrawn the trial for any reason, cannot enter again.‬
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‭7.‬
‭TREATMENT DESCRIPTION‬
‭For‬‭the‬‭purpose‬‭of‬‭this‬‭study,‬‭the‬‭investigational‬‭products‬‭as‬‭defined‬‭by‬‭(ICH‬‭E6‬‭1.33)‬‭are‬
‭atezolizumab, cisplatin and gemcitabine.‬
‭7.1.‬
‭Study medication‬
‭​‬
‭7.1.1.‬ ‭Atezolizumab‬
‭Atezolizumab‬ ‭will‬ ‭be‬ ‭supplied‬ ‭as‬ ‭60‬ ‭mg/mL‬ ‭glass‬ ‭vials‬ ‭of‬ ‭20-mL,‬ ‭nominal‬ ‭atezolizumab‬
‭amount per vial, 1200 mg.‬
‭Packaging‬ ‭and‬‭labeling‬‭will‬‭be‬‭in‬‭accordance‬‭with‬‭applicable‬‭local‬‭regulatory‬‭requirements‬
‭and applicable Good Manufacturing Practice (GMP) guidelines.‬
‭The‬ ‭information‬ ‭on‬ ‭the‬ ‭study‬ ‭treatment‬ ‭will‬ ‭be‬ ‭in‬ ‭accordance‬ ‭with‬ ‭approved‬ ‭submission‬
‭documents.‬
‭AUREA‬‭is‬‭an‬‭Investigator‬‭Initiated‬‭Study,‬‭the‬‭Sponsor‬‭will‬‭supply‬‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬
‭months‬‭of‬‭treatment‬‭for‬‭each‬‭patient.‬‭For‬‭those‬‭patients‬‭in‬‭which‬‭the‬‭PI‬‭considers‬‭that‬‭the‬‭best‬
‭option‬ ‭for‬ ‭the‬ ‭patient‬ ‭is‬ ‭continuing‬ ‭atezolizumab‬ ‭for‬ ‭more‬ ‭than‬ ‭24‬ ‭months,‬ ‭available‬
‭commercial Site supplies should be used, after managed local administrative regulation.‬
‭7.1.2.‬
‭Gemcitabine and Cisplatin‬
‭Gemcitabine and cisplatin will be supplied as per site clinical standards.‬
‭Packaging‬ ‭and‬‭labeling‬‭will‬‭be‬‭in‬‭accordance‬‭with‬‭applicable‬‭local‬‭regulatory‬‭requirements‬
‭and‬ ‭applicable‬ ‭Good‬ ‭Manufacturing‬ ‭Practice‬ ‭(GMP)‬ ‭guidelines,‬ ‭under‬ ‭commercial‬
‭presentation and each site availability.‬
‭The‬ ‭information‬ ‭on‬ ‭the‬ ‭study‬ ‭treatment‬ ‭will‬ ‭be‬ ‭in‬ ‭accordance‬ ‭with‬ ‭approved‬ ‭submission‬
‭documents.‬
‭7.2.‬
‭Treatment accountability and compliance‬
‭According‬ ‭to‬ ‭local‬ ‭legislation,‬ ‭the‬ ‭investigator‬ ‭will‬ ‭record‬ ‭in‬ ‭the‬ ‭medical‬ ‭history‬ ‭that‬ ‭the‬
‭patient is taking the medication as prescribed for each new cycle in the study.‬
‭7.2.1.‬ ‭Atezolizumab accountability and compliance‬
‭Atezolizumab‬ ‭will‬ ‭be‬ ‭dosed‬ ‭at‬ ‭the‬ ‭investigational‬ ‭site,‬ ‭compliance‬ ‭will‬ ‭be‬ ‭assessed‬ ‭by‬
‭reviewing‬‭the‬‭consistency‬‭of‬‭information‬‭in‬‭the‬‭IWRS,‬‭the‬‭eCRF,‬‭patient‬‭records,‬‭nurse‬‭sheets,‬
‭and in the pharmacy source documentation.‬
‭7.2.2.‬ ‭Gemcitabine and Cisplatin accountability and compliance‬
‭Compliance‬‭of‬‭the‬‭split-dose‬‭GC‬‭chemotherapy‬‭will‬‭be‬‭assessed‬‭by‬‭reviewing‬‭the‬‭consistency‬
‭of‬ ‭information‬ ‭in‬ ‭the‬ ‭eCRF,‬ ‭patient‬ ‭records,‬ ‭nurse‬ ‭sheets,‬ ‭and‬ ‭in‬ ‭the‬ ‭pharmacy‬ ‭source‬
‭documentation.‬
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‭7.3.‬
‭Preparation and Dispensing‬
‭Only‬‭qualified‬‭personnel‬‭who‬‭are‬‭familiar‬‭with‬‭procedures‬‭that‬‭minimize‬‭undue‬‭exposure‬‭to‬
‭them‬‭and‬‭to‬‭the‬‭environment‬‭should‬‭undertake‬‭the‬‭preparation,‬‭handling,‬‭and‬‭safe‬‭disposal‬‭of‬
‭chemotherapeutic agents.‬
‭Investigational‬‭products‬‭should‬‭be‬‭prepared‬‭and‬‭dispensed‬‭by‬‭an‬‭appropriately‬‭qualified‬‭and‬
‭experienced‬ ‭member‬ ‭of‬ ‭the‬ ‭study‬ ‭staff‬ ‭(e.g.,‬ ‭physician,‬ ‭nurse,‬ ‭physician’s‬ ‭assistant,‬
‭practitioner, or pharmacist) as allowed by local, state, and institutional guidance.‬
‭7.3.1.‬ ‭Atezolizumab preparation and dispensing‬
‭Atezolizumab‬‭will‬‭be‬‭dosed‬‭at‬‭the‬‭investigational‬‭site.‬‭Atezolizumab‬‭must‬‭not‬‭be‬‭used‬‭for‬‭any‬
‭purpose‬‭other‬‭than‬‭the‬‭trial.‬‭The‬‭administration‬‭of‬‭trial‬‭investigational‬‭products‬‭to‬‭patients‬‭who‬
‭have not been enrolled into the trial is not covered by the trial insurance.‬
‭7.3.2.‬ ‭Gemcitabine plus cisplatin preparation and dispensing‬
‭The‬‭GC‬‭treatment‬‭will‬‭be‬‭administered‬‭in‬‭quantities‬‭appropriate‬‭for‬‭the‬‭study‬‭visit‬‭schedule‬
‭and‬‭according‬‭to‬‭local‬‭practice.‬‭A‬‭qualified‬‭staff‬‭member‬‭will‬‭record‬‭all‬‭the‬‭study‬‭treatment‬
‭using‬ ‭the‬ ‭local‬ ‭practise.‬ ‭Procedures‬ ‭described‬ ‭in‬ ‭each‬ ‭institution’s‬ ‭pharmacy‬ ‭or‬ ‭hospital‬
‭standard operating procedure manual should be followed when handling hazardous drugs.‬
‭7.4.‬
‭Investigational Medical Products Administration‬
‭7.4.1.‬ ‭Atezolizumab administration‬
‭Atezolizumab‬‭will‬‭be‬‭administered‬‭after‬‭all‬‭procedures/assessments‬‭have‬‭been‬‭completed‬‭as‬
‭described‬‭in‬‭the‬‭Schedule‬‭of‬‭Activities‬‭(‬‭Table‬‭4‬‭),‬‭as‬‭a‬‭1-hour‬‭IV‬‭infusion‬‭once‬‭every‬‭3‬‭weeks‬
‭until‬‭disease‬‭progression,‬‭unacceptable‬‭toxicity‬‭or‬‭absence‬‭of‬‭clinical‬‭benefitbenefitt.‬‭AUREA‬
‭is‬‭an‬‭Investigator‬‭Initiated‬‭Study,‬‭the‬‭Sponsor‬‭will‬‭supply‬‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬‭months‬‭of‬
‭treatment‬‭for‬‭each‬‭patient.‬‭For‬‭those‬‭patients‬‭in‬‭which‬‭the‬‭PI‬‭considers‬‭that‬‭the‬‭best‬‭option‬‭for‬
‭the‬ ‭patient‬ ‭is‬ ‭continuing‬‭atezolizumab‬‭for‬‭more‬‭than‬‭24‬‭months,‬‭available‬‭commercial‬‭Site‬
‭supplies should be used, after managed local administrative regulation.‬
‭The‬‭infusions‬‭must‬‭not‬‭be‬‭administered‬‭as‬‭an‬‭intravenous‬‭push‬‭or‬‭bolus.‬‭The‬‭initial‬‭dose‬‭of‬
‭atezolizumab‬‭must‬‭be‬‭administered‬‭over‬‭60‬‭minutes.‬‭If‬‭the‬‭first‬‭infusion‬‭is‬‭well‬‭tolerated,‬‭all‬
‭subsequent infusions may be administered over 30 minutes.‬
‭Atezolizumab‬ ‭will‬ ‭be‬ ‭administered‬ ‭in‬ ‭IV‬ ‭infusion‬ ‭bags‬ ‭containing‬ ‭0.9%‬ ‭sodium‬ ‭chloride‬
‭(NaCl)‬ ‭and‬ ‭infusion‬ ‭lines‬ ‭equipped‬ ‭with‬ ‭0.2‬ ‭or‬ ‭0.22‬‭m‬‭in-line‬‭filters.‬‭The‬‭IV‬‭bag‬‭may‬‭be‬
‭constructed‬‭of‬‭polyvinyl‬‭chloride,‬‭polyolefin,‬‭polyethylene,‬‭or‬‭polypropylene.‬‭The‬‭IV‬‭infusion‬
‭line‬‭may‬‭be‬‭constructed‬‭of‬‭polyvinyl‬‭chloride,‬‭polyethylene,‬‭polybutadiene,‬‭or‬‭polyurethane‬
‭and‬‭the‬‭0.2‬‭or‬‭0.22‬‭m‬‭in-line‬‭filter‬‭may‬‭be‬‭constructed‬‭of‬‭polyethersulfone‬‭or‬‭polysulfone.‬‭The‬
‭use‬‭of‬‭administration‬‭supplies‬‭composed‬‭of‬‭materials‬‭other‬‭than‬‭those‬‭listed‬‭should‬‭be‬‭avoided‬
‭if‬ ‭possible.‬ ‭Atezolizumab‬ ‭can‬ ‭be‬ ‭diluted‬ ‭to‬ ‭concentrations‬ ‭between‬ ‭3.2‬ ‭mg/mL‬ ‭and‬ ‭16.8‬
‭mg/mL‬ ‭in‬ ‭IV‬ ‭bags‬ ‭containing‬ ‭0.9%‬ ‭NaCl.‬ ‭Atezolizumab‬ ‭must‬ ‭be‬ ‭prepared/diluted‬ ‭under‬
‭appropriate aseptic conditions as it does not contain antimicrobial preservatives.‬
‭The‬‭prepared‬‭solution‬‭for‬‭infusion‬‭should‬‭be‬‭used‬‭immediately‬‭to‬‭limit‬‭microbial‬‭growth‬‭in‬
‭case‬‭of‬‭potential‬‭accidental‬‭contamination.‬‭If‬‭not‬‭used‬‭immediately,‬‭in-use‬‭storage‬‭time‬‭and‬
‭conditions‬‭prior‬‭to‬‭use‬‭are‬‭the‬‭responsibility‬‭of‬‭the‬‭user.‬‭For‬‭flat‬‭or‬‭fixed‬‭dosing‬‭(1200‬‭mg‬‭for‬
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‭this‬‭clinical‬‭trial)‬‭in‬ ‭IV‬‭infusion‬‭bags,‬‭the‬‭dose‬‭solution‬‭may‬‭be‬‭stored‬‭at‬‭2°C–8°C‬‭(36°F‬‭–‬
‭46°F)‬‭for‬‭24‬‭hours‬‭or‬‭at‬‭ambient‬‭temperature‬‭≤‬‭25°C‬‭(77°F)‬‭for‬‭8‬‭hours.‬‭This‬‭time‬‭includes‬
‭storage‬ ‭and‬ ‭time‬ ‭for‬ ‭administration‬ ‭for‬ ‭infusion..‬ ‭Do‬ ‭not‬ ‭shake‬ ‭or‬ ‭freeze‬ ‭infusion‬ ‭bags‬
‭containing the dose solution.‬
‭Detailed‬‭information‬‭on‬‭infusion‬‭bags‬‭and‬‭medical‬‭devices‬‭to‬‭be‬‭used‬‭for‬‭the‬‭preparation‬‭of‬
‭the‬‭dilutions‬‭and‬‭subsequent‬‭administration‬‭will‬‭be‬‭provided‬‭in‬‭the‬‭Dosage‬‭and‬‭Administration‬
‭Instruction‬ ‭contained‬ ‭in‬ ‭the‬ ‭Summary‬ ‭of‬ ‭Product‬‭Characteristics,‬‭and‬‭when‬‭applicable,‬‭the‬
‭corresponding Pharmacy Guidelines.‬
‭Any‬‭unused‬‭portion‬‭of‬‭the‬‭solution‬‭should‬‭be‬‭discarded‬‭in‬‭biohazard‬‭waste‬‭disposal‬‭with‬‭final‬
‭disposal by accepted local and national standards of incineration.‬
‭No‬ ‭premedication‬‭is‬‭indicated‬‭for‬‭the‬‭administration‬‭of‬‭Cycle‬‭1‬‭of‬‭atezolizumab.‬‭However,‬
‭patients‬ ‭who‬ ‭experience‬ ‭an‬ ‭infusion-related‬ ‭reaction‬ ‭(IRR)‬ ‭or‬ ‭cytokine-release‬ ‭syndrome‬
‭(CRS)‬‭with‬‭atezolizumab‬‭may‬‭receive‬‭premedication‬‭with‬‭antihistamines,‬‭antipyretics,‬‭and/or‬
‭analgesics‬‭(e.g.,‬‭acetaminophen)‬‭for‬‭subsequent‬‭infusions.‬‭See‬‭more‬‭information‬‭in‬‭Appendix‬
‭1‬‭.‬
‭7.4.1.1.‬‭Intrapatient Atezolizumab Dose Reduction‬
‭The‬‭dose‬‭amount‬‭required‬‭to‬‭prepare‬‭the‬‭atezolizumab‬‭infusion‬‭solution‬‭will‬‭be‬‭based‬‭on‬‭the‬
‭corresponding‬‭flat‬‭dose‬‭of‬‭1200‬‭mg‬‭established‬‭in‬‭this‬‭protocol.‬‭Overall,‬‭Atezolizumab‬‭dose‬
‭reduction‬ ‭for‬ ‭toxicity‬ ‭management‬ ‭is‬ ‭not‬ ‭permitted.‬ ‭Toxicity‬ ‭management‬ ‭(dose‬ ‭delay‬ ‭or‬
‭discontinuation) in case of immune-mediated events is described in‬‭Appendix 1‬‭.‬
‭7.4.2.‬ ‭Gemcitabine and cisplatin administration‬
‭The‬‭infusions‬‭must‬‭not‬‭be‬‭administered‬‭as‬‭an‬‭intravenous‬‭push‬‭or‬‭bolus.‬‭The‬‭estimated‬‭total‬
‭infusion‬‭time‬‭for‬‭this‬‭treatment‬‭takes‬‭up‬‭to‬‭two‬‭hours‬‭for‬‭Day‬‭1‬‭and‬‭Day‬‭8‬‭of‬‭each‬‭21-days‬
‭cycle.‬‭Typically,‬‭IV‬‭hydration‬‭is‬‭given‬‭both‬‭before‬‭and‬‭after‬‭cisplatin‬‭and‬‭can‬‭add‬‭up‬‭to‬‭two‬
‭hours‬‭on‬‭administration‬‭days.‬‭Infusion‬‭times‬‭may‬‭vary‬‭depending‬‭on‬‭physician‬‭preference‬‭or‬
‭patient tolerability.‬
‭7.4.2.1. Gemcitabine administration‬
‭Gemcitabine‬ ‭will‬ ‭be‬ ‭administered‬ ‭after‬ ‭all‬‭procedures/assessments‬‭have‬‭been‬‭completed‬‭as‬
‭described‬‭in‬‭the‬‭Schedule‬‭of‬‭Activities‬‭(‬‭Table‬‭4‬‭),‬‭as‬‭a‬‭30-minutes‬‭IV‬‭infusion‬‭on‬‭days‬‭1‬‭and‬‭8‬
‭once every 3 weeks for a maximum of 6 cycles.‬
‭Gemcitabine‬ ‭is‬ ‭tolerated‬ ‭well‬ ‭during‬ ‭infusion‬ ‭and‬ ‭may‬ ‭be‬ ‭administered‬ ‭ambulant.‬ ‭If‬
‭extravasation‬‭occurs,‬‭generally‬‭the‬‭infusion‬‭must‬‭be‬‭stopped‬‭immediately‬‭and‬‭started‬‭again‬‭in‬
‭another‬ ‭blood‬ ‭vessel.‬ ‭The‬ ‭patient‬ ‭should‬ ‭be‬ ‭monitored‬ ‭carefully‬ ‭after‬ ‭the‬ ‭administration.‬
‭Treatment‬‭omitted‬‭will‬‭not‬‭be‬‭reinstated‬‭within‬‭a‬‭cycle.‬‭Treatment‬‭will‬‭start‬‭on‬‭day‬‭1‬‭of‬‭the‬
‭next‬‭cycle‬‭once‬‭the‬‭absolute‬‭granulocyte‬‭count‬‭reaches‬‭at‬‭least‬‭1,500‬‭(x10‬‭6‬‭/l)‬‭and‬‭the‬‭platelet‬
‭count reaches 100,000 (x10‬‭6‬‭/l)‬‭.‬
‭7.4.2.2.‬‭Cisplatin administration‬
‭Cisplatin‬‭should‬‭be‬‭administered‬‭by‬‭intravenous‬‭infusion‬‭over‬‭a‬‭period‬‭of‬‭6‬‭to‬‭8‬‭hours‬‭on‬‭days‬
‭1‬ ‭and‬ ‭8‬ ‭once‬ ‭every‬ ‭3‬ ‭weeks‬ ‭for‬ ‭a‬ ‭maximum‬ ‭of‬ ‭6‬ ‭cycles.‬ ‭Adequate‬ ‭hydration‬ ‭must‬ ‭be‬
‭maintained‬ ‭from‬ ‭2‬ ‭to‬ ‭12‬ ‭hours‬ ‭prior‬ ‭to‬ ‭administration‬ ‭until‬ ‭minimum‬ ‭6‬ ‭hours‬ ‭after‬ ‭the‬
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‭administration‬‭of‬‭cisplatin.‬‭Hydration‬‭is‬‭necessary‬‭to‬‭cause‬‭sufficient‬‭diuresis‬‭during‬‭and‬‭after‬
‭treatment‬‭with‬‭cisplatin.‬‭It‬‭is‬‭realised‬‭by‬‭intravenous‬‭infusion‬‭of‬‭one‬‭of‬‭the‬‭following‬‭solutions‬
‭specified on the SmPC.‬
‭7.4.2.3.‬‭Intrapatient Gemcitabine and Cisplatin Dose Reduction‬
‭According‬ ‭to‬ ‭the‬ ‭current‬ ‭version‬ ‭of‬ ‭Gemcitabine‬ ‭Summary‬ ‭of‬ ‭Product‬ ‭Characteristics‬
‭(‬‭Gemcitabine‬‭SmPC‬‭)‬‭at‬‭the‬‭time‬‭of‬‭this‬‭study‬‭design‬‭(March‬‭2020),‬‭dose‬‭modifications‬‭are‬
‭considered‬‭in‬‭case‬‭of‬‭haematological‬‭toxicity‬‭as‬‭described‬‭below.‬‭For‬‭the‬‭matter‬‭of‬‭this‬‭study,‬
‭information‬‭on‬‭dose‬‭modification‬‭recommendations‬‭for‬‭gemcitabine‬‭given‬‭in‬‭monotherapy‬‭or‬
‭in combination with cisplatin for bladder cancer are described.‬
‭Dose modifications due to haematological toxicity: Initiation of a cycle‬
‭For‬‭all‬‭indications,‬‭the‬‭patient‬‭must‬‭be‬‭monitored‬‭before‬‭each‬‭dose‬‭for‬‭platelet‬‭and‬‭granulocyte‬
‭counts.‬ ‭Patients‬ ‭should‬ ‭have‬ ‭an‬ ‭absolute‬‭granulocyte‬‭count‬‭of‬‭at‬‭least‬‭1,500‬‭(x‬‭10‬‭6‬ ‭/l)‬‭and‬
‭platelet account of 100,000 (x 10‬‭6‬‭/l) prior to the‬‭initiation of a cycle.‬
‭Dose modifications due to haematological toxicity: Within a cycle‬
‭Dose modifications of gemcitabine within a cycle should be performed according to‬‭Table 2‬‭:‬
‭Table‬‭2.‬‭Dose‬‭modification‬‭of‬‭gemcitabine‬‭within‬‭a‬‭cycle‬‭for‬‭bladder‬‭cancer,‬‭NSCLC‬‭and‬
‭pancreatic cancer, given in monotherapy or in combination with cisplatin‬
‭Absolute granulocyte count‬
‭(x 10‬‭6‬‭/l)‬
‭Platelet count‬
‭(x 10‬‭6‬‭/l)‬
‭Percentage of standard dose‬
‭of Gemcitabine (%)‬
‭> 1,000                              and‬
‭> 100,000‬
‭100‬
‭500 - 1,000                        or‬
‭50,000-100,000‬
‭75‬
‭<500                                  or‬
‭< 50,000‬
‭Omit dose*‬
‭*Treatment‬‭omitted‬‭will‬‭not‬‭be‬‭reinstated‬‭within‬‭a‬‭cycle‬‭before‬‭the‬‭absolute‬‭granulocyte‬‭count‬‭reaches‬
‭at least 500 (x106 /l) and the platelet count reaches 50,000 (x10‬‭6‬‭/l).‬
‭Dose modifications due to haematological toxicity: Subsequent cycles for all indications‬
‭The‬‭gemcitabine‬‭dose‬‭should‬‭be‬‭reduced‬‭to‬‭75%‬‭of‬‭the‬‭original‬‭cycle‬‭initiation‬‭dose,‬‭in‬‭the‬
‭case of the following hematologic toxicities (‬‭Table‬‭3‬‭):‬
‭Table 3. Dose modification of gemcitabine in subsequent cycles for all indications‬
‭Count‬
‭(x 10‬‭6‬‭/l)‬
‭Time‬
‭Percentage of standard‬
‭dose of Gemcitabine (%)‬
‭Absolute granulocyte‬
‭< 500‬
‭> 5 days‬
‭75‬
‭< 100‬
‭> 3 days‬
‭75‬
‭Platelet count‬
‭< 25,000‬
‭Not applicable‬
‭75‬
‭Febrile neutropenia‬
‭-‬
‭-‬
‭75‬
‭Cycle delay > 1 week to toxicity‬
‭-‬
‭-‬
‭75‬
‭Patients‬ ‭will‬ ‭be‬ ‭monitored‬ ‭closely‬ ‭for‬ ‭toxicity;‬ ‭Gemcitabine‬ ‭may‬ ‭be‬ ‭adjusted‬ ‭by‬ ‭dosing‬
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‭interruption with or without dose reduction as indicated in‬‭Table 2‬‭and‬‭Table‬‭3.‬
‭Management‬‭of‬‭patients‬‭requiring‬‭more‬‭than‬‭2‬‭dose‬‭reductions‬‭of‬‭any‬‭of‬‭the‬‭IMPs‬‭(one‬‭dose‬
‭level decrease at a time) should be discussed with the Coordinating Investigator.‬
‭Patients‬‭who‬‭have‬‭undergone‬‭dose‬‭reduction‬‭may‬‭also‬‭undergo‬‭dose‬‭re-escalation‬‭back‬‭to‬‭the‬
‭previous‬ ‭dose‬ ‭level‬ ‭at‬ ‭the‬ ‭discretion‬ ‭of‬ ‭the‬ ‭Investigator‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬ ‭Grade‬ ‭≥2‬
‭non-hematologic treatment-related toxicity for at least 28 days.‬
‭7.5.‬
‭Special Precautions for Investigational Medical Products‬
‭7.5.1.‬ ‭Special Precautions for Atezolizumab‬
‭In‬‭order‬‭to‬‭improve‬‭the‬‭traceability‬‭of‬‭biological‬‭medicinal‬‭products,‬‭the‬‭trade‬‭name‬‭and‬‭the‬
‭batch‬‭number‬‭of‬‭the‬‭administered‬‭product‬‭should‬‭be‬‭clearly‬‭recorded‬‭(or‬‭stated)‬‭in‬‭the‬‭patient‬
‭file.‬
‭Pneumonitis‬ ‭secondary‬ ‭to‬ ‭PD1/PDL1‬ ‭inhibitor‬ ‭drugs‬ ‭is‬ ‭a‬ ‭rare‬ ‭but‬ ‭potentially‬ ‭serious‬ ‭side‬
‭effect,‬‭patients‬‭should‬‭be‬‭monitored‬‭for‬‭signs‬‭and‬‭symptoms‬‭of‬‭pneumonitis‬‭during‬‭physical‬
‭examination‬‭(PE),‬‭and‬‭causes‬‭other‬‭than‬‭immune-mediated‬‭pneumonitis‬‭should‬‭be‬‭ruled‬‭out‬‭in‬
‭the case of findings during PE.‬
‭7.5.1.1.‬‭Hepatic impairment‬
‭No‬ ‭dedicated‬ ‭studies‬ ‭of‬ ‭atezolizumab‬ ‭have‬ ‭been‬ ‭conducted‬ ‭in‬ ‭patients‬ ‭with‬ ‭hepatic‬
‭impairment.‬ ‭In‬ ‭the‬ ‭population‬ ‭pharmacokinetic‬ ‭analysis,‬‭there‬‭were‬‭no‬‭clinically‬‭important‬
‭differences‬‭in‬‭the‬‭clearance‬‭of‬‭atezolizumab‬‭between‬‭patients‬‭with‬‭mild‬‭hepatic‬‭impairment‬
‭(bilirubin‬ ‭≤‬ ‭ULN‬ ‭and‬ ‭AST‬ ‭>‬ ‭ULN‬ ‭or‬ ‭bilirubin‬ ‭1.0‬ ‭to‬‭1.5‬‭ULN‬‭and‬‭any‬‭AST,‬‭n=71)‬‭and‬
‭normal‬‭hepatic‬‭function‬‭(bilirubin‬‭and‬‭AST‬‭≤‬‭ULN,‬‭n=401).‬‭No‬‭data‬‭are‬‭available‬‭in‬‭patients‬
‭with‬‭either‬‭moderate‬‭(bilirubin‬‭>‬‭1.5‬‭to‬‭3.0‬‭x‬‭ULN‬‭and‬‭any‬‭AST)‬‭or‬‭severe‬‭(bilirubin‬‭>‬‭3.0‬
‭ULN‬ ‭and‬ ‭any‬ ‭AST)‬ ‭hepatic‬ ‭impairment.‬ ‭Hepatic‬ ‭impairment‬ ‭was‬ ‭defined‬‭by‬‭the‬‭National‬
‭Cancer‬ ‭Institute‬ ‭criteria‬ ‭of‬ ‭hepatic‬ ‭dysfunction.‬ ‭More‬ ‭information‬ ‭available‬ ‭in‬ ‭the‬ ‭current‬
‭version of Atezolizumab Investigator’s Brochure.‬
‭7.5.1.2.‬‭Renal impairment‬
‭No‬‭dedicated‬‭studies‬‭of‬‭atezolizumab‬‭have‬‭been‬‭conducted‬‭in‬‭patients‬‭with‬‭renal‬‭impairment.‬
‭More information available in the current version of Atezolizumab Investigator’s Brochure.‬
‭7.5.1.3.‬‭Reproductive and Developmental Toxicity‬
‭Reproductive‬‭and‬‭developmental‬‭toxicity‬‭studies‬‭with‬‭atezolizumab‬‭have‬‭not‬‭been‬‭conducted.‬
‭The‬‭PD-L1/‬‭programmed‬‭death‬‭1‬‭(PD-1)‬‭signaling‬‭pathway‬‭is‬‭well‬‭established‬‭as‬‭essential‬‭in‬
‭maternal/fetal‬ ‭tolerance‬ ‭and‬ ‭embryo-fetal‬ ‭survival‬ ‭during‬ ‭gestation‬ ‭(‬‭Guleria‬ ‭et‬ ‭al.‬ ‭2005;‬
‭Habicht‬‭et‬‭al.‬‭2007;‬‭D’Addio‬‭et‬‭al.‬‭2011‬‭).‬‭Administration‬‭of‬‭atezolizumab‬‭is‬‭expected‬‭to‬‭have‬
‭an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality.‬
‭7.5.1.4.‬‭Immune-mediated adverse reactions‬
‭Most‬‭immune-mediated‬‭adverse‬‭reactions‬‭that‬‭occur‬‭during‬‭treatment‬‭with‬‭atezolizumab‬‭are‬
‭reversible‬ ‭with‬ ‭the‬ ‭interruptions‬ ‭of‬ ‭atezolizumab‬ ‭and‬ ‭initiation‬ ‭of‬ ‭corticosteroids‬ ‭and/or‬
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‭supportive‬ ‭care.‬ ‭Immune-mediated‬ ‭adverse‬ ‭reactions‬ ‭affecting‬ ‭more‬ ‭than‬ ‭one‬‭body‬‭system‬
‭have been observed; these may occur after the last dose of atezolizumab.‬
‭For‬‭suspected‬‭immune-mediated‬‭adverse‬‭reactions,‬‭thorough‬‭evaluation‬‭to‬‭confirm‬‭aetiology‬
‭or‬‭exclude‬‭other‬‭causes‬‭should‬‭be‬‭performed.‬‭Based‬‭on‬‭the‬‭severity‬‭of‬‭the‬‭adverse‬‭reaction,‬
‭atezolizumab‬ ‭should‬ ‭be‬ ‭withheld‬ ‭and‬ ‭corticosteroids‬ ‭administered.‬ ‭Upon‬ ‭improvement‬ ‭to‬
‭Grade‬ ‭≤‬ ‭1,‬ ‭corticosteroid‬ ‭should‬ ‭be‬ ‭tapered‬ ‭over‬ ‭≥‬ ‭1‬ ‭month.‬ ‭Based‬ ‭on‬ ‭limited‬ ‭data‬‭from‬
‭clinical‬‭studies‬‭in‬‭patients‬‭whose‬‭immune-mediated‬‭adverse‬‭reactions‬‭could‬‭not‬‭be‬‭controlled‬
‭with‬ ‭systemic‬ ‭corticosteroid‬ ‭use,‬ ‭the‬ ‭administration‬ ‭of‬ ‭other‬‭systemic‬‭immunosuppressants‬
‭may be considered.‬
‭Atezolizumab‬‭must‬‭be‬‭permanently‬‭discontinued‬‭for‬‭any‬‭Grade‬‭3‬‭immune-mediated‬‭adverse‬
‭reaction‬ ‭that‬ ‭recurs‬ ‭and‬ ‭for‬ ‭any‬ ‭Grade‬ ‭4‬ ‭immune-mediated‬ ‭adverse‬ ‭reactions,‬ ‭except‬ ‭for‬
‭endocrinopathies‬‭that‬‭are‬‭controlled‬‭with‬‭replacement‬‭hormones.‬‭Specific‬‭guidelines‬‭for‬‭the‬
‭management of atezolizumab-specific adverse events is available in‬‭Appendix 1‬‭.‬
‭1)‬
‭Pulmonary events‬
‭Pneumonitis‬ ‭secondary‬ ‭to‬ ‭PD1/PDL1‬ ‭inhibitor‬ ‭drugs‬ ‭is‬ ‭a‬ ‭rare‬ ‭but‬ ‭potentially‬ ‭serious‬ ‭side‬
‭effect,‬‭patients‬‭should‬‭be‬‭monitored‬‭for‬‭signs‬‭and‬‭symptoms‬‭of‬‭pneumonitis‬‭during‬‭physical‬
‭examination‬‭(PE),‬‭and‬‭causes‬‭other‬‭than‬‭immune-mediated‬‭pneumonitis‬‭should‬‭be‬‭ruled‬‭out‬‭in‬
‭the case of findings during PE.‬
‭Cases‬‭of‬‭pulmonary‬‭events,‬‭including‬‭dyspnea,‬‭cough,‬‭fatigue‬‭and‬‭pulmonary‬‭infiltrates,‬‭have‬
‭been‬‭observed‬‭in‬‭clinical‬‭trials‬‭with‬‭atezolizumab.‬‭Patients‬‭should‬‭be‬‭monitored‬‭for‬‭pulmonary‬
‭signs and symptoms.‬
‭Treatment‬ ‭with‬ ‭atezolizumab‬ ‭should‬ ‭be‬ ‭withheld‬ ‭for‬ ‭Grade‬ ‭2‬ ‭pulmonary‬ ‭event‬ ‭,‬ ‭and‬
‭corticosteroids‬ ‭equivalent‬‭1‬‭to‬‭2‬‭mg/kg/day‬‭oral‬‭prednisone‬‭should‬‭be‬‭started.‬‭If‬‭symptoms‬
‭improve‬ ‭to‬ ‭≤‬ ‭Grade‬ ‭1,‬ ‭corticosteroids‬ ‭should‬ ‭be‬ ‭tapered‬ ‭over‬ ‭≥‬ ‭1‬ ‭month.‬ ‭Treatment‬‭with‬
‭atezolizumab‬ ‭may‬ ‭be‬ ‭resumed‬ ‭if‬ ‭the‬ ‭event‬ ‭improves‬ ‭to‬ ‭≤‬ ‭Grade‬ ‭1‬ ‭within‬ ‭12‬ ‭weeks,‬ ‭and‬
‭corticosteroids‬‭have‬‭been‬‭reduced‬‭to‬‭≤‬‭10‬‭mg‬‭prednisone‬‭or‬‭equivalent‬‭per‬‭day.‬‭Treatment‬‭with‬
‭atezolizumab must be permanently discontinued for Grade 3 or 4 pulmonary events.‬
‭2)‬
‭Hepatic events‬
‭Immune-mediated‬ ‭hepatitis‬ ‭has‬ ‭been‬ ‭associated‬ ‭with‬ ‭the‬ ‭administration‬ ‭of‬ ‭atezolizumab.‬
‭Eligible‬‭patients‬‭must‬‭have‬‭adequate‬‭liver‬‭function,‬‭as‬‭manifested‬‭by‬‭measurements‬‭of‬‭total‬
‭bilirubin‬ ‭and‬ ‭hepatic‬ ‭transaminases,‬ ‭and‬ ‭liver‬ ‭function‬‭will‬‭be‬‭monitored‬‭throughout‬‭study‬
‭treatment. Management guidelines for hepatic events are provided in‬‭Appendix 1‬‭.‬
‭3)‬
‭Gastrointestinal events‬
‭Immune-mediated‬ ‭colitis‬ ‭has‬ ‭been‬ ‭associated‬ ‭with‬ ‭the‬ ‭administration‬ ‭of‬ ‭atezolizumab.‬‭All‬
‭events‬‭of‬‭diarrhea‬‭or‬‭colitis‬‭should‬‭be‬‭thoroughly‬‭evaluated‬‭for‬‭other‬‭common‬‭etiologies.‬‭For‬
‭events‬ ‭of‬ ‭significant‬ ‭duration‬ ‭or‬ ‭or‬ ‭magnitude‬ ‭or‬ ‭associated‬ ‭with‬ ‭signs‬ ‭of‬ ‭systemic‬
‭inflammation‬ ‭or‬ ‭acute-phase‬ ‭reactants‬ ‭(e.g.,‬ ‭increased‬ ‭C-reactive‬‭protein,‬‭platelet‬‭count,‬‭or‬
‭bandemia):‬‭Perform‬‭sigmoidoscopy‬‭(or‬‭colonoscopy,‬‭if‬‭appropriate)‬‭with‬‭colonic‬‭biopsy,‬‭with‬
‭three‬‭to‬‭five‬‭specimens‬‭for‬‭standard‬‭paraffin‬‭block‬‭to‬‭check‬‭for‬‭inflammation‬‭and‬‭lymphocytic‬
‭infiltrates to confirm colitis diagnosis. More information provided in‬‭Appendix 1‬‭.‬
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‭4)‬
‭Endocrine events‬
‭Thyroid‬‭disorders,‬‭adrenal‬‭insufficiency,‬‭diabetes‬‭mellitus,‬‭and‬‭pituitary‬‭disorders‬‭have‬‭been‬
‭associated with the administration of atezolizumab.‬
‭Patients‬ ‭with‬ ‭unexplained‬ ‭symptoms‬ ‭such‬ ‭as‬ ‭headache,‬ ‭fatigue,‬ ‭myalgias,‬ ‭impotence,‬
‭constipation,‬ ‭or‬ ‭mental‬ ‭status‬ ‭changes‬ ‭should‬ ‭be‬ ‭investigated‬ ‭for‬ ‭the‬ ‭presence‬ ‭of‬ ‭thyroid,‬
‭pituitary,‬‭or‬‭adrenal‬‭endocrinopathies.‬‭The‬‭patient‬‭should‬‭be‬‭referred‬‭to‬‭an‬‭endocrinologist‬‭if‬
‭an endocrinopathy is suspected.‬
‭Thyroid-stimulating‬‭hormone‬‭(TSH)‬‭and‬‭free‬‭triiodothyronine‬‭(T3)‬‭and‬‭thyroxine‬‭(T4)‬‭levels‬
‭should‬‭be‬‭measured‬‭to‬‭determine‬‭whether‬‭thyroid‬‭abnormalities‬‭are‬‭present.‬‭Pituitary‬‭hormone‬
‭levels‬‭and‬‭function‬‭tests‬‭(e.g.,‬‭TSH,‬‭GH,‬‭luteinizing‬‭hormone,‬‭follicle-stimulating‬‭hormone,‬
‭testosterone,‬ ‭prolactin,‬ ‭adrenocorticotropic‬‭hormone‬‭[ACTH]‬‭levels,‬‭and‬‭ACTH‬‭stimulation‬
‭test)‬‭and‬‭magnetic‬‭resonance‬‭imaging‬‭(MRI)‬‭of‬‭the‬‭brain‬‭(with‬‭detailed‬‭pituitary‬‭sections)‬‭may‬
‭help‬‭to‬‭differentiate‬‭primary‬‭pituitary‬‭insufficiency‬‭from‬‭primary‬‭adrenal‬‭insufficiency.‬‭More‬
‭information provided in‬‭Appendix 1‬‭.‬
‭5)‬
‭Ocular events‬
‭An‬ ‭ophthalmologist‬ ‭should‬ ‭evaluate‬ ‭visual‬ ‭complaints‬ ‭(e.g.,‬ ‭uveitis,‬ ‭retinal‬ ‭events).‬ ‭More‬
‭information provided in‬‭Appendix 1‬‭.‬
‭6)‬
‭Immune-Mediated Myocarditis‬
‭Immune-mediated‬ ‭myocarditis‬ ‭has‬ ‭been‬ ‭associated‬‭with‬‭the‬‭administration‬‭of‬‭atezolizumab‬
‭and‬ ‭should‬ ‭be‬ ‭suspected‬ ‭in‬ ‭any‬ ‭patient‬ ‭presenting‬ ‭with‬ ‭signs‬ ‭or‬ ‭symptoms‬ ‭suggestive‬ ‭of‬
‭myocarditis,‬ ‭including,‬ ‭but‬ ‭not‬ ‭limited‬ ‭to,‬ ‭laboratory‬ ‭(e.g.,‬ ‭B-type‬ ‭Natriuretic‬ ‭Peptide])‬ ‭or‬
‭cardiac‬‭imaging‬‭abnormalities,‬‭dyspnea,‬‭chest‬‭pain,‬‭palpitations,‬‭fatigue,‬‭decreased‬‭exercise‬
‭tolerance, or syncope.‬
‭Immune-mediated‬ ‭myocarditis‬ ‭needs‬ ‭to‬ ‭be‬ ‭distinguished‬ ‭from‬ ‭myocarditis‬ ‭resulting‬ ‭from‬
‭infection‬ ‭(commonly‬‭viral,‬‭e.g.,‬‭in‬‭a‬‭patient‬‭who‬‭reports‬‭a‬‭recent‬‭history‬‭of‬‭gastrointestinal‬
‭illness),‬ ‭ischemic‬ ‭events,‬ ‭underlying‬ ‭arrhythmias,‬ ‭exacerbation‬ ‭of‬ ‭pre-existing‬ ‭cardiac‬
‭conditions, or progression of malignancy.‬
‭All‬ ‭patients‬ ‭with‬ ‭possible‬ ‭myocarditis‬ ‭should‬ ‭be‬ ‭urgently‬ ‭evaluated‬‭by‬‭performing‬‭cardiac‬
‭enzyme‬ ‭assessment,‬ ‭an‬ ‭ECG,‬ ‭a‬ ‭chest‬ ‭X-ray,‬ ‭an‬ ‭echocardiogram,‬ ‭and‬ ‭a‬ ‭cardiac‬ ‭MRI‬ ‭as‬
‭appropriate‬ ‭per‬ ‭institutional‬ ‭guidelines.‬ ‭A‬ ‭cardiologist‬ ‭should‬ ‭be‬ ‭consulted.‬ ‭An‬
‭endomyocardial‬ ‭biopsy‬ ‭may‬ ‭be‬ ‭considered‬‭to‬‭enable‬‭a‬‭definitive‬‭diagnosis‬‭and‬‭appropriate‬
‭treatment,‬ ‭if‬ ‭clinically‬ ‭indicated.‬ ‭Patients‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭myocarditis,‬ ‭in‬ ‭the‬
‭absence‬ ‭of‬ ‭an‬ ‭identified‬‭alternate‬‭etiology,‬‭should‬‭be‬‭treated‬‭according‬‭to‬‭the‬‭guidelines‬‭in‬
‭Appendix 1‬‭.‬
‭7)‬
‭Infusion-Related Reactions and Cytokine-Release Syndrome‬
‭No‬ ‭premedication‬‭is‬‭indicated‬‭for‬‭the‬‭administration‬‭of‬‭Cycle‬‭1‬‭of‬‭atezolizumab.‬‭However,‬
‭patients‬ ‭who‬ ‭experience‬ ‭an‬ ‭infusion-related‬ ‭reaction‬ ‭(IRR)‬ ‭or‬ ‭cytokine-release‬ ‭syndrome‬
‭(CRS)‬‭with‬‭atezolizumab‬‭may‬‭receive‬‭premedication‬‭with‬‭antihistamines,‬ ‭antipyretics,‬‭and/or‬
‭analgesics‬‭(e.g.,‬‭acetaminophen)‬‭for‬‭subsequent‬‭infusions.‬‭Metamizole‬‭(dipyrone)‬‭is‬‭prohibited‬
‭in‬ ‭treating‬ ‭atezolizumab-associated‬ ‭infusion-related‬ ‭reactions,‬ ‭due‬ ‭to‬ ‭IRRs‬ ‭because‬ ‭of‬ ‭its‬
‭potential for causing agranulocytosis.‬
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‭IRRs‬ ‭are‬ ‭known‬ ‭to‬ ‭occur‬ ‭with‬ ‭the‬‭administration‬‭of‬‭monoclonal‬‭antibodies‬‭and‬‭have‬‭been‬
‭reported‬ ‭with‬ ‭atezolizumab.‬ ‭These‬ ‭reactions,‬ ‭which‬ ‭are‬ ‭thought‬ ‭to‬ ‭be‬ ‭due‬ ‭to‬ ‭release‬ ‭of‬
‭cytokines‬ ‭and/or‬ ‭other‬ ‭chemical‬ ‭mediators,‬ ‭occur‬ ‭within‬ ‭24‬ ‭hours‬ ‭of‬ ‭atezolizumab‬
‭administration and are generally mild to moderate in severity.‬
‭CRS‬ ‭is‬ ‭defined‬ ‭as‬ ‭a‬ ‭supraphysiologic‬ ‭response‬ ‭following‬ ‭administration‬ ‭of‬ ‭any‬ ‭immune‬
‭therapy‬‭that‬‭results‬‭in‬‭activation‬‭or‬‭engagement‬‭of‬‭endogenous‬‭or‬‭infused‬‭T‬‭cells‬‭and/or‬‭other‬
‭immune‬‭effector‬‭cells.‬‭Symptoms‬‭can‬‭be‬‭progressive,‬‭always‬‭include‬‭fever‬‭at‬‭the‬‭onset,‬‭and‬
‭may‬ ‭include‬ ‭hypotension,‬ ‭capillary‬ ‭leak‬ ‭(hypoxia),‬ ‭and‬ ‭end‬ ‭-organ‬ ‭dysfunction‬‭(Lee‬‭et‬‭al.‬
‭2019).‬ ‭CRS‬ ‭has‬ ‭been‬ ‭well‬‭documented‬‭with‬‭chimeric‬‭antigen‬‭receptor‬‭T-cell‬‭therapies‬‭and‬
‭bispecific‬‭T-cell‬‭engager‬‭antibody‬‭therapies‬‭but‬‭has‬‭also‬‭been‬‭reported‬‭with‬‭immunotherapies‬
‭that‬ ‭target‬ ‭PD-1‬ ‭or‬ ‭PD-L1‬ ‭(‬‭Rotz‬ ‭et‬ ‭al.‬ ‭2017‬‭;‬ ‭Adashek‬ ‭and‬ ‭Feldman‬ ‭2019‬‭),‬ ‭including‬
‭atezolizumab.‬
‭There‬‭may‬‭be‬‭significant‬‭overlap‬‭in‬‭signs‬‭and‬‭symptoms‬‭of‬‭IRRs‬‭and‬‭CRS,‬‭and‬‭in‬‭recognition‬
‭of‬ ‭the‬ ‭challenges‬ ‭in‬ ‭clinically‬ ‭distinguishing‬ ‭between‬ ‭the‬ ‭two,‬ ‭consolidated‬ ‭guidelines‬ ‭for‬
‭medical management of IRRs during Cycle 1 and CRS are provided in‬‭Appendix 1‬‭.‬
‭8)‬
‭Pancreatic events‬
‭Symptoms‬‭of‬‭abdominal‬‭pain‬‭associated‬‭with‬‭elevations‬‭of‬‭amylase‬‭and‬‭lipase,‬‭suggestive‬‭of‬
‭pancreatitis,‬ ‭have‬ ‭been‬ ‭associated‬ ‭with‬‭the‬‭administration‬‭of‬‭atezolizumab.‬‭The‬‭differential‬
‭diagnosis‬ ‭of‬ ‭acute‬ ‭abdominal‬‭pain‬‭should‬‭include‬‭pancreatitis.‬‭Appropriate‬‭work-up‬‭should‬
‭include‬ ‭an‬ ‭evaluation‬ ‭for‬ ‭ductal‬ ‭obstruction,‬ ‭as‬ ‭well‬ ‭as‬ ‭serum‬ ‭amylase‬ ‭and‬ ‭lipase‬ ‭tests.‬
‭Management‬‭guidelines‬‭for‬‭pancreatic‬‭events,‬‭including‬‭pancreatitis,‬‭are‬‭provided‬‭in‬‭Appendix‬
‭1‬‭.‬
‭9)‬
‭Dermatologic events‬
‭Treatment-emergent‬‭rash‬‭has‬‭been‬‭associated‬‭with‬‭atezolizumab.‬‭The‬‭majority‬‭of‬‭cases‬‭of‬‭rash‬
‭were‬ ‭mild‬ ‭in‬ ‭severity‬ ‭and‬ ‭self-limited,‬ ‭with‬ ‭or‬ ‭without‬ ‭pruritus.‬ ‭A‬ ‭dermatologist‬ ‭should‬
‭evaluate‬ ‭persistent‬ ‭and/or‬ ‭severe‬ ‭rash‬ ‭or‬ ‭pruritus.‬ ‭A‬ ‭biopsy‬ ‭should‬ ‭be‬ ‭considered‬ ‭unless‬
‭contraindicated. Management guidelines for dermatologic events are provided in‬‭Appendix 1‬‭.‬
‭10)‬
‭Neurologic Disorders‬
‭Myasthenia‬ ‭gravis‬ ‭and‬ ‭Guillain-Barré‬ ‭syndrome‬ ‭have‬ ‭been‬ ‭observed‬ ‭with‬ ‭single-agent‬
‭atezolizumab.‬ ‭Patients‬ ‭may‬ ‭present‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭sensory‬ ‭and/or‬ ‭motor‬
‭neuropathy.‬ ‭Diagnostic‬ ‭work-up‬ ‭is‬‭essential‬‭for‬‭an‬‭accurate‬‭characterization‬‭to‬‭differentiate‬
‭between‬‭alternative‬‭etiologies.‬‭Management‬‭guidelines‬‭for‬‭neurologic‬‭disorders‬‭are‬‭provided‬
‭in‬‭Appendix 1‬‭.‬
‭11)‬
‭Immune-Mediated Meningoencephalitis‬
‭Immune-mediated‬‭meningoencephalitis‬‭is‬‭an‬‭identified‬‭risk‬‭associated‬‭with‬‭the‬‭administration‬
‭of‬ ‭atezolizumab.‬ ‭Immune-mediated‬‭meningoencephalitis‬‭should‬‭be‬‭suspected‬‭in‬‭any‬‭patient‬
‭presenting‬‭with‬‭signs‬‭or‬‭symptoms‬‭suggestive‬‭of‬‭meningitis‬‭or‬‭encephalitis,‬‭including,‬‭but‬‭not‬
‭limited‬‭to,‬‭headache,‬‭neck‬‭pain,‬‭confusion,‬‭seizure,‬‭motor‬‭or‬‭sensory‬‭dysfunction,‬‭and‬‭altered‬
‭or depressed level of consciousness.‬
‭Encephalopathy‬ ‭from‬ ‭metabolic‬ ‭or‬ ‭electrolyte‬ ‭imbalances‬ ‭needs‬ ‭to‬ ‭be‬ ‭distinguished‬ ‭from‬
‭potential‬ ‭meningoencephalitis‬ ‭resulting‬ ‭from‬ ‭infection‬ ‭(bacterial,‬ ‭viral,‬ ‭or‬ ‭fungal)‬ ‭or‬
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‭progression‬ ‭of‬ ‭malignancy,‬ ‭or‬ ‭secondary‬ ‭to‬ ‭a‬ ‭paraneoplastic‬ ‭process.‬ ‭All‬ ‭patients‬ ‭being‬
‭considered‬‭for‬‭meningoencephalitis‬‭should‬‭be‬‭urgently‬‭evaluated‬‭with‬‭a‬‭CT‬‭scan‬‭and/or‬‭MRI‬
‭scan‬‭of‬‭the‬‭brain‬‭to‬‭evaluate‬‭for‬‭metastasis,‬‭inflammation,‬‭or‬‭edema.‬‭If‬‭deemed‬‭safe‬‭by‬‭the‬
‭treating‬ ‭physician,‬ ‭a‬ ‭lumbar‬ ‭puncture‬ ‭should‬ ‭be‬ ‭performed‬ ‭and‬ ‭a‬ ‭neurologist‬ ‭should‬ ‭be‬
‭consulted.‬
‭Patients‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭meningoencephalitis,‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬ ‭an‬‭identified‬
‭alternate etiology, should be treated according to the guidelines in‬‭Appendix 1‬
‭12)‬
‭Renal events‬
‭Immune-mediated‬ ‭nephritis‬ ‭has‬ ‭been‬ ‭associated‬ ‭with‬ ‭the‬ ‭administration‬ ‭of‬ ‭atezolizumab.‬
‭Eligible‬‭patients‬‭must‬‭have‬‭adequate‬‭renal‬‭function,‬‭and‬‭renal.‬‭Renal‬‭function,‬‭including‬‭serum‬
‭creatinine,‬ ‭should‬ ‭be‬ ‭monitored‬ ‭throughout‬ ‭study‬ ‭treatment.‬ ‭Patients‬ ‭with‬ ‭abnormal‬ ‭renal‬
‭function‬‭should‬‭be‬‭evaluated‬‭and‬‭treated‬‭for‬‭other‬‭more‬‭common‬‭etiologies‬‭(including‬‭prerenal‬
‭and‬ ‭postrenal‬ ‭causes,‬ ‭and‬‭concomitant‬‭medications‬‭such‬‭as‬‭non-steroidal‬‭anti-inflammatory‬
‭drugs).‬ ‭Refer‬‭the‬‭patient‬‭to‬‭a‬‭renal‬‭specialist‬‭if‬‭clinically‬‭indicated.‬‭A‬‭renal‬‭biopsy‬‭may‬‭be‬
‭required to enable a definitive diagnosis and appropriate treatment.‬
‭Patients‬ ‭with‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭nephritis,‬ ‭in‬ ‭the‬ ‭absence‬ ‭of‬ ‭an‬ ‭identified‬ ‭alternate‬
‭etiology, should be treated according to the guidelines in‬‭Appendix 1‬‭.‬
‭13)‬
‭Immune-Mediated Myositis‬
‭Immune-mediated‬ ‭myositis‬ ‭has‬ ‭been‬ ‭associated‬ ‭with‬ ‭the‬ ‭administration‬ ‭of‬ ‭atezolizumab.‬
‭Myositis‬‭or‬‭inflammatory‬‭myopathies‬‭are‬‭a‬‭group‬‭of‬‭disorders‬‭sharing‬‭the‬‭common‬‭feature‬‭of‬
‭inflammatory‬‭muscle‬‭injury;‬‭dermatomyositis‬‭and‬‭polymyositis‬‭are‬‭among‬‭the‬‭most‬‭common‬
‭disorders.‬‭Initial‬‭diagnosis‬‭is‬‭based‬‭on‬‭clinical‬‭(muscle‬‭weakness,‬‭muscle‬‭pain,‬‭skin‬‭rash‬‭in‬
‭dermatomyositis),‬
‭biochemical‬
‭(serum‬
‭creatine‬ ‭kinase/CK‬ ‭increase),‬ ‭and‬ ‭imaging‬
‭(electromyography/MRI) features, and is confirmed with a muscle biopsy.‬
‭14)‬
‭Severe Cutaneous Adverse Reactions (SCAR)‬
‭SCARs‬ ‭are‬ ‭a‬ ‭heterogeneous‬ ‭group‬ ‭of‬ ‭immunologically‬ ‭mediated‬ ‭drug‬‭eruptions.‬‭Although‬
‭rare,‬‭these‬‭events‬‭are‬‭potentially‬‭fatal,‬‭and‬‭mainly‬‭constituted‬‭by‬‭erythema‬‭multiforme,‬‭acute‬
‭generalised‬ ‭exanthematous‬ ‭pustulosis,‬ ‭Stevens-Johnson‬ ‭syndrome‬ ‭(SJS),‬ ‭Toxic‬ ‭Epidermal‬
‭Necrolysis‬‭(TEN)‬‭and‬‭drug‬‭rash‬‭with‬‭eosinophilia‬‭and‬‭systemic‬‭symptoms‬‭(DRESS).‬‭As‬‭per‬
‭epidemiology‬ ‭data,‬ ‭the‬ ‭incidence‬‭of‬‭SJS‬‭and‬‭TEN‬‭ranges‬‭from‬‭0.8‬‭to‬‭5.3‬‭and‬‭1.2‬‭to‬‭6‬‭per‬
‭million person-years respectively.‬
‭A‬‭cumulative‬‭analysis‬‭of‬‭the‬‭company‬‭safety‬‭database‬‭across‬‭the‬‭TECENTRIQ‬‭(atezolizumab)‬
‭program‬ ‭identified‬ ‭at‬ ‭total‬ ‭of‬ ‭99‬ ‭cases‬ ‭of‬ ‭SCARs,‬ ‭of‬ ‭which‬ ‭36‬ ‭were‬ ‭confirmed‬ ‭by‬
‭histopathology‬ ‭or‬ ‭specialist‬ ‭diagnosis,‬ ‭in‬ ‭patients‬ ‭who‬ ‭have‬ ‭received‬ ‭TECENTRIQ‬
‭(atezolizumab).‬ ‭Approximately‬ ‭23,654‬ ‭clinical‬ ‭trial‬ ‭patients‬ ‭and‬ ‭106,316‬ ‭patients‬ ‭in‬
‭post-marketing‬ ‭settings‬ ‭have‬ ‭been‬ ‭exposed‬ ‭to‬ ‭TECENTRIQ‬ ‭(atezolizumab)‬ ‭as‬ ‭of‬ ‭17‬ ‭May‬
‭2020.‬ ‭The‬ ‭incidence‬ ‭rates‬ ‭of‬ ‭SCAR,‬ ‭regardless‬ ‭of‬ ‭severity,‬ ‭from‬ ‭pooled‬ ‭atezolizumab‬
‭monotherapy‬ ‭(N=3178)‬ ‭and‬ ‭combination‬ ‭therapy‬ ‭(N=4371)‬ ‭company‬ ‭sponsored‬ ‭clinical‬
‭studies‬‭were‬‭0.7%‬‭and‬‭0.6%‬‭respectively.‬‭One‬‭fatal‬‭case‬‭of‬‭TEN‬‭was‬‭reported‬‭in‬‭a‬‭77‬‭year‬‭old‬
‭female patient who received atezolizumab monotherapy.‬
‭Patients‬‭with‬‭signs‬‭and‬‭symptoms‬‭of‬‭SCAR‬‭should‬‭be‬‭treated‬‭according‬‭to‬‭the‬‭guidelines‬‭in‬
‭Appendix 1‬‭.‬
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‭7.5.2.‬ ‭Special Precautions for Gemcitabine‬
‭Prolongation‬‭of‬‭the‬‭infusion‬‭time‬‭and‬‭increased‬‭dosing‬‭frequency‬‭have‬‭been‬‭shown‬‭to‬‭increase‬
‭toxicity.‬‭Further‬‭information‬‭on‬‭particular‬‭risk‬‭for‬‭toxicity‬‭(including‬‭haematological‬‭toxicity,‬
‭hepatic‬ ‭insufficiency,‬ ‭concomitant‬ ‭radiotherapy,‬ ‭live‬ ‭vaccinations,‬ ‭cardiovascular‬ ‭risk,‬
‭pulmonary effects, renal, fertility or sodium control are displayed in the Gemcitabine SmPC.‬
‭7.5.3.‬ ‭Special Precautions for Cisplatin‬
‭This‬‭agent‬‭should‬‭only‬‭be‬‭administered‬‭under‬‭the‬‭direction‬‭of‬‭oncologists‬‭in‬‭specialist‬‭units‬
‭under‬ ‭conditions‬ ‭permitting‬ ‭adequate‬ ‭monitoring‬ ‭and‬ ‭surveillance.‬ ‭Supportive‬ ‭equipment‬
‭should be available to control anaphylactic reactions.‬
‭Cisplatin‬ ‭reacts‬ ‭with‬ ‭metallic‬ ‭aluminium‬ ‭to‬ ‭form‬ ‭a‬ ‭black‬ ‭precipitate‬ ‭of‬ ‭platinum.‬ ‭All‬
‭aluminium‬‭containing‬‭IV‬‭sets,‬‭needles,‬‭catheters‬‭and‬‭syringes‬‭should‬‭be‬‭avoided.‬‭The‬‭solution‬
‭for infusion should not be mixed with other drugs or additives.‬
‭Appropriate‬ ‭monitoring‬ ‭and‬ ‭management‬ ‭of‬ ‭the‬ ‭treatment‬ ‭and‬ ‭its‬ ‭complications‬ ‭are‬ ‭only‬
‭possible if adequate diagnosis and exact treatment conditions are available.‬
‭Further‬ ‭information‬ ‭on‬ ‭particular‬ ‭risks‬ ‭including‬ ‭nephrotoxicity,‬ ‭neuropathies,‬ ‭ototoxicity,‬
‭allergic‬ ‭reactions,‬ ‭hepatic‬ ‭function‬ ‭and‬ ‭haematological‬ ‭formula,‬ ‭carcinogenic‬ ‭potential,‬
‭injection site reactions are displayed in the Cisplatin SmPC.‬
‭7.6.‬
‭Investigational Product Storage‬
‭The‬‭investigational‬‭products‬‭should‬‭be‬‭stored‬‭in‬‭a‬‭secure‬‭area‬‭according‬‭to‬‭local‬‭regulations.‬‭It‬
‭is‬ ‭the‬ ‭responsibility‬ ‭of‬ ‭the‬ ‭investigator‬ ‭to‬ ‭ensure‬ ‭that‬ ‭investigational‬ ‭products‬ ‭are‬ ‭only‬
‭dispensed‬ ‭to‬ ‭study‬ ‭participants.‬ ‭The‬ ‭investigational‬ ‭product‬ ‭must‬ ‭be‬ ‭dispensed‬ ‭only‬ ‭from‬
‭official study sites by authorized personnel according to local regulations.‬
‭The‬ ‭investigator,‬ ‭or‬ ‭an‬ ‭approved‬ ‭representative‬ ‭(eg,‬ ‭pharmacist),‬ ‭will‬ ‭ensure‬ ‭that‬ ‭all‬
‭investigational‬ ‭products‬ ‭are‬ ‭stored‬ ‭in‬ ‭a‬ ‭secured‬ ‭area‬‭with‬‭controlled‬‭access‬‭under‬‭required‬
‭storage conditions and in accordance with applicable regulatory requirements.‬
‭Storage‬‭conditions‬‭stated‬‭in‬‭the‬‭SRSD‬‭(ie,‬‭IB)‬‭will‬‭be‬‭superseded‬‭by‬‭the‬‭storage‬‭conditions‬
‭stated‬‭on‬‭the‬‭label.‬‭Site‬‭systems‬‭must‬‭be‬‭capable‬‭of‬‭measuring‬‭and‬‭documenting‬‭(for‬‭example,‬
‭via‬ ‭a‬ ‭log),‬ ‭at‬ ‭a‬ ‭minimum,‬ ‭daily‬ ‭minimum‬ ‭and‬ ‭maximum‬ ‭temperatures‬ ‭for‬ ‭all‬‭site‬‭storage‬
‭locations‬ ‭(as‬ ‭applicable,‬ ‭including‬ ‭frozen,‬ ‭refrigerated‬ ‭and/or‬ ‭room‬ ‭temperature‬ ‭products).‬
‭This‬‭should‬‭be‬‭captured‬‭from‬‭the‬‭time‬‭of‬‭investigational‬‭product‬‭receipt‬‭throughout‬‭the‬‭study.‬
‭Even‬ ‭for‬ ‭continuous‬ ‭monitoring‬ ‭systems,‬ ‭a‬ ‭log‬ ‭or‬ ‭site‬ ‭procedure‬ ‭that‬ ‭ensures‬‭active‬‭daily‬
‭evaluation‬ ‭for‬ ‭excursions‬‭should‬‭be‬‭available.‬‭The‬‭operation‬‭of‬‭the‬‭temperature‬‭monitoring‬
‭device‬‭and‬‭storage‬‭unit‬‭(for‬‭example,‬‭refrigerator),‬‭as‬‭applicable,‬‭should‬‭be‬‭regularly‬‭inspected‬
‭to ensure it is maintained in working order.‬
‭Any excursions from the product label storage conditions should be reported upon discovery.‬
‭The‬‭site‬‭should‬‭actively‬‭pursue‬‭options‬‭for‬‭returning‬‭the‬‭product‬‭to‬‭the‬‭storage‬‭conditions‬‭as‬
‭described‬ ‭in‬ ‭the‬ ‭labeling,‬ ‭as‬ ‭soon‬ ‭as‬ ‭possible.‬ ‭Deviations‬ ‭from‬ ‭the‬ ‭storage‬ ‭requirements,‬
‭including any actions taken must be documented and reported to the sponsor.‬
‭Once‬‭an‬‭excursion‬‭is‬‭identified,‬‭the‬‭investigational‬‭product‬‭must‬‭be‬‭quarantined‬‭and‬‭not‬‭used‬
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‭until‬‭the‬‭sponsor‬‭provides‬‭documentation‬‭of‬‭permission‬‭to‬‭use‬‭the‬‭investigational‬‭product.‬‭It‬
‭will‬ ‭not‬ ‭be‬ ‭considered‬ ‭a‬ ‭protocol‬ ‭deviation‬ ‭if‬ ‭the‬ ‭sponsor‬ ‭approves‬ ‭the‬ ‭use‬ ‭of‬ ‭the‬
‭investigational‬ ‭product‬ ‭after‬ ‭the‬ ‭temperature‬ ‭excursion.‬ ‭Use‬ ‭of‬ ‭the‬ ‭investigational‬ ‭product‬
‭prior to sponsor approval will be considered a protocol deviation.‬
‭Specific‬ ‭details‬ ‭regarding‬ ‭information‬ ‭the‬ ‭site‬ ‭should‬ ‭report‬ ‭for‬ ‭each‬ ‭excursion‬ ‭will‬ ‭be‬
‭provided to the site.‬
‭Receipt‬‭of‬‭materials,‬‭door‬‭opening‬‭and‬‭closing,‬‭and‬‭other‬‭routine‬‭handling‬‭operations‬‭where‬
‭the‬ ‭product(s)‬ ‭are‬ ‭briefly‬ ‭out‬ ‭of‬ ‭the‬ ‭temperature‬ ‭range‬ ‭described‬ ‭in‬ ‭the‬ ‭labeling‬ ‭are‬ ‭not‬
‭considered excursions.‬
‭Site‬ ‭staff‬ ‭will‬ ‭instruct‬ ‭patients‬ ‭on‬ ‭the‬ ‭proper‬ ‭storage‬ ‭requirements‬ ‭for‬ ‭take-home‬
‭investigational products.‬
‭7.6.1.‬ ‭Atezolizumab storage‬
‭Atezolizumab‬ ‭must‬ ‭be‬ ‭refrigerated‬ ‭at‬ ‭2°C‬ ‭-‬ ‭8°C‬ ‭(36°F‬ ‭-‬ ‭46°F)‬ ‭upon‬ ‭receipt‬ ‭until‬ ‭use.‬
‭Atezolizumab‬‭and‬‭the‬‭diluent‬‭vials‬‭should‬‭not‬‭be‬‭used‬‭beyond‬‭the‬‭expiration‬‭date‬‭provided‬‭by‬
‭the‬ ‭manufacturer.‬‭No‬‭preservative‬‭is‬‭used‬‭in‬‭the‬‭atezolizumab‬‭Drug‬‭Product‬‭or‬‭the‬‭diluent;‬
‭therefore,‬ ‭the‬ ‭vial‬ ‭is‬ ‭intended‬ ‭for‬ ‭single‬ ‭use‬ ‭only.‬ ‭Discard‬ ‭any‬ ‭unused‬ ‭portion‬ ‭of‬ ‭drug‬
‭remaining‬‭in‬‭a‬‭vial.‬‭Vial‬‭contents‬‭should‬‭not‬‭be‬‭frozen‬‭or‬‭shaken‬‭and‬‭should‬‭be‬‭protected‬‭from‬
‭light‬‭by‬‭keeping‬‭the‬‭vial‬‭in‬‭the‬‭outer‬‭carton.‬‭This‬‭information‬‭is‬‭also‬‭available‬‭in‬‭the‬‭pharmacy‬
‭manual.‬
‭7.6.2.‬ ‭Gemcitabine and cisplatin storage‬
‭Gemcitabine and cisplatin must be stored and controlled as specified in the product label.‬
‭7.7.‬
‭Investigational Product Accountability‬
‭The‬‭delegated‬‭investigation‬‭site‬‭staff‬‭must‬‭maintain‬‭adequate‬‭records‬‭documenting‬‭the‬‭receipt,‬
‭use,‬‭loss,‬‭or‬‭other‬‭disposition‬‭of‬‭the‬‭investigational‬‭product‬‭supplies.‬‭All‬‭bottles‬‭of‬‭study‬‭drug‬
‭must‬‭be‬‭returned‬‭to‬‭the‬‭investigator‬‭by‬‭the‬‭patient‬‭at‬‭the‬‭end‬‭of‬‭each‬‭cycle‬‭and‬‭at‬‭the‬‭end‬‭of‬‭the‬
‭trial,‬‭tThe‬‭sponsor‬‭will‬‭provide‬‭instructions‬‭as‬‭to‬‭the‬‭disposition‬‭of‬‭any‬‭unused‬‭investigational‬
‭product if the investigative site is unable to destroy at site per local procedures.‬
‭7.8.‬
‭Destruction of Investigational Product Supplies‬
‭The‬‭sponsor‬‭or‬‭designee‬‭will‬‭provide‬‭guidance‬‭on‬‭the‬‭destruction‬‭of‬‭unused‬‭investigational‬
‭product‬‭Atezolizumab‬‭(e.g.,‬‭at‬‭the‬‭site).‬‭If‬‭destruction‬‭is‬‭authorized‬‭to‬‭take‬‭place‬‭at‬‭the‬‭study‬
‭site,‬ ‭the‬ ‭investigator‬ ‭must‬ ‭ensure‬ ‭that‬ ‭the‬ ‭materials‬ ‭are‬ ‭destroyed‬ ‭in‬ ‭compliance‬ ‭with‬
‭applicable‬ ‭environmental‬ ‭regulations,‬ ‭institutional‬ ‭policy,‬ ‭and‬ ‭any‬ ‭special‬ ‭instructions‬
‭provided by the Sponsor, and all destruction must be adequately documented.‬
‭7.9.‬
‭Concomitant Treatments‬
‭Medications‬ ‭or‬ ‭vaccinations‬ ‭specifically‬ ‭prohibited‬ ‭in‬ ‭the‬ ‭Exclusion‬ ‭Criteria‬ ‭are‬ ‭also‬ ‭not‬
‭allowed‬ ‭during‬ ‭the‬ ‭active‬ ‭treatment‬ ‭period,‬ ‭except‬ ‭for‬ ‭the‬ ‭administration‬ ‭of‬ ‭inactivated‬
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‭influenza vaccine.‬
‭If‬ ‭there‬ ‭is‬ ‭a‬ ‭clinical‬ ‭indication‬ ‭for‬ ‭one‬ ‭of‬ ‭these‬ ‭or‬ ‭other‬ ‭medications‬ ‭or‬ ‭vaccinations‬
‭specifically‬
‭prohibited‬
‭during‬
‭the‬
‭trial,‬
‭discontinuation‬
‭from‬
‭study‬
‭therapy‬ ‭or‬
‭medication/vaccination‬ ‭may‬ ‭be‬ ‭required.‬ ‭The‬ ‭final‬ ‭decision‬ ‭on‬ ‭any‬ ‭supportive‬ ‭therapy‬ ‭or‬
‭vaccination‬ ‭rests‬ ‭with‬‭the‬‭investigator‬‭and/or‬‭the‬‭patient’s‬‭primary‬‭physician.‬‭However,‬‭the‬
‭decision‬‭to‬‭continue‬‭the‬‭patient‬‭on‬‭study‬‭therapy‬‭or‬‭medication/vaccination‬‭schedule‬‭requires‬
‭the mutual agreement of the investigator, the sponsor, and the patient.‬
‭Concomitant‬‭treatment‬‭considered‬‭necessary‬‭for‬‭the‬‭patient’s‬‭wellbeing‬‭may‬‭be‬‭given‬‭at‬‭the‬
‭discretion‬ ‭of‬ ‭the‬ ‭treating‬ ‭physician.‬‭All‬‭concomitant‬‭treatments,‬‭blood‬‭products,‬‭as‬‭well‬‭as‬
‭non-drug‬‭interventions‬‭received‬‭by‬‭patients‬‭from‬‭screening‬‭until‬‭the‬‭end‬‭of‬‭study‬‭visit‬‭will‬‭be‬
‭recorded on the CRF.‬
‭Concomitant‬‭medications‬‭and‬‭treatments,‬‭including‬‭herbal‬‭supplements,‬‭will‬‭be‬‭recorded‬‭from‬
‭28‬ ‭days‬ ‭prior‬‭to‬‭the‬‭start‬‭of‬‭study‬‭treatment‬‭and‬‭up‬‭to‬‭90‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭study‬
‭treatment.‬‭All‬‭concomitant‬‭medications‬‭should‬‭be‬‭recorded‬‭in‬‭the‬‭CRF‬‭including‬‭supportive‬
‭care‬ ‭drugs‬ ‭(e.g.,‬‭antiemetic‬‭treatment‬‭and‬‭prophylaxis),‬‭and‬‭the‬‭drugs‬‭used‬‭to‬‭treat‬‭adverse‬
‭events or chronic diseases, and non-drug supportive interventions (e.g., transfusions).‬
‭Concurrent‬‭anticancer‬‭therapy‬‭with‬‭agents‬‭other‬‭than‬‭atezolizumab‬‭and‬‭GC‬‭are‬‭not‬‭allowed.‬
‭Medications‬‭intended‬‭solely‬‭for‬‭supportive‬‭care‬‭(i.e.,‬‭antiemetics,‬‭analgesics,‬‭megestrol‬‭acetate‬
‭for anorexia) are allowed.‬
‭7.9.1.‬ ‭Inhibitors and Inducers of CYP Enzymes‬
‭Because‬‭antibodies‬‭are‬‭cleared‬‭principally‬‭by‬‭catabolism‬‭(i.e.,‬‭cleavage‬‭to‬‭small‬‭peptides‬‭and‬
‭amino‬‭acids),‬‭atezolizumab‬‭is‬‭not‬‭expected‬‭to‬‭show‬‭pharmacokinetic‬‭interactions‬‭with‬‭other‬
‭drugs,‬ ‭and‬ ‭is‬ ‭therefore‬ ‭not‬ ‭expected‬ ‭to‬ ‭interact‬ ‭with‬ ‭other‬ ‭drugs‬ ‭through‬ ‭protein‬ ‭binding,‬
‭effects‬ ‭on‬ ‭cytochrome‬ ‭P450‬ ‭activity,‬ ‭renal‬ ‭excretion‬ ‭or‬ ‭competition‬ ‭for‬ ‭common‬ ‭drug‬
‭transporter‬ ‭proteins.‬ ‭No‬ ‭formal‬ ‭pharmacokinetic‬ ‭drug‬ ‭interaction‬ ‭studies‬ ‭have‬ ‭thus‬ ‭been‬
‭undertaken with atezolizumab.‬
‭7.9.2.‬ ‭Concomitant Surgery‬
‭No specific information on the effect of Atezolizumab on wound healing are reported in the‬
‭current version of IB nor SmPC.‬
‭7.9.3.‬ ‭Concomitant Radiotherapy‬
‭Toxicity‬‭of‬‭concurrent‬‭administration‬‭of‬‭gemcitabine‬‭(simultaneous‬‭or‬‭≤‬‭7‬‭days‬‭apart)‬‭depends‬
‭on‬ ‭many‬‭different‬‭factors,‬‭including‬‭the‬‭dose‬‭of‬‭gemcitabine,‬‭the‬‭frequency‬‭of‬‭gemcitabine‬
‭administration,‬ ‭radiation‬ ‭dose,‬ ‭radiotherapy‬ ‭planning‬ ‭technique,‬ ‭tissue‬ ‭to‬ ‭radiate‬ ‭and‬ ‭the‬
‭theoretical‬‭irradiation‬‭volume.‬‭For‬‭the‬‭matter‬‭of‬‭this‬‭study,‬‭radiotherapy‬‭within‬‭4‬‭weeks‬‭prior‬
‭to inclusion is considered an exclusion criteria.‬
‭For‬ ‭non-concurrent‬ ‭gemcitabine‬ ‭administration‬ ‭(administered>‬ ‭7‬ ‭days‬ ‭apart),‬ ‭data‬‭analysis‬
‭does‬‭not‬‭indicate‬‭an‬‭increased‬‭toxicity‬‭when‬‭gemcitabine‬‭is‬‭administered‬‭at‬‭least‬‭7‬‭days‬‭before‬
‭or‬‭after‬‭radiotherapy,‬‭except‬‭for‬‭late‬‭skin‬‭toxicity.‬‭The‬‭data‬‭that‬‭can‬‭be‬‭started‬‭administration‬‭of‬
‭gemcitabine when the acute effects of radiation therapy have resolved or at least one‬
‭week‬ ‭after‬ ‭radiation‬ ‭therapy.‬ ‭Radiation‬ ‭injury‬ ‭has‬ ‭been‬ ‭detected‬ ‭in‬ ‭irradiated‬ ‭tissues‬ ‭(e.g.‬
‭esophagitis,‬‭colitis,‬‭and‬‭pneumonitis)‬‭in‬‭association‬‭with‬‭both‬‭concurrent‬‭and‬‭non-concurrent‬
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‭use‬‭of‬‭gemcitabine.‬‭Further‬‭information‬‭can‬‭be‬‭obtained‬‭in‬‭the‬‭current‬‭version‬‭of‬‭Gemcitabine‬
‭SmPC.‬
‭7.9.4.‬ ‭Other Prohibited Concomitant Medications and Therapies‬
‭Clarifications‬‭about‬‭Steroid‬‭Use:‬‭Data‬‭indicate‬‭that‬‭corticosteroids‬‭have‬‭an‬‭adverse‬‭effect‬‭on‬
‭T-cell‬‭function‬‭and‬‭that‬‭they‬‭inhibit‬‭and‬‭damage‬‭lymphocytes‬‭(‬‭Schleimer‬‭RP,‬‭et‬‭al.‬‭1984;‬‭Khan‬
‭MM, 2008‬‭).‬
‭Furthermore,‬‭as‬‭with‬‭all‬‭immunotherapies‬‭intended‬‭to‬‭augment‬‭cell-mediated‬‭immunity,‬‭there‬
‭is‬‭a‬‭risk‬‭that‬‭concomitant‬‭immunosuppressants‬‭such‬‭as‬‭steroids‬‭will‬‭counteract‬‭the‬‭intended‬
‭benefit‬ ‭of‬ ‭the‬ ‭proposed‬ ‭study‬ ‭treatment.‬ ‭However,‬ ‭studies‬ ‭with‬ ‭anti-CTLA4‬ ‭compounds‬
‭indicate‬ ‭that‬ ‭short-term‬ ‭use‬ ‭of‬ ‭steroids‬ ‭may‬ ‭be‬ ‭employed‬ ‭without‬ ‭compromising‬ ‭clinical‬
‭outcomes (‬‭Weber JS, et al. 2012‬‭).‬
‭Therefore, the use of steroids during this trial is restricted as follows:‬
‭●‬ ‭Therapeutic‬ ‭use:‬ ‭for‬ ‭the‬ ‭treatment‬ ‭of‬ ‭infusion-related‬ ‭reactions‬ ‭and‬ ‭short-term‬
‭treatment‬ ‭of‬ ‭irAEs,‬ ‭steroids‬ ‭are‬ ‭permitted‬ ‭according‬ ‭to‬ ‭the‬ ‭modalities‬‭indicated‬‭in‬
‭Appendix 1‬‭.‬
‭●‬ ‭Physiologic‬‭use:‬‭steroid‬‭replacement‬‭for‬‭adrenal‬‭insufficiency‬‭at‬‭doses‬‭equivalent‬‭to‬
‭≤10 mg prednisone daily is acceptable.‬
‭●‬ ‭Prophylactic‬ ‭use‬‭,‬ ‭e.g.,‬ ‭for‬ ‭the‬ ‭prevention‬ ‭of‬ ‭acute‬ ‭infusion-related‬ ‭reactions,‬ ‭is‬
‭prohibited,‬‭except‬‭prior to CT or MRI.‬
‭7.10.‬ ‭Rescue Medications and Supportive Care‬
‭7.10.1.‬ ‭Supportive Care Guidelines‬
‭Patients‬ ‭should‬ ‭receive‬ ‭appropriate‬ ‭supportive‬ ‭care‬ ‭measures‬ ‭as‬ ‭deemed‬ ‭necessary‬ ‭by‬ ‭the‬
‭treating investigator including but not limited to the items outlined below:‬
‭●‬ ‭Diarrhea:‬ ‭All‬ ‭patients‬ ‭who‬ ‭experience‬ ‭diarrhea‬ ‭should‬ ‭be‬ ‭advised‬ ‭to‬ ‭drink‬‭liberal‬
‭quantities‬ ‭of‬ ‭clear‬ ‭fluids.‬ ‭If‬ ‭sufficient‬ ‭oral‬ ‭fluid‬ ‭intake‬ ‭is‬ ‭not‬ ‭feasible,‬ ‭fluid‬ ‭and‬
‭electrolytes should be substituted via IV infusion.‬
‭●‬ ‭Nausea/Vomiting‬‭:‬ ‭Nausea‬ ‭and‬ ‭vomiting‬ ‭should‬ ‭be‬ ‭treated‬ ‭aggressively,‬ ‭and‬
‭consideration‬ ‭should‬ ‭be‬ ‭given‬ ‭in‬ ‭subsequent‬ ‭cycles‬ ‭to‬ ‭the‬ ‭administration‬ ‭of‬
‭prophylactic‬ ‭antiemetic‬‭therapy‬‭according‬‭to‬‭standard‬‭institutional‬‭practice.‬‭Patients‬
‭should be strongly encouraged to maintain liberal oral fluid intake.‬
‭●‬ ‭Anti-infectives:‬ ‭Patients‬ ‭with‬ ‭a‬ ‭documented‬ ‭infectious‬ ‭complication‬ ‭should‬ ‭receive‬
‭oral‬‭or‬‭IV‬‭antibiotics‬‭or‬‭other‬‭anti-infective‬‭agents‬‭as‬‭considered‬‭appropriate‬‭by‬‭the‬
‭treating‬ ‭investigator‬ ‭for‬ ‭a‬ ‭given‬ ‭infectious‬ ‭condition,‬ ‭according‬ ‭to‬ ‭standard‬
‭institutional‬‭practice.‬‭Prophylactic‬‭administration‬‭should‬‭be‬‭considered‬‭for‬‭the‬‭cases‬
‭outlined in‬‭Appendix 1‬‭.‬
‭●‬ ‭Anti-inflammatory‬
‭or‬
‭narcotic‬
‭analgesics‬
‭may‬
‭be‬
‭offered‬
‭as‬
‭needed.‬
‭Acetaminophen/paracetamol‬‭to‬‭a‬‭maximum‬‭total‬‭daily‬‭dose‬‭of‬‭2‬‭g‬‭is‬‭permitted.‬‭Daily‬
‭intake over 2 g is prohibited.‬
‭●‬ ‭Patients‬‭who‬‭need‬‭to‬‭be‬‭on‬‭anticoagulant‬‭therapy‬‭during‬‭treatment‬‭should‬‭be‬‭treated‬
‭with‬ ‭low‬ ‭molecular‬ ‭weight‬ ‭heparin.‬ ‭If‬ ‭low‬ ‭molecular‬ ‭weight‬ ‭heparin‬ ‭cannot‬ ‭be‬
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‭administered,‬ ‭coumadin‬ ‭or‬ ‭other‬ ‭coumarin‬ ‭derivatives‬ ‭or‬ ‭other‬ ‭anticoagulants‬
‭(including‬‭direct‬‭Xa‬‭inhibitors)‬‭may‬‭be‬‭allowed;‬‭however,‬‭appropriate‬‭monitoring‬‭of‬
‭prothrombin time/international normalized ratio (PT/INR) should be performed.‬
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‭8.‬
‭STUDY PROCEDURES AND EVALUATIONS‬
‭8.1.‬
‭Definition of efficacy variables‬
‭●‬ ‭Overall‬ ‭Response‬ ‭Rate‬ ‭(ORR):‬ ‭Assessed‬ ‭by‬ ‭the‬ ‭investigator‬ ‭using‬ ‭the‬ ‭Response‬
‭Evaluation‬ ‭Criteria‬‭in‬‭Solid‬‭Tumors‬‭(RECIST)‬‭v1.1.‬‭This‬‭will‬‭be‬‭considered‬‭as‬‭the‬
‭percentage/proportion‬ ‭of‬ ‭patients‬‭with‬‭confirmed‬‭complete‬‭response‬‭(CR)‬‭or‬‭partial‬
‭response (PR) as their overall best response throughout the study period.‬
‭●‬ ‭Duration‬‭of‬‭response‬‭(DoR):‬‭Time‬‭from‬‭first‬‭confirmed‬‭response‬‭(CR‬‭or‬‭PR)‬‭to‬‭the‬
‭date‬‭of‬‭the‬‭documented‬‭PD‬‭as‬‭determined‬‭using‬‭RECIST‬‭1.1‬‭criteria‬‭or‬‭death‬‭due‬‭to‬
‭any cause, whichever occurs first.‬
‭●‬ ‭Time‬ ‭to‬‭response‬‭(TtR):‬‭Time‬‭from‬‭first‬‭dosing‬‭date‬‭to‬‭the‬‭date‬‭of‬‭the‬‭documented‬
‭ORR as determined using RECIST 1.1 criteria.‬
‭●‬ ‭Progression-Free‬‭Survival‬‭(PFS):‬‭Time‬‭from‬‭first‬‭dosing‬‭date‬‭to‬‭the‬‭date‬‭of‬‭confirmed‬
‭PD.‬‭A‬‭subject‬‭who‬‭has‬‭not‬‭died‬‭will‬‭be‬‭censored‬‭at‬‭the‬‭last‬‭known‬‭date‬‭alive.‬‭PFS‬‭rate‬
‭will be assessed through the proportion of patients free of PD at the end of follow-up.‬
‭●‬ ‭Clinical‬‭benefit‬‭(CB)‬‭:‬‭Percentage/proportion‬‭of‬‭patients‬‭with‬‭complete‬‭response‬‭(CR)‬
‭or‬ ‭partial‬ ‭response‬ ‭(PR)‬ ‭or‬ ‭maintained‬ ‭stable‬ ‭disease‬ ‭(SD)‬ ‭as‬ ‭their‬ ‭overall‬ ‭best‬
‭response‬‭throughout‬‭the‬‭study‬‭period,‬‭assessed‬‭by‬‭imaging‬‭follow-up‬‭(CT‬‭scan/MRI),‬
‭on week 9, week 18 and then, every 12 weeks.‬
‭●‬ ‭Overall‬ ‭Survival‬ ‭(OS):‬ ‭Time‬ ‭from‬ ‭first‬ ‭dosing‬ ‭date‬ ‭to‬ ‭the‬ ‭date‬ ‭of‬ ‭death‬ ‭and‬ ‭the‬
‭proportion/percentage‬‭of‬‭patients‬‭alive‬‭at‬‭the‬‭end‬‭of‬‭follow-up.‬‭A‬‭subject‬‭who‬‭has‬‭not‬
‭died‬ ‭will‬ ‭be‬ ‭censored‬ ‭at‬ ‭the‬ ‭last‬ ‭known‬ ‭date‬ ‭alive.‬ ‭Survival‬ ‭will‬ ‭be‬ ‭assessed‬ ‭by‬
‭recording‬‭patient‬‭status‬‭at‬‭each‬‭visit‬‭according‬‭to‬‭Table‬‭4‬‭.‬‭Long‬‭term‬‭follow‬‭up‬‭to‬‭be‬
‭performed every 6 months.‬
‭8.2.‬
‭Safety and tolerability‬
‭Safety‬ ‭assessments:‬ ‭Safety‬ ‭parameters‬ ‭are‬ ‭AE,‬ ‭SAE,‬ ‭AESI,‬ ‭pregnancy,‬ ‭medication‬ ‭error,‬
‭overdose.‬‭Additional‬‭safety‬‭information‬‭could‬‭be‬‭derived‬‭from‬‭ECG,‬‭lab‬‭test,‬‭pregnancy‬‭test,‬
‭or vital sign exam.‬
‭The‬‭assessment‬‭of‬‭adverse‬‭events‬‭will‬‭include‬‭the‬‭type‬‭of‬‭event‬‭(including‬‭symptoms,‬‭physical‬
‭exam‬‭findings‬‭and‬‭laboratory‬‭abnormalities),‬‭the‬‭incidence,‬‭severity,‬‭timing,‬‭seriousness,‬‭and‬
‭relatedness‬‭regarding‬‭the‬‭treatment‬‭under‬‭study.‬‭Adverse‬‭events‬‭will‬‭be‬‭recorded‬‭and‬‭reported‬
‭in‬‭the‬‭corresponding‬‭section‬‭of‬‭the‬‭case‬‭report‬‭form.‬‭The‬‭grade‬‭of‬‭adverse‬‭events‬‭will‬‭be‬‭coded‬
‭according‬ ‭to‬ ‭the‬ ‭National‬ ‭Cancer‬ ‭Institute’s‬ ‭Common‬ ‭Toxicity‬ ‭criteria‬ ‭(NCI-CTCAE‬ ‭v5.0‬
‭scoring‬ ‭system).‬ ‭The‬ ‭worst‬ ‭toxicity‬ ‭score‬ ‭will‬ ‭be‬ ‭recorded.‬ ‭In‬‭case‬‭of‬‭SAE‬‭and‬‭AESI‬‭the‬
‭investigator‬‭should‬‭immediately‬‭fill‬‭in‬‭the‬‭dedicated‬‭SAE‬‭form‬‭and‬‭send‬‭it‬‭by‬‭as‬‭detailed‬‭in‬
‭Section 9.2.‬
‭●‬ ‭Adverse events (AE) assessment:‬‭type, frequency, outcome‬‭of adverse events.‬
‭●‬ ‭Treatment-related‬‭AEs:‬‭An‬‭event‬‭is‬‭assessed‬‭as‬‭related‬‭to‬‭study‬‭treatment‬‭when‬‭there‬
‭is‬ ‭a‬ ‭reasonable‬ ‭possibility‬ ‭that‬ ‭study‬ ‭treatment‬ ‭caused‬ ‭the‬ ‭event.‬ ‭Reasonable‬
‭possibility‬ ‭means‬ ‭there‬ ‭is‬ ‭evidence‬ ‭to‬ ‭suggest‬ ‭a‬ ‭causal‬ ‭relationship‬ ‭between‬‭study‬
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‭treatment‬‭and‬‭the‬‭event.‬‭This‬‭event‬‭is‬‭called‬‭a‬‭suspected‬‭adverse‬‭reaction.‬‭A‬‭suspected‬
‭adverse‬ ‭reaction‬ ‭implies‬ ‭a‬ ‭lesser‬ ‭degree‬ ‭of‬ ‭certainty‬ ‭about‬ ‭causality‬ ‭than‬ ‭adverse‬
‭reaction, which means any AE caused by a drug.‬
‭●‬ ‭Serious‬‭adverse‬‭events‬‭(SAEs)‬‭assessment:‬‭type,‬‭frequency,‬‭grade,‬‭outcome,‬‭relation‬
‭with‬ ‭study‬ ‭treatment,‬ ‭all‬ ‭considering‬ ‭the‬‭total‬‭number‬‭and‬‭proportion‬‭based‬‭on‬‭the‬
‭intention-to-treat and per protocol populations.‬
‭8.3.‬
‭Study determinations‬
‭Table 4‬‭details the study determinations to be performed‬‭and the corresponding timeline.‬
‭Table 4. Study determinations‬
‭Visit‬
‭SCR‬
‭Cycle 1‬
‭Cycle 2‬
‭Cycle 3‬
‭Cycle 4‬
‭Cycle 5‬
‭Cycle 6‬
‭Cycle 7‬
‭up to‬
‭Cycle N‬
‭Safety‬
‭Visit‬
‭PFS‬
‭FU‬
‭EOS‬
‭FU‬
‭Timeline‬
‭≤ 28 D‬
‭prior to‬
‭inclusion‬
‭D1‬ ‭D8‬ ‭D1‬ ‭D8‬
‭D1‬
‭D8‬ ‭D1‬ ‭D8‬ ‭D1‬ ‭D8‬
‭D1‬
‭D8‬
‭D1‬
‭within‬
‭30d‬
‭after‬
‭EOT‬
‭Q12W‬
‭Q6‬
‭months‬
‭Visit window‬
‭+/- 3d‬
‭Q3W‬
‭+/-3d‬
‭+/-3d‬
‭+/- 7d‬
‭Clinical Assessments‬
‭Informed consent‬
‭x‬
‭Medical History‬
‭(Medical  and‬
‭oncology specific)‬
‭x‬
‭Physical Exam‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭ECOG‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Contraception check‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Vital signs (BP, PR)‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Laboratory and biological sample studies‬
‭Archival tumor‬
‭block‬
‭x‬
‭Blood collection‬
‭(biomarkers)‬
‭x‬
‭x‬
‭x‬
‭(D1C7)‬
‭x‬
‭at DP‬
‭Faecal sample‬
‭(biomarkers)‬
‭x‬
‭x‬
‭x‬
‭at DP‬
‭Coagulation‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Hematology*‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Blood chemistry*‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Thyroid function‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭HBV/HCV test‬
‭x‬
‭Pregnancy test‬
‭(serum/urine)‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Urinalysis‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Cardiac monitoring‬
‭ECG‬
‭x‬
‭If clinically indicated‬
‭x‬
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‭FEVI‬
‭x‬
‭If clinically indicated‬
‭x‬
‭Disease assessment‬
‭Tumor evaluation‬
‭x‬
‭On week 9 , week 18 (prior starting atezolizumab monotherapy and every 12 weeks +/-7‬
‭days thereafter until the of objective disease progression or death (whichever comes‬
‭first)‬
‭Survival‬
‭assessment‬
‭x‬
‭IMP follow-up‬
‭Treatment dosing‬
‭compliance‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Chemotherapy‬
‭administration‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Atezolizumab‬
‭administration‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭Concomitant‬
‭medications‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭New systemic cancer‬
‭treatment‬
‭x‬
‭x‬
‭Safety assessment‬
‭Adverse events‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭x‬
‭D:‬‭Day/s;‬‭Q3W:‬‭Every‬‭3‬‭weeks;‬‭Q12W:‬‭Every‬‭12‬‭weeks;‬‭EOT:‬‭End‬‭of‬‭treatment;‬‭PFS:‬‭Progression-free‬‭survival;‬
‭EOS: End of study.‬
‭Informed‬‭consent:‬‭Informed‬‭consent‬‭of‬‭study‬‭procedures‬‭may‬‭be‬‭obtained‬‭prior‬‭to‬‭the‬‭screening.‬‭If‬‭laboratory‬‭or‬
‭imaging‬‭procedures‬‭were‬‭performed‬‭for‬‭different‬‭reasons‬‭prior‬‭to‬‭signing‬‭consent,‬‭these‬‭can‬‭be‬‭used‬‭for‬‭screening‬
‭purposes‬ ‭with‬ ‭the‬ ‭consent‬ ‭of‬ ‭the‬ ‭patient.‬ ‭However,‬ ‭all‬‭screening‬‭laboratory‬‭and‬‭imaging‬‭results‬‭must‬‭have‬‭been‬
‭obtained within 28 days of inclusion.‬
‭Medical‬‭History:‬‭Should‬‭include‬‭information‬‭on‬‭prior‬‭systemic‬‭adjuvant‬‭or‬‭neoadjuvant‬‭therapy‬‭regimens,‬‭surgery‬
‭and‬ ‭radiation‬ ‭therapy.‬ ‭Comorbidities:‬ ‭cardiovascular‬ ‭disease,‬ ‭previous‬ ‭cancer‬ ‭and‬ ‭diabetes,‬ ‭pulmonary‬ ‭disease,‬
‭dementia, etc.‬
‭Physical‬‭exam:‬‭Includes‬‭an‬‭examination‬‭of‬‭major‬‭body‬‭systems‬‭and‬‭weight‬‭(height‬‭at‬‭screening‬‭only).‬‭Additional‬
‭PE‬ ‭may‬ ‭be‬ ‭performed‬ ‭as‬ ‭clinically‬ ‭indicated.‬ ‭During‬ ‭the‬ ‭physical‬ ‭examination,‬ ‭a‬ ‭stethoscope‬ ‭will‬ ‭be‬ ‭used‬ ‭to‬
‭carefully‬‭auscultate‬‭the‬‭lungs,‬‭additional‬‭respiratory‬‭functional‬‭tests‬‭should‬‭be‬‭performed‬‭as‬‭per‬‭local‬‭practise‬‭when‬
‭suspecting pneumonitis (more information is provided in annex 1 of this protocol).‬
‭ECOG PS:‬‭ECOG may be recorded by telephone if the‬‭patient is not coming to site for other reasons.‬
‭Contraception‬‭check:‬‭Male‬‭patients‬‭who‬‭are‬‭able‬‭to‬‭father‬‭children‬‭and‬‭female‬‭patients‬‭who‬‭are‬‭of‬‭childbearing‬
‭potential‬‭will‬‭need‬‭to‬‭affirm‬‭that‬‭they‬‭meet‬‭the‬‭criteria‬‭for‬‭correct‬‭use‬‭of‬‭2‬‭of‬‭the‬‭selected‬‭methods‬‭of‬‭contraception.‬
‭The‬‭investigator‬‭or‬‭his‬‭or‬‭her‬‭designee‬‭will‬‭discuss‬‭with‬‭the‬‭patient‬‭the‬‭need‬‭to‬‭use‬‭2‬‭highly‬‭effective‬‭contraception‬
‭methods‬ ‭consistently‬ ‭and‬ ‭correctly‬ ‭and‬ ‭document‬ ‭such‬ ‭conversation‬ ‭in‬ ‭the‬ ‭patient’s‬ ‭chart.‬ ‭In‬ ‭addition,‬ ‭the‬
‭investigator‬‭or‬‭his/her‬‭designee‬‭will‬‭instruct‬‭the‬‭patient‬‭to‬‭call‬‭immediately‬‭if‬‭one‬‭or‬‭both‬‭contraception‬‭methods‬‭are‬
‭discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner.‬
‭Vital signs:‬‭To include blood pressure (BP) and pulse‬‭rate (PR). Body weight is to be recorded at each visit along‬
‭with vital signs.‬
‭*Laboratory‬‭Studies:‬‭Complete‬‭blood‬‭count‬‭that‬‭includes‬‭total‬‭white‬‭blood‬‭cell‬‭count‬‭with‬‭leukocyte‬‭formula,‬‭Hb,‬
‭and‬‭platelet‬‭count.‬‭The‬‭analytical‬‭studies‬‭may‬‭be‬‭performed‬‭up‬‭to‬‭72‬‭hours‬‭before‬‭the‬‭scheduled‬‭visits‬‭in‬‭order‬‭to‬
‭have‬ ‭the‬ ‭results‬ ‭at‬ ‭the‬ ‭time‬ ‭of‬ ‭the‬ ‭patient’s‬ ‭visit.‬ ‭During‬ ‭the‬ ‭first‬ ‭6‬ ‭cycles‬ ‭of‬ ‭treatment‬ ‭with‬ ‭split‬ ‭doses‬ ‭of‬
‭gemcitabine‬‭plus‬‭cisplatin,‬‭complete‬‭blood‬‭count‬‭and‬‭biochemistry‬‭(liver,‬‭renal‬‭and‬‭electrolytes)‬‭on‬‭D1‬‭and‬‭D8‬
‭are‬ ‭mandatory‬ ‭for‬ ‭patient‬ ‭safety‬ ‭assurance‬ ‭and‬ ‭treatment‬ ‭continuation‬‭.‬ ‭Biochemistry‬ ‭tests‬ ‭include‬ ‭albumin,‬
‭alkaline‬ ‭phosphatase,‬ ‭lactate‬ ‭dehydrogenase‬ ‭(LDH),‬ ‭calcium,‬ ‭magnesium,‬ ‭phosphorus,‬ ‭sodium,‬ ‭potassium,‬
‭creatinine,‬‭creatine‬‭kinase,‬‭direct‬‭bilirubin,‬‭indirect‬‭bilirubin,‬‭total‬‭bilirubin,‬‭total‬‭protein,‬‭urea,‬‭uric‬‭acid,‬‭amylase,‬
‭lipase,‬ ‭and‬ ‭glucose‬ ‭tests.‬ ‭Liver‬ ‭test‬ ‭panel‬ ‭functions‬ ‭include‬ ‭alanine‬ ‭transaminase‬ ‭(ALT),‬ ‭aspartate‬‭transaminase‬
‭(AST),‬‭alkaline‬‭phosphatase‬‭(ALP),‬‭and‬‭gamma-glutamyl‬‭transpeptidase‬‭(GGT)‬‭tests.‬‭Tests‬‭for‬‭pancreatic‬‭enzymes‬
‭include‬ ‭lipase,‬ ‭protease,‬ ‭amylase,‬ ‭and‬ ‭trypsinogen‬ ‭tests.‬ ‭If‬ ‭screening‬ ‭clinical‬ ‭chemistry‬ ‭and‬ ‭haematology‬
‭assessments are performed within 3 days prior to day 1 (first infusion day), they do not need to be repeated at day 1.‬
‭Faecal‬ ‭samples:‬ ‭Specimens‬ ‭will‬ ‭be‬ ‭collected‬ ‭at‬ ‭baseline‬ ‭(before‬ ‭start‬ ‭of‬ ‭treatment),‬ ‭Cycle‬ ‭4‬ ‭Day‬ ‭1‬ ‭and‬ ‭after‬
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‭progression;‬ ‭the‬ ‭sample‬ ‭must‬ ‭be‬ ‭processed‬ ‭and‬ ‭retained‬ ‭in‬ ‭the‬ ‭local‬ ‭laboratory‬ ‭until‬ ‭Sponsor‬ ‭indications‬ ‭for‬
‭shipment.‬
‭Thyroid Function:‬‭TSH and free T4.‬
‭HBV/HCV test:‬‭Serology including HIV, hepatitis B‬‭(HBsAg and anti-HBc), and hepatitis C virus (HCV).‬
‭Pregnancy‬ ‭test‬ ‭(serum/urine):‬ ‭For‬ ‭women‬ ‭of‬ ‭childbearing‬ ‭potential‬ ‭only.‬ ‭A‬ ‭urine‬ ‭or‬ ‭serum‬ ‭pregnancy‬ ‭test‬ ‭is‬
‭acceptable.‬‭Women‬‭of‬‭childbearing‬‭potential‬‭are‬‭required‬‭to‬‭have‬‭a‬‭pregnancy‬‭test‬‭within‬‭7‬‭days‬‭prior‬‭to‬‭the‬‭first‬
‭dose‬‭of‬‭the‬‭study‬‭drug,‬‭and‬‭every‬‭4‬‭weeks‬‭thereafter.‬‭Pregnancy‬‭tests‬‭may‬‭occur‬‭on‬‭day‬‭1,‬‭but‬‭the‬‭results‬‭must‬‭be‬
‭available and reviewed by the treating physician or investigator prior to commencing an infusion.‬
‭Urinalysis:‬‭Protein,‬‭glucose,‬‭blood,‬‭Urine‬‭dipstick/other‬‭semiquantitative‬‭method,‬‭for‬‭urine‬‭protein:‬‭if‬‭≥‬‭2+,‬‭collect‬
‭24-hour.‬
‭ECG:‬‭12-lead ECG. Any clinically significant abnormalities‬‭detected require triplicate ECG results.‬
‭FEVI:‬‭MUGA‬‭Scan‬‭or‬‭ECHO,‬‭the‬‭technique‬‭used‬‭at‬‭screening‬‭will‬‭be‬‭consistently‬‭used‬‭throughout‬‭the‬‭study,‬‭in‬
‭the following assessments.‬
‭Tumor‬‭assessments:‬‭CT‬‭scan‬‭or‬‭MRI‬‭is‬‭to‬‭be‬‭performed‬‭at‬‭baseline,‬‭on‬‭week‬‭9,‬‭on‬‭week‬‭18‬‭and‬‭q12w‬‭±‬‭1w‬‭until‬
‭the‬ ‭confirmation‬ ‭of‬ ‭objective‬ ‭disease‬ ‭progression‬‭or‬‭death‬‭(whichever‬‭comes‬‭first).‬‭The‬‭same‬‭imaging‬‭technique‬
‭used‬ ‭to‬ ‭characterize‬ ‭each‬ ‭identified‬ ‭and‬ ‭reported‬ ‭lesion‬ ‭at‬ ‭screening‬ ‭will‬ ‭be‬ ‭employed‬ ‭in‬ ‭the‬ ‭following‬ ‭tumor‬
‭assessments.‬ ‭This‬ ‭schedule‬ ‭must‬ ‭be‬ ‭followed‬ ‭regardless‬ ‭of‬ ‭any‬ ‭delays‬ ‭in‬ ‭dosing,‬ ‭in‬ ‭case‬ ‭of‬ ‭suspected‬
‭pseudo-progression;‬ ‭treatment‬ ‭should‬ ‭be‬ ‭continued‬ ‭until‬ ‭progression‬ ‭of‬ ‭disease‬ ‭is‬ ‭confirmed‬ ‭from‬ ‭the‬ ‭imaging‬
‭results.‬‭RECIST‬‭assessments‬‭will‬‭be‬‭performed‬‭on‬‭images‬‭from‬‭CT‬‭scans‬‭(preferred)‬‭or‬‭MRI,‬‭each‬‭preferably‬‭with‬
‭IV‬‭contrast‬‭of‬‭the‬‭neck,‬‭chest,‬‭abdomen‬‭(including‬‭liver‬‭and‬‭adrenal‬‭glands),‬‭and‬‭pelvis.‬‭Additional‬‭anatomy‬‭should‬
‭be‬ ‭imaged‬ ‭based‬ ‭on‬ ‭signs‬ ‭and‬ ‭symptoms‬‭of‬‭individual‬‭patients‬‭at‬‭baseline‬‭and‬‭follow-up.‬ ‭Baseline‬‭assessments‬
‭should‬‭be‬‭performed‬‭no‬‭more‬‭than‬‭28‬‭days‬‭before‬‭the‬‭date‬‭of‬‭inclusion‬‭and,‬‭ideally,‬‭should‬‭be‬‭performed‬‭as‬‭close‬‭as‬
‭possible‬‭to‬‭and‬‭prior‬‭to‬‭the‬‭start‬‭of‬‭treatment.‬‭CR‬‭and‬‭PR‬‭must‬‭be‬‭confirmed‬‭with‬‭repeated‬‭imaging‬‭performed‬‭at‬
‭least‬‭4‬‭weeks‬‭after‬‭initial‬‭documentation‬‭of‬‭response.‬‭Assessment‬‭of‬‭response‬‭will‬‭be‬‭performed‬‭using‬‭RECIST‬‭1.1.‬
‭If‬‭radiologic‬‭imaging‬‭shows‬‭disease‬‭progression,‬‭the‬‭confirmatory‬‭scans‬‭should‬‭be‬‭performed‬‭preferably‬‭at‬‭the‬‭next‬
‭scheduled‬ ‭imaging‬ ‭visit‬ ‭and‬ ‭no‬ ‭less‬ ‭than‬ ‭4‬ ‭weeks‬ ‭after‬ ‭the‬ ‭prior‬‭assessment‬‭of‬‭PD‬‭(in‬‭the‬‭absence‬‭of‬‭clinically‬
‭significant‬ ‭deterioration).‬ ‭If‬ ‭an‬ ‭unscheduled‬‭assessment‬‭was‬‭performed‬‭and‬‭the‬‭patient‬‭has‬‭not‬‭progressed,‬‭every‬
‭attempt should be made to perform the subsequent assessment at the next scheduled visit.‬
‭Treatment‬‭dosing‬‭compliance:‬‭Study‬‭drug‬‭compliance‬‭will‬‭be‬‭assessed‬‭by‬‭the‬‭Investigator‬‭and/or‬‭study‬‭personnel‬
‭at‬ ‭each‬ ‭patient’s‬ ‭visit,‬ ‭and‬ ‭it‬ ‭will‬ ‭be‬ ‭captured‬ ‭in‬ ‭the‬ ‭patient’s‬ ‭records‬ ‭as‬ ‭part‬ ‭of‬ ‭source‬ ‭documentation‬ ‭at‬ ‭each‬
‭patient’s visit. Corresponding drug administration information will be reported also in the eCRF.‬
‭Chemotherapy‬‭dispensing/administration:‬‭Results‬‭for‬‭LTFs,‬‭electrolytes,‬‭and‬‭creatinine‬‭must‬‭be‬‭available‬‭before‬
‭commencing‬ ‭an‬ ‭infusion‬ ‭(within‬ ‭3‬ ‭days)‬ ‭and‬ ‭reviewed‬ ‭by‬ ‭the‬ ‭treating‬‭physician‬‭or‬‭investigator‬‭prior‬‭to‬‭dosing.‬
‭Specific‬ ‭details‬ ‭on‬ ‭haematological‬ ‭and‬ ‭renal‬ ‭function‬ ‭parameters‬ ‭for‬ ‭treatment‬ ‭interruption‬ ‭and‬ ‭resuming‬ ‭are‬
‭detailed in the gemcitabine and cisplatin administration section.‬
‭Atezolizumab‬ ‭dispensing/administration:‬ ‭Every‬ ‭3‬ ‭weeks‬ ‭until‬ ‭PD‬ ‭or‬ ‭unacceptable‬ ‭toxicity.‬ ‭Continuation‬ ‭of‬
‭atezolizumab‬ ‭treatment‬ ‭could‬ ‭be‬ ‭considered‬ ‭for‬ ‭patients‬ ‭who‬ ‭have‬ ‭been‬ ‭reported‬ ‭with‬ ‭PD‬ ‭on‬ ‭the‬ ‭week‬ ‭9‬
‭radiological evaluation but, according to the PI’s criteria, might be considered as with clinical benefit.‬
‭Adverse‬ ‭events:‬ ‭Adverse‬‭events‬‭should‬‭be‬‭documented‬‭and‬‭recorded‬‭at‬‭each‬‭visit‬‭using‬‭NCI-CTCAE‬‭v5.0.‬‭AEs‬
‭(serious‬‭and‬‭non-serious)‬‭should‬‭be‬‭recorded‬‭in‬‭the‬‭eCRF‬‭and‬‭patient‬‭records,‬‭from‬‭the‬‭time‬‭the‬‭patient‬‭has‬‭taken‬‭at‬
‭least‬‭1‬‭dose‬‭of‬‭study‬‭treatment‬‭through‬‭and‬‭including‬‭90‬‭calendar‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭IMP.‬‭If‬‭a‬‭patent‬‭begins‬
‭a‬‭new‬‭anticancer‬‭therapy,‬‭the‬‭AE‬‭reporting‬‭period‬‭for‬‭non-serious‬‭AEs‬‭ends‬‭at‬‭the‬‭time‬‭the‬‭new‬‭treatment‬‭is‬‭started.‬
‭For‬ ‭SAEs,‬ ‭the‬ ‭active‬ ‭reporting‬‭period‬‭to‬‭Sponsor‬‭or‬‭it‬‭designated,‬‭begins‬‭from‬‭the‬‭time‬‭that‬‭the‬‭patient‬‭provides‬
‭informed‬ ‭consent,‬ ‭which‬ ‭is‬ ‭obtained‬ ‭prior‬ ‭to‬ ‭the‬ ‭patient’s‬ ‭participation‬ ‭in‬ ‭this‬ ‭study,‬ ‭through‬ ‭and‬ ‭including‬ ‭90‬
‭calendar days after the last administration of the investigational products.‬
‭Concomitant‬‭medications:‬‭Concomitant‬‭medication‬‭will‬‭be‬‭recorded‬‭from‬‭28‬‭days‬‭prior‬‭to‬‭start‬‭of‬‭study‬‭treatment‬
‭and‬‭up‬‭to‬‭90‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭study‬‭treatment.‬‭All‬‭concomitant‬‭medications‬‭should‬‭be‬‭recorded‬‭in‬‭the‬‭CRF‬
‭including‬‭supportive‬‭care‬‭drugs‬‭(i.e.,‬‭antiemetics‬‭treatment‬‭and‬‭prophylaxis),‬‭the‬‭drugs‬‭used‬‭to‬‭treat‬‭adverse‬‭events‬
‭or chronic diseases, and non-drug supportive interventions (e.g. transfusions).‬
‭Biomarker‬‭study:‬‭Archival‬‭Tumor‬‭block‬‭at‬‭baseline‬‭and‬‭processed‬‭blood‬‭samples‬‭at‬‭baseline,‬‭day‬‭1‬‭of‬‭cycle‬‭4‬‭and‬
‭7‬ ‭(D1),‬ ‭and‬ ‭at‬ ‭EOT/progression.‬ ‭Blood‬ ‭samples‬ ‭should‬ ‭be‬ ‭obtained‬ ‭in‬ ‭all‬‭patients‬‭at‬‭the‬‭time‬‭of‬‭EOT‬‭(even‬‭by‬
‭toxicity‬‭without‬‭progressing)‬‭and‬‭samples‬‭are‬‭to‬‭be‬‭stored‬‭at‬‭site‬‭at‬‭-80‬‭ºC‬‭and‬‭are‬‭to‬‭be‬‭sent‬‭at‬‭the‬‭end‬‭of‬‭study‬‭(1‬
‭dry ice shipment per site).‬
‭New‬ ‭systemic‬ ‭cancer‬ ‭treatment:‬‭Information‬‭on‬‭subsequent‬‭treatments‬‭should‬‭include‬‭the‬‭list‬‭of‬‭post-treatment‬
‭therapies,‬ ‭drugs‬ ‭administered,‬ ‭and‬ ‭the‬ ‭date‬ ‭of‬‭initiation‬‭and‬‭discontinuation‬‭of‬‭each‬‭drug,‬‭and‬‭the‬‭corresponding‬
‭disease progression date (if applicable). All the data will be recorded in the medical record and in the eCRF.‬
‭Survival‬ ‭assessment‬ ‭(EOS):‬ ‭After‬ ‭progression,‬ ‭the‬ ‭patient‬ ‭will‬ ‭be‬ ‭followed‬ ‭for‬ ‭survival‬ ‭until‬ ‭death,‬ ‭loss‬ ‭of‬
‭follow-up,‬ ‭total‬ ‭patient‬ ‭consent‬ ‭withdrawal‬ ‭(refusing‬ ‭to‬ ‭any‬ ‭trial‬ ‭procedure),‬ ‭or‬ ‭end‬ ‭of‬ ‭study.‬‭Patient‬‭long‬‭term‬
‭follow-up‬‭to‬‭determine‬‭status‬‭(alive,‬‭death,‬‭loss‬‭of‬‭follow‬‭up,‬‭etc.)‬‭may‬‭be‬‭performed‬‭by‬‭phone,‬‭if‬‭the‬‭patient‬‭is‬‭not‬
‭coming‬‭to‬‭the‬‭clinic‬‭due‬‭to‬‭other‬‭reasons.‬‭The‬‭investigator‬‭must‬‭document‬‭in‬‭writing‬‭the‬‭results‬‭of‬‭the‬‭phone‬‭call‬‭in‬
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‭the patient records and in the eCRF.‬
‭8.4.‬
‭Determinations‬
‭in‬
‭the‬
‭selection‬
‭phase‬
‭(screening‬
‭and‬
‭baseline‬
‭determinations)‬
‭Within 28 days prior to inclusion:‬
‭●‬ ‭Informed consent‬
‭●‬ ‭Medical History (Medical and oncology specific)‬
‭●‬ ‭Archival tumor block‬
‭●‬ ‭HBV/HCV test‬
‭●‬ ‭ECG‬
‭●‬ ‭FEVI‬
‭●‬ ‭Tumor assessment‬
‭●‬ ‭Thyroid function‬
‭●‬ ‭Urinalysis‬
‭Within‬‭3‬‭days‬‭prior‬‭to‬‭inclusion‬‭(not‬‭needed‬‭to‬‭be‬‭repeated‬‭if‬‭it‬‭is‬‭performed‬‭within‬‭3‬‭days‬‭to‬
‭treatment initiation)‬
‭●‬ ‭Physical Exam‬
‭●‬ ‭ECOG‬
‭●‬ ‭Contraception check‬
‭●‬ ‭Vital signs (BP, PR)‬
‭●‬ ‭Coagulation‬
‭●‬ ‭Hematology‬
‭●‬ ‭Blood chemistry‬
‭●‬ ‭Pregnancy test (serum/urine)‬
‭●‬ ‭Blood collection (biomarkers)‬
‭●‬ ‭Faecal sample collection (biomarkers)‬
‭●‬ ‭Adverse events‬
‭●‬ ‭Concomitant medications‬
‭8.5.‬
‭Determinations and procedures during the treatment period (up to cycle 6)‬
‭8.5.1.‬ ‭Day 1 (considering 3 week cycles)‬
‭●‬ ‭Physical Exam‬
‭●‬ ‭ECOG‬
‭●‬ ‭Contraception check‬
‭●‬ ‭Vital signs (BP, PR)‬
‭●‬ ‭Coagulation‬
‭●‬ ‭Hematology‬
‭●‬ ‭Blood chemistry‬
‭●‬ ‭Thyroid function‬
‭●‬ ‭Pregnancy test (serum/urine)‬
‭●‬ ‭Urinalysis‬
‭●‬ ‭Adverse events‬
‭●‬ ‭Concomitant medications‬
‭●‬ ‭Treatment dosing compliance‬
‭●‬ ‭Atezolizumab administration‬
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‭●‬ ‭Split doses of gemcitabine and cisplatin administration‬
‭●‬ ‭Blood collection (biomarkers) only D1 C4.‬
‭●‬ ‭Faecal sample collection (biomarkers) only D1 C4.‬
‭8.5.2.‬ ‭Day 8 (considering 3 week cycles)‬
‭●‬ ‭Physical Exam‬
‭●‬ ‭ECOG‬
‭●‬ ‭Vital signs‬
‭●‬ ‭Hematology‬
‭●‬ ‭Blood chemistry‬
‭●‬ ‭Adverse events‬
‭●‬ ‭Treatment dosing compliance‬
‭●‬ ‭Concomitant medication‬
‭●‬ ‭Split doses of gemcitabine and cisplatin administration‬
‭8.5.3.‬ ‭Other determinations during treatment‬
‭●‬ ‭Tumor‬‭assessment:‬‭On‬‭week‬‭9,‬‭week‬‭18‬‭(prior‬‭starting‬‭atezolizumab‬‭monotherapy‬
‭and‬ ‭every‬‭12‬‭weeks‬‭+/-7‬‭days‬‭thereafter‬‭until‬‭the‬‭confirmation‬‭of‬‭objective‬‭disease‬
‭progression or death (whichever comes first).‬
‭●‬ ‭Safety‬ ‭determinations:‬‭Hematology‬‭and‬‭Blood‬‭chemistry‬‭(including‬‭renal‬‭function‬
‭assessment‬ ‭with‬ ‭urea‬ ‭and‬‭creatinine)‬‭should‬‭be‬‭evaluated‬‭weekly‬‭during‬‭the‬‭first‬‭6‬
‭cycles of treatment as per recommendations for gemcitabine treatment.‬
‭●‬ ‭When clinically indicated:‬‭ECG, and FEVI.‬
‭8.5.4.‬ ‭Determinations‬ ‭and‬ ‭procedures‬ ‭on‬ ‭day‬ ‭1‬ ‭of‬ ‭cycle‬ ‭7‬ ‭(D1-C7)‬ ‭and‬
‭subsequent cycles (D1-Cn)‬
‭●‬ ‭Physical Exam‬
‭●‬ ‭ECOG‬
‭●‬ ‭Contraception check‬
‭●‬ ‭Vital signs (BP, PR)‬
‭●‬ ‭Coagulation‬
‭●‬ ‭Hematology‬
‭●‬ ‭Blood chemistry‬
‭●‬ ‭Thyroid function‬
‭●‬ ‭Pregnancy test (serum/urine)‬
‭●‬ ‭Urinalysis‬
‭●‬ ‭Treatment compliance dosing‬
‭●‬ ‭Atezolizumab administration‬
‭●‬ ‭Concomitant medication‬
‭●‬ ‭Adverse event‬
‭When clinically indicated:‬‭urinalysis, ECG, and FEVI.‬
‭Additionally at D1-C7:‬
‭●‬ ‭Blood collection (biomarkers) only D1 C7.‬
‭●‬ ‭Tumor‬ ‭assessment:‬ ‭CT‬ ‭Scan‬ ‭or‬ ‭MRI‬ ‭prior‬ ‭to‬ ‭D1C7‬ ‭(on‬ ‭week‬ ‭18‬ ‭from‬ ‭treatment‬
‭starting).‬
‭When applicable‬
‭●‬ ‭Tumor‬‭assessment:‬‭CT‬‭Scan‬‭or‬‭MRI‬‭is‬‭to‬‭be‬‭performed‬‭on‬‭week‬‭9,‬‭week‬‭18‬‭and‬‭every‬
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‭12‬‭weeks‬‭until‬‭the‬‭confirmation‬‭of‬‭objective‬‭disease‬‭progression‬‭or‬‭death‬‭(whichever‬
‭comes first).‬
‭●‬ ‭When clinically indicated:‬‭ECG, and FEVI.‬
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‭8.6.‬
‭Determinations at safety visit‬
‭●‬ ‭Physical Exam‬
‭●‬ ‭ECOG‬
‭●‬ ‭Contraception check‬
‭●‬ ‭Vital signs (BP, PR)‬
‭●‬ ‭Coagulation‬
‭●‬ ‭Hematology‬
‭●‬ ‭Blood chemistry‬
‭●‬ ‭Thyroid function‬
‭●‬ ‭Pregnancy test (serum/urine)‬
‭●‬ ‭Urinalysis‬
‭●‬ ‭ECG‬
‭●‬ ‭FEVI‬
‭●‬ ‭Adverse events‬
‭●‬ ‭Concomitant medications‬
‭8.7.‬
‭Follow-up determinations‬
‭8.7.1. Follow up after end of treatment (prior PD)‬
‭Every 12 weeks:‬
‭●‬ ‭Tumor‬ ‭assessment:‬ ‭CT‬ ‭Scan‬‭or‬‭MRI‬‭is‬‭to‬‭be‬‭performed‬‭on‬‭week‬‭9,‬‭week‬‭18‬‭and‬
‭every‬ ‭12‬ ‭weeks‬ ‭until‬ ‭the‬ ‭confirmation‬ ‭of‬ ‭objective‬ ‭disease‬ ‭progression‬ ‭or‬ ‭death‬
‭(whichever comes first).‬
‭●‬ ‭New systemic cancer treatment.‬
‭●‬ ‭By‬ ‭the‬ ‭time‬ ‭of‬ ‭disease‬‭progression,‬‭Blood‬‭collection‬‭(biomarkers),‬‭Faecal‬‭sample‬
‭collection.‬
‭8.7.2. Follow up after end of treatment (after PD)‬
‭Every 6 months:‬
‭●‬ ‭New systemic cancer treatment‬
‭●‬ ‭Survival assessment‬
‭9.‬
‭SAFETY EVALUATION‬
‭ICH‬ ‭GCP‬ ‭requires‬ ‭that‬ ‭both‬ ‭investigators‬ ‭and‬ ‭sponsors‬ ‭follow‬ ‭specific‬ ‭procedures‬ ‭when‬
‭reporting‬ ‭adverse‬ ‭events/reactions‬ ‭in‬ ‭clinical‬ ‭trials.‬ ‭These‬ ‭procedures‬ ‭are‬ ‭described‬‭in‬‭this‬
‭section of the protocol.‬
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‭Any‬‭event‬‭involving‬‭adverse‬‭drug‬‭reactions‬‭(ADR),‬‭illnesses‬‭with‬‭onset‬‭during‬‭the‬‭study‬‭or‬
‭exacerbations of pre-existing illnesses should be recorded.‬
‭In‬ ‭addition,‬ ‭clinically‬ ‭significant‬ ‭changes‬ ‭in‬ ‭physical‬ ‭examination‬ ‭findings‬ ‭and‬ ‭abnormal‬
‭objective‬ ‭test‬ ‭findings‬ ‭(e.g.,‬ ‭x-ray,‬ ‭ECG)‬ ‭should‬ ‭also‬ ‭be‬ ‭recorded‬ ‭as‬ ‭AE.‬ ‭The‬ ‭criteria‬ ‭for‬
‭determining‬‭whether‬‭an‬‭abnormal‬‭objective‬‭test‬‭finding‬‭should‬‭be‬‭reported‬‭as‬‭an‬‭AE‬‭are‬‭as‬
‭follows:‬
‭●‬ ‭test result is associated with clinically significant symptoms, and/or‬
‭●‬ ‭test‬ ‭result‬ ‭leads‬ ‭to‬ ‭a‬ ‭change‬ ‭in‬ ‭study‬ ‭dosing‬ ‭or‬ ‭discontinuation‬ ‭from‬ ‭the‬ ‭study,‬
‭significant additional concomitant drug treatment or other therapy, and/or‬
‭●‬ ‭test result leads to any of the outcomes included in the definition of a SAE, and/or test‬
‭result is considered to be an AE by the investigator.‬
‭9.1.‬
‭Definitions‬
‭The definitions from ICH GCP apply in this trial protocol.‬
‭9.1.1.‬ ‭Adverse event (AE)‬
‭An‬ ‭adverse‬ ‭event‬ ‭is‬ ‭any‬‭untoward‬‭medical‬‭occurrence‬‭in‬‭a‬‭patient‬‭or‬‭clinical‬‭investigation‬
‭subject which does not necessarily have a causal relationship with the study treatment.‬
‭Examples of AEs include but are not limited to:‬
‭●‬ ‭Abnormal test findings;‬
‭●‬ ‭Clinically significant symptoms and signs;‬
‭●‬ ‭Changes in physical examination findings;‬
‭●‬ ‭Hypersensitivity;‬
‭●‬ ‭Drug abuse;‬
‭●‬ ‭Drug dependency.‬
‭Additionally, they may include signs or symptoms resulting from:‬
‭●‬ ‭Drug overdose;‬
‭●‬ ‭Drug withdrawal;‬
‭●‬ ‭Drug misuse;‬
‭●‬ ‭Drug interactions;‬
‭●‬ ‭Extravasation;‬
‭●‬ ‭Exposure during pregnancy (EDP);‬
‭●‬ ‭Exposure via breastfeeding;‬
‭●‬ ‭Medication error;‬
‭●‬ ‭Occupational exposure;‬
‭●‬ ‭Worsening‬‭of‬‭signs‬‭and‬‭symptoms‬‭of‬‭the‬‭malignancy‬‭under‬‭study‬‭should‬‭be‬‭reported‬
‭as‬ ‭AEs‬ ‭in‬ ‭the‬ ‭appropriate‬ ‭section‬ ‭of‬ ‭the‬ ‭CRF.‬ ‭Disease‬ ‭progression‬ ‭assessed‬ ‭by‬
‭measurement‬ ‭of‬ ‭malignant‬ ‭lesions‬ ‭on‬ ‭radiographs‬ ‭or‬ ‭other‬ ‭methods‬ ‭should‬ ‭not‬ ‭be‬
‭reported as AEs.‬
‭9.1.2.‬ ‭Atezolizumab Adverse Event of Special Interest‬
‭Adverse‬‭events‬‭of‬‭special‬‭interest‬‭are‬‭required‬‭to‬‭be‬‭reported‬‭by‬‭the‬‭investigator‬‭to‬‭the‬‭Sponsor‬
‭immediately‬ ‭(i.e.,‬ ‭no‬ ‭more‬ ‭than‬ ‭24‬ ‭hours‬ ‭after‬ ‭learning‬ ‭of‬ ‭the‬ ‭event;‬ ‭see‬ ‭Section‬ ‭9.2‬ ‭for‬
‭reporting instructions).‬
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‭Adverse events of special interest for this study are as follows:‬
‭●‬ ‭Cases‬‭of‬‭potential‬‭drug-induced‬‭liver‬‭injury‬‭that‬‭include‬‭an‬‭elevated‬‭ALT‬‭or‬‭AST‬‭in‬
‭combination‬‭with‬‭either‬‭an‬‭elevated‬‭bilirubin‬‭or‬‭clinical‬‭jaundice,‬‭as‬‭defined‬‭by‬‭Hy's‬
‭Law.‬
‭●‬ ‭Suspected transmission of an infectious agent by the study treatment, as defined below‬
‭●‬ ‭Any‬ ‭organism,‬ ‭virus,‬ ‭or‬ ‭infectious‬ ‭particle‬ ‭(e.g.,‬ ‭prion‬ ‭protein‬ ‭transmitting‬
‭transmissible‬ ‭spongiform‬ ‭encephalopathy),‬ ‭pathogenic‬ ‭or‬ ‭non-pathogenic,‬ ‭is‬
‭considered‬ ‭an‬ ‭infectious‬ ‭agent.‬ ‭A‬ ‭transmission‬ ‭of‬ ‭an‬ ‭infectious‬ ‭agent‬ ‭may‬ ‭be‬
‭suspected‬‭from‬‭clinical‬‭symptoms‬‭or‬‭laboratory‬‭findings‬‭that‬‭indicate‬‭an‬‭infection‬‭in‬‭a‬
‭patient‬‭exposed‬‭to‬‭a‬‭medicinal‬‭product.‬‭This‬‭term‬‭applies‬‭only‬‭when‬‭a‬‭contamination‬
‭of study treatment is suspected.‬
‭●‬ ‭Systemic lupus erythematosus‬
‭●‬ ‭Events‬ ‭suggestive‬ ‭of‬ ‭hypersensitivity,‬ ‭infusion-related‬ ‭reactions,‬ ‭cytokine-release‬
‭syndrome, HLH, and MAS‬
‭●‬ ‭Nephritis‬
‭●‬ ‭Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)‬
‭●‬ ‭Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)‬
‭●‬ ‭Vasculitis‬
‭●‬ ‭Autoimmune hemolytic anemia‬
‭●‬ ‭Severe‬‭cutaneous‬‭reactions‬‭(e.g.,‬‭Stevens-Johnson‬‭syndrome,‬‭dermatitis‬‭bullous,‬‭toxic‬
‭epidermal necrolysis)‬
‭9.1.3.‬ ‭Laboratory Abnormalities‬
‭All‬ ‭laboratory‬ ‭data‬ ‭required‬ ‭by‬ ‭this‬ ‭protocol‬ ‭and‬ ‭any‬ ‭other‬ ‭clinical‬ ‭investigations‬ ‭will‬ ‭be‬
‭reviewed.‬ ‭Any‬ ‭abnormal‬ ‭value‬ ‭that‬ ‭leads‬ ‭to‬ ‭a‬ ‭change‬ ‭in‬ ‭subject‬ ‭management‬ ‭(eg,‬ ‭dose‬
‭reduction‬ ‭or‬ ‭delay‬ ‭or‬ ‭requirement‬ ‭for‬ ‭additional‬ ‭medication‬ ‭or‬ ‭monitoring)‬ ‭or‬ ‭that‬ ‭is‬
‭considered‬‭to‬‭be‬‭of‬‭clinical‬‭significance‬‭by‬‭the‬‭Investigator‬‭will‬‭be‬‭reported‬‭as‬‭an‬‭AE‬‭or‬‭SAE‬
‭as‬ ‭appropriate,‬ ‭unless‬ ‭this‬ ‭value‬ ‭is‬ ‭consistent‬ ‭with‬ ‭the‬ ‭subject’s‬‭present‬‭disease‬‭state‬‭or‬‭is‬
‭consistent with values obtained prior to entry into the study.‬
‭9.1.4.‬ ‭Medication errors‬
‭Medication‬ ‭errors‬ ‭may‬ ‭result,‬ ‭in‬ ‭this‬ ‭study,‬‭from‬‭the‬‭administration‬‭or‬‭consumption‬‭of‬‭the‬
‭wrong product, the wrong patient at the wrong time, or at the wrong dosage strength.‬
‭Such‬‭medication‬‭errors‬‭occurring‬‭to‬‭a‬‭study‬‭participant‬‭are‬‭to‬‭be‬‭captured‬‭on‬‭the‬‭eCRF,‬‭and‬
‭reported‬‭through‬‭the‬‭SAE‬‭form‬‭when‬‭appropriate.‬‭In‬‭the‬‭event‬‭of‬‭medication‬‭dosing‬‭error,‬‭the‬
‭sponsor should be notified immediately.‬
‭Medication‬ ‭errors‬ ‭are‬ ‭reportable‬ ‭irrespective‬ ‭of‬ ‭the‬ ‭presence‬ ‭of‬ ‭an‬ ‭associated‬ ‭AE/SAE,‬
‭including:‬
‭●‬ ‭Medication errors involving patient exposure to the investigational product;‬
‭●‬ ‭Potential‬‭medication‬‭errors‬‭or‬‭uses‬‭outside‬‭of‬‭what‬‭is‬‭foreseen‬‭in‬‭the‬‭protocol‬‭that‬‭do‬
‭or do not involve the participating patient.‬
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‭Whether‬ ‭or‬ ‭not‬ ‭the‬ ‭medication‬ ‭error‬ ‭is‬ ‭accompanied‬ ‭by‬ ‭an‬ ‭AE,‬ ‭as‬ ‭determined‬ ‭by‬ ‭the‬
‭investigator,‬‭the‬‭medication‬‭error‬‭is‬‭captured‬‭on‬‭the‬‭medication‬‭error‬‭version‬‭of‬‭the‬‭AE‬‭page‬
‭and, if applicable, any associated AEs are captured on an AE CRF page.‬
‭The guidance on reporting of medication errors also applies to the reporting of overdose.‬
‭9.1.4.1. Atezolizumab overdose‬
‭The‬‭standard‬‭fixed‬‭dose‬‭of‬‭Atezolizumab‬‭is‬‭1200‬‭mg‬‭is‬‭equivalent‬‭to‬‭15‬‭mg/kg‬‭in‬‭a‬‭typical‬
‭patient.‬‭No‬‭dose-limiting‬‭toxicities‬‭were‬‭observed‬‭at‬‭the‬‭20‬‭mg/kg‬‭dose‬‭level‬‭and‬‭the‬‭incidence‬
‭and‬ ‭intensity‬ ‭of‬‭AEs‬‭reported‬‭have‬‭not‬‭been‬‭shown‬‭to‬‭be‬‭dependent‬‭on‬‭dose.‬‭A‬‭maximum‬
‭tolerated dose has not been established.‬
‭Atezolizumab‬‭is‬‭supplied‬‭in‬‭vials‬‭containing‬‭the‬‭fixed‬‭1200‬‭mg‬‭dose‬‭of‬‭drug‬‭substance,‬‭which‬
‭minimizes‬‭the‬‭chance‬‭of‬‭overdose.‬‭Because‬‭the‬‭dose‬‭per‬‭patient‬‭is‬‭not‬‭based‬‭on‬‭weight‬‭or‬‭body‬
‭surface‬‭area,‬‭and‬‭no‬‭dose‬‭calculation‬‭is‬‭required,‬‭the‬‭risk‬‭of‬‭overdose‬‭due‬‭to‬‭medication‬‭errors‬
‭is minimal.‬
‭The data available to date suggest that the potential for harm from overdose is very low.‬
‭9.1.4.2. Gemcitabine overdose‬
‭There‬‭is‬‭no‬‭known‬‭antidote‬‭for‬‭overdose‬‭of‬‭gemcitabine.‬‭Doses‬‭as‬‭high‬‭as‬‭5700‬‭mg/m2‬‭have‬
‭been‬ ‭administered‬ ‭by‬ ‭intravenous‬ ‭infusion‬ ‭over‬ ‭30-minutes‬ ‭every‬ ‭2‬ ‭weeks‬ ‭with‬ ‭clinically‬
‭acceptable‬‭toxicity.‬‭In‬‭the‬‭event‬‭of‬‭suspected‬‭overdose,‬‭the‬‭patient‬‭should‬‭be‬‭monitored‬‭with‬
‭appropriate blood counts and receive supportive therapy, as necessary.‬
‭9.1.4.3. Cisplatin overdose‬
‭An‬ ‭acute‬ ‭overdose‬ ‭of‬ ‭cisplatin‬ ‭may‬ ‭result‬ ‭in‬ ‭renal‬ ‭failure,‬ ‭liver‬ ‭failure,‬ ‭deafness,‬ ‭ocular‬
‭toxicity‬‭(including‬‭detachment‬‭of‬‭the‬‭retina),‬‭significant‬‭myelosuppression,‬‭untreatable‬‭nausea‬
‭and vomiting and/or neuritis. An overdose may be fatal.‬
‭There‬‭is‬‭no‬‭specific‬‭antidote‬‭in‬‭the‬‭event‬‭of‬‭an‬‭over‬‭dosage‬‭of‬‭cisplatin.‬‭Even‬‭if‬‭haemodialysis‬
‭is‬‭initiated‬‭4‬‭hours‬‭after‬‭the‬‭overdose‬‭it‬‭has‬‭little‬‭effect‬‭on‬‭the‬‭elimination‬‭of‬‭cisplatin‬‭from‬‭the‬
‭body following a strong and rapid fixation of cisplatin to proteins.‬
‭Treatment in the event of an overdose consists of general support measures.‬
‭9.1.5.‬ ‭Adverse reaction (AR)‬
‭All‬‭untoward‬‭and‬‭unintended‬‭responses‬‭to‬‭an‬‭investigational‬‭medicinal‬‭product‬‭related‬‭to‬‭any‬
‭dose administered.‬
‭9.1.6.‬ ‭Serious Adverse Event (SAE)‬
‭Any untoward medical occurrence or effect that at any dose:‬
‭1.‬ ‭Results in death (is fatal),‬
‭2.‬ ‭Is life-threatening,‬
‭3.‬ ‭Requires or prolongs inpatient hospitalization,‬
‭4.‬ ‭Results in persistent or significant disability or incapacity,‬
‭5.‬ ‭Is a congenital anomaly or birth defect, or‬
‭6.‬ ‭Is medically significant.‬
‭Progression‬ ‭of‬ ‭the‬ ‭malignancy‬ ‭under‬ ‭study‬ ‭(including‬‭signs‬‭and‬‭symptoms‬‭of‬‭progression)‬
‭should‬ ‭not‬ ‭be‬ ‭reported‬ ‭as‬ ‭an‬ ‭SAE‬ ‭unless‬ ‭the‬ ‭outcome‬ ‭is‬ ‭fatal‬ ‭within‬ ‭the‬ ‭safety‬‭reporting‬
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‭period.‬ ‭Hospitalization‬ ‭due‬ ‭to‬ ‭signs‬ ‭and‬ ‭symptoms‬ ‭of‬ ‭disease‬ ‭progression‬ ‭should‬ ‭not‬ ‭be‬
‭reported as an SAE.‬
‭Medical‬‭and‬‭scientific‬‭judgement‬‭should‬‭be‬‭exercised‬‭in‬‭deciding‬‭whether‬‭urgent‬‭reporting‬‭is‬
‭appropriate‬‭in‬‭other‬‭situations‬‭such‬‭as‬‭important‬‭medical‬‭events‬‭that‬‭may‬‭not‬‭be‬‭immediately‬
‭life-threatening‬ ‭or‬ ‭result‬ ‭in‬ ‭hospitalization‬ ‭but‬ ‭may‬ ‭jeopardize‬ ‭the‬ ‭patient‬ ‭or‬ ‭may‬ ‭require‬
‭intervention to prevent one of the outcomes listed in the above definition.‬
‭Any‬‭suspected‬‭transmission‬‭of‬‭an‬‭infectious‬‭agent‬‭through‬‭the‬‭medication‬‭is‬‭also‬‭considered‬‭a‬
‭SAE.‬
‭The‬‭terms‬‭"severe"‬‭and‬‭"serious"‬‭are‬‭not‬‭synonymous.‬ ‭Severity‬‭refers‬‭to‬‭the‬‭intensity‬‭of‬‭an‬
‭adverse‬‭event‬‭(e.g.,‬‭rated‬‭as‬‭mild,‬‭moderate,‬‭or‬‭severe,‬‭or‬‭according‬‭to‬‭NCI‬‭CTCAE;‬‭the‬‭event‬
‭itself‬‭may‬‭be‬‭of‬‭relatively‬‭minor‬‭medical‬‭significance‬‭(such‬‭as‬‭severe‬‭headache‬‭without‬‭any‬
‭further findings).‬
‭Severity‬‭and‬‭seriousness‬‭need‬‭to‬‭be‬‭independently‬‭assessed‬‭for‬‭each‬‭adverse‬‭event‬‭recorded‬‭on‬
‭the eCRF.‬
‭Serious‬ ‭adverse‬ ‭events‬ ‭are‬ ‭required‬ ‭to‬ ‭be‬ ‭reported‬ ‭by‬ ‭the‬ ‭investigator‬ ‭to‬ ‭the‬ ‭Sponsor‬
‭immediately‬ ‭(i.e.,‬ ‭no‬ ‭more‬ ‭than‬ ‭24‬ ‭hours‬ ‭after‬ ‭learning‬ ‭of‬ ‭the‬ ‭event;‬ ‭see‬ ‭Section‬ ‭9.2‬ ‭for‬
‭reporting instructions).‬
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‭9.1.7.‬ ‭Protocol-Specified Serious Adverse Events‬
‭There‬ ‭are‬ ‭no‬ ‭protocol-specified‬ ‭SAEs‬ ‭in‬ ‭this‬ ‭study.‬ ‭All‬ ‭SAEs‬ ‭will‬ ‭be‬ ‭reported‬ ‭by‬ ‭the‬
‭investigator‬‭as‬‭described‬‭in‬‭the‬‭previous‬‭sections,‬‭and‬‭will‬‭be‬‭handled‬‭as‬‭SAEs‬‭in‬‭the‬‭safety‬
‭database.‬
‭9.1.8.‬ ‭Life Threatening Event‬
‭It‬‭is‬‭any‬‭event‬‭in‬‭which‬‭the‬‭subject‬‭was‬‭at‬‭risk‬‭of‬‭death‬‭at‬‭the‬‭time‬‭of‬‭the‬‭event;‬‭it‬‭does‬‭not‬
‭refer to an event which hypothetically might have caused death if it were more severe.‬
‭9.1.9.‬ ‭Hospitalization / Prolongation of Hospitalization‬
‭Any‬‭event‬‭requiring‬‭hospitalization‬‭(or‬‭prolongation‬‭of‬‭hospitalization)‬‭that‬‭occurs‬‭or‬‭worsens‬
‭during‬‭a‬‭patient’s‬‭participation‬‭in‬‭a‬‭clinical‬‭study‬‭must‬‭be‬‭reported‬‭as‬‭a‬‭serious‬‭adverse‬‭event.‬
‭Prolongation‬ ‭of‬ ‭hospitalization‬ ‭is‬ ‭defined‬ ‭as‬ ‭any‬ ‭extension‬ ‭of‬ ‭an‬ ‭inpatient‬ ‭hospitalization‬
‭beyond‬‭the‬‭stay‬‭anticipated/required‬‭for‬‭the‬‭initial‬‭admission,‬‭as‬‭determined‬‭by‬‭the‬‭investigator‬
‭or treating physician.‬
‭Hospitalizations that do not meet the criteria for serious adverse event reporting are:‬
‭1.‬ ‭Reasons‬ ‭described‬ ‭in‬ ‭protocol‬ ‭(e.g.,‬ ‭drug‬ ‭administration,‬ ‭protocol-required‬
‭investigations).‬ ‭Hospitalizations‬ ‭or‬ ‭prolonged‬ ‭hospitalization‬ ‭for‬ ‭a‬ ‭complication‬ ‭of‬
‭therapy administration or procedures will be reported as a Serious Adverse Event.‬
‭2.‬ ‭Hospitalization‬‭or‬‭prolonged‬‭hospitalization‬‭for‬‭technical,‬‭practical‬‭or‬‭social‬‭reasons,‬
‭in the absence of an adverse event.‬
‭3.‬ ‭Pre-planned‬ ‭hospitalizations‬ ‭(i.e.,‬ ‭planned‬ ‭before‬ ‭study‬ ‭entry).‬ ‭Any‬ ‭surgery‬ ‭or‬
‭procedure planned before study entry must be documented on the case report form.‬
‭9.1.10.‬ ‭Unexpected adverse event (not listed)‬
‭An‬‭unexpected‬‭AA,‬‭whose‬‭nature‬‭or‬‭severity‬‭does‬‭not‬‭correspond‬‭to‬‭the‬‭product‬‭information.‬
‭The reference documents to establish the expectedness will be:‬
‭●‬ ‭Atezolizumab, last version of Investigator Brochure available for the Sponsor‬
‭●‬ ‭Gemcitabine, last version of the SmPC.‬
‭●‬ ‭Cisplatin, last version of the SmPC.‬
‭9.1.11.‬ ‭Adverse Event Associated With the Use of the Drug (Adverse Reaction)‬
‭The‬ ‭investigator’s‬ ‭assessment‬ ‭of‬ ‭causality‬ ‭must‬ ‭be‬ ‭provided‬ ‭for‬ ‭all‬ ‭AEs‬ ‭(serious‬ ‭and‬
‭non-serious);‬‭the‬‭investigator‬‭must‬‭record‬‭the‬‭causal‬‭relationship‬‭in‬‭the‬‭CRF,‬‭as‬‭appropriate,‬
‭and‬‭report‬‭such‬‭an‬‭assessment‬‭in‬‭accordance‬‭with‬‭the‬‭serious‬‭adverse‬‭reporting‬‭requirements‬‭if‬
‭applicable.‬‭An‬‭investigator’s‬‭causality‬‭assessment‬‭is‬‭the‬‭determination‬‭of‬‭whether‬‭there‬‭exists‬
‭a‬ ‭reasonable‬ ‭possibility‬ ‭that‬ ‭the‬ ‭investigational‬ ‭product‬ ‭caused‬ ‭or‬ ‭contributed‬ ‭to‬ ‭an‬ ‭AE;‬
‭generally‬ ‭the‬ ‭facts‬ ‭(evidence)‬ ‭or‬ ‭arguments‬ ‭to‬ ‭suggest‬ ‭a‬ ‭causal‬ ‭relationship‬ ‭should‬ ‭be‬
‭provided.‬‭If‬‭the‬‭investigator‬‭does‬‭not‬‭know‬‭whether‬‭or‬‭not‬‭the‬‭investigational‬‭product‬‭caused‬
‭the‬‭event,‬‭then‬‭the‬‭event‬‭will‬‭be‬‭handled‬‭as‬‭“related‬‭to‬‭investigational‬‭product”‬‭for‬‭reporting‬
‭purposes,‬ ‭as‬ ‭defined‬ ‭by‬ ‭the‬ ‭sponsor‬ ‭(see‬ ‭the‬ ‭section‬ ‭on‬ ‭Reporting‬ ‭Requirements).‬ ‭If‬ ‭the‬
‭investigator's‬‭causality‬‭assessment‬‭is‬‭“unknown‬‭but‬‭not‬‭related‬‭to‬‭investigational‬‭product”,‬‭this‬
‭should be clearly documented on study records.‬
‭In‬ ‭addition,‬ ‭if‬ ‭the‬ ‭investigator‬ ‭determines‬‭an‬‭SAE‬‭is‬‭associated‬‭with‬‭study‬‭procedures,‬‭the‬
‭investigator‬ ‭must‬ ‭record‬ ‭this‬ ‭causal‬ ‭relationship‬ ‭in‬ ‭the‬ ‭source‬ ‭documents‬ ‭and‬ ‭CRF,‬ ‭as‬
‭appropriate,‬ ‭and‬ ‭report‬ ‭such‬ ‭an‬ ‭assessment‬ ‭in‬ ‭accordance‬ ‭with‬ ‭the‬ ‭SAE‬ ‭reporting‬
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‭requirements, if applicable.‬
‭For‬‭combination‬‭treatments,‬‭causality‬‭assessment‬‭will‬‭be‬‭performed‬‭for‬‭each‬‭of‬‭the‬‭individual‬
‭drugs included in the combination.‬
‭An‬‭adverse‬‭event‬‭is‬‭considered‬‭associated‬‭with‬‭the‬‭use‬‭of‬‭the‬‭drug‬‭(Adverse‬‭Reaction)‬‭if‬‭the‬
‭attribution is possible, probable, or very likely by the definitions listed below.‬
‭9.1.12.‬ ‭Attribution Definitions‬
‭Not Related‬
‭An adverse event that is not related to the use of the drug.‬
‭Doubtful‬
‭An‬‭adverse‬‭event‬‭for‬‭which‬‭an‬‭alternative‬‭explanation‬‭is‬‭more‬‭likely,‬‭e.g.,‬‭concomitant‬‭drug(s),‬
‭concomitant‬ ‭disease(s),‬ ‭or‬ ‭the‬ ‭relationship‬ ‭in‬ ‭time‬ ‭suggests‬ ‭that‬ ‭a‬ ‭causal‬ ‭relationship‬ ‭is‬
‭unlikely.‬
‭Possible‬
‭An‬‭adverse‬‭event‬‭that‬‭might‬‭be‬‭due‬‭to‬‭the‬‭use‬‭of‬‭the‬‭drug.‬‭An‬‭alternative‬‭explanation,‬‭e.g.,‬
‭concomitant‬ ‭drug(s),‬ ‭concomitant‬ ‭disease(s),‬ ‭is‬ ‭inconclusive.‬ ‭The‬ ‭relationship‬ ‭in‬ ‭time‬ ‭is‬
‭reasonable; therefore, the causal relationship cannot be excluded.‬
‭Probable‬
‭An‬ ‭adverse‬ ‭event‬ ‭that‬ ‭might‬ ‭be‬ ‭due‬ ‭to‬ ‭the‬ ‭use‬ ‭of‬ ‭the‬ ‭drug.‬ ‭The‬ ‭relationship‬ ‭in‬ ‭time‬ ‭is‬
‭suggestive‬ ‭(e.g.,‬ ‭confirmed‬ ‭by‬ ‭de-challenge).‬ ‭An‬‭alternative‬‭explanation‬‭is‬‭less‬‭likely,‬‭e.g.,‬
‭concomitant drug(s), concomitant disease(s).‬
‭Very Likely‬
‭An‬ ‭adverse‬ ‭event‬ ‭that‬ ‭is‬ ‭listed‬ ‭as‬ ‭a‬ ‭possible‬ ‭adverse‬ ‭reaction‬ ‭and‬ ‭cannot‬ ‭be‬ ‭reasonably‬
‭explained‬‭by‬‭an‬‭alternative‬‭explanation,‬‭e.g.,‬‭concomitant‬‭drug(s),‬‭concomitant‬‭disease(s).‬‭The‬
‭relationship in time is very suggestive (e.g., it is confirmed by dechallenge and rechallenge).‬
‭9.1.3.‬ ‭Intensity (Severity) Criteria‬
‭The‬‭intensity‬‭of‬‭AEs‬‭will‬‭be‬‭classified‬‭using‬‭the‬‭Common‬‭Terminology‬‭Criteria‬‭for‬‭AEs‬‭of‬‭the‬
‭National‬ ‭Cancer‬ ‭Institute,‬ ‭version‬ ‭5.0‬ ‭(NCI-CTCAE)‬ ‭and‬ ‭will‬ ‭be‬ ‭recorded‬ ‭in‬ ‭detail‬ ‭as‬
‭instructed‬ ‭in‬ ‭the‬ ‭eCRF.‬ ‭If‬ ‭an‬ ‭AE‬ ‭occurs‬ ‭that‬ ‭is‬ ‭not‬ ‭listed‬ ‭in‬ ‭the‬ ‭NCI-CTCAE‬ ‭V5.0‬
‭classification system, the 5-point scale detailed below will be used instead:‬
‭-‬
‭Mild: General malaise, without interruption of normal daily activity.‬
‭-‬
‭Moderate: Sufficient general malaise to reduce or affect normal daily activity.‬
‭-‬
‭Severe: Incapacity for work or the development of normal daily activity.‬
‭-‬
‭Life threatening or disabling: Represents an immediate threat to life.‬
‭-‬
‭Death: AE-related.‬
‭Grade‬
‭Grade‬
‭Severity‬
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‭1‬
‭Mild;‬ ‭asymptomatic‬ ‭or‬ ‭mild‬ ‭symptoms;‬ ‭clinical‬‭or‬‭diagnostic‬‭observations‬‭only;‬‭or‬
‭intervention not indicated‬
‭2‬
‭Moderate;‬ ‭minimal,‬ ‭local,‬ ‭or‬ ‭non-invasive‬ ‭intervention‬ ‭indicated;‬ ‭or‬ ‭limiting‬
‭age-appropriate instrumental activities of daily living‬‭a‬
‭3‬
‭Severe‬‭or‬‭medically‬‭significant,‬‭but‬‭not‬‭immediately‬‭life-threatening;‬‭hospitalization‬
‭or‬‭prolongation‬‭of‬‭hospitalization‬‭indicated;‬‭disabling;‬‭or‬‭limiting self-care‬‭activities‬
‭of daily living‬‭b, c‬
‭4‬
‭Life-threatening consequences or urgent intervention indicated‬‭d‬
‭5‬
‭Death related to adverse event‬‭d‬
‭NCI CTCAE‬‭ ‬‭=‬‭ ‬‭National Cancer Institute Common Terminology‬‭Criteria for Adverse Events.‬
‭Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:‬
‭http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm‬
‭a‬ ‭Instrumental activities of daily living refer to‬‭preparing meals, shopping for groceries or clothes,‬
‭using the telephone, managing money, etc.‬
‭b‬ ‭Examples of self-care activities of daily living‬‭include bathing, dressing and undressing, feeding‬
‭oneself, using the toilet, and taking medications, as performed by patients who are not bedridden.‬
‭c‬ ‭If an event is assessed as a "significant medical‬‭event," it must be reported as a serious adverse event‬
‭(see Section 5.4.2 for reporting instructions), per the definition of serious adverse event in‬
‭Section 5.2.2.‬
‭d‬ ‭Grade 4 and 5 events must be reported as serious‬‭adverse events (see Section 9.2  for reporting‬
‭instructions), per the definition of serious adverse event in Section 9.1.‬
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‭9.1.14.‬ ‭Exposure during Pregnancy‬
‭If,‬‭following‬‭initiation‬‭of‬‭the‬‭investigational‬‭product,‬‭it‬‭is‬‭subsequently‬‭discovered‬‭that‬‭a‬‭study‬
‭participant‬ ‭is‬ ‭pregnant‬ ‭or‬ ‭may‬ ‭have‬ ‭been‬ ‭pregnant‬ ‭at‬ ‭the‬ ‭time‬ ‭of‬ ‭investigational‬ ‭product‬
‭exposure,‬‭within‬‭5‬‭months‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭atezolizumab‬‭,‬‭or‬‭within‬‭6‬‭months‬‭after‬‭the‬‭last‬
‭dose‬ ‭of‬ ‭atezolizumab,‬ ‭the‬ ‭investigational‬ ‭product‬ ‭will‬ ‭be‬ ‭permanently‬ ‭discontinued‬ ‭in‬ ‭an‬
‭appropriate manner (e.g., dose tapering if necessary for participant).‬
‭Any‬ ‭pregnancy‬ ‭that‬ ‭occurs‬ ‭in‬ ‭a‬ ‭female‬ ‭partner‬ ‭of‬ ‭a‬‭male‬‭study‬‭participant‬‭should‬‭also‬‭be‬
‭reported‬‭to‬‭the‬‭sponsor‬‭within‬‭24‬‭hours‬‭of‬‭becoming‬‭aware.‬‭Male‬‭patients‬‭will‬‭be‬‭instructed‬
‭through‬ ‭the‬ ‭Informed‬ ‭Consent‬ ‭Form‬ ‭to‬ ‭immediately‬ ‭inform‬ ‭the‬ ‭investigator‬ ‭if‬ ‭his‬ ‭partner‬
‭becomes‬‭pregnant‬‭during‬‭the‬‭chemotherapy‬‭treatment‬‭period‬‭or‬‭within‬‭6‬‭months‬‭after‬‭the‬‭last‬
‭dose‬‭of‬‭chemotherapy.‬‭In‬‭order‬‭for‬‭Sponsor‬‭or‬‭designee‬‭to‬‭collect‬‭any‬‭pregnancy‬‭surveillance‬
‭information‬‭from‬‭the‬‭female‬‭partner,‬‭the‬‭female‬‭partner‬‭must‬‭sign‬‭an‬‭informed‬‭consent‬‭form‬
‭for disclosure of this information.‬
‭In‬‭both‬‭cases,‬‭the‬‭investigator‬‭must‬‭immediately‬‭notify‬‭the‬‭Sponsor‬‭Pharmacovigilance‬‭Office‬
‭by sending the Pregnancy form (see ISF).‬
‭Follow-up‬‭information‬‭regarding‬‭the‬‭course‬‭of‬‭the‬‭pregnancy,‬‭including‬‭perinatal‬‭and‬‭neonatal‬
‭outcome‬‭and,‬‭where‬‭applicable,‬‭offspring‬‭information,‬‭study‬‭discontinuation‬‭must‬‭be‬‭reported‬
‭following the before procedure described during at least 1 year after child-bearing.‬
‭Any‬‭serious‬‭adverse‬‭events‬‭associated‬‭with‬‭the‬‭pregnancy‬‭(e.g.,‬‭an‬‭event‬‭in‬‭the‬‭fetus,‬‭an‬‭event‬
‭in‬‭the‬‭mother‬‭during‬‭or‬‭after‬‭the‬‭pregnancy,‬‭or‬‭a‬‭congenital‬‭anomaly/birth‬‭defect‬‭in‬‭the‬‭child)‬
‭or abortion should be reported as a SAE.‬
‭9.1.15.‬ ‭Occupational Exposure‬
‭An‬ ‭occupational‬ ‭exposure‬ ‭occurs‬ ‭when,‬ ‭during‬ ‭the‬ ‭performance‬ ‭of‬ ‭job‬ ‭duties,‬ ‭a‬ ‭person‬
‭(whether‬ ‭a‬ ‭healthcare‬ ‭professional‬ ‭or‬ ‭otherwise)‬ ‭gets‬ ‭in‬ ‭unplanned‬ ‭direct‬ ‭contact‬‭with‬‭the‬
‭product, which may or may not lead to the occurrence of an AE.‬
‭An‬ ‭occupational‬ ‭exposure‬ ‭is‬ ‭reported‬ ‭to‬ ‭the‬ ‭drug‬ ‭safety‬ ‭unit‬ ‭within‬ ‭24‬ ‭hours‬ ‭of‬ ‭the‬
‭investigator’s‬ ‭awareness,‬ ‭using‬ ‭the‬ ‭SAE‬ ‭report‬ ‭form,‬ ‭regardless‬ ‭of‬ ‭whether‬ ‭there‬ ‭is‬ ‭an‬
‭associated‬‭AE/SAE.‬‭Since‬‭the‬‭information‬‭does‬‭not‬‭pertain‬‭to‬‭a‬‭patient‬‭enrolled‬‭in‬‭the‬‭study,‬
‭the‬‭information‬‭is‬‭not‬‭reported‬‭on‬‭a‬‭CRF;‬‭however,‬‭a‬‭copy‬‭of‬‭the‬‭completed‬‭SAE‬‭report‬‭form‬
‭is maintained in the investigator site file.‬
‭9.1.16.‬ ‭Expedited reporting‬
‭The‬ ‭sponsor‬ ‭assumes‬ ‭responsibility‬ ‭for‬ ‭appropriate‬ ‭reporting‬ ‭of‬ ‭adverse‬ ‭events‬ ‭to‬ ‭the‬
‭regulatory‬‭authorities.‬‭The‬‭sponsor‬‭will‬‭also‬‭report‬‭all‬‭serious‬‭adverse‬‭events‬‭that‬‭are‬‭unlisted‬
‭(unexpected)‬‭and‬‭be‬‭associated‬‭with‬‭the‬‭use‬‭of‬‭the‬‭study‬‭drug.‬‭The‬‭sponsor‬‭must‬‭report‬‭these‬
‭events to investigators and competent authorities in accordance with current regulations.‬
‭9.2.‬
‭Collection and reporting of Adverse Events information‬
‭The sponsor will collect AEs up to 30 days after administration of the last dose of study drug.‬
‭All‬‭adverse‬‭events‬‭must‬‭be‬‭recorded‬‭using‬‭medical‬‭terminology‬‭in‬‭the‬‭source‬‭document‬‭and‬
‭the‬‭eCRF.‬‭Investigators‬‭must‬‭assess‬‭the‬‭severity‬‭(grade)‬‭of‬‭the‬‭event‬‭following‬‭NCI-CTCAE‬‭V‬
‭5.0‬ ‭Criteria‬ ‭and‬ ‭assign‬ ‭a‬ ‭relationship‬ ‭to‬ ‭study‬ ‭therapy‬ ‭and‬ ‭pursue‬ ‭and‬ ‭obtain‬ ‭information‬
‭adequate‬ ‭both‬ ‭to‬ ‭determine‬ ‭the‬ ‭outcome‬ ‭and‬ ‭to‬ ‭assess‬ ‭whether‬ ‭it‬ ‭meets‬ ‭the‬ ‭criteria‬ ‭for‬
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‭classification‬‭as‬‭a‬‭SAE‬‭requiring‬‭immediate‬‭notification.‬‭The‬‭investigator‬‭must‬‭provide‬‭any‬
‭information as requested by the sponsor in addition to that on the eCRF.‬
‭Any‬‭serious‬‭adverse‬‭event‬‭which‬‭occurs‬‭from‬‭patient‬‭informed‬‭consent‬‭signature,‬‭during‬‭the‬
‭clinical‬‭study‬‭or‬‭within‬‭90‬‭days‬‭of‬‭receiving‬‭the‬‭last‬‭dose‬‭of‬‭study‬‭medication,‬‭whether‬‭or‬‭not‬
‭related to the study drug, must be reported by the investigator.‬
‭If‬‭a‬‭patient‬‭begins‬‭a‬‭new‬‭anticancer‬‭therapy,‬‭the‬‭AE‬‭reporting‬‭period‬‭for‬‭non-serious‬‭AEs‬‭ends‬
‭at‬‭the‬‭time‬‭the‬‭new‬‭treatment‬‭is‬‭started.‬‭Death‬‭must‬‭be‬‭reported‬‭if‬‭it‬‭occurs‬‭during‬‭the‬‭SAE‬
‭reporting‬‭period‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭investigational‬‭product,‬‭irrespective‬‭of‬‭any‬‭intervening‬
‭treatment.‬
‭In‬‭addition,‬‭any‬‭SAEs‬‭which‬‭occur‬‭as‬‭a‬‭result‬‭of‬‭protocol‬‭specific‬‭diagnostic‬‭procedures‬‭or‬
‭interventions‬‭must‬‭also‬‭be‬‭reported.‬ ‭Beyond‬‭this‬‭period‬‭of‬‭time,‬‭only‬‭those‬‭SAEs‬‭suspected‬‭to‬
‭be related to the study drug will be reported.‬
‭All‬ ‭SAEs‬ ‭suspected‬ ‭to‬ ‭be‬ ‭related‬ ‭to‬ ‭study‬ ‭treatment‬ ‭should‬ ‭be‬ ‭followed‬ ‭after‬ ‭the‬
‭treatment/study‬ ‭withdrawal‬ ‭until‬‭the‬‭event‬‭or‬‭its‬‭symptoms‬‭have‬‭resolved‬‭or‬‭stabilized‬‭at‬‭a‬
‭grade acceptable to the Investigator, Chief investigator and/or Sponsor.‬
‭Site‬‭staff‬‭should‬‭notify‬‭the‬‭sponsor,‬‭all‬‭the‬‭pregnancies‬‭of‬‭female‬‭subjects‬‭and‬‭female‬‭partners‬
‭of‬‭male‬‭subjects‬‭that‬‭occurred‬‭during‬‭the‬‭clinical‬‭trial‬‭within‬‭24‬‭hours‬‭from‬‭becoming‬‭aware.‬
‭Site‬‭staff‬‭should‬‭also‬‭communicate‬‭the‬‭outcome‬‭of‬‭the‬‭pregnancy‬‭within‬‭24‬‭hours‬‭since‬‭the‬
‭awareness.‬
‭The‬‭cause‬‭of‬‭death‬‭of‬‭a‬‭deceased‬‭patient‬‭in‬‭a‬‭clinical‬‭trial,‬‭whether‬‭the‬‭case‬‭of‬‭an‬‭expected‬
‭event‬‭or‬‭associated‬‭with‬‭the‬‭investigational‬‭agent,‬‭is‬‭considered‬‭an‬‭SAE‬‭and‬‭therefore‬‭must‬‭be‬
‭communicated‬‭using‬‭the‬‭SAE‬‭form.‬‭The‬‭autopsy‬‭report‬‭should‬‭be‬‭sent‬‭to‬‭Sponsor‬‭identified‬
‭only with the patient inclusion number.‬
‭All serious adverse events, AESIs and pregnancy cases must be reported by fax within 24‬
‭h to MFAR Clinical Research, S.L. by fax (+ 34 93 253 11 68) or e-mail to‬
‭investigacion@mfar.net‬
‭The‬ ‭SAE‬ ‭report‬ ‭should‬ ‭comprise‬ ‭a‬ ‭full‬ ‭written‬ ‭summary,‬ ‭detailing‬ ‭relevant‬‭aspects‬‭of‬‭the‬
‭adverse‬‭events‬‭in‬‭question.‬‭Where‬‭applicable,‬‭information‬‭from‬‭relevant‬‭hospital‬‭case‬‭records‬
‭and‬‭autopsy‬‭reports‬‭should‬‭be‬‭included.‬‭Follow-up‬‭information‬‭should‬‭be‬‭forwarded‬‭to‬‭MFAR‬
‭Clinical‬‭Research,‬‭S.L.‬‭by‬‭fax‬‭(+‬‭34‬‭93‬‭253‬‭11‬‭68)‬‭or‬‭e-mail‬‭to‬‭investigacion@mfar.net‬
‭within 24 hours.‬
‭All‬‭SAEs‬‭suspected‬‭to‬‭be‬‭related‬‭to‬‭study‬‭drug‬‭must‬‭be‬‭followed‬‭up‬‭after‬‭the‬‭time‬‭of‬‭therapy‬
‭discontinuation‬‭until‬‭the‬‭event‬‭or‬‭its‬‭consequences‬‭resolve‬‭or‬‭stabilize‬‭at‬‭an‬‭acceptable‬‭level‬
‭for the investigator, the Trial Chief Investigator and/or Sponsor.‬
‭Non-Serious Adverse Event Reporting Requirements‬
‭All‬‭AEs‬‭will‬‭be‬‭reported‬‭on‬‭the‬‭AE‬‭page(s)‬‭of‬‭the‬‭CRF.‬‭It‬‭should‬‭be‬‭noted‬‭that‬‭the‬‭form‬‭for‬
‭collection‬ ‭of‬ ‭SAE‬ ‭information‬ ‭is‬ ‭not‬ ‭the‬ ‭same‬ ‭as‬ ‭the‬ ‭AE‬ ‭CRF.‬ ‭Where‬ ‭the‬ ‭same‬ ‭data‬‭are‬
‭collected,‬‭the‬‭forms‬‭must‬‭be‬‭completed‬‭in‬‭a‬‭consistent‬‭manner.‬‭For‬‭example,‬‭the‬‭same‬‭AE‬‭term‬
‭should‬‭be‬‭used‬‭on‬‭both‬‭forms.‬‭AEs‬‭should‬‭be‬‭reported‬‭using‬‭concise‬‭medical‬‭terminology‬‭on‬
‭the CRFs as well as on the form for collection of SAE information.‬
‭Sponsor’s Reporting Requirements to Regulatory Authorities‬
‭Adverse‬ ‭event‬ ‭reporting,‬ ‭including‬ ‭suspected‬ ‭unexpected‬‭serious‬‭adverse‬‭reactions,‬‭will‬‭be‬
‭carried out in accordance with applicable local regulations.‬
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‭10.‬
‭STATISTICAL CONSIDERATIONS‬
‭Detailed‬‭methodology‬‭for‬‭summary‬‭and‬‭statistical‬‭analyses‬‭of‬‭the‬‭data‬‭collected‬‭in‬‭this‬‭study‬
‭will‬ ‭be‬ ‭documented‬ ‭in‬ ‭a‬ ‭statistical‬ ‭analysis‬ ‭plan‬ ‭(SAP),‬ ‭which‬ ‭will‬ ‭be‬ ‭maintained‬ ‭by‬ ‭the‬
‭Sponsor.‬
‭This‬ ‭document‬ ‭may‬ ‭modify‬ ‭the‬ ‭plans‬ ‭outlined‬ ‭in‬ ‭the‬ ‭protocol;‬ ‭however,‬ ‭any‬ ‭major‬
‭modifications‬‭of‬‭the‬‭primary‬‭endpoint‬‭and/or‬‭its‬‭analysis‬‭will‬‭also‬‭be‬‭reflected‬‭in‬‭a‬‭protocol‬
‭amendment.‬
‭10.1.‬ ‭Sample size calculation‬
‭Fleming's‬‭phase‬‭II‬‭procedure‬‭(‬‭Fleming‬‭TR,‬‭1982‬‭)‬‭will‬‭be‬‭used.‬‭The‬‭null‬‭hypothesis‬‭that‬‭the‬
‭smallest‬‭response‬‭probability‬‭is‬‭0.3‬‭will‬‭be‬‭tested‬‭against‬‭a‬‭one-sided‬‭alternative.‬‭In‬‭the‬‭first‬
‭stage,‬‭46‬‭patients‬‭will‬‭be‬‭accrued.‬‭An‬‭intermediate‬‭analysis‬‭will‬‭be‬‭performed‬‭once‬‭these‬‭first‬
‭46‬‭patients‬‭reach‬‭6‬‭months‬‭after‬‭study‬‭treatment‬‭initiation.‬‭If‬‭there‬‭are‬‭16‬‭or‬‭fewer‬‭responses‬‭in‬
‭these‬ ‭46‬ ‭patients,‬ ‭the‬ ‭study‬ ‭will‬ ‭be‬ ‭stopped.‬ ‭This‬ ‭intermediate‬‭analysis‬‭is‬‭established‬‭as‬‭a‬
‭cut-off‬‭point‬‭to‬‭stop‬‭the‬‭study‬‭if‬‭the‬‭benefit‬‭for‬‭the‬‭patient‬‭in‬‭terms‬‭of‬‭objective‬‭response‬‭does‬
‭not‬‭justify‬‭its‬‭continuation‬‭with‬‭sufficient‬‭clarity.‬‭If‬‭there‬‭is‬‭no‬‭preliminary‬‭evidence‬‭in‬‭the‬‭first‬
‭46‬‭patients,‬‭which‬‭allows‬‭enough‬‭statistical‬‭power‬‭to‬‭reject‬‭the‬‭null‬‭hypothesis,‬‭the‬‭recruitment‬
‭will‬‭stop‬‭as‬‭it‬‭is‬‭considered‬‭that‬‭the‬‭efficacy‬‭of‬‭the‬‭treatment‬‭is‬‭not‬‭sufficient‬‭to‬‭justify‬‭the‬
‭inclusion‬‭of‬‭more‬‭patients.‬‭Otherwise,‬‭20‬‭additional‬‭patients‬‭will‬‭be‬‭accrued‬‭for‬‭a‬‭total‬‭of‬‭66.‬
‭The‬‭null‬‭hypothesis‬‭will‬‭be‬‭rejected‬‭if‬‭25‬‭or‬‭more‬‭responses‬‭are‬‭observed‬‭in‬‭66‬‭patients.‬‭This‬
‭design yields a type I error rate of 0.05 and power of 0.9 when the true response rate is 0.5.‬
‭Variables‬
‭Descriptions‬
‭α‬
‭Probability of type I error: 0.05‬
‭β‬
‭Probability of type II error: 0.1‬
‭p‬‭0‬
‭Response Probability of Poor Drug (P0) ---> 0.30‬
‭P1‬
‭Response Probability of Good Drug (P1) ---> 0.50‬
‭Nmax‬
‭Maximum number of patients to be recruited: 66‬
‭Numstage‬
‭Number of stages in Phase II clinical trial: 2‬
‭n‬‭i‬
‭Number of patients to be recruited in stage i= 46‬
‭R1‬
‭Upper Limit For 1st Stage Rejection of Drug (r1)= 16‬
‭R‬
‭Upper Limit for 2nd Stage Rejection of Drug (r)= 25‬
‭10.2.‬ ‭Study endpoints‬
‭10.2.1.‬ ‭Primary endpoint‬
‭Overall Response Rate (ORR):‬‭Percentage/proportion‬‭of patients with confirmed complete‬
‭response (CR) or partial response (PR) as their overall best response throughout the study‬
‭period.‬
‭10.2.2. Secondary endpoints‬
‭Efficacy endpoints:‬
‭●‬ ‭Duration of response‬‭(DoR):‬‭Time from first confirmed‬‭response (CR or PR) to the‬
‭date of the documented PD as determined using RECIST 1.1 criteria or death due to‬
‭any cause, whichever occurs first.‬
‭●‬ ‭Time to response‬‭(TtR):‬‭Time from first dosing date‬‭to the date of the documented‬
‭ORR as determined using RECIST 1.1 criteria.‬
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‭●‬ ‭Clinical benefit‬‭:‬‭Percentage/proportion of patients with confirmed complete response‬
‭(CR) or partial response (PR), or stable disease (SD) as their overall best response‬
‭throughout the study period.‬
‭●‬ ‭Overall Survival‬‭(OS)‬
‭○‬ ‭Time‬‭from‬‭first‬‭dosing‬‭date‬‭to‬‭the‬‭date‬‭of‬‭death.‬‭A‬‭subject‬‭who‬‭has‬‭not‬‭died‬
‭will be censored at the last known date alive.‬
‭○‬ ‭Proportion‬‭of‬‭patients‬‭alive‬‭at‬‭the‬‭end‬‭of‬‭the‬‭atezolizumab‬‭plus‬‭split‬‭dose‬‭of‬
‭gemcitabine and cisplatin combination stage.‬
‭○‬ ‭Proportion of patients alive at the end of follow-up.‬
‭●‬ ‭Progression-Free Survival‬‭(PFS)‬
‭○‬ ‭Time‬‭from‬‭first‬‭dosing‬‭date‬‭to‬‭the‬‭date‬‭of‬‭confirmed‬‭PD.‬‭A‬‭subject‬‭who‬‭has‬
‭not died will be censored at the last known date alive.‬
‭○‬ ‭Proportion of patients free of PD at 6 months since start of treatment.‬
‭○‬ ‭Proportion of patients free of PD at the end of follow-up.‬
‭Safety endpoints‬
‭●‬ ‭Adverse‬‭events‬‭(AE)‬‭assessment:‬‭Type,‬‭frequency,‬‭severity‬‭and‬‭outcome‬‭of‬‭adverse‬
‭events .‬
‭●‬ ‭Treatment-related AEs:‬‭Type, frequency, severity and‬‭outcome.‬
‭Exploratory endpoints‬
‭●‬ ‭Biomarkers and/or genes expression and participant outcomes.‬
‭10.3.‬ ‭Efficacy assessment‬
‭10.3.1.‬ ‭Efficacy variables‬
‭Overall‬‭Response‬‭Rate‬‭(ORR)‬‭at‬‭6‬‭months‬‭from‬‭first‬‭dose:‬‭includes‬‭patients‬‭with‬‭confirmed‬
‭persistent‬‭partial‬‭(PR)‬‭and‬‭complete‬‭response‬‭(CR)‬‭as‬‭best‬‭response‬‭according‬‭to‬‭RECIST‬‭v‬
‭1.1, at 6 months from adaptive the study treatment initiation.‬
‭Overall‬‭Response‬‭Rate‬‭(ORR)‬‭from‬‭first‬‭dose:‬‭includes‬‭patients‬‭with‬‭confirmed‬‭persistent‬
‭partial‬‭(PR)‬‭and‬‭complete‬‭response‬‭(CR)‬‭as‬‭best‬‭response‬‭according‬‭to‬‭RECIST‬‭1.1,‬‭at‬‭the‬‭end‬
‭of their participation in the study.‬
‭Time‬ ‭to‬ ‭response:‬ ‭Time‬ ‭to‬ ‭response‬ ‭(TTR)‬ ‭is‬ ‭defined‬‭as‬‭the‬‭time‬‭from‬‭the‬‭start‬‭of‬‭study‬
‭treatment‬ ‭to‬ ‭the‬ ‭first‬ ‭objective‬ ‭tumor‬ ‭response‬ ‭(tumor‬ ‭shrinkage‬ ‭of‬ ‭≥30%)‬ ‭observed‬ ‭for‬
‭patients who achieved a CR or PR.‬
‭Duration‬ ‭of‬ ‭response‬ ‭(DOR):‬ ‭DOR‬ ‭is‬ ‭calculated‬ ‭as‬ ‭the‬ ‭time‬ ‭from‬ ‭the‬ ‭date‬ ‭of‬ ‭first‬
‭documented‬‭CR‬‭or‬‭PR,‬‭as‬‭per‬‭RECIST‬‭1.1,‬‭to‬‭the‬‭first‬‭documented‬‭progression‬‭or‬‭death‬‭due‬‭to‬
‭underlying cancer.‬
‭Overall‬‭Survival‬‭(OS):‬‭Median‬‭Overall‬‭Survival‬‭(mOS)‬‭is‬‭calculated‬‭as‬‭the‬‭time‬‭from‬‭the‬
‭date of inclusion to date of death due to any cause.‬
‭Progression-free‬‭Survival‬‭(PFS):‬‭Median‬‭Progression‬‭free‬‭survival‬‭(mPFS)‬‭is‬‭defined‬‭as‬‭the‬
‭time‬‭from‬‭the‬‭date‬‭of‬‭inclusion‬‭to‬‭the‬‭date‬‭of‬‭the‬‭first‬‭documented‬‭disease‬‭progression‬‭or‬‭death‬
‭due‬‭to‬‭any‬‭cause,‬‭whichever‬‭occurs‬‭first.‬‭PFS‬‭will‬‭be‬‭determined‬‭based‬‭on‬‭tumour‬‭assessment‬
‭(RECIST‬‭version‬‭1.1‬‭criteria).‬‭The‬‭local‬‭Investigator's‬‭assessments‬‭will‬‭be‬‭used‬‭for‬‭analyses.‬
‭Patients‬‭who‬‭are‬‭alive‬‭and‬‭have‬‭not‬‭progressed‬‭at‬‭the‬‭last‬‭follow-up‬‭will‬‭be‬‭censored‬‭at‬‭the‬
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‭date‬‭of‬‭the‬‭last‬‭available‬‭image‬‭determination‬‭(CT‬‭scan‬‭or‬‭MRI).‬‭Patients‬‭with‬‭no‬‭additional‬
‭image‬ ‭test‬ ‭other‬ ‭than‬ ‭that‬ ‭at‬ ‭baseline‬ ‭will‬ ‭be‬ ‭censored‬ ‭to‬ ‭the‬‭day‬‭after‬‭inclusion.‬‭Patients‬
‭initiating‬‭new‬‭anticancer‬‭therapy‬‭(without‬‭progression‬‭to‬‭the‬‭study‬‭treatment)‬‭will‬‭be‬‭censored‬
‭to the date of new anticancer therapy initiation.‬
‭Clinical‬ ‭Benefit‬ ‭(CB)‬ ‭Rate:‬ ‭Clinical‬ ‭Benefit‬ ‭Rate‬ ‭(CBR)‬ ‭is‬ ‭defined‬ ‭as‬ ‭the‬‭percentage‬‭of‬
‭patients‬‭who‬‭achieved‬‭complete‬‭response,‬‭partial‬‭response‬‭and‬‭stable‬‭disease.‬‭Stable‬‭disease‬
‭should be maintained for at least 6 months to be considered as a CBR event.‬
‭10.4.‬ ‭Safety assessment‬
‭The‬‭safety‬‭population‬‭(SP)‬‭consists‬‭of‬‭all‬‭enrolled‬‭subjects‬‭who‬‭received‬‭at‬‭least‬‭one‬‭dose‬‭of‬
‭study‬‭treatment.‬‭Patients‬‭will‬‭be‬‭monitored‬‭for‬‭safety‬‭during‬‭all‬‭the‬‭stages‬‭of‬‭the‬‭study.‬‭All‬
‭safety and tolerability assessments will be done at pre-dosing time, unless otherwise specified.‬
‭Safety‬‭parameters‬‭are‬‭AE,‬‭SAE,‬‭AESI,‬‭pregnancy,‬‭medication‬‭error,‬‭and‬‭overdose.‬‭Additional‬
‭safety information could be derived from ECG, lab test, pregnancy test, or vital sign exam.‬
‭The‬‭assessment‬‭of‬‭adverse‬‭events‬‭will‬‭include‬‭the‬‭type‬‭of‬‭event‬‭(including‬‭symptoms,‬‭physical‬
‭exam‬‭findings‬‭and‬‭laboratory‬‭abnormalities),‬‭the‬‭incidence,‬‭severity,‬‭timing,‬‭seriousness,‬‭and‬
‭relatedness‬‭regarding‬‭the‬‭treatment‬‭under‬‭study.‬‭Adverse‬‭events‬‭will‬‭be‬‭recorded‬‭and‬‭reported‬
‭in‬‭the‬‭corresponding‬‭section‬‭of‬‭the‬‭case‬‭report‬‭form.‬‭The‬‭grade‬‭of‬‭adverse‬‭events‬‭will‬‭be‬‭coded‬
‭according‬ ‭to‬ ‭the‬ ‭National‬ ‭Cancer‬ ‭Institute’s‬ ‭Common‬ ‭Toxicity‬ ‭criteria‬ ‭(NCI-CTCAE‬ ‭v5.0‬
‭scoring system). The worst toxicity score will be recorded.‬
‭10.5.‬ ‭Definition of study populations‬
‭Data will be analysed in the following populations:‬
‭1.‬ ‭Intent-To-Treat (ITT):‬‭All patients that have been‬‭enrolled in the trial.‬
‭2.‬ ‭Evaluable‬‭population‬‭per‬‭protocol‬‭(PP):‬‭All‬‭patients‬‭fulfilling‬‭all‬‭eligibility‬‭criteria‬
‭without‬‭any‬‭protocol‬‭deviation‬‭that‬‭makes‬‭the‬‭patient‬‭invalid‬‭for‬‭the‬‭primary‬‭endpoint‬
‭evaluation.‬
‭3.‬ ‭Safety population (SP):‬‭All patients receiving at‬‭least one dose of the study treatments.‬
‭10.6.‬ ‭Data quality control‬
‭A‬‭Data‬‭Management‬‭Plan‬‭(DMP)‬‭will‬‭be‬‭elaborated‬‭for‬‭this‬‭trial‬‭in‬‭order‬‭to‬‭outline‬‭the‬‭data‬
‭management‬ ‭procedures‬‭and‬‭the‬‭related‬‭responsibilities‬‭of‬‭trial‬‭staff.‬‭The‬‭DMP‬‭will‬‭clearly‬
‭specify‬ ‭the‬ ‭data‬‭quality‬‭control‬‭tasks‬‭to‬‭be‬‭performed‬‭and‬‭the‬‭corresponding‬‭responsibility,‬
‭timelines, etc., according to international guidelines in the subject and GCPs.‬
‭Following‬‭data‬‭entry‬‭of‬‭the‬‭investigator‬‭staff‬‭into‬‭the‬‭data‬‭capture‬‭system‬‭(eCRF),‬‭the‬‭data‬
‭entered‬ ‭will‬ ‭be‬ ‭reconciled‬ ‭against‬ ‭the‬ ‭original‬ ‭case‬ ‭report‬ ‭form,‬ ‭review‬ ‭form/clinic‬
‭notes/laboratory‬‭reports‬‭by‬‭CRA‬‭during‬‭monitoring‬‭visits,‬‭according‬‭to‬‭the‬‭monitoring‬‭plan.‬
‭Any‬‭identified‬‭issues‬‭should‬‭be‬‭clarified‬‭with‬‭the‬‭Investigator‬‭staff.‬‭Any‬‭necessary‬‭corrections‬
‭should be made in the corresponding field of the eCRF.‬
‭The‬‭monitoring‬‭plan‬‭will‬‭establish‬‭that‬‭source‬‭data‬‭verification‬‭(SDV)‬‭is‬‭expected‬‭for‬‭a‬‭subset‬
‭of‬ ‭variables,‬ ‭according‬ ‭to‬ ‭study‬ ‭status,‬‭starting‬‭on‬‭the‬‭approval‬‭of‬‭this‬‭DMP‬‭and‬‭the‬‭SDV‬
‭strategy agreed.‬
‭Remote‬ ‭QC‬ ‭activities‬ ‭will‬ ‭be‬ ‭outlined‬ ‭in‬ ‭the‬ ‭Monitoring‬ ‭Plan‬ ‭for‬ ‭relevant‬ ‭variables‬ ‭as‬
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‭eligibility, primary endpoints, safety endpoints and relevant secondary endpoints.‬
‭Performance‬‭of‬‭these‬‭checks‬‭is‬‭expected‬‭on‬‭all‬‭the‬‭patients‬‭included‬‭(this‬‭estimate‬‭may‬‭vary‬
‭according to the quality of the data reported by the research team).‬
‭Any‬‭finding‬‭will‬‭be‬‭reflected‬‭in‬‭the‬‭monitoring‬‭report‬‭and‬‭will‬‭be‬‭conveniently‬‭managed‬‭with‬
‭sites‬‭(including‬‭Principal‬‭Investigator)‬‭and‬‭informed‬‭to‬‭the‬‭Coordinating‬‭Investigator,‬‭as‬‭the‬
‭representative‬ ‭of‬ ‭the‬ ‭Sponsor‬ ‭in‬ ‭this‬ ‭study,‬ ‭and‬ ‭when‬ ‭applicable,‬ ‭notified‬ ‭to‬ ‭competent‬
‭authorities according to local regulations.‬
‭10.7.‬ ‭Statistical analysis‬
‭For‬ ‭each‬ ‭categorical‬ ‭variable,‬ ‭the‬ ‭results‬ ‭will‬ ‭be‬ ‭summarised‬ ‭by‬ ‭frequencies‬ ‭and‬
‭percentages/proportions along with 95 % confidence intervals (95% CIs) when applicable.‬
‭For‬‭each‬‭continuous‬‭variable,‬‭the‬‭results‬‭will‬‭be‬‭summarised‬‭by‬‭descriptive‬‭statistics‬‭such‬‭as‬
‭median,‬‭range,‬‭and‬‭range‬‭or‬‭by‬‭means,‬‭standard‬‭deviations,‬‭and‬‭(95%‬‭CIs).‬‭For‬‭time‬‭to‬‭event‬
‭endpoints,‬‭Kaplan-Meier‬‭estimates‬‭at‬‭selected‬‭time‬‭points‬‭and‬‭corresponding‬‭curves‬‭will‬‭be‬
‭presented.‬‭Time‬‭to‬‭event‬‭is‬‭derived‬‭relative‬‭to‬‭the‬‭first‬‭study‬‭treatment‬‭administration‬‭and‬‭will‬
‭be expressed in weeks and/or months.‬
‭Vital‬‭signs,‬‭ECG‬‭parameters,‬‭clinical‬‭laboratory‬‭data‬‭(haematology,‬‭serum‬‭biochemistry,‬‭and‬
‭urinalysis)‬‭will‬‭be‬‭presented‬‭in‬‭tabular‬‭form.‬‭Laboratory‬‭values‬‭will‬‭be‬‭expressed‬‭as‬‭absolute‬
‭values‬ ‭and‬ ‭in‬ ‭grades‬ ‭(ordinal‬ ‭categorical‬ ‭variables),‬ ‭when‬ ‭feasible.‬ ‭In‬ ‭case‬ ‭of‬ ‭laboratory‬
‭findings‬ ‭reported‬ ‭as‬ ‭adverse‬‭events,‬‭values‬‭will‬‭be‬‭presented‬‭and/or‬‭classified‬‭according‬‭to‬
‭NCI CTCAE v 5.0.‬
‭All‬‭adverse‬‭events,‬‭including‬‭treatment-emergent‬‭AE‬‭(AEs‬‭starting‬‭after‬‭the‬‭administration‬‭of‬
‭study‬‭treatment‬‭and‬‭up‬‭to‬‭study‬‭completion)‬‭will‬‭be‬‭summarised‬‭by‬‭system‬‭organ‬‭class‬‭and‬
‭preferred‬‭term.‬‭Grading‬‭will‬‭be‬‭presented‬‭by‬‭type‬‭and‬‭in‬‭tables‬‭showing‬‭the‬‭frequency‬‭and‬
‭percentage‬‭of‬‭the‬‭within-patient‬‭worst‬‭grades.‬‭In‬‭addition,‬‭grade‬‭≥‬‭3‬‭AEs‬‭will‬‭be‬‭summarised‬
‭separately. Further analyses could be performed.‬
‭Analysis‬‭will‬‭be‬‭based‬‭on‬‭observed‬‭data,‬‭and‬‭missing‬‭data‬‭for‬‭drop-outs‬‭are‬‭not‬‭replaced‬‭by‬
‭methods like LOCF (last option carried forward).‬
‭Full analysis details will be outlined in the statistical analysis plan (SAP).‬
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‭11.‬
‭LEGAL AND ETHICS CONSIDERATION‬
‭11.1.‬
‭Ethical conduct of the study‬
‭The‬ ‭study‬ ‭will‬ ‭be‬ ‭conducted‬ ‭in‬ ‭accordance‬‭with‬‭the‬‭principles‬‭of‬‭the‬‭Helsinki‬‭Declaration‬
‭Adopted‬‭by‬‭the‬‭18th‬‭World‬‭Medical‬‭Assembly,‬‭Helsinki,‬‭Finland,‬‭June‬‭1964‬‭updated‬‭to‬‭its‬
‭latest‬ ‭version‬ ‭Fortaleza,‬ ‭Brazil,‬ ‭October‬ ‭2013.‬ ‭With‬ ‭the‬ ‭Good‬ ‭Clinical‬ ‭Practice‬ ‭(GCP)‬
‭standards‬ ‭issued‬ ‭by‬ ‭the‬ ‭Working‬ ‭Party‬ ‭on‬ ‭Medicinal‬ ‭Product‬ ‭Efficacy‬ ‭of‬ ‭the‬ ‭European‬
‭Economic Community (1990) (CPMP / ICH / 135/95).‬
‭And the laws and regulations in force in Spain:‬
‭●‬ ‭The‬‭Oviedo‬‭Convention‬‭of‬‭April‬‭4,‬‭1997‬‭on‬‭human‬‭rights‬‭and‬‭biomedicine,‬‭ratified‬‭in‬
‭the BOE in October 1999.‬
‭●‬ ‭The‬‭rules‬‭for‬‭the‬‭adequate‬‭protection‬‭of‬‭personal‬‭data,‬‭in‬‭accordance‬‭with‬‭Law‬‭3/2018‬
‭Protection of Personal Data and guarantee of digital rights.‬
‭●‬ ‭The‬ ‭rights‬ ‭and‬ ‭obligations‬ ‭regarding‬ ‭information‬ ‭and‬ ‭clinical‬ ‭documentation,‬ ‭as‬
‭provided in Law 41/2002, of November 14, basic regulation of patient autonomy.‬
‭●‬ ‭Royal‬ ‭Decree‬ ‭1090/2015,‬ ‭of‬ ‭4‬ ‭December,‬ ‭regulating‬ ‭clinical‬ ‭trials‬ ‭with‬ ‭medicinal‬
‭products,‬ ‭Ethics‬ ‭Committees‬ ‭for‬ ‭Investigation‬ ‭with‬ ‭medicinal‬ ‭products‬ ‭and‬ ‭the‬
‭Spanish Clinical Studies Registry.‬
‭●‬ ‭Law 14/2007, of July 3, on Biomedical Research.‬
‭11.2.‬
‭Independent Ethical Committee (IEC) Review‬
‭Prior‬ ‭to‬ ‭the‬ ‭commencement‬ ‭of‬ ‭the‬ ‭trial‬ ‭at‬ ‭a‬ ‭given‬ ‭site,‬ ‭this‬ ‭clinical‬ ‭trial‬ ‭protocol‬ ‭will‬‭be‬
‭submitted‬‭together‬‭with‬‭its‬‭associated‬‭documents‬‭to‬‭the‬‭Central‬‭IEC‬‭for‬‭its‬‭approval,‬‭which‬
‭will be filed in the Investigator Site File. A copy will be filed in the Sponsor Trial Master File.‬
‭The‬‭IEC‬‭will‬‭be‬‭asked‬‭to‬‭document‬‭the‬‭date‬‭of‬‭the‬‭meeting‬‭at‬‭which‬‭the‬‭favourable‬‭opinion‬‭or‬
‭approval‬ ‭was‬ ‭given,‬ ‭with‬ ‭the‬ ‭members‬ ‭and‬ ‭voting‬ ‭members‬ ‭present.‬ ‭Written‬ ‭evidence‬ ‭of‬
‭favourable‬‭opinion‬‭or‬‭approval‬‭that‬‭clearly‬‭identifies‬‭the‬‭trial,‬‭the‬‭clinical‬‭trial‬‭protocol‬‭and‬‭the‬
‭version, the Subject Information and Informed Consent Form, should be provided.‬
‭Amendments‬‭to‬‭this‬‭clinical‬‭trial‬‭protocol‬‭will‬‭also‬‭be‬‭submitted‬‭to‬‭the‬‭concerned‬‭IEC,‬‭before‬
‭implementation‬‭of‬‭substantial‬‭changes.‬‭Relevant‬‭safety‬‭information‬‭will‬‭be‬‭submitted‬‭to‬‭the‬
‭IEC during the course of the trial, in accordance with national regulations and requirements.‬
‭Initial‬‭IEC‬‭positive‬‭vote,‬‭and‬‭all‬‭materials‬‭approved‬‭by‬‭the‬‭IEC‬‭for‬‭this‬‭study‬‭including‬‭the‬
‭patient‬ ‭consent‬ ‭form‬ ‭and‬‭recruitment‬‭materials‬‭must‬‭be‬‭maintained‬‭by‬‭the‬‭Investigator‬‭and‬
‭made available for inspection.‬
‭11.3.‬
‭Authorities‬
‭The‬‭study‬‭protocol‬‭and/or‬‭related‬‭documents‬‭will‬‭be‬‭submitted‬‭to‬‭regulatory‬‭authorities‬‭before‬
‭commencement‬ ‭of‬ ‭the‬ ‭clinical‬‭trial,‬‭as‬‭national‬‭authorities‬‭in‬‭the‬‭country‬‭where‬‭the‬‭trial‬‭is‬
‭taking place.‬
‭11.4.‬
‭Informed consent‬
‭The‬‭patient‬‭should‬‭sign‬‭an‬‭informed‬‭consent‬‭that‬‭will‬‭include‬‭the‬‭information‬‭for‬‭the‬‭clinical‬
‭trial and associated translational research.‬
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‭The‬ ‭clinician‬ ‭will‬ ‭have‬ ‭to‬ ‭explain‬ ‭the‬ ‭nature,‬ ‭objectives‬ ‭and‬‭possible‬‭consequences‬‭of‬‭the‬
‭clinical‬‭trial‬‭in‬‭a‬‭manner‬‭that‬‭is‬‭understandable‬‭by‬‭the‬‭patient.‬‭The‬‭patient‬‭must‬‭give‬‭his/her‬
‭consent before being admitted into the study and before biological samples are taken.‬
‭The‬‭study‬‭subject‬‭will‬‭provide‬‭his/her‬‭consent,‬‭signing‬‭by‬‭duplicate‬‭the‬‭appropriate‬‭model.‬‭For‬
‭this‬‭purpose,‬‭each‬‭model‬‭must‬‭carry‬‭the‬‭signature‬‭of‬‭investigator‬‭and‬‭patient.‬‭The‬‭investigator‬
‭will retain one copy of the original of each patient signed consent form.‬
‭The‬‭investigator‬‭will‬‭not‬‭start‬‭any‬‭investigation‬‭related‬‭with‬‭the‬‭study‬‭until‬‭the‬‭written‬‭consent‬
‭has been obtained.‬
‭The‬‭informed‬‭consent‬‭form‬‭used‬‭in‬‭this‬‭study,‬‭and‬‭any‬‭changes‬‭made‬‭during‬‭the‬‭course‬‭of‬‭the‬
‭study, must be prospectively approved by the Ethics Committee.‬
‭11.5.‬
‭Confidentiality‬
‭In‬‭order‬‭to‬‭guarantee‬‭the‬‭confidentiality‬‭of‬‭the‬‭clinical‬‭trial‬‭data‬‭according‬‭to‬‭the‬‭provisions‬‭of‬
‭The‬ ‭rules‬ ‭for‬ ‭the‬ ‭adequate‬ ‭protection‬ ‭of‬ ‭personal‬ ‭data,‬ ‭in‬ ‭accordance‬ ‭with‬ ‭Law‬ ‭3/2018‬
‭Protection‬‭of‬‭Personal‬‭Data‬‭and‬‭guarantee‬‭of‬‭digital‬‭rights,‬‭only‬‭the‬‭personnel‬‭designated‬‭by‬
‭the‬‭Sponsor‬‭will‬‭have‬‭access‬‭to‬‭the‬‭patient‬‭data‬‭for‬‭monitoring/auditing‬‭purposes,‬‭Investigators‬
‭and his/her staff, the Ethic Committee and the pertinent Competent Authorities.‬
‭The‬‭investigator‬‭should‬‭facilitate‬‭access‬‭to‬‭the‬‭source‬‭documents‬‭and‬‭data‬‭for‬‭monitoring‬‭and‬
‭auditing purposes.‬
‭The‬‭content‬‭of‬‭the‬‭case‬‭report‬‭forms‬‭(CRF),‬‭as‬‭well‬‭as‬‭the‬‭documents‬‭generated‬‭during‬‭the‬
‭study‬‭will‬‭be‬‭protected‬‭from‬‭non-permitted‬‭uses‬‭by‬‭persons‬‭not‬‭involved‬‭in‬‭the‬‭investigation,‬
‭and‬‭will‬‭therefore‬‭be‬‭considered‬‭strictly‬‭confidential‬‭and‬‭not‬‭revealed‬‭to‬‭third‬‭parties,‬‭except‬
‭those specified in the previous paragraphs.‬
‭11.6.‬
‭Insurance Policy‬
‭The‬ ‭insurance‬ ‭or‬ ‭indemnity‬ ‭in‬ ‭accordance‬ ‭with‬ ‭pertinent‬ ‭regulatory‬ ‭requirements‬ ‭will‬ ‭be‬
‭provided.‬‭All‬‭patients‬‭in‬‭this‬‭study‬‭are‬‭insured‬‭through‬‭the‬‭corresponding‬‭insurance‬‭policy‬‭that‬
‭satisfies the conditions stipulated by the RD 1090/2015 in Spain.‬
‭11.7.‬
‭End of study definition‬
‭The‬‭end‬‭of‬‭study‬‭is‬‭defined‬‭as‬‭the‬‭Last‬‭Patient‬‭Last‬‭Visit‬‭(LPLV)‬‭and‬‭will‬‭be‬‭considered‬‭at‬‭24‬
‭months‬‭after‬‭last‬‭patient‬‭first‬‭visit‬‭(LPFV),‬‭Sponsor‬‭will‬‭ask‬‭survival‬‭status‬‭of‬‭all‬‭patients‬‭at‬
‭the‬‭final‬‭clinical‬‭trial‬‭database‬‭closing,‬‭in‬‭order‬‭to‬‭maximise‬‭the‬‭median‬‭follow‬‭up‬‭of‬‭patients‬
‭for overall survival data.‬
‭11.8.‬
‭Early study termination‬
‭The‬ ‭clinical‬ ‭trial‬ ‭may‬ ‭be‬ ‭terminated‬ ‭prematurely‬ ‭or‬ ‭suspended‬ ‭at‬ ‭the‬ ‭request‬ ‭of‬ ‭Health‬
‭Authorities‬ ‭or‬ ‭if‬ ‭new‬ ‭safety‬ ‭or‬ ‭efficacy‬ ‭information‬ ‭leads‬ ‭to‬ ‭an‬ ‭unfavourable‬ ‭risk‬ ‭benefit‬
‭judgment‬‭for‬‭any‬‭IMP.‬‭The‬‭Sponsor‬‭may‬‭discontinue‬‭the‬‭trial‬‭if‬‭it‬‭becomes‬‭unjustifiable‬‭for‬
‭medical‬‭or‬‭ethical‬‭reasons,‬‭poor‬‭enrolment,‬‭or‬‭the‬‭discontinuation‬‭of‬‭clinical‬‭development‬‭of‬
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‭the IMP or withdrawal of the IMP from the market for safety reasons.‬
‭Health‬ ‭Authorities‬ ‭and‬ ‭Independent‬ ‭Ethics‬ ‭Committees‬ ‭(IECs)‬ ‭will‬ ‭be‬ ‭informed‬ ‭about‬‭the‬
‭discontinuation of the trial in accordance with applicable regulations.‬
‭In‬ ‭case‬ ‭of‬ ‭early‬‭termination‬‭of‬‭the‬‭study,‬‭all‬‭the‬‭study‬‭material‬‭(study‬‭drugs,‬‭etc.)‬‭must‬‭be‬
‭returned to the Sponsor.‬
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‭12.‬
‭STUDY PROCEDURES‬
‭12.1.‬ ‭Responsibilities according to Good Clinical Practice‬
‭Responsibilities‬ ‭of‬ ‭the‬ ‭principal‬ ‭investigator‬ ‭of‬ ‭each‬ ‭participating‬ ‭center‬ ‭includes‬ ‭what‬ ‭is‬
‭detailed in section 4 of the‬‭Guideline for good clinical‬‭practice E6 (R2)‬‭.‬
‭12.2.‬ ‭Instructions for e-CRF completion‬
‭The‬‭data‬‭will‬‭be‬‭recorded‬‭using‬‭the‬‭Electronic‬‭Data‬‭Capture‬‭software‬‭property‬‭of‬‭MFAR‬‭S.L.‬
‭The‬‭MFAR‬‭e-CRF‬‭environment‬‭will‬‭be‬‭used‬‭for‬‭data‬‭collection‬‭in‬‭this‬‭study.‬‭The‬‭database‬‭can‬
‭be‬ ‭accessed‬ ‭through‬ ‭the‬ ‭following‬ ‭link:‬ ‭www.mfar.es/access‬‭.‬ ‭Access‬ ‭to‬ ‭data‬ ‭is‬‭secure‬‭and‬
‭restricted‬‭for‬‭authorised‬‭users.‬‭Each‬‭user‬‭requires‬‭a‬‭username‬‭and‬‭password‬‭for‬‭exclusively‬
‭personal use, as per good clinical practice.‬
‭All‬ ‭the‬ ‭EDC‬ ‭users‬ ‭are‬ ‭uniquely‬‭identified‬‭by‬‭name,‬‭all‬‭the‬‭access‬‭to‬‭the‬‭software‬‭is‬‭made‬
‭through a secure, encrypted connection and all the activities are logged and audited.‬
‭All‬‭the‬‭EDC‬‭forms‬‭are‬‭designed‬‭according‬‭to‬‭the‬‭eCRF‬‭defined‬‭by‬‭the‬‭study‬‭protocol,‬‭and‬‭are‬
‭validated‬ ‭according‬ ‭to‬ ‭the‬ ‭DVP‬ ‭(Data‬ ‭Validation‬ ‭Plan).‬ ‭There‬ ‭will‬‭be‬‭eCRFs‬‭for‬‭different‬
‭visits,‬‭and‬‭whether‬‭these‬‭are‬‭mandatory‬‭(m)‬‭and‬‭non-mandatory‬‭eCRFs‬‭(such‬‭as‬‭laboratory‬
‭testing and the corresponding validation of variables, rules and extraction).‬
‭Data‬ ‭on‬ ‭Adverse‬ ‭Event‬ ‭(AE),‬ ‭Adverse‬ ‭Reactions‬ ‭(AR),‬ ‭Serious‬ ‭Adverse‬ ‭Events‬ ‭(SAEs),‬
‭Serious‬ ‭Adverse‬ ‭Reactions‬ ‭(SARs)‬ ‭and‬ ‭Suspected‬ ‭Unexpected‬ ‭SARs‬ ‭(SUSARs)‬ ‭will‬ ‭be‬
‭undertaken‬‭by‬‭Sites‬‭in‬‭the‬‭eCRF‬‭and‬‭are‬‭transferred‬‭to‬‭the‬‭study‬‭database‬‭along‬‭with‬‭the‬‭rest‬‭of‬
‭variables.‬
‭Electronic‬‭Case‬‭Report‬‭Form‬‭(eCRF)‬‭includes‬‭the‬‭CTCAE‬‭version‬‭5.0‬‭terms‬‭as‬‭a‬‭pulldown‬‭list‬
‭in‬‭order‬‭to‬‭categorise‬‭the‬‭events,‬‭additionally‬‭when‬‭the‬‭variable‬‭“SAE”‬‭is‬‭marked‬‭as‬‭“yes”,‬‭an‬
‭automatic‬‭email‬‭is‬‭sent‬‭to‬‭the‬‭MFAR‬‭Staff‬‭in‬‭order‬‭to‬‭be‬‭aware‬‭of‬‭the‬‭paper‬‭based‬‭SAE‬‭form‬‭is‬
‭expected‬‭to‬‭be‬‭received,‬‭for‬‭regulatory‬‭reporting‬‭purposes.‬‭As‬‭data‬‭cleaning‬‭procedure,‬‭SAE‬
‭received‬‭in‬‭paper‬‭based‬‭form‬‭are‬‭conciliate‬‭with‬‭the‬‭adverse‬‭events‬‭data‬‭collected‬‭in‬‭the‬‭eCRF‬
‭and‬‭is‬‭ensured‬‭that‬‭all‬‭the‬‭events‬‭reported‬‭by‬‭means‬‭of‬‭SAE‬‭form‬‭are‬‭also‬‭collected‬‭in‬‭the‬
‭eCRF,‬‭that‬‭is‬‭the‬‭final‬‭destination‬‭of‬‭any‬‭adverse‬‭event‬‭(whether‬‭be‬‭AE,‬‭AR,‬‭SAE,‬‭SAR‬‭or‬
‭SUSAR).‬
‭12.3.‬ ‭Drug supply‬
‭AUREA‬ ‭is‬ ‭an‬ ‭Investigator‬ ‭Initiated‬ ‭Study,‬ ‭Atezolizumab‬ ‭will‬ ‭be‬ ‭supplied‬ ‭by‬ ‭the‬‭Sponsor‬
‭through‬‭Roche,‬‭the‬‭Sponsor‬‭will‬‭supply‬‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬‭months‬‭of‬‭treatment‬‭for‬
‭each‬‭patient.‬‭The‬‭treatment‬‭for‬‭patients‬‭not‬‭progressing‬‭at‬‭24‬‭months‬‭will‬‭be‬‭according‬‭to‬‭PI‬
‭criteria,‬‭following‬‭his/her‬‭local‬‭normal‬‭practise.‬‭If‬‭as‬‭per‬‭Treating‬‭Physician‬‭criteria,‬‭the‬‭best‬
‭option‬ ‭for‬ ‭the‬ ‭patient‬ ‭would‬ ‭be‬ ‭to‬ ‭continue‬ ‭with‬ ‭Atezolizumab,‬ ‭the‬ ‭administration‬ ‭may‬
‭continue‬‭but‬‭following‬‭Site’s‬‭supply‬‭channels‬‭(other‬‭than‬‭those‬‭provided‬‭by‬‭Sponsor),‬‭after‬
‭managing local administrative approvals‬
‭Gemcitabine and Cisplatin will be provided by the sites as per standard care criteria.‬
‭12.3.1. Packaging and labelling‬
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‭Packaging‬ ‭and‬ ‭labeling‬ ‭of‬ ‭study‬ ‭treatment‬ ‭will‬ ‭be‬ ‭in‬ ‭accordance‬ ‭with‬ ‭applicable‬ ‭local‬
‭regulatory requirements and applicable Good Manufacturing Practice (GMP) guidelines.‬
‭12.4.‬ ‭Final report and Publications‬
‭As‬‭stated‬‭in‬‭article‬‭42‬‭of‬‭RD‬‭1090/2015‬‭of‬‭clinical‬‭trials,‬‭the‬‭Sponsor‬‭is‬‭obliged‬‭to‬‭publish‬
‭both‬‭positive‬‭and‬‭negative‬‭results‬‭of‬‭the‬‭authorized‬‭clinical‬‭trials‬‭in‬‭scientific‬‭journals‬‭and‬‭with‬
‭mention to the Ethical Committee of Clinical Research that approved the study.‬
‭The‬‭clinical‬‭publication‬‭will‬‭be‬‭carried‬‭out‬‭by‬‭the‬‭Coordinating‬‭Investigator‬‭in‬‭collaboration‬
‭and‬ ‭Principal‬ ‭Investigators.‬ ‭Coordinating‬ ‭Investigator‬ ‭and‬ ‭Principal‬ ‭Investigators‬ ‭who‬
‭contributed‬ ‭with‬ ‭at‬ ‭least‬ ‭3%‬ ‭of‬ ‭the‬ ‭patients‬ ‭will‬ ‭be‬‭the‬‭authors.‬‭The‬‭order‬‭of‬‭authors‬‭will‬
‭strictly depend on the number of patients included by the Investigators.‬
‭The‬‭anonymity‬‭of‬‭the‬‭source‬‭subjects‬‭of‬‭the‬‭data‬‭and‬‭biological‬‭samples‬‭will‬‭be‬‭maintained‬‭at‬
‭all times.‬
‭The‬ ‭results‬ ‭or‬ ‭conclusions‬ ‭of‬ ‭the‬ ‭study‬ ‭will‬ ‭be‬ ‭communicated‬ ‭primarily‬ ‭in‬ ‭scientific‬
‭publications before being released to the non-health public.‬
‭No efficacy study outcome will be reported prematurely or sensationalistically.‬
‭Participating‬ ‭investigators‬ ‭should‬‭not‬‭publish‬‭any‬‭patient‬‭data‬‭that‬‭is‬‭directly‬‭related‬‭to‬‭the‬
‭study objectives until the trial report is published.‬
‭The‬ ‭trial‬ ‭will‬ ‭be‬ ‭registered‬ ‭in‬ ‭the‬ ‭Spanish‬ ‭Registry‬ ‭of‬ ‭Clinical‬ ‭Studies‬ ‭(REEC)‬ ‭and‬
‭www.clinicaltrials.gov‬‭.‬
‭12.5.‬ ‭Monitoring‬
‭The‬‭study‬‭will‬‭be‬‭monitored‬‭through‬‭local‬‭visits,‬‭telephone‬‭calls‬‭and‬‭periodic‬‭inspection‬‭of‬
‭CRFs.‬ ‭During‬ ‭the‬ ‭study,‬ ‭according‬ ‭to‬ ‭monitoring‬ ‭plan,‬ ‭a‬ ‭monitor‬ ‭from‬ ‭MFAR‬ ‭Clinical‬
‭Research‬ ‭or‬ ‭a‬ ‭representative‬ ‭will‬ ‭have‬ ‭regular‬‭contact‬‭with‬‭the‬‭investigational‬‭site,‬‭for‬‭the‬
‭following:‬
‭●‬ ‭Provide information and support to the investigator(s)‬
‭●‬ ‭Confirm that facilities remain acceptable‬
‭●‬ ‭Confirm‬ ‭that‬ ‭the‬ ‭investigational‬ ‭team‬ ‭is‬ ‭adhering‬ ‭to‬ ‭the‬ ‭protocol,‬ ‭data‬ ‭are‬ ‭being‬
‭accurately‬ ‭recorded‬ ‭in‬ ‭the‬ ‭case‬ ‭report‬ ‭forms,‬ ‭and‬ ‭that‬ ‭investigational‬ ‭product‬
‭accountability checks are being performed‬
‭●‬ ‭Perform‬‭source‬‭data‬‭verification.‬‭This‬‭includes‬‭a‬‭comparison‬‭of‬‭the‬‭data‬‭in‬‭the‬‭case‬
‭report‬‭forms‬‭with‬‭the‬‭patient’s‬‭medical‬‭records‬‭at‬‭the‬‭hospital‬‭or‬‭practice,‬‭and‬‭other‬
‭records‬‭relevant‬‭to‬‭the‬‭study.‬‭This‬‭will‬‭require‬‭direct‬‭access‬‭to‬‭all‬‭original‬‭records‬‭for‬
‭each patient (e.g., clinic charts).‬
‭●‬ ‭Record‬ ‭and‬ ‭report‬ ‭any‬ ‭protocol‬ ‭deviations‬ ‭not‬ ‭previously‬ ‭sent‬ ‭to‬ ‭MFAR‬ ‭Clinical‬
‭Research.‬
‭●‬ ‭Confirm‬‭that‬‭AEs‬‭and‬‭SAEs‬‭have‬‭been‬‭properly‬‭documented‬‭on‬‭eCRFs,‬‭all‬‭SAEs‬‭have‬
‭been‬ ‭forwarded‬ ‭to‬ ‭MFAR‬‭Clinical‬‭Research,‬‭and‬‭all‬‭the‬‭SAEs‬‭that‬‭met‬‭criteria‬‭for‬
‭reporting have been forwarded to the IEC‬
‭The‬‭monitor‬‭will‬‭be‬‭available‬‭between‬‭visits‬‭if‬‭the‬‭investigator(s)‬‭or‬‭other‬‭staff‬‭members‬‭need‬
‭information or advice.‬
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‭12.6.‬ ‭Clinical Study Report‬
‭According‬‭to‬‭local‬‭regulation,‬‭the‬‭summary‬‭of‬‭results‬‭of‬‭the‬‭trial‬‭will‬‭be‬‭sent‬‭to‬‭the‬‭AEMPS‬
‭and‬‭the‬‭CEIm‬‭no‬‭later‬‭than‬‭one‬‭year‬‭after‬‭the‬‭date‬‭of‬‭the‬‭end‬‭of‬‭the‬‭trial‬‭globally.‬‭The‬‭summary‬
‭of results will follow the European format required for EudraCT.‬
‭12.7.‬ ‭Protocol Amendments‬
‭Supplements‬‭and‬‭changes‬‭to‬‭the‬‭protocol‬‭can‬‭be‬‭performed‬‭exclusively‬‭by‬‭the‬‭Sponsor,‬‭who‬
‭must‬ ‭submit‬ ‭them‬ ‭to‬ ‭the‬ ‭Ethics‬ ‭Committee‬ ‭and‬ ‭the‬ ‭local‬ ‭Regulatory‬ ‭Authority‬ ‭protocol‬
‭amendments.‬
‭Relevant‬ ‭safety‬ ‭information‬ ‭will‬ ‭be‬ ‭submitted‬ ‭to‬‭the‬‭IEC‬‭during‬‭the‬‭course‬‭of‬‭the‬‭trial,‬‭in‬
‭accordance with national regulations and requirements.‬
‭Initial‬‭IEC‬‭positive‬‭vote,‬‭and‬‭all‬‭materials‬‭approved‬‭by‬‭the‬‭IEC‬‭for‬‭this‬‭study‬‭including‬‭the‬
‭patient‬ ‭consent‬ ‭form‬ ‭and‬‭recruitment‬‭materials‬‭must‬‭be‬‭maintained‬‭by‬‭the‬‭Investigator‬‭and‬
‭made available for inspection.‬
‭12.8.‬ ‭Data Handling‬
‭The‬‭data‬‭will‬‭be‬‭recorded‬‭using‬‭the‬‭Electronic‬‭Data‬‭Capture‬‭software‬‭property‬‭of‬‭MFAR‬‭S.L.,‬
‭which‬ ‭is‬ ‭developed‬ ‭and‬ ‭maintained‬ ‭with‬ ‭strict‬ ‭observance‬ ‭of‬ ‭the‬ ‭regulatory‬ ‭standards‬ ‭for‬
‭Clinical EDC systems, with special observance of the guidelines specified at:‬
‭●‬
‭CPMP/ICH/135/95. ICH E6. Note for Guidance on Good Clinical Practice.‬
‭●‬
‭Good‬ ‭Clinical‬ ‭Data‬ ‭Management‬ ‭Practice,‬ ‭Version‬ ‭4,‬ ‭Society‬ ‭for‬ ‭Clinical‬ ‭Data‬
‭Management (SCDM), October 2005.‬
‭●‬
‭EMEA.‬‭Reflection‬‭on‬‭expectations‬‭for‬‭electronic‬‭source‬‭documents‬‭used‬‭in‬‭clinical‬
‭trials. London, 17 October 2007.‬
‭●‬
‭Directive‬ ‭9‬ ‭Guidance‬ ‭for‬ ‭Industry.‬ ‭Part‬ ‭11,‬ ‭Electronic‬ ‭Records;‬ ‭Electronic‬
‭Signatures – Scope and Application (August 2003).‬
‭●‬
‭FDA.‬‭Guidance‬‭for‬‭Industry.‬‭Computerised‬‭Systems‬‭Used‬‭in‬‭Clinical‬‭Investigations‬
‭(May 2007).‬
‭●‬
‭FDA.‬‭Guidance‬‭for‬‭Industry.‬‭Part‬‭11,‬‭Electronic‬‭Records;‬‭Electronic‬‭Signatures‬‭–‬
‭Scope and Application (August 2003)‬
‭●‬
‭Organic‬‭Law‬‭3/2018,‬‭of‬‭December‬‭5,‬‭Protection‬‭of‬‭Personal‬‭Data‬‭and‬‭guarantee‬‭of‬
‭digital rights‬
‭The‬‭EDC‬‭database‬‭is‬‭hosted‬‭at‬‭a‬‭data‬‭server‬‭located‬‭at‬‭the‬‭Data‬‭Centre‬‭maintained‬‭by‬‭Claranet‬
‭SAU‬‭located‬‭at‬‭“‬‭Calle‬‭Juan‬‭Gris,‬‭10-18,‬‭08014‬‭Barcelona‬‭”‬‭.‬‭The‬‭physical‬‭access‬‭to‬‭the‬‭Data‬
‭Centre‬ ‭is‬ ‭restricted‬ ‭to‬ ‭authorised‬ ‭Claranet‬ ‭personnel,‬ ‭and‬ ‭logical‬ ‭access‬ ‭to‬‭the‬‭database‬‭is‬
‭restricted to named MFAR personnel.‬
‭All‬ ‭the‬ ‭EDC‬ ‭users‬ ‭are‬ ‭uniquely‬‭identified‬‭by‬‭name,‬‭all‬‭the‬‭access‬‭to‬‭the‬‭software‬‭is‬‭made‬
‭through a secure, encrypted connection and all the activities are logged and audited.‬
‭All‬‭the‬‭EDC‬‭forms‬‭are‬‭designed‬‭according‬‭to‬‭the‬‭eCRF‬‭defined‬‭by‬‭the‬‭study‬‭protocol,‬‭and‬‭are‬
‭validated according to the DVP (Data Validation Plan).‬
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‭12.9.‬ ‭Documentation‬
‭The‬ ‭Investigator/Institution‬ ‭should‬ ‭maintain‬ ‭trial‬ ‭documents‬ ‭according‬ ‭to‬ ‭ICH‬ ‭Topic‬ ‭E6‬
‭Section‬‭8‬‭,‬‭and‬‭as‬‭required‬‭by‬‭pertinent‬‭regulatory‬‭requirements.‬‭According‬‭to‬‭RD‬‭1090/2015‬
‭on Clinical trial, the archive period for all essential documents is 25 years.‬
‭Essential‬‭documents‬‭should‬‭be‬‭stored‬‭according‬‭to‬‭ICH‬‭GCP‬‭guidelines‬‭for‬‭a‬‭longer‬‭period‬‭of‬
‭time,‬‭if‬‭required‬‭by‬‭pertinent‬‭regulations.‬‭The‬‭original‬‭patient‬‭data‬‭(clinical‬‭record)‬‭must‬‭be‬
‭kept archived for the time stipulated by the study centre regulations.‬
‭All‬ ‭original‬ ‭subject‬ ‭files‬ ‭(medical‬ ‭records)‬ ‭must‬ ‭be‬ ‭stored‬ ‭at‬ ‭the‬ ‭site‬ ‭(hospital,‬ ‭research‬
‭institution,‬‭or‬‭practice)‬‭for‬‭the‬‭longest‬‭possible‬‭time‬‭permitted‬‭by‬‭the‬‭applicable‬‭regulations,‬
‭and/or‬‭as‬‭per‬‭ICH‬‭GCP‬‭guidelines,‬‭whichever‬‭is‬‭longer‬‭(In‬‭Spain‬‭25‬‭years).‬‭In‬‭any‬‭case,‬‭the‬
‭Investigator‬ ‭should‬ ‭ensure‬ ‭that‬ ‭no‬ ‭destruction‬ ‭of‬‭medical‬‭records‬‭is‬‭performed‬‭without‬‭the‬
‭written approval of the Sponsor.‬
‭12.10.‬ ‭Audits and inspections‬
‭Authorised‬ ‭representatives‬ ‭of‬ ‭Sponsor,‬ ‭a‬ ‭regulatory‬ ‭authority,‬ ‭an‬ ‭Independent‬ ‭Ethics‬
‭Committee‬ ‭may‬ ‭visit‬ ‭the‬ ‭site‬ ‭to‬ ‭perform‬ ‭audits‬ ‭or‬ ‭inspections,‬ ‭including‬ ‭source‬ ‭data‬
‭verification.‬ ‭The‬ ‭purpose‬ ‭of‬ ‭a‬ ‭Sponsor‬ ‭audit‬ ‭or‬ ‭inspection‬ ‭is‬ ‭to‬ ‭systematically‬ ‭and‬
‭independently‬‭examine‬‭all‬‭study-related‬‭activities‬‭and‬‭documents‬‭to‬‭determine‬‭whether‬‭these‬
‭activities‬‭were‬‭conducted,‬‭and‬‭data‬‭were‬‭recorded,‬‭analysed,‬‭and‬‭accurately‬‭reported‬‭according‬
‭to‬ ‭the‬ ‭protocol,‬ ‭Good‬ ‭Clinical‬ ‭Practice‬ ‭guidelines‬ ‭of‬ ‭the‬ ‭International‬ ‭Conference‬ ‭on‬
‭Harmonisation,‬‭and‬‭any‬‭applicable‬‭regulatory‬‭requirements.‬‭The‬‭investigator‬‭should‬‭contact‬
‭the‬ ‭Sponsor‬ ‭through‬ ‭MFAR‬ ‭immediately‬ ‭if‬ ‭contacted‬ ‭by‬ ‭a‬ ‭regulatory‬ ‭agency‬ ‭about‬ ‭an‬
‭inspection.‬
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‭13.‬
‭TRANSLATIONAL SUBSTUDIES‬
‭A‬‭key‬‭objective‬‭of‬‭the‬‭biomarker‬‭analyses‬‭that‬‭will‬‭be‬‭performed‬‭in‬‭this‬‭study‬‭is‬‭to‬‭investigate‬
‭candidate‬‭biomarkers‬‭that‬‭may‬‭have‬‭predictive‬‭value‬‭in‬‭identifying‬‭those‬‭patients‬‭who‬‭may‬
‭benefit‬‭from‬‭treatment‬‭with‬‭the‬‭combination‬‭of‬‭atezolizumab‬‭1‬‭and‬‭split‬‭dose‬‭GC.‬‭In‬‭addition,‬
‭analyses‬ ‭of‬ ‭blood‬ ‭biomarkers‬ ‭obtained‬ ‭before,‬ ‭during‬ ‭and‬ ‭after‬ ‭treatment‬ ‭will‬ ‭provide‬ ‭an‬
‭opportunity‬ ‭to‬ ‭investigate‬ ‭pharmacodynamic‬ ‭effects.‬ ‭Samples‬ ‭collected‬ ‭at‬ ‭the‬ ‭End‬ ‭of‬
‭Treatment/Withdrawal‬‭visit‬‭enable‬‭investigation‬‭of‬‭potential‬‭mechanisms‬‭of‬‭resistance‬‭to‬‭the‬
‭drug combination.‬
‭The following biological samples are required:‬
‭●‬ ‭Tumor‬ ‭sample,‬ ‭archive‬ ‭tumor‬ ‭sample‬ ‭in‬ ‭order‬ ‭to‬ ‭evaluate‬ ‭changes‬ ‭in‬ ‭signaling‬
‭molecules in response to study treatment in tumour tissue.‬
‭●‬ ‭Processed‬ ‭blood‬ ‭samples‬ ‭obtained‬ ‭before‬ ‭treatment,‬ ‭at‬ ‭D1‬ ‭of‬‭cycles‬‭41‬‭and‬‭C7‬‭of‬
‭treatment,‬ ‭and‬ ‭at‬ ‭the‬ ‭end‬ ‭of‬ ‭treatment/progression,‬ ‭in‬‭order‬‭to‬‭evaluate‬‭changes‬‭in‬
‭signaling molecules in response to study treatment in blood.‬
‭●‬ ‭Faecal‬ ‭samples‬ ‭for‬ ‭microbiome‬ ‭analyses,‬ ‭before‬ ‭treatment,‬ ‭at‬ ‭D1‬ ‭of‬ ‭cycle‬ ‭4‬ ‭of‬
‭treatment, and at the end of treatment/progression..‬
‭13.1.‬ ‭Archived Tumor Biospecimens‬
‭Somatic‬‭alterations‬‭in‬‭tumours‬‭including‬‭proteomics,‬‭transcriptomics‬‭and‬‭metabolics‬‭will‬‭be‬
‭analyzed. No germinal line determinations will be performed.‬
‭Tumor‬‭biological‬‭specimens‬‭from‬‭archived‬‭tissue‬‭samples‬‭will‬‭be‬‭used‬‭to‬‭analyze‬‭candidate‬
‭DNA,‬‭RNA,‬‭or‬‭protein‬‭markers,‬‭or‬‭relevant‬‭signature‬‭of‬‭markers‬‭for‬‭their‬‭ability‬‭to‬‭identify‬
‭those patients who are most likely to benefit from treatment with the study drugs.‬
‭Tumor‬‭tissue‬‭biomarker‬‭analyses,‬‭including‬‭determination‬‭of‬‭PD-L1‬‭status,‬‭will‬‭be‬‭performed‬
‭retrospectively‬‭in‬‭a‬‭central‬‭laboratory.‬‭PD-L1‬‭status‬‭will‬‭be‬‭assessed‬‭using‬‭a‬‭validated‬‭PD-L1‬
‭IHC‬ ‭test‬ ‭kit‬ ‭manufactured‬ ‭under‬ ‭GMP‬ ‭specifications,‬ ‭in‬ ‭conjunction‬ ‭with‬ ‭a‬ ‭pre-specified‬
‭scoring‬ ‭algorithm‬ ‭and‬ ‭cutoff‬ ‭defining‬ ‭PD-L1‬ ‭positive‬ ‭versus‬ ‭negative‬ ‭status‬ ‭that‬ ‭will‬ ‭be‬
‭established prior to initiation of scoring of PD-L1.‬
‭Additional‬‭tumor‬‭tissue‬‭biomarkers‬‭that‬‭may‬‭be‬‭analyzed‬‭include,‬‭but‬‭may‬‭not‬‭necessarily‬‭be‬
‭limited‬ ‭to,‬ ‭gene‬ ‭expression‬ ‭profiles‬ ‭and/or‬ ‭quantitation‬ ‭of‬ ‭tumor-infiltrating‬ ‭CD8+‬ ‭T‬
‭lymphocytes by IHC and/or tissue FoxP3, PD-1, or PD-L2.‬
‭13.2.‬ ‭Peripheral Blood‬
‭Specimens‬‭will‬‭be‬‭processed‬‭and‬‭retained‬‭in‬‭local‬‭laboratories‬‭until‬‭Sponsor‬‭indications‬‭for‬
‭shipments.‬‭It‬‭will‬‭include‬‭whole‬‭blood,‬‭serum‬‭and‬‭plasma‬‭samples‬‭that‬‭will‬‭be‬‭retained‬‭in‬‭the‬
‭central laboratory for exploratory assessments.‬
‭Samples‬‭may‬‭be‬‭used‬‭to‬‭identify‬‭or‬‭characterize‬‭cells,‬‭DNA,‬‭RNA,‬‭or‬‭protein‬‭markers‬‭known‬
‭or‬‭suspected‬‭to‬‭be‬‭of‬‭relevance‬‭to‬‭the‬‭mechanisms‬‭of‬‭action,‬‭or‬‭the‬‭development‬‭of‬‭resistance‬
‭to‬ ‭study‬ ‭treatment.‬ ‭These‬ ‭include‬ ‭biomarkers‬ ‭that‬ ‭may‬ ‭aid‬ ‭in‬ ‭the‬ ‭identification‬ ‭of‬ ‭those‬
‭patients‬
‭who‬
‭might‬
‭preferentially‬
‭benefit‬
‭from‬
‭treatment‬
‭with‬ ‭split‬ ‭doses‬ ‭of‬
‭gemcitabine-cisplatinIMP‬‭1‬‭in‬‭combination‬‭with‬‭atezolizumabIMP‬‭2,‬‭which‬‭may‬‭include‬‭but‬
‭are‬‭not‬‭limited‬‭to‬‭biomarkers‬‭related‬‭to‬‭anti-tumor‬‭immune‬‭response‬‭or‬‭target‬‭modulation,‬‭such‬
‭as (not necessarily be limited to) soluble IL-8 or IFNγ.‬
‭Information‬ ‭regarding‬ ‭sample‬ ‭collection,‬ ‭management‬ ‭and‬ ‭shipments‬ ‭are‬ ‭provided‬ ‭in‬ ‭the‬
‭translational research manual.‬
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‭13.3.‬ ‭F‬‭aecal samples‬
‭Specimens‬‭will‬‭be‬‭processed‬‭and‬‭retained‬‭in‬‭local‬‭laboratories‬‭until‬‭Sponsor‬‭indications‬‭for‬
‭shipments.‬‭It‬‭will‬‭include‬‭a‬‭total‬‭of‬‭3‬‭samples:‬‭basal‬‭faecal‬‭sample‬‭collected‬‭prior‬‭treatment‬
‭initiation,‬‭faecal‬‭sample‬‭at‬‭Cycle‬‭4‬‭Day‬‭1‬‭and‬‭after‬‭progression.‬‭ ‬‭Information‬‭regarding‬‭sample‬
‭collection, management and shipments are provided in the translational research manual.‬
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‭14.‬
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‭Marrow Transplant. 2019 Apr;25(4):625-38.‬
‭Loehrer‬‭PJ‬‭Sr,‬‭Einhorn‬‭LH,‬‭Elson‬‭PJ,‬‭et‬‭al.‬‭A‬‭randomized‬‭comparison‬‭of‬‭cisplatin‬‭alone‬‭or‬‭in‬
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‭Maughan‬ ‭BL,‬ ‭Agarwal‬ ‭N,‬‭Hussain‬‭SA,‬‭et‬‭al.‬‭Pooled‬‭analysis‬‭of‬‭phase‬‭II‬‭trials‬‭evaluating‬
‭weekly‬‭or‬‭conventional‬‭cisplatin‬‭as‬‭first-line‬‭therapy‬‭for‬‭advanced‬‭urothelial‬‭carcinoma.‬‭Clin‬
‭Genitourin Cancer. 2013;11:316-20.‬
‭McDermott‬‭DF,‬‭Sosman‬‭JA,‬‭Sznol‬‭M,‬‭et‬‭al.‬‭Atezolizumab,‬‭an‬‭anti-programmed‬‭death-ligand‬
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‭Morales-Barrera‬‭R,‬‭Bellmunt‬‭J,‬‭Suárez‬‭C,‬‭et‬‭al.‬‭Cisplatin‬‭and‬‭gemcitabine‬‭administered‬‭every‬
‭two‬‭weeks‬‭in‬‭patients‬‭with‬‭locally‬‭advanced‬‭or‬‭metastatic‬‭urothelial‬‭carcinoma‬‭and‬‭impaired‬
‭renal function. Eur J Cancer. 2012; 48:1816-21.‬
‭Mu‬‭CY,‬‭Huang‬‭JA,‬‭Chen‬‭Y,‬‭et‬‭al.‬‭High‬‭expression‬‭of‬‭PD-L1‬‭in‬‭lung‬‭cancer‬‭may‬‭contribute‬‭to‬
‭poor‬ ‭prognosis‬ ‭and‬ ‭tumor‬ ‭cells‬ ‭immune‬ ‭escape‬ ‭through‬ ‭suppressing‬ ‭tumor‬ ‭infiltrating‬
‭dendritic cells maturation. Med Oncol 2011;28:682-8.‬
‭Okazaki‬ ‭T,‬ ‭Honjo‬ ‭T.‬ ‭PD-1‬ ‭and‬ ‭PD-1‬ ‭ligands:‬ ‭from‬ ‭discovery‬ ‭to‬ ‭clinical‬ ‭application.‬ ‭Int‬
‭Immunolo 2007;9:813-24.‬
‭Plimack‬ ‭ER,‬ ‭Hoffman-Censits‬ ‭JH,‬‭Viterbo‬‭R,‬‭Trabulsi‬‭EJ,‬‭Ross‬‭EA,‬‭Greenberg‬‭RE,‬‭et‬‭al.‬
‭Accelerated‬ ‭methotrexate,‬ ‭vinblastine,‬ ‭doxorubicin,‬ ‭and‬ ‭cisplatin‬ ‭is‬ ‭safe,‬ ‭effective,‬ ‭and‬
‭efficient‬‭neoadjuvant‬‭treatment‬‭for‬‭muscle-invasive‬‭bladder‬‭cancer:‬‭results‬‭of‬‭a‬‭multicenter‬
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‭2014;32(18):1895-901.‬
‭Powles‬ ‭T,‬ ‭Eder‬ ‭JP,‬ ‭Fine‬ ‭GD,‬ ‭et‬ ‭al.‬ ‭MPDL3280A‬‭(anti-PD-L1)‬‭treatment‬‭leads‬‭to‬‭clinical‬
‭activity in metastatic bladder cancer. Nature. 2014; 515:558-62.‬
‭Riegler‬ ‭LL,‬ ‭Jones‬ ‭GP,‬ ‭Lee‬ ‭DW.‬ ‭Current‬ ‭approaches‬ ‭in‬ ‭the‬ ‭grading‬ ‭and‬ ‭management‬ ‭of‬
‭cytokine‬ ‭release‬ ‭syndrome‬ ‭after‬ ‭chimeric‬ ‭antigen‬ ‭receptor‬ ‭T-cell‬ ‭therapy.‬ ‭Ther‬ ‭Clin‬ ‭Risk‬
‭Manag. 2019;15:323-35.‬
‭Rosenberg‬ ‭JE,‬ ‭Hoffman-Censits‬ ‭J,‬ ‭Powles‬ ‭T,‬ ‭et‬ ‭al.‬ ‭Atezolizumab‬ ‭in‬ ‭patients‬‭with‬‭locally‬
‭advanced‬‭and‬‭metastatic‬‭urothelial‬‭carcinoma‬‭who‬‭have‬‭progressed‬‭following‬‭treatment‬‭with‬
‭platinum-based‬ ‭chemotherapy:‬ ‭A‬ ‭single-arm,‬ ‭multicentre,‬ ‭phase‬ ‭2‬ ‭trial.‬ ‭Lancet.‬ ‭2016;‬
‭387:1909-20.‬
‭Rotz‬‭SJ,‬‭Leino‬‭D,‬‭Szabo‬‭S,‬‭et‬‭al.‬‭Severe‬‭cytokine‬‭release‬‭syndrome‬‭in‬‭a‬‭patient‬‭receiving‬
‭PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642.‬
‭Saxman‬‭SB.,‬‭Propert‬‭KJ,‬‭Einhorn,‬‭LH,‬‭Crawford,‬‭ED.,‬‭Tannock‬‭I,‬‭Raghavan,‬‭D.‬‭Long-term‬
‭follow-up‬ ‭of‬ ‭a‬ ‭phase‬ ‭III‬ ‭intergroup‬ ‭study‬ ‭of‬ ‭cisplatin‬ ‭alone‬ ‭or‬ ‭in‬ ‭combination‬ ‭with‬
‭methotrexate,‬‭vinblastine,‬‭and‬‭doxorubicin‬‭in‬‭patients‬‭with‬‭metastatic‬‭urothelial‬‭carcinoma:‬‭A‬
‭cooperative group study. J Clin Oncol. 1997; 15:2564-69.‬
‭Schleimer‬ ‭RP,‬ ‭Jacques‬ ‭A,‬ ‭Shin‬ ‭HS,‬ ‭et‬ ‭al.‬ ‭Inhibition‬ ‭of‬ ‭T‬ ‭cell-mediated‬ ‭cytotoxicity‬ ‭by‬
‭anti-inflammatory steroids. J Immunol. 1984;132:266-71.‬
‭Sellers‬‭LE,‬‭Harper‬‭A,‬‭Linch‬‭MD,‬‭et‬‭al.‬‭Split‬‭dose‬‭gemcitabine/cisplatin‬‭(GC)‬‭in‬‭urothelial‬
‭carcinoma of the bladder: Review of toxicity and response. J Clin Oncol. 2016;34:15_suppl.‬
‭Spiess‬‭PE,‬‭Agarwal‬‭N,‬‭Bangs‬‭R,‬‭Boorjian‬‭SA,‬‭Buyyounouski‬‭MK,‬‭Clark‬‭PE,‬‭et‬‭al.‬‭Bladder‬
‭Cancer,‬ ‭Version‬ ‭5.2017,‬ ‭NCCN‬ ‭Clinical‬ ‭Practice‬ ‭Guidelines‬ ‭in‬ ‭Oncology.‬ ‭J‬ ‭Natl‬ ‭Compr‬
‭Cancer Netw. 2017;15:1240-67.‬
‭Sternberg‬‭CN,‬‭de‬‭Mulder‬‭P,‬‭Schornagel‬‭JH,‬‭et‬‭al.‬‭Seven‬‭year‬‭update‬‭of‬‭an‬‭EORTC‬‭phase‬‭III‬
‭trial‬ ‭of‬ ‭high-dose‬ ‭intensity‬ ‭M-VAC‬ ‭chemotherapy‬ ‭and‬ ‭G-CSF‬ ‭versus‬ ‭classic‬ ‭M-VAC‬ ‭in‬
‭advanced urothelial tract tumours. Eur J Cancer. 2006;42:50-54.‬
‭Summary‬ ‭of‬ ‭Product‬ ‭Characteristics‬ ‭Atezolizumab,‬ ‭last‬ ‭updated‬ ‭23/10/2019‬ ‭available‬ ‭at:‬
‭https://www.ema.europa.eu/en/medicines/human/EPAR/tecentriq‬
‭Thompson‬ ‭RH,‬ ‭Kuntz‬ ‭SM,‬ ‭Leibovich‬ ‭BC,‬ ‭et‬ ‭al.‬ ‭Tumor‬ ‭B7-H1‬ ‭is‬ ‭associated‬ ‭with‬ ‭poor‬
‭prognosis‬ ‭in‬ ‭renal‬ ‭cell‬ ‭carcinoma‬ ‭patients‬ ‭with‬ ‭long-term‬ ‭follow-up.‬ ‭Cancer‬ ‭Res.‬
‭2006;66:3381-5.‬
‭van‬‭Leenders‬‭GJLH.‬‭PD-L1‬‭testing‬‭in‬‭urothelial‬‭carcinoma:‬‭are‬‭we‬‭there‬‭yet?‬‭Transl‬‭Androl‬
‭Urol. 2019;8:S466-8.‬
‭Von‬ ‭der‬ ‭Maase‬ ‭H,‬ ‭Hansen‬ ‭SW,‬ ‭Roberts‬ ‭PI,‬ ‭et‬ ‭al.‬ ‭Gemcitabine‬ ‭and‬ ‭cisplatin‬ ‭versus‬
‭methotrexate,‬ ‭vinblastine,‬ ‭doxorubicin,‬ ‭and‬ ‭cisplatin‬ ‭in‬ ‭advanced‬ ‭or‬ ‭metastatic‬ ‭bladder‬
‭cancer:‬ ‭results‬ ‭of‬ ‭a‬ ‭large,‬ ‭randomized,‬ ‭multinational,‬ ‭phase‬ ‭III‬ ‭study.‬ ‭J‬ ‭Clin‬ ‭Oncol.‬
‭2000;18:3068-77.‬
‭Witjes‬ ‭AJ,‬‭Lebret‬‭T,‬‭Compérat‬‭EM,‬‭Cowan‬‭NC,‬‭De‬‭Santis‬‭M,‬‭Bruins‬‭HM,‬‭et‬‭al.‬‭Updated‬
‭2016‬ ‭EAU‬ ‭Guidelines‬ ‭on‬ ‭Muscle-invasive‬ ‭and‬ ‭Metastatic‬ ‭Bladder‬ ‭Cancer.‬ ‭Eur‬ ‭Urol.‬
‭2017;71:462-75.‬
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‭APPENDICES‬
‭Appendix 1. Management of Atezolizumab-specific Adverse Events‬
‭A)‬ ‭Management Guidelines for Pulmonary Events, Including Pneumonitis‬
‭Event‬
‭Management‬
‭Pulmonary event, Grade 1‬
‭●‬
‭Continue atezolizumab and monitor closely.‬
‭●‬
‭Re-evaluate on serial imaging.‬
‭●‬
‭Consider patient referral to pulmonary specialist.‬
‭Pulmonary event, Grade 2‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Refer‬ ‭patient‬ ‭to‬ ‭pulmonary‬ ‭and‬ ‭infectious‬ ‭disease‬
‭specialists and consider bronchoscopy or BAL.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone or equivalent.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭●‬
‭For recurrent events, treat as a Grade 3 or 4 event.‬
‭Pulmonary event, Grade 3‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭●‬
‭Bronchoscopy or BAL is recommended.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over 1 month.‬
‭BAL‬‭=‬‭bronchoscopic‬‭alveolar‬‭lavage.‬‭CTCAE‬ ‭Common‬‭Terminology‬‭Criteria‬‭for‬‭Adverse‬‭Events;‬‭NCI‬
‭National Cancer Institute.‬
‭Note:‬ ‭Management‬ ‭guidelines‬ ‭are‬ ‭presented‬ ‭by‬ ‭adverse‬‭event‬‭severity‬‭based‬‭on‬‭NCI‬‭CTCAE‬‭and‬‭are‬
‭applicable to both CTCAE Version 4.0 and CTCAE Version 5.0.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭agreed‬ ‭upon‬ ‭by‬ ‭the‬ ‭investigator‬ ‭and‬ ‭the‬
‭Medical Monitor.‬
‭b‬ ‭If‬ ‭corticosteroids‬ ‭have‬ ‭been‬ ‭initiated,‬ ‭they‬ ‭must‬ ‭be‬ ‭tapered‬ ‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬‭from‬‭the‬‭immune-mediated‬‭event.‬‭Patients‬‭can‬‭be‬‭re-challenged‬‭with‬‭atezolizumab‬‭only‬‭after‬
‭approval‬ ‭has‬ ‭been‬ ‭documented‬ ‭by‬ ‭both‬ ‭the‬ ‭investigator‬ ‭(or‬ ‭an‬ ‭appropriate‬‭delegate)‬‭and‬‭the‬‭Medical‬
‭Monitor.‬
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‭B)‬ ‭Management Guidelines for Hepatic Events‬
‭Event‬
‭Management‬
‭Hepatic event,‬
‭Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Monitor‬‭LFTs‬‭until‬‭values‬‭resolve‬‭to‬‭within‬‭normal‬‭limits‬
‭or to baseline values.‬
‭Hepatic event,‬
‭Grade 2‬
‭All events:‬
‭●‬
‭Monitor‬ ‭LFTs‬ ‭more‬ ‭frequently‬ ‭until‬ ‭return‬ ‭to‬ ‭baseline‬
‭values.‬
‭Events of  5 days’ duration:‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset. a‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab. b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Hepatic event,‬
‭Grade 2‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset. a‬
‭●‬
‭Refer‬ ‭patient‬ ‭to‬ ‭GI‬ ‭specialist‬ ‭for‬ ‭evaluation‬ ‭and‬
‭confirmatory biopsy.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Hepatic event,‬
‭Grade 3 or 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭●‬
‭Consider‬ ‭patient‬ ‭referral‬ ‭to‬ ‭gastrointestinal‬ ‭specialist‬‭for‬
‭evaluation‬‭and‬‭liver‬‭biopsy‬‭to‬‭establish‬‭etiology‬‭of‬‭hepatic‬
‭injury.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over 1 month.‬
‭CTCAE  Common Terminology Criteria for Adverse Events; LFT  liver function tests; NCI  National‬
‭Cancer Institute.‬
‭Note: Management guidelines are presented by adverse event severity based on NCI CTCAE and are‬
‭applicable to both CTCAE Version 4.0 and CTCAE Version 5.0, except where indicated.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>‬‭12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭agreed‬ ‭upon‬ ‭by‬ ‭the‬ ‭investigator‬ ‭and‬ ‭the‬
‭Medical Monitor.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬‭from‬‭the‬‭immune-mediated‬‭event.‬‭Patients‬‭can‬‭be‬‭re-challenged‬‭with‬‭atezolizumab‬‭only‬‭after‬
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‭approval‬ ‭has‬ ‭been‬ ‭documented‬ ‭by‬ ‭both‬ ‭the‬ ‭investigator‬ ‭(or‬ ‭an‬ ‭appropriate‬‭delegate)‬‭and‬‭the‬‭Medical‬
‭Monitor‬
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‭C)‬ ‭Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis)‬
‭Event‬
‭Management‬
‭Diarrhea or colitis,‬
‭Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Initiate symptomatic treatment.‬
‭●‬
‭Endoscopy is recommended if symptoms persist for 7 days.‬
‭●‬
‭Monitor closely.‬
‭Diarrhea or colitis,‬
‭Grade 2‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Initiate symptomatic treatment.‬
‭●‬
‭Patient referral to GI specialist is recommended.‬
‭●‬
‭For‬ ‭recurrent‬ ‭events‬ ‭or‬ ‭events‬ ‭that‬ ‭persist‬ ‭>‬ ‭5‬ ‭days,‬
‭initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Diarrhea or colitis,‬
‭Grade 3‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Refer‬ ‭patient‬ ‭to‬ ‭GI‬ ‭specialist‬ ‭for‬ ‭evaluation‬ ‭and‬
‭confirmatory biopsy.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Diarrhea or colitis,‬
‭Grade 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭●‬
‭Refer‬ ‭patient‬ ‭to‬ ‭GI‬ ‭specialist‬ ‭for‬ ‭evaluation‬ ‭and‬
‭confirmation biopsy.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over 1 month.‬
‭CTCAE‬
‭Common‬ ‭Terminology‬ ‭Criteria‬ ‭for‬ ‭Adverse‬ ‭Events;‬ ‭GI‬ ‭=‬ ‭gastrointestinal‬‭;‬ ‭NCI‬ ‭National‬
‭Cancer Institute.‬
‭Note:‬ ‭Management‬ ‭guidelines‬ ‭are‬ ‭presented‬ ‭by‬ ‭adverse‬‭event‬‭severity‬‭based‬‭on‬‭NCI‬‭CTCAE‬‭and‬‭are‬
‭applicable to both CTCAE Version 4.0 and CTCAE Version 5.0, except where indicated.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>‬‭12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭agreed‬ ‭upon‬ ‭by‬ ‭the‬ ‭investigator‬ ‭and‬ ‭the‬
‭Medical Monitor.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
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‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬‭from‬‭the‬‭immune-mediated‬‭event.‬‭Patients‬‭can‬‭be‬‭re-challenged‬‭with‬‭atezolizumab‬‭only‬‭after‬
‭approval‬ ‭has‬ ‭been‬ ‭documented‬ ‭by‬ ‭both‬ ‭the‬ ‭investigator‬ ‭(or‬ ‭an‬ ‭appropriate‬‭delegate)‬‭and‬‭the‬‭Medical‬
‭Monitor.‬
‭D)‬ ‭Management Guidelines for Hepatic Events‬
‭Event‬
‭Management‬
‭Hepatic event,‬
‭Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Monitor‬‭LFTs‬‭until‬‭values‬‭resolve‬‭to‬‭within‬‭normal‬‭limits‬
‭or to baseline values.‬
‭Hepatic event,‬
‭Grade 2‬
‭All events:‬
‭●‬
‭Monitor‬ ‭LFTs‬ ‭more‬ ‭frequently‬ ‭until‬ ‭return‬ ‭to‬ ‭baseline‬
‭values.‬
‭Events of  5 days’ duration:‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset. a‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab. b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Hepatic event,‬
‭Grade 2‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset. a‬
‭●‬
‭Refer‬ ‭patient‬ ‭to‬ ‭GI‬ ‭specialist‬ ‭for‬ ‭evaluation‬ ‭and‬
‭confirmatory biopsy.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Hepatic event,‬
‭Grade 3 or 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭●‬
‭Consider‬ ‭patient‬ ‭referral‬ ‭to‬ ‭gastrointestinal‬ ‭specialist‬‭for‬
‭evaluation‬‭and‬‭liver‬‭biopsy‬‭to‬‭establish‬‭etiology‬‭of‬‭hepatic‬
‭injury.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over 1 month.‬
‭CTCAE  Common Terminology Criteria for Adverse Events; LFT  liver function tests; NCI  National‬
‭Cancer Institute.‬
‭Note: Management guidelines are presented by adverse event severity based on NCI CTCAE and are‬
‭applicable to both CTCAE Version 4.0 and CTCAE Version 5.0, except where indicated.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>‬‭12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭agreed‬ ‭upon‬ ‭by‬ ‭the‬ ‭investigator‬ ‭and‬ ‭the‬
‭Medical Monitor.‬
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‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬‭from‬‭the‬‭immune-mediated‬‭event.‬‭Patients‬‭can‬‭be‬‭re-challenged‬‭with‬‭atezolizumab‬‭only‬‭after‬
‭approval‬ ‭has‬ ‭been‬ ‭documented‬ ‭by‬ ‭both‬ ‭the‬ ‭investigator‬ ‭(or‬ ‭an‬ ‭appropriate‬‭delegate)‬‭and‬‭the‬‭Medical‬
‭Monitor‬
‭E)‬ ‭Management Guidelines for Endocrine Events‬
‭Event‬
‭Management‬
‭Asymptomatic‬
‭hypothyroidism‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Initiate treatment with thyroid replacement hormone.‬
‭●‬
‭Monitor TSH weekly.‬
‭Symptomatic‬
‭hypothyroidism‬
‭●‬
‭Withhold atezolizumab.‬
‭●‬
‭Initiate treatment with thyroid replacement hormone.‬
‭●‬
‭Monitor TSH weekly.‬
‭●‬
‭Consider patient referral to endocrinologist.‬
‭●‬
‭Resume‬ ‭atezolizumab‬ ‭when‬‭symptoms‬‭are‬‭controlled‬‭and‬
‭thyroid function is improving.‬
‭Asymptomatic‬
‭hyperthyroidism‬
‭TSH‬‭≥‬‭0.1 mU/L and < 0.5 mU/L:‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Monitor TSH every 4 weeks.‬
‭TSH < 0.1 mU/L:‬
‭●‬
‭Follow guidelines for symptomatic hyperthyroidism.‬
‭Symptomatic‬
‭hyperthyroidism‬
‭●‬
‭Withhold atezolizumab.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭anti-thyroid‬ ‭drug‬ ‭such‬ ‭as‬
‭methimazole or carbimazole as needed.‬
‭●‬
‭Consider patient referral to endocrinologist.‬
‭●‬
‭Resume‬ ‭atezolizumab‬ ‭when‬‭symptoms‬‭are‬‭controlled‬‭and‬
‭thyroid function is improving.‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical‬ ‭Monitor‬ ‭for‬ ‭life-threatening‬ ‭immune-mediated‬
‭hyperthyroidism.‬
‭Symptomatic adrenal‬
‭insufficiency,‬
‭Grade 2 - 4‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Refer patient to endocrinologist.‬
‭●‬
‭Perform appropriate imaging.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better‬‭and‬‭patient‬‭is‬‭stable‬
‭on replacement therapy, resume atezolizumab.‬‭b‬
‭●‬
‭If‬‭event‬‭does‬‭not‬‭resolve‬‭to‬‭Grade‬‭1‬‭or‬‭better‬‭or‬‭patient‬‭is‬
‭not‬ ‭stable‬ ‭on‬ ‭replacement‬ ‭therapy‬ ‭while‬ ‭withholding‬
‭atezolizumab,‬ ‭permanently‬ ‭discontinue‬ ‭atezolizumab‬ ‭and‬
‭contact Medical Monitor.‬‭c‬
‭Hyperglycemia,‬
‭Grade 1 or 2‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Investigate‬ ‭for‬ ‭diabetes.‬ ‭If‬ ‭patient‬ ‭has‬ ‭Type‬ ‭1‬ ‭diabetes,‬
‭treat‬ ‭as‬ ‭a‬ ‭Grade‬ ‭3‬ ‭event.‬ ‭If‬‭patient‬‭does‬‭not‬‭have‬‭Type‬‭1‬
‭diabetes, treat as per institutional guidelines.‬
‭●‬
‭Monitor for glucose control.‬
‭Hyperglycemia,‬
‭Grade 3 or 4‬
‭●‬
‭Withhold atezolizumab.‬
‭●‬
‭Initiate treatment with insulin.‬
‭●‬
‭Monitor for glucose control.‬
‭●‬
‭Resume‬‭atezolizumab‬‭when‬‭symptoms‬‭resolve‬‭and‬‭glucose‬
‭levels are stable.‬
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‭Hypophysitis‬
‭(pan-hypopituitarism),‬
‭Grade 2 or 3‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset. a‬
‭●‬
‭Refer patient to endocrinologist.‬
‭●‬
‭Perform brain MRI (pituitary protocol).‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭Initiate hormone replacement if clinically indicated.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab. b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭●‬
‭For recurrent hypophysitis, treat as a Grade 4 event.‬
‭Hypophysitis‬
‭(pan-hypopituitarism),‬
‭Grade 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor. c‬
‭●‬
‭Refer patient to endocrinologist.‬
‭●‬
‭Perform brain MRI (pituitary protocol).‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭Initiate hormone replacement if clinically indicated.‬
‭IV=‬‭intravenous;‬‭CTCAE‬ ‭Common‬‭Terminology‬‭Criteria‬‭for‬‭Adverse‬‭Events;‬‭MRI‬‭magnetic‬‭resonance‬
‭imaging; TSH  thyroid-stimulating hormone; NCI  National Cancer Institute.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭agreed‬ ‭upon‬ ‭by‬ ‭the‬ ‭investigator‬ ‭and‬ ‭the‬
‭Medical Monitor.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬‭from‬‭the‬‭immune-mediated‬‭event.‬‭Patients‬‭can‬‭be‬‭re-challenged‬‭with‬‭atezolizumab‬‭only‬‭after‬
‭approval‬ ‭has‬ ‭been‬ ‭documented‬ ‭by‬ ‭both‬ ‭the‬ ‭investigator‬ ‭(or‬ ‭an‬ ‭appropriate‬‭delegate)‬‭and‬‭the‬‭Medical‬
‭Monitor.‬
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‭F)‬ ‭Management Guidelines for Ocular Events‬
‭Event‬
‭Management‬
‭Ocular event,‬
‭Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Patient‬
‭referral‬
‭to‬
‭ophthalmologist‬
‭is‬
‭strongly‬
‭recommended.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭topical‬ ‭corticosteroid‬ ‭eye‬ ‭drops‬
‭and topical immunosuppressive therapy.‬
‭●‬
‭If symptoms persist, treat as a Grade 2 event.‬
‭Ocular event,‬
‭Grade 2‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.a‬
‭●‬
‭Patient‬
‭referral‬
‭to‬
‭ophthalmologist‬
‭is‬
‭strongly‬
‭recommended.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭topical‬ ‭corticosteroid‬ ‭eye‬ ‭drops‬
‭and topical immunosuppressive therapy.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Ocular event,‬
‭Grade 3 or 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor. c Refer patient to ophthalmologist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over 1 month.‬
‭CTCAE‬ ‭Common‬ ‭Terminology‬ ‭Criteria‬ ‭for‬ ‭Adverse‬ ‭Events;‬ ‭MRI‬ ‭magnetic‬ ‭resonance‬‭imaging;‬‭TSH‬
‭thyroid-stimulating hormone; NCI  National Cancer Institute.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭agreed‬ ‭upon‬ ‭by‬ ‭the‬ ‭investigator‬ ‭and‬ ‭the‬
‭Medical Monitor.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬‭from‬‭the‬‭immune-mediated‬‭event.‬‭Patients‬‭can‬‭be‬‭re-challenged‬‭with‬‭atezolizumab‬‭only‬‭after‬
‭approval‬ ‭has‬ ‭been‬ ‭documented‬ ‭by‬ ‭both‬ ‭the‬ ‭investigator‬ ‭(or‬ ‭an‬ ‭appropriate‬‭delegate)‬‭and‬‭the‬‭Medical‬
‭Monitor.‬
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‭G)‬ ‭Management Guidelines for Immune-Mediated Myocarditis‬
‭Event‬
‭Management‬
‭Immune-mediated‬
‭myocarditis, Grade 2‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset‬‭a‬‭and contact Medical Monitor.‬
‭●‬
‭Refer patient to cardiologist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭as‬ ‭per‬ ‭institutional‬ ‭guidelines‬ ‭and‬
‭consider‬ ‭antiarrhythmic‬ ‭drugs,‬ ‭temporary‬ ‭pacemaker,‬
‭ECMO, or VAD as appropriate.‬
‭●‬
‭Consider‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬‭to‬‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor. c‬
‭●‬
‭Refer patient to cardiologist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭as‬ ‭per‬ ‭institutional‬ ‭guidelines‬ ‭and‬
‭consider‬ ‭antiarrhythmic‬ ‭drugs,‬ ‭temporary‬ ‭pacemaker,‬
‭ECMO, or VAD as appropriate.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over  1 month.‬
‭CTCAE  Common Terminology Criteria for Adverse Events; ECMO extracorporeal membrane‬
‭oxygenation; NCI  National Cancer Institute; VAD  ventricular assist device.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭agreed‬ ‭upon‬ ‭by‬ ‭the‬ ‭investigator‬ ‭and‬ ‭the‬
‭Medical Monitor.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬‭from‬‭the‬‭immune-mediated‬‭event.‬‭Patients‬‭can‬‭be‬‭re-challenged‬‭with‬‭atezolizumab‬‭only‬‭after‬
‭approval‬ ‭has‬ ‭been‬ ‭documented‬ ‭by‬ ‭both‬ ‭the‬ ‭investigator‬ ‭(or‬ ‭an‬ ‭appropriate‬‭delegate)‬‭and‬‭the‬‭Medical‬
‭Monitor.‬
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‭H)‬ ‭Management‬ ‭Guidelines‬ ‭for‬ ‭Infusion-Related‬ ‭Reactions‬ ‭and‬ ‭Cytokine-Release‬
‭Syndrome‬
‭Event‬
‭Management‬
‭Grade 1‬‭a‬
‭Fever‬‭b‬‭with or‬
‭without‬
‭constitutional‬
‭symptoms‬
‭●‬
‭Immediately interrupt infusion.‬
‭●‬
‭Upon‬ ‭symptom‬ ‭resolution,‬ ‭wait‬ ‭for‬ ‭30‬ ‭minutes‬ ‭and‬ ‭then‬
‭restart‬ ‭infusion‬ ‭at‬‭half‬‭the‬‭rate‬‭being‬‭given‬‭at‬‭the‬‭time‬‭of‬
‭event onset.‬
‭●‬
‭If‬ ‭the‬ ‭infusion‬ ‭is‬ ‭tolerated‬ ‭at‬ ‭the‬ ‭reduced‬ ‭rate‬ ‭for‬ ‭30‬
‭minutes,‬‭the‬‭infusion‬‭rate‬‭may‬‭be‬‭increased‬‭to‬‭the‬‭original‬
‭rate.‬
‭●‬
‭If symptoms recur, discontinue infusion of this dose.‬
‭●‬
‭Administer‬
‭symptomatic‬
‭treatment,‬
‭c‬
‭including‬
‭maintenance of IV fluids for hydration.‬
‭●‬
‭In‬ ‭case‬ ‭of‬ ‭rapid‬ ‭decline‬ ‭or‬ ‭prolonged‬‭CRS‬‭(2‬‭days)‬‭or‬‭in‬
‭patients‬ ‭with‬ ‭significant‬ ‭symptoms‬ ‭and/or‬ ‭comorbidities,‬
‭consider managing as per Grade 2.‬
‭●‬
‭For‬ ‭subsequent‬ ‭infusions,‬ ‭consider‬‭administration‬‭of‬‭oral‬
‭premedication‬ ‭with‬ ‭antihistamines,‬ ‭anti-pyretics,‬ ‭and/or‬
‭analgesics, and monitor closely for IRRs and/or CRS.‬
‭Grade 2‬‭a‬
‭Fever‬‭b‬‭with‬
‭hypotension not‬
‭requiring‬
‭vasopressors‬
‭and/or‬
‭Hypoxia requiring‬
‭low-flow oxygen d‬
‭by nasal cannula or‬
‭blow-by‬
‭●‬
‭Immediately interrupt infusion.‬
‭●‬
‭Upon‬ ‭symptom‬ ‭resolution,‬ ‭wait‬ ‭for‬ ‭30‬ ‭minutes‬ ‭and‬ ‭then‬
‭restart‬ ‭infusion‬ ‭at‬‭half‬‭the‬‭rate‬‭being‬‭given‬‭at‬‭the‬‭time‬‭of‬
‭event onset.‬
‭●‬
‭If symptoms recur, discontinue infusion of this dose.‬
‭●‬
‭Administer symptomatic treatment.‬‭c‬
‭●‬
‭For hypotension, administer IV fluid bolus as needed.‬
‭●‬
‭Monitor‬ ‭cardiopulmonary‬ ‭and‬ ‭other‬ ‭organ‬ ‭function‬
‭closely‬ ‭(in‬ ‭the‬ ‭ICU,‬ ‭if‬ ‭appropriate).‬ ‭Administer‬‭IV‬‭fluids‬
‭as‬
‭clinically‬
‭indicated,‬
‭and‬
‭manage‬
‭constitutional‬
‭symptoms‬ ‭and‬ ‭organ‬ ‭toxicities‬ ‭as‬ ‭per‬ ‭institutional‬
‭practice.‬
‭●‬
‭Rule‬ ‭out‬ ‭other‬ ‭inflammatory‬ ‭conditions‬ ‭that‬ ‭can‬ ‭mimic‬
‭CRS‬ ‭(e.g.,‬ ‭sepsis).‬ ‭If‬ ‭no‬ ‭improvement‬ ‭within‬ ‭24‬ ‭hours,‬
‭initiate‬‭workup‬‭and‬‭assess‬‭for‬‭signs‬‭and‬‭symptoms‬‭of‬‭HLH‬
‭or MAS.‬
‭●‬
‭Consider‬ ‭IV‬ ‭corticosteroids‬ ‭(e.g.,‬ ‭methylprednisolone‬ ‭2‬
‭mg/kg/day or dexamethasone 10 mg every 6 hours).‬
‭●‬
‭Consider anti-cytokine therapy.‬‭e‬
‭●‬
‭Consider‬ ‭hospitalization‬ ‭until‬ ‭complete‬ ‭resolution‬ ‭of‬
‭symptoms.‬‭If‬‭no‬‭improvement‬‭within‬‭24‬‭hours,‬‭manage‬‭as‬
‭per‬‭Grade‬‭3,‬‭that‬‭is,‬‭hospitalize‬‭patient‬‭(monitoring‬‭in‬‭the‬
‭ICU‬
‭is‬
‭recommended),‬
‭permanently‬
‭discontinue‬
‭atezolizumab, and contact Medical Monitor.‬
‭●‬
‭If‬‭symptoms‬‭resolve‬‭to‬‭Grade‬‭1‬‭or‬‭better‬‭for‬‭3‬‭consecutive‬
‭days,‬ ‭the‬‭next‬‭dose‬‭of‬‭atezolizumab‬‭may‬‭be‬‭administered.‬
‭For‬ ‭subsequent‬ ‭infusions,‬ ‭consider‬‭administration‬‭of‬‭oral‬
‭premedication‬ ‭with‬ ‭antihistamines,‬ ‭anti-pyretics,‬ ‭and/or‬
‭analgesics and monitor closely for IRRs and/or CRS.‬
‭●‬
‭If‬ ‭symptoms‬ ‭do‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭for‬ ‭3‬
‭consecutive days, contact Medical Monitor.‬
‭Grade 3‬‭a‬
‭Fever‬‭b‬‭with‬
‭hypotension‬
‭requiring a‬
‭vasopressor (with‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭f‬
‭●‬
‭Administer symptomatic treatment.‬‭c‬
‭●‬
‭For‬
‭hypotension,‬
‭administer‬
‭IV‬
‭fluid‬
‭bolus‬
‭and‬
‭vasopressor as needed.‬
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‭or without‬
‭vasopressin)‬
‭and/or‬
‭Hypoxia requiring‬
‭high-flow oxygen d‬
‭by nasal cannula,‬
‭face mask,‬
‭non-rebreather‬
‭mask, or venturi‬
‭mask‬
‭●‬
‭Monitor‬ ‭cardiopulmonary‬ ‭and‬ ‭other‬ ‭organ‬ ‭function‬
‭closely;‬
‭monitoring‬
‭in‬
‭the‬ ‭ICU‬ ‭is‬ ‭recommended.‬
‭Administer‬ ‭IV‬ ‭fluids‬ ‭as‬ ‭clinically‬ ‭indicated,‬ ‭and‬ ‭manage‬
‭constitutional‬ ‭symptoms‬ ‭and‬ ‭organ‬ ‭toxicities‬ ‭as‬ ‭per‬
‭institutional practice.‬
‭●‬
‭Rule‬ ‭out‬ ‭other‬ ‭inflammatory‬ ‭conditions‬ ‭that‬ ‭can‬ ‭mimic‬
‭CRS‬ ‭(e.g.,‬ ‭sepsis).‬ ‭If‬ ‭no‬ ‭improvement‬ ‭within‬ ‭24‬ ‭hours,‬
‭initiate‬‭workup‬‭and‬‭assess‬‭for‬‭signs‬‭and‬‭symptoms‬‭of‬‭HLH‬
‭or MAS.‬
‭●‬
‭Administer‬ ‭IV‬ ‭corticosteroids‬ ‭(e.g.,‬ ‭methylprednisolone‬‭2‬
‭mg/kg/day or dexamethasone 10 mg every 6 hours).‬
‭●‬
‭Consider anti-cytokine therapy.‬‭e‬
‭●‬
‭Hospitalize‬‭patient‬‭until‬‭complete‬‭resolution‬‭of‬‭symptoms.‬
‭If‬‭no‬‭improvement‬‭within‬‭24‬‭hours,‬‭manage‬‭as‬‭per‬‭Grade‬
‭4,‬‭that‬‭is,‬‭admit‬‭patient‬‭to‬‭ICU‬‭and‬‭initiate‬‭hemodynamic‬
‭monitoring,‬ ‭mechanical‬ ‭ventilation,‬ ‭and/or‬ ‭IV‬ ‭fluids‬ ‭and‬
‭vasopressors‬‭as‬‭needed;‬‭for‬‭patients‬‭who‬‭are‬‭refractory‬‭to‬
‭anti-cytokine‬ ‭therapy,‬ ‭experimental‬ ‭treatments‬ ‭may‬ ‭be‬
‭considered‬ ‭at‬ ‭the‬ ‭discretion‬ ‭of‬ ‭the‬ ‭investigator‬ ‭and‬ ‭in‬
‭consultation with the Medical Monitor.‬
‭Grade 4‬‭a‬
‭Fever‬‭b‬‭with‬
‭hypotension‬
‭requiring multiple‬
‭vasopressors‬
‭(excluding‬
‭vasopressin)‬
‭and/or‬
‭Hypoxia requiring‬
‭oxygen by positive‬
‭pressure (e.g.,‬
‭CPAP, BiPAP,‬
‭intubation and‬
‭mechanical‬
‭ventilation)‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭f‬
‭●‬
‭Administer symptomatic treatment.‬‭c‬
‭●‬
‭Admit‬
‭patient‬ ‭to‬ ‭ICU‬ ‭and‬ ‭initiate‬ ‭hemodynamic‬
‭monitoring,‬ ‭mechanical‬ ‭ventilation,‬ ‭and/or‬ ‭IV‬ ‭fluids‬ ‭and‬
‭vasopressors‬ ‭as‬ ‭needed.‬ ‭Monitor‬ ‭other‬ ‭organ‬ ‭function‬
‭closely.‬ ‭Manage‬ ‭constitutional‬ ‭symptoms‬ ‭and‬ ‭organ‬
‭toxicities as per institutional practice.‬
‭●‬
‭Rule‬ ‭out‬ ‭other‬ ‭inflammatory‬ ‭conditions‬ ‭that‬ ‭can‬ ‭mimic‬
‭CRS‬ ‭(e.g.,‬ ‭sepsis).‬ ‭If‬ ‭no‬ ‭improvement‬ ‭within‬ ‭24‬ ‭hours,‬
‭initiate‬‭workup‬‭and‬‭assess‬‭for‬‭signs‬‭and‬‭symptoms‬‭of‬‭HLH‬
‭or MAS.‬
‭●‬
‭Administer‬ ‭IV‬ ‭corticosteroids‬ ‭(e.g.,‬ ‭methylprednisolone‬‭2‬
‭mg/kg/day or dexamethasone 10 mg every 6 hours).‬
‭●‬
‭Consider‬ ‭anti-cytokine‬ ‭therapy.‬ ‭e‬ ‭For‬ ‭patients‬ ‭who‬ ‭are‬
‭refractory‬
‭to‬
‭anti-cytokine‬
‭therapy,‬
‭experimental‬
‭treatments‬ ‭g‬ ‭may‬ ‭be‬ ‭considered‬ ‭at‬ ‭the‬ ‭discretion‬ ‭of‬ ‭the‬
‭investigator and in consultation with the Medical Monitor.‬
‭●‬
‭Hospitalize patient until complete resolution of symptoms.‬
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‭ASTCT‬‭=‬‭American‬‭Society‬‭for‬‭Transplantation‬‭and‬‭Cellular‬‭Therapy;‬‭BiPAP‬‭=‬‭bi-level‬‭positive‬‭airway‬
‭pressure;‬ ‭CAR‬ ‭=‬ ‭chimeric‬ ‭antigen‬ ‭receptor;‬ ‭CPAP‬ ‭=‬ ‭continuous‬ ‭positive‬ ‭airway‬ ‭pressure;‬ ‭CRS‬ ‭=‬
‭cytokine-release‬ ‭syndrome;‬ ‭CTCAE‬ ‭=‬ ‭Common‬ ‭Terminology‬ ‭Criteria‬ ‭for‬ ‭Adverse‬ ‭Events;‬ ‭eCRF‬ ‭=‬
‭electronic‬‭Case‬‭Report‬‭Form;‬‭HLH‬‭=‬‭hemophagocytic‬‭lymphohistiocytosis;‬‭ICU‬‭=‬‭intensive‬‭care‬‭unit;‬
‭IRR‬ ‭=‬ ‭infusion-related‬ ‭reaction;‬ ‭MAS‬ ‭=‬ ‭macrophage‬ ‭activation‬‭syndrome;‬‭NCCN‬‭=‬‭National‬‭Cancer‬
‭Comprehensive Network; NCI  National Cancer Institute.‬
‭Note:‬‭The‬‭management‬‭guidelines‬‭have‬‭been‬‭adapted‬‭from‬‭NCCN‬‭guidelines‬‭for‬‭management‬‭of‬‭CAR‬
‭T-cell-related toxicities (Version 2.2019).‬
‭a‬ ‭Grading‬ ‭system‬ ‭for‬ ‭management‬ ‭guidelines‬ ‭is‬ ‭based‬ ‭on‬ ‭ASTCT‬ ‭consensus‬ ‭grading‬ ‭for‬ ‭CRS.‬ ‭NCI‬
‭CTCAE‬‭(version‬‭as‬‭specified‬‭in‬‭the‬‭protocol)‬‭should‬‭be‬‭used‬‭when‬‭reporting‬‭severity‬‭of‬‭IRRs,‬‭CRS,‬‭or‬
‭organ‬‭toxicities‬‭associated‬‭with‬‭CRS‬‭on‬‭the‬‭Adverse‬‭Event‬‭eCRF.‬‭Organ‬‭toxicities‬‭associated‬‭with‬‭CRS‬
‭should not influence overall CRS grading.‬
‭b‬ ‭Fever‬‭is‬‭defined‬‭as‬‭temperature‬ ‭38C‬‭not‬‭attributable‬‭to‬‭any‬‭other‬‭cause.‬‭In‬‭patients‬‭who‬‭develop‬‭CRS‬
‭and‬‭then‬‭receive‬‭anti-pyretic,‬‭anti-cytokine,‬‭or‬‭corticosteroid‬‭therapy,‬‭fever‬‭is‬‭no‬‭longer‬‭required‬‭when‬
‭subsequently‬ ‭determining‬ ‭event‬ ‭severity‬ ‭(grade).‬ ‭In‬ ‭this‬ ‭case,‬ ‭the‬ ‭grade‬ ‭is‬ ‭driven‬ ‭by‬ ‭the‬‭presence‬‭of‬
‭hypotension and/or hypoxia.‬
‭c‬ ‭Symptomatic‬ ‭treatment‬ ‭may‬ ‭include‬ ‭oral‬ ‭or‬ ‭IV‬ ‭antihistamines,‬ ‭anti-pyretics,‬ ‭analgesics,‬
‭bronchodilators,‬ ‭and/or‬ ‭oxygen.‬ ‭For‬‭bronchospasm,‬‭urticaria,‬‭or‬‭dyspnea,‬‭additional‬‭treatment‬‭may‬‭be‬
‭administered as per institutional practice.‬
‭d‬ ‭Low‬‭flow‬‭is‬‭defined‬‭as‬‭oxygen‬‭delivered‬‭at‬ ‭6‬‭L/min,‬‭and‬‭high‬‭flow‬‭is‬‭defined‬‭as‬‭oxygen‬‭delivered‬‭at‬
‭6 L/min.‬
‭e‬ ‭There‬‭are‬‭case‬‭reports‬‭where‬‭anti-cytokine‬‭therapy‬‭has‬‭been‬‭used‬‭for‬‭treatment‬‭of‬‭CRS‬‭with‬‭immune‬
‭checkpoint‬ ‭inhibitors/ICI‬‭(‬‭Rotz‬‭et‬‭al.‬‭2017‬‭;‬‭Adashek‬‭and‬‭Feldman‬‭2019‬‭),‬‭but‬‭data‬‭are‬‭limited,‬‭and‬‭the‬
‭role of such treatment in the setting of antibody-associated CRS has not been established.‬
‭f‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬ ‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬‭from‬‭the‬‭event.‬‭Patients‬‭can‬‭be‬‭re-challenged‬‭with‬‭atezolizumab‬‭only‬‭after‬‭approval‬‭has‬‭been‬
‭documented‬ ‭by‬ ‭both‬ ‭the‬ ‭investigator‬ ‭(or‬ ‭an‬ ‭appropriate‬ ‭delegate)‬ ‭and‬ ‭the‬ ‭Medical‬ ‭Monitor.‬ ‭For‬
‭subsequent‬ ‭infusions,‬ ‭administer‬ ‭oral‬ ‭premedication‬ ‭with‬ ‭antihistamines,‬ ‭anti-pyretics,‬ ‭and/or‬
‭analgesics,‬‭and‬‭monitor‬‭closely‬‭for‬‭IRRs‬‭and/or‬‭CRS.‬‭Premedication‬‭with‬‭corticosteroids‬‭and‬‭extending‬
‭the‬ ‭infusion‬ ‭time‬ ‭may‬ ‭also‬ ‭be‬ ‭considered‬ ‭after‬ ‭consulting‬ ‭the‬ ‭Medical‬ ‭Monitor‬ ‭and‬ ‭considering‬ ‭the‬
‭benefit-risk ratio.‬
‭g‬‭Refer to‬‭Riegler et al. (2019)‬‭for information on‬‭experimental treatments for CRS.‬
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‭I)‬ ‭Management Guidelines for Pancreatic Events, Including Pancreatitis‬
‭Event‬
‭Management‬
‭Amylase and/or lipase‬
‭elevation, Grade 2‬
‭Amylase and/or lipase > 1.5 - 2.0 ULN:‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Monitor amylase and lipase weekly.‬
‭●‬
‭For‬ ‭prolonged‬ ‭elevation‬ ‭(e.g.,‬ ‭>‬ ‭3‬ ‭weeks),‬ ‭consider‬
‭treatment‬
‭●‬
‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭10‬ ‭mg/day‬ ‭oral‬
‭prednisone.‬
‭Asymptomatic with amylase and/or lipase > 2.0 - 5.0 x ULN:‬
‭●‬
‭Treat as a Grade 3 event.‬
‭Amylase and/or lipase‬
‭elevation, Grade 3 or 4‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Refer patient to GI specialist.‬
‭●‬
‭Monitor amylase and lipase every other day.‬
‭●‬
‭If‬
‭no‬
‭improvement,‬
‭consider‬
‭treatment‬
‭with‬
‭corticosteroids‬
‭equivalent‬
‭to‬
‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭●‬
‭For‬
‭recurrent‬
‭events,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Immune-mediated‬
‭pancreatitis, Grade 2 or 3‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Refer patient to GI specialist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭●‬
‭For‬
‭recurrent‬
‭events,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Immune-mediated‬
‭pancreatitis, Grade 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭●‬
‭Refer patient to GI specialist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over‬‭≥‬‭1 month.‬
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‭CTCAE‬‭Common‬‭Terminology‬‭Criteria‬‭for‬‭Adverse‬‭Events;‬‭GI‬ ‭gastrointestinal;‬‭NCI‬ ‭National‬‭Cancer‬
‭Institute.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭agreed‬ ‭upon‬ ‭by‬ ‭the‬ ‭investigator‬ ‭and‬ ‭the‬
‭Medical Monitor.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬‭from‬‭the‬‭immune-mediated‬‭event.‬‭Patients‬‭can‬‭be‬‭re-challenged‬‭with‬‭atezolizumab‬‭only‬‭after‬
‭approval‬ ‭has‬ ‭been‬ ‭documented‬ ‭by‬ ‭both‬ ‭the‬ ‭investigator‬ ‭(or‬ ‭an‬ ‭appropriate‬‭delegate)‬‭and‬‭the‬‭Medical‬
‭Monitor.‬
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‭J)‬ ‭Management Guidelines for Dermatologic Events‬
‭Event‬
‭Management‬
‭Dermatologic‬
‭event, Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Consider‬ ‭treatment‬ ‭with‬ ‭topical‬ ‭corticosteroids‬ ‭and/or‬
‭other symptomatic therapy (e.g., antihistamines).‬
‭Dermatologic‬
‭event, Grade 2‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Consider patient referral to dermatologist.‬
‭●‬
‭Initiate treatment with topical corticosteroids.‬
‭●‬
‭Consider‬
‭treatment‬
‭with‬
‭higher-potency‬
‭topical‬
‭corticosteroids if event does not improve.‬
‭Dermatologic‬
‭event, Grade 3‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Refer patient to dermatologist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭10‬
‭mg/day‬ ‭oral‬‭prednisone,‬‭increasing‬‭dose‬‭to‬‭1-2‬‭mg/kg/day‬
‭if event does not improve within 48-72 hours.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Dermatologic‬
‭event, Grade 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭CTCAE Common Terminology Criteria for Adverse Events; NCI  National Cancer Institute.‬
‭Note:‬ ‭Management‬ ‭guidelines‬ ‭are‬ ‭presented‬ ‭by‬ ‭adverse‬‭event‬‭severity‬‭based‬‭on‬‭NCI‬‭CTCAE‬‭and‬‭are‬
‭applicable to both CTCAE Version 4.0 and CTCAE Version 5.0.‬
‭a‬‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬ ‭12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬‭for‬‭corticosteroids‬‭(if‬
‭initiated) to be reduced to the equivalent‬
‭of‬ ‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬‭acceptable‬‭length‬‭of‬‭the‬‭extended‬‭period‬‭of‬‭time‬‭must‬‭be‬‭agreed‬‭upon‬‭by‬‭the‬‭investigator‬
‭and the Medical Monitor.‬
‭b‬‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬ ‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬ ‭10‬‭mg/day‬‭oral‬‭prednisone‬
‭before atezolizumab can be resumed.‬
‭c‬‭Resumption‬‭of‬‭atezolizumab‬‭may‬‭be‬‭considered‬‭in‬‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬‭recovered‬‭from‬‭the‬
‭immune-mediated‬‭event.‬‭Patients‬‭can‬‭be‬‭re-challenged‬‭with‬‭atezolizumab‬‭only‬‭after‬‭approval‬‭has‬‭been‬‭documented‬‭by‬‭both‬
‭the investigator (or an appropriate delegate) and the Medical Monitor.‬
‭●‬ ‭For‬ ‭suspected‬ ‭SCARs‬ ‭the‬ ‭patients‬ ‭should‬ ‭be‬ ‭referred‬ ‭to‬ ‭a‬ ‭dermatologist‬ ‭for‬ ‭further‬ ‭diagnosis‬ ‭and‬
‭management‬
‭● Atezolizumab should be withheld for patients with suspected SJS or TEN‬
‭● Atezolizumab should be permanently withdrawn for any grade confirmed SJS or TEN‬
‭●‬ ‭Caution‬ ‭should‬ ‭be‬ ‭used‬ ‭when‬ ‭considering‬ ‭the‬ ‭use‬ ‭of‬‭atezolizumab‬‭in‬‭a‬‭patient‬‭who‬‭has‬‭previously‬
‭experienced‬ ‭a‬ ‭severe‬ ‭or‬ ‭life-threatening‬ ‭skin‬ ‭adverse‬ ‭reaction‬ ‭on‬ ‭prior‬ ‭treatment‬ ‭with‬ ‭other‬
‭immune-stimulatory anticancer agents.‬
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‭K)‬ ‭Management Guidelines for Neurologic Disorders‬
‭Event‬
‭Management‬
‭Immune-mediated‬
‭neuropathy, Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Investigate etiology‬
‭Immune-mediated‬
‭neuropathy, Grade 2‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Investigate etiology.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Immune-mediated‬
‭neuropathy, Grade 3‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭Myasthenia gravis and‬
‭Guillain-Barré syndrome‬
‭(any grade)‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭●‬
‭Refer patient to neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭●‬
‭Consider‬ ‭initiation‬ ‭of‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral or IV prednisone.‬
‭CTCAE Common Terminology Criteria for Adverse Events; NCI  National Cancer Institute.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭agreed‬ ‭upon‬ ‭by‬ ‭the‬ ‭investigator‬ ‭and‬ ‭the‬
‭Medical Monitor.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬‭from‬‭the‬‭immune-mediated‬‭event.‬‭Patients‬‭can‬‭be‬‭re-challenged‬‭with‬‭atezolizumab‬‭only‬‭after‬
‭approval‬ ‭has‬ ‭been‬ ‭documented‬ ‭by‬ ‭both‬ ‭the‬ ‭investigator‬ ‭(or‬ ‭an‬ ‭appropriate‬‭delegate)‬‭and‬‭the‬‭Medical‬
‭Monitor.‬
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‭L)‬ ‭Management Guidelines for Immune-Mediated Meningoencephalitis‬
‭Event‬
‭Management‬
‭Immune-mediated‬
‭meningoencephalitis, all‬
‭grades‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭a‬
‭●‬
‭Refer‬ ‭patient‬ ‭to‬ ‭neurologist.‬
‭Initiate‬ ‭treatment‬ ‭with‬
‭corticosteroids‬
‭equivalent‬
‭to‬
‭1-2‬
‭mg/kg/day‬
‭IV‬
‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬ ‭mg/kg/day‬ ‭oral‬
‭prednisone or equivalent upon improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over‬‭≥‬‭1 month‬
‭CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute.‬
‭a‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬‭from‬‭the‬‭immune-mediated‬‭event.‬‭Patients‬‭can‬‭be‬‭re-challenged‬‭with‬‭atezolizumab‬‭only‬‭after‬
‭approval‬ ‭has‬ ‭been‬ ‭documented‬ ‭by‬ ‭both‬ ‭the‬ ‭investigator‬ ‭(or‬ ‭an‬ ‭appropriate‬‭delegate)‬‭and‬‭the‬‭Medical‬
‭Monitor.‬
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‭Page‬‭312‬‭of‬‭315‬


‭M)‬‭Management Guidelines for Renal Events‬
‭Event‬
‭Management‬
‭Renal event, Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Monitor‬‭kidney‬‭function,‬‭including‬‭creatinine,‬‭closely‬‭until‬
‭values resolve to within normal limits or to baseline values.‬
‭Renal event, Grade 2‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset.‬‭a‬
‭●‬
‭Refer patient to renal specialist.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Renal event, Grade 3 or 4‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬
‭●‬
‭Refer patient to renal specialist and consider renal biopsy.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day oral prednisone.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭taper‬
‭corticosteroids over‬‭≥‬‭1 month.‬
‭CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭agreed‬ ‭upon‬ ‭by‬ ‭the‬ ‭investigator‬ ‭and‬ ‭the‬
‭Medical Monitor.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬‭from‬‭the‬‭immune-mediated‬‭event.‬‭Patients‬‭can‬‭be‬‭re-challenged‬‭with‬‭atezolizumab‬‭only‬‭after‬
‭approval‬ ‭has‬ ‭been‬ ‭documented‬ ‭by‬ ‭both‬ ‭the‬ ‭investigator‬ ‭(or‬ ‭an‬ ‭appropriate‬‭delegate)‬‭and‬‭the‬‭Medical‬
‭Monitor.‬
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‭Page‬‭313‬‭of‬‭315‬


‭N)‬ ‭Management Guidelines for Immune-Mediated Myositis‬
‭Event‬
‭Management‬
‭Immune-mediated myositis,‬
‭Grade 1‬
‭●‬
‭Continue atezolizumab.‬
‭●‬
‭Refer patient to rheumatologist or neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭Immune-mediated myositis,‬
‭Grade 2‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset a and contact Medical Monitor.‬
‭●‬
‭Refer patient to rheumatologist or neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭●‬
‭Consider‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬‭to‬‭1-2‬
‭mg/kg/day‬ ‭IV‬ ‭methylprednisolone‬ ‭and‬ ‭convert‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬
‭oral‬
‭prednisone‬
‭or‬
‭equivalent‬
‭upon‬
‭improvement.‬
‭●‬
‭If‬‭corticosteroids‬‭are‬‭initiated‬‭and‬‭event‬‭does‬‭not‬‭improve‬
‭within‬ ‭48‬ ‭hours‬ ‭after‬ ‭initiating‬ ‭corticosteroids,‬ ‭consider‬
‭adding an immunosuppressive agent.‬
‭●‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬‭b‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better‬ ‭while‬
‭withholding‬
‭atezolizumab,‬
‭permanently‬
‭discontinue‬
‭atezolizumab and contact Medical Monitor.‬‭c‬
‭Immune-mediated myositis,‬
‭Grade 3‬
‭●‬
‭Withhold‬ ‭atezolizumab‬ ‭for‬ ‭up‬ ‭to‬ ‭12‬ ‭weeks‬ ‭after‬ ‭event‬
‭onset a and contact Medical Monitor.‬
‭●‬
‭Refer patient to rheumatologist or neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭●‬
‭Respiratory support may be required in more severe cases.‬
‭●‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬‭methylprednisolone,‬‭or‬‭higher-dose‬‭bolus‬‭if‬
‭patient‬
‭is‬ ‭severely‬ ‭compromised‬ ‭(e.g.,‬ ‭cardiac‬ ‭or‬
‭respiratory‬ ‭symptoms,‬ ‭dysphagia,‬ ‭or‬ ‭weakness‬ ‭that‬
‭severely‬ ‭limits‬ ‭mobility);‬ ‭convert‬ ‭to‬ ‭1-2‬ ‭mg/kg/day‬ ‭oral‬
‭prednisone or equivalent upon improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭If‬ ‭event‬ ‭resolves‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬ ‭better,‬ ‭resume‬
‭atezolizumab.‬ ‭b‬ ‭If‬ ‭event‬ ‭does‬ ‭not‬ ‭resolve‬ ‭to‬ ‭Grade‬ ‭1‬ ‭or‬
‭better‬ ‭while‬ ‭withholding‬ ‭atezolizumab,‬ ‭permanently‬
‭discontinue atezolizumab and contact Medical Monitor.‬‭c‬
‭●‬
‭For recurrent events, treat as a Grade 4 event.‬
‭Immune-mediated myositis,‬
‭Grade 4‬
‭(CTCAE v5.0 guidelines‬
‭only)‬
‭●‬
‭Permanently‬
‭discontinue‬
‭atezolizumab‬
‭and‬
‭contact‬
‭Medical Monitor.‬‭c‬
‭●‬
‭Refer patient to rheumatologist or neurologist.‬
‭●‬
‭Initiate treatment as per institutional guidelines.‬
‭●‬
‭Respiratory‬‭support‬‭may‬‭be‬‭required‬‭in‬‭more‬‭severe‬‭cases.‬
‭Initiate‬ ‭treatment‬ ‭with‬ ‭corticosteroids‬ ‭equivalent‬ ‭to‬ ‭1-2‬
‭mg/kg/day‬ ‭IV‬‭methylprednisolone,‬‭or‬‭higher-dose‬‭bolus‬‭if‬
‭patient‬
‭is‬ ‭severely‬ ‭compromised‬ ‭(e.g.,‬ ‭cardiac‬ ‭or‬
‭respiratory‬ ‭symptoms,‬ ‭dysphagia,‬ ‭or‬ ‭weakness‬ ‭that‬
‭severely‬ ‭limits‬ ‭mobility);‬ ‭convert‬ ‭to‬ ‭12‬ ‭mg/kg/day‬ ‭oral‬
‭prednisone or equivalent upon improvement.‬
‭●‬
‭If‬ ‭event‬ ‭does‬ ‭not‬‭improve‬‭within‬‭48‬‭hours‬‭after‬‭initiating‬
‭corticosteroids,‬ ‭consider‬ ‭adding‬ ‭an‬ ‭immunosuppressive‬
‭agent.‬
‭●‬
‭If‬‭event‬‭resolves‬‭to‬‭Grade‬‭1‬‭or‬‭better,‬‭taper‬‭corticosteroids‬
‭over‬‭≥‬‭1 month.‬
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‭CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute.‬
‭a‬ ‭Atezolizumab‬‭may‬‭be‬‭withheld‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time‬‭(i.e.,‬‭>12‬‭weeks‬‭after‬‭event‬‭onset)‬‭to‬‭allow‬
‭for‬ ‭corticosteroids‬ ‭(if‬ ‭initiated)‬ ‭to‬ ‭be‬ ‭reduced‬ ‭to‬ ‭the‬ ‭equivalent‬ ‭of‬‭≤‬‭10‬‭mg/day‬‭oral‬‭prednisone.‬‭The‬
‭acceptable‬ ‭length‬ ‭of‬ ‭the‬ ‭extended‬ ‭period‬ ‭of‬ ‭time‬ ‭must‬ ‭be‬ ‭agreed‬ ‭upon‬ ‭by‬ ‭the‬ ‭investigator‬ ‭and‬ ‭the‬
‭Medical Monitor.‬
‭b‬ ‭If‬‭corticosteroids‬‭have‬‭been‬‭initiated,‬‭they‬‭must‬‭be‬‭tapered‬‭over‬‭≥‬‭1‬‭month‬‭to‬‭the‬‭equivalent‬‭of‬‭≤‬‭10‬
‭mg/day oral prednisone before atezolizumab can be resumed.‬
‭c‬ ‭Resumption‬ ‭of‬ ‭atezolizumab‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬‭who‬‭are‬‭deriving‬‭benefit‬‭and‬‭have‬‭fully‬
‭recovered‬‭from‬‭the‬‭immune-mediated‬‭event.‬‭Patients‬‭can‬‭be‬‭re-challenged‬‭with‬‭atezolizumab‬‭only‬‭after‬
‭approval‬ ‭has‬ ‭been‬ ‭documented‬ ‭by‬ ‭both‬ ‭the‬ ‭investigator‬ ‭(or‬ ‭an‬ ‭appropriate‬‭delegate)‬‭and‬‭the‬‭Medical‬
‭Monitor.‬
‭AUREA -  SOGUG-2020-IEC(VEJ)-1 - Protocol version 1.1 6.NOV.2020‬
‭Page‬‭315‬‭of‬‭315‬

SAP_001.pdf: 
‭AUREA‬
‭Phase II, multicenter, non-randomized, single-arm, open-label‬
‭trial of atezolizumab in combination of split-doses of‬
‭gemcitabine plus cisplatin in patients with locally advanced‬
‭or metastatic urothelial carcinoma‬
‭STATISTICAL ANALYSIS REPORT‬
‭JULY 2023‬
‭Done by: MFAR CLINICAL RESEARCH S.L‬
‭Page‬‭1‬‭of‬‭77‬


‭1.‬ ‭T‬‭ABLE‬‭OF‬‭C‬‭ONTENTS‬
‭2. Study design‬
‭4‬
‭3. Screening failure‬
‭5‬
‭4. Study populations‬
‭7‬
‭4.1. Intent-To-Treat‬
‭7‬
‭4.2. Per protocol‬
‭8‬
‭4.3. Safety population‬
‭9‬
‭5. Basal information‬
‭10‬
‭5.1. Non-cisplatin eligible‬
‭10‬
‭5.2. Cancer history‬
‭12‬
‭5.2.1. Primary cancer‬
‭12‬
‭5.3. Demographic data‬
‭20‬
‭5.4. Comorbidities and concomitant medication‬
‭22‬
‭5.5. Hematology and coagulation‬
‭23‬
‭5.6. Biochemistry, serology and thyroid function‬
‭24‬
‭5.7. Other determinations‬
‭26‬
‭6. Treatment compliance‬
‭27‬
‭6.1. Initial phase: Combined treatment (C1-C6) atezolizumab, cisplatin and‬
‭gemcitabine‬
‭27‬
‭6.2. Monotherapy phase: Adherence to atezolizumab and entire treatment‬
‭36‬
‭7. End of treatment‬
‭40‬
‭8. Efficacy analysis‬
‭45‬
‭8.1. Primary objective‬
‭45‬
‭8.1.1. Overall response rate (ORR)‬
‭45‬
‭8.1.1.1. ORR vs Age>70‬
‭47‬
‭8.1.1.2. ORR vs Renal Impairment‬
‭48‬
‭8.1.1.3. ORR vs ECOG 2‬
‭49‬
‭8.1.1.4. ORR vs HEMOGLOBIN‬
‭50‬
‭8.1.1.5. ORR vs LIVER METASTASIS‬
‭51‬
‭8.2. Secondary objectives‬
‭52‬
‭8.2.1. Time to response‬
‭52‬
‭8.2.2. Duration of response‬
‭52‬
‭8.2.3. Clinical benefit rate‬
‭54‬
‭8.2.4. Follow-up time‬
‭54‬
‭8.2.5. PFS‬
‭55‬
‭8.2.5.1. PFS vs Age>70‬
‭57‬
‭8.2.5.2. PFS vs Renal Impairment‬
‭58‬
‭Page‬‭2‬‭of‬‭77‬


‭8.2.5.3. PFS vs ECOG 2‬
‭59‬
‭8.2.5.4. PFS vs HEMOGLOBIN‬
‭60‬
‭8.2.5.5. PFS vs LIVER METASTASIS‬
‭61‬
‭8.2.6. OS‬
‭62‬
‭8.2.6.1. OS vs Age>70‬
‭64‬
‭8.2.6.2. OS vs Renal Impairment‬
‭64‬
‭8.2.6.3. OS vs ECOG 2‬
‭66‬
‭8.2.6.4. OS vs HEMOGLOBIN‬
‭67‬
‭8.2.6.5. OS vs LIVER METASTASIS‬
‭68‬
‭9. Safety analysis‬
‭69‬
‭9.1. Annex 1‬
‭74‬
‭Page‬‭3‬‭of‬‭77‬


‭The database was locked down on XXX.‬
‭2.‬‭S‬‭TUDY‬‭DESIGN‬
‭The‬ ‭SOGUG-AUREA‬ ‭study‬ ‭is‬ ‭a‬ ‭multicenter,‬ ‭open‬‭labelled,‬‭single‬‭arm,‬‭Phase‬‭II‬
‭clinical‬‭trial‬‭of‬‭atezolizumab‬‭in‬‭combination‬‭of‬‭split-dose‬‭cisplatin‬‭plus‬‭gemcitabine‬
‭in‬ ‭patients‬ ‭with‬ ‭locally‬ ‭advanced‬ ‭or‬ ‭metastatic‬ ‭urothelial‬ ‭carcinoma‬ ‭(additional‬
‭details‬ ‭on‬ ‭the‬ ‭eligibility‬ ‭criteria‬ ‭of‬ ‭the‬ ‭study‬ ‭are‬ ‭found‬ ‭in‬ ‭section‬ ‭6‬ ‭of‬ ‭the‬‭study‬
‭protocol).‬
‭The‬ ‭design‬ ‭includes‬ ‭screening‬ ‭phase,‬ ‭combined‬ ‭treatment‬ ‭initial‬ ‭phase,‬
‭monotherapy‬ ‭treatment‬ ‭phase,‬ ‭follow-up‬ ‭phase‬ ‭and‬ ‭translational‬ ‭research‬ ‭with‬
‭biopsies, blood samples and faecal samples.‬
‭The‬ ‭dose‬ ‭scheme‬ ‭includes‬ ‭the‬ ‭initial‬ ‭dose‬ ‭of‬ ‭atezolizumab‬ ‭(1200‬ ‭mg)‬
‭intravenously‬‭administered‬‭every‬‭21‬‭days‬‭(one‬‭cycle)‬‭up‬‭to‬‭disease‬‭progression,‬
‭unacceptable‬ ‭toxicity‬ ‭or‬ ‭absence‬ ‭of‬ ‭clinical‬ ‭benefit.‬ ‭Dose‬ ‭adjustment‬ ‭or‬ ‭dose‬
‭reductions‬ ‭of‬ ‭atezolizumab‬ ‭are‬ ‭not‬ ‭expected.‬ ‭Additional‬ ‭information‬ ‭on‬ ‭the‬
‭treatment,‬ ‭modifications,‬ ‭and‬ ‭dose‬ ‭delays‬ ‭is‬ ‭available‬ ‭in‬ ‭section‬ ‭7‬ ‭of‬ ‭the‬ ‭study‬
‭protocol.‬‭SOGUG-AUREA‬‭is‬‭an‬‭Investigator‬‭Initiated‬‭Study,‬‭the‬‭Sponsor‬‭will‬‭supply‬
‭Atezolizumab‬‭for‬‭up‬‭to‬‭24‬‭months‬‭of‬‭treatment‬‭for‬‭each‬‭patient.‬‭For‬‭those‬‭patients‬
‭in‬ ‭which‬ ‭the‬ ‭PI‬ ‭considers‬ ‭that‬ ‭the‬ ‭best‬ ‭option‬ ‭for‬ ‭the‬ ‭patient‬ ‭is‬ ‭continuing‬
‭atezolizumab‬‭for‬‭more‬‭than‬‭24‬‭months,‬‭available‬‭commercial‬‭Site‬‭supplies‬‭should‬
‭be used, after managed local administrative regulation.‬
‭Page‬‭4‬‭of‬‭77‬


‭3.‬‭S‬‭CREENING‬‭FAILURE‬
‭Table 1: Frequency screening failures‬
‭Overall‬
‭Overall (N=)‬
‭Screening Failing‬
‭   No‬
‭   Yes‬
‭Screening Failure Specify‬
‭Table 2: List of patients with screening failure‬
‭Patient number‬
‭Screening Failing‬
‭Screening Failure Specify‬
‭Page‬‭5‬‭of‬‭77‬


‭Table 3: Patients without screening failure by hospital‬
‭Overall‬
‭Overall (N=)‬
‭Hospital‬
‭   COMPLEJO HOSPITALARIO DE JAÉN‬
‭   COMPLEXO HOSPITALARIO UNIVERSITARIO DE OURENSE‬
‭   CONSORCIO HOSPITALARIO PROVINCIAL DE CASTELLÓN‬
‭   HOSPITAL CLÍNICO SAN CARLOS‬
‭   HOSPITAL DE LA SANTA CREU I SANT PAU‬
‭   HOSPITAL SON LLATZER‬
‭   HOSPITAL UNIVERSITARIO 12 DE OCTUBRE‬
‭   HOSPITAL UNIVERSITARIO CENTRAL DE ASTURIAS‬
‭   HOSPITAL UNIVERSITARIO INSULAR DE GRAN CANARIA‬
‭   HOSPITAL UNIVERSITARIO LA PAZ‬
‭   HOSPITAL VIRGEN DE LA SALUD‬
‭   INSTITUT CATALÀ D´ONCOLOGIA L´HOSPITALET ICO‬
‭Page‬‭6‬‭of‬‭77‬


‭4.‬‭S‬‭TUDY‬‭POPULATIONS‬
‭4.1.‬ ‭I‬‭NTENT‬‭-T‬‭O‬‭-T‬‭REAT‬
‭Intent-To-Treat (ITT)‬‭: All patients that have been‬‭enrolled in the trial.‬
‭Table 4: ITT population‬
‭Overall‬
‭Overall (N=)‬
‭Intent-to-treat population‬
‭   No‬
‭   Yes‬
‭ITT population exclusion‬
‭reason‬
‭   NA‬
‭   Screening Failure‬
‭Table 5: ITT exclusion reason‬
‭Patient number‬
‭Intent-to-treat population‬
‭ITT population exclusion reason‬
‭Page‬‭7‬‭of‬‭77‬


‭4.2.‬ ‭P‬‭ER‬‭PROTOCOL‬
‭Evaluable‬ ‭population‬ ‭per‬ ‭protocol‬‭(PP)‬‭:‬‭All‬‭patients‬‭fulfilling‬‭all‬‭eligibility‬‭criteria‬
‭without‬ ‭any‬ ‭protocol‬ ‭deviation‬ ‭that‬ ‭makes‬ ‭the‬ ‭patient‬ ‭invalid‬ ‭for‬ ‭the‬ ‭primary‬
‭endpoint evaluation.‬
‭Table 6: PP population‬
‭Overall‬
‭Overall (N=)‬
‭Per protocol population‬
‭   No‬
‭   Yes‬
‭PP population exclusion‬
‭reason‬
‭   NA‬
‭   Screening Failure‬
‭Table 7: PP exclusion reason‬
‭Patient number‬
‭Per protocol population‬
‭PP population exclusion reason‬
‭Page‬‭8‬‭of‬‭77‬


‭4.3.‬ ‭S‬‭AFETY‬‭POPULATION‬
‭Safety‬ ‭population‬ ‭(SP)‬‭:‬ ‭All‬ ‭patients‬ ‭receiving‬ ‭at‬ ‭least‬ ‭one‬ ‭dose‬ ‭of‬ ‭the‬ ‭study‬
‭treatments.‬
‭Table 8: Safety population‬
‭Overall‬
‭Overall (N=)‬
‭Safety population‬
‭   No‬
‭   Yes‬
‭Safety population exclusion‬
‭reason‬
‭   NA‬
‭   Screening Failure‬
‭Table 9: Safety exclusion reason‬
‭Patient number‬
‭Safety population‬
‭Safety population exclusion reason‬
‭Page‬‭9‬‭of‬‭77‬


‭5.‬‭B‬‭ASAL‬‭INFORMATION‬
‭This section is carried out in the ITT population (N = XX patients).‬
‭5.1.‬ ‭N‬‭ON‬‭-‬‭CISPLATIN‬‭ELIGIBLE‬
‭Table 10: Frequency non-cisplatin eligible‬
‭Overall‬
‭Overall (N=)‬
‭ECOG 2‬
‭   Yes‬
‭   No‬
‭Age > 70 years‬
‭   Yes‬
‭   No‬
‭Creatinine clearance >30 µmol/L and <60 µmol/L‬
‭   Yes‬
‭   No‬
‭Other non-cisplatino elegible reason‬
‭   Yes‬
‭   No‬
‭Specify other non-cisplatino elegible reason‬
‭Page‬‭10‬‭of‬‭77‬


‭Table 11: Frequency non-cisplatin eligible combined‬
‭Overall‬
‭Overall (N=)‬
‭Non-cisplatino elegible reasons combined‬
‭Page‬‭11‬‭of‬‭77‬


‭5.2.‬ ‭C‬‭ANCER‬‭HISTORY‬
‭5.2.1.‬‭P‬‭RIMARY‬‭CANCER‬
‭Table 12: Frequency primary cancer location‬
‭Overall‬
‭Overall (N=)‬
‭Cancer‬
‭Location‬
‭   Urothelial‬
‭cancer‬
‭Location‬
‭Specify‬
‭   Renal pelvis‬
‭   Ureter‬
‭   Bladder‬
‭   Urethra‬
‭Table 13: Frequency TNM status at diagnosis‬
‭Overall‬
‭Overall (N=)‬
‭Initial T Stage‬
‭   T1‬
‭   T2‬
‭   T2a‬
‭   T2b‬
‭   T3‬
‭   T3b‬
‭   T4‬
‭   T4a‬
‭   T4b‬
‭   Tis‬
‭   Ta‬
‭   Tx‬
‭Initial N Stage‬
‭   N0‬
‭   N1‬
‭   N2‬
‭   N3‬
‭   Nx‬
‭Initial M Stage‬
‭   M0‬
‭   M1‬
‭   M1a‬
‭   M1b‬
‭   Mx‬
‭Cancer Stage‬
‭   0a‬
‭   0is‬
‭   I‬
‭   II‬
‭   III‬
‭Page‬‭12‬‭of‬‭77‬


‭Overall‬
‭Overall (N=)‬
‭   IIIA‬
‭   IIIB‬
‭   IV‬
‭   IVA‬
‭   IVB‬
‭   Unknown‬
‭Differentiation‬
‭   Well differentiated‬
‭   Moderately‬
‭differentiated‬
‭   Poorly differentiated‬
‭   Undifferentiated‬
‭   Unknown‬
‭Cancer History Grade‬
‭   High‬
‭   Low‬
‭   Unknown‬
‭Table 14: List of patients with Unknown Cancer Stage‬
‭Patient Number‬
‭Hospital‬
‭Cancer Stage‬
‭004-007‬
‭HOSPITAL UNIVERSITARIO LA PAZ‬
‭Unknown‬
‭Page‬‭13‬‭of‬‭77‬


‭Table 15: Frequency metastasis location‬
‭Overall‬
‭Overall‬
‭(N=66)‬
‭Metastasis‬
‭   Yes‬
‭28 (42.4%)‬
‭   No‬
‭38 (57.6%)‬
‭Metastasis Liver‬
‭   NA‬
‭61 (92.4%)‬
‭   Liver‬
‭5 (7.6%)‬
‭Metastasis Peritoneum‬
‭   NA‬
‭64 (97.0%)‬
‭   Peritoneum‬
‭2 (3.0%)‬
‭Metastasis Pleura‬
‭   NA‬
‭65 (98.5%)‬
‭   Pleura‬
‭1 (1.5%)‬
‭Metastasis Lung‬
‭   NA‬
‭52 (78.8%)‬
‭   Lung‬
‭14 (21.2%)‬
‭Metastasis Kidney‬
‭   NA‬
‭65 (98.5%)‬
‭   Kidney‬
‭1 (1.5%)‬
‭Metastasis Bone‬
‭   NA‬
‭60 (90.9%)‬
‭   Bone‬
‭6 (9.1%)‬
‭Metastasis Renal‬
‭   NA‬
‭65 (98.5%)‬
‭   Renal‬
‭1 (1.5%)‬
‭Metastasis Soft tissues‬
‭   NA‬
‭65 (98.5%)‬
‭   Soft tissues‬
‭1 (1.5%)‬
‭Metastasis Skin‬
‭   NA‬
‭65 (98.5%)‬
‭   Skin‬
‭1 (1.5%)‬
‭Metastasis Lymph‬
‭nodes‬
‭   NA‬
‭48 (72.7%)‬
‭   Lymph nodes‬
‭18 (27.3%)‬
‭Metastasis Other‬
‭   NA‬
‭64 (97.0%)‬
‭   Other‬
‭2 (3.0%)‬
‭Metastasis Other‬
‭specify‬
‭   NA‬
‭64 (97.0%)‬
‭   Adrenal‬
‭1 (1.5%)‬
‭   Suprarrenal‬
‭1 (1.5%)‬
‭Page‬‭14‬‭of‬‭77‬


‭Table 16: Frequency current metastasis location‬
‭Overall‬
‭Overall (N=)‬
‭Current status‬
‭   Locally advanced‬
‭   Metastasic‬
‭Current Metastasis Colon‬
‭   NA‬
‭   Colon‬
‭Current Metastasis Pleural‬
‭effusion‬
‭   NA‬
‭   Pleural effusion‬
‭Current Metastasis Liver‬
‭   NA‬
‭   Liver‬
‭Current Metastasis Large‬
‭intestine‬
‭   NA‬
‭   Large intestine‬
‭Current Metastasis Mediastinum‬
‭   NA‬
‭   Mediastinum‬
‭Current Metastasis Pancreas‬
‭   NA‬
‭   Pancreas‬
‭Current Metastasis Peritoneum‬
‭   NA‬
‭   Peritoneum‬
‭Current Metastasis Lung‬
‭   NA‬
‭   Lung‬
‭Current Metastasis Kidney‬
‭   NA‬
‭   Kidney‬
‭Current Metastasis Bone‬
‭   NA‬
‭   Bone‬
‭Current Metastasis Renal‬
‭   NA‬
‭   Renal‬
‭Current Metastasis Soft tissues‬
‭   NA‬
‭   Soft tissues‬
‭Current Metastasis Skin‬
‭   NA‬
‭   Skin‬
‭Current Metastasis Jejunum‬
‭   NA‬
‭   Jejunum‬
‭Current Metastasis Lymph nodes‬
‭   NA‬
‭   Lymph nodes‬
‭Page‬‭15‬‭of‬‭77‬


‭Overall‬
‭Overall (N=)‬
‭Current Metastasis Other‬
‭   NA‬
‭   Other‬
‭Current Metastasis Other specify‬
‭   NA‬
‭   Adrenal‬
‭   Paraaortic‬
‭   Vagina‬
‭Table 17: Frequency calculated metastasis location‬
‭Overall‬
‭Overall‬
‭(N=)‬
‭Lung - Metastasis‬
‭   No‬
‭   Yes‬
‭Other - Adrenal - Metastasis‬
‭   No‬
‭   Yes‬
‭Renal - Metastasis‬
‭   No‬
‭   Yes‬
‭Peritoneum - Metastasis‬
‭   No‬
‭   Yes‬
‭Lymph nodes - Metastasis‬
‭   No‬
‭   Yes‬
‭Mediastinum - Metastasis‬
‭   No‬
‭   Yes‬
‭Diaphragma - Metastasis‬
‭   No‬
‭   Yes‬
‭Other - left cardiophrenic fat - Metastasis‬
‭   No‬
‭   Yes‬
‭Liver - Metastasis‬
‭   No‬
‭   Yes‬
‭Kidney - Metastasis‬
‭   No‬
‭   Yes‬
‭Bone - Metastasis‬
‭   No‬
‭   Yes‬
‭Other Metastasis‬
‭   No‬
‭   Yes‬
‭Large intestine - Metastasis‬
‭Page‬‭16‬‭of‬‭77‬


‭Overall‬
‭Overall‬
‭(N=)‬
‭   No‬
‭   Yes‬
‭Jejunum - Metastasis‬
‭   No‬
‭   Yes‬
‭Mesenterium - Metastasis‬
‭   No‬
‭   Yes‬
‭Other - penile implant - Metastasis‬
‭   No‬
‭   Yes‬
‭Ileus - Metastasis‬
‭   No‬
‭   Yes‬
‭Other - supraclavicular - Metastasis‬
‭   No‬
‭   Yes‬
‭Other-inter-aortocava - Metastasis‬
‭   No‬
‭   Yes‬
‭Pleural effusion - Metastasis‬
‭   No‬
‭   Yes‬
‭Pleura - Metastasis‬
‭   No‬
‭   Yes‬
‭Pancreas - Metastasis‬
‭   No‬
‭   Yes‬
‭Other - Gallbladder - Metastasis‬
‭   No‬
‭   Yes‬
‭Other: omentum - Metastasis‬
‭   No‬
‭   Yes‬
‭Soft tissues - Metastasis‬
‭   No‬
‭   Yes‬
‭Ascites - Metastasis‬
‭   No‬
‭   Yes‬
‭Skin - Metastasis‬
‭   No‬
‭   Yes‬
‭Colon - Metastasis‬
‭   No‬
‭   Yes‬
‭Page‬‭17‬‭of‬‭77‬


‭Table 18: Frequency treatments‬
‭Overall‬
‭Overall (N=)‬
‭Surgery‬
‭   Yes‬
‭   No‬
‭Primary Surgery‬
‭   NA‬
‭   Yes‬
‭Surgery Outcome‬
‭   NA‬
‭   R0‬
‭   R1‬
‭   R2‬
‭   Unknown‬
‭Radiotherapy‬
‭   Yes‬
‭   No‬
‭Radiotherapy cycles‬
‭   NA‬
‭   1‬
‭  2‬
‭   Unknown‬
‭Radiotherapy cycles‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Radiotherapy Cumulative dose‬
‭(Gy)‬
‭Radiotherapy Cumulative dose‬
‭(Gy)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Previous treatment‬
‭   Yes‬
‭   No‬
‭   Unknown‬
‭Other cancer history‬
‭   Yes‬
‭   No‬
‭Cancer History Type‬
‭Cancer History Treatment‬
‭Page‬‭18‬‭of‬‭77‬


‭Overall‬
‭Overall (N=)‬
‭Page‬‭19‬‭of‬‭77‬


‭5.3.‬ ‭D‬‭EMOGRAPHIC‬‭DATA‬
‭Table 19: Frequency demographic data‬
‭Overall‬
‭Overall (N=)‬
‭Patient Age‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Gender‬
‭   Male‬
‭   Female‬
‭Weight (Kg)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Race‬
‭   Caucasian‬
‭   Latin‬
‭Systolic Blood Pressure (mmHG)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Diastolic Blood Pressure (mmHG)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Temperature (ºC)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Height (cm)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Respiratory rate (breaths per‬
‭minute)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭Page‬‭20‬‭of‬‭77‬


‭Overall‬
‭Overall (N=)‬
‭   Median (95%CI)‬
‭   Range‬
‭Pulse rate (bpm)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Body Mass Index (kg/m2)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭ECOG‬
‭   0‬
‭   1‬
‭   2‬
‭Physical exam‬
‭   Normal‬
‭   Abnormal‬
‭Page‬‭21‬‭of‬‭77‬


‭5.4.‬ ‭C‬‭OMORBIDITIES‬‭AND‬‭CONCOMITANT‬‭MEDICATION‬
‭Table 20: Frequency comorbidities and concomitant medication‬
‭Overall‬
‭Overall (N=)‬
‭Comorbidities‬
‭   No‬
‭   Yes‬
‭Concomitant‬
‭Medication‬
‭   No‬
‭   Yes‬
‭Table 21: Frequency comorbidities in patients‬
‭Comorbidities‬
‭N‬
‭%‬
‭*Some patients can have several comorbidities‬
‭Table 22: Frequency other comorbidities in patients‬
‭Comorbidities‬
‭N‬
‭%‬
‭*Some patients can have several comorbidities‬
‭Page‬‭22‬‭of‬‭77‬


‭Table 23: Frequency concomitant medication in patients‬
‭Concomitant medication‬
‭N‬
‭%‬
‭*Some patients can have several concomitant medications‬
‭Table 24: Frequency other concomitant medication in patients‬
‭Other concomitant medication‬
‭N‬
‭%‬
‭*Some patients can have several concomitant medications‬
‭5.5.‬ ‭H‬‭EMATOLOGY‬‭AND‬‭COAGULATION‬
‭Table 25: Frequency hematology and coagulation‬
‭Overall‬
‭Overall (N=)‬
‭Hemoglobin Value (g/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Platelets Value (10e3/µL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Neutrophils Value‬
‭(10e3/µL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Page‬‭23‬‭of‬‭77‬


‭5.6.‬ ‭B‬‭IOCHEMISTRY‬‭,‬‭SEROLOGY‬‭AND‬‭THYROID‬‭FUNCTION‬
‭Table 26: Frequency biochemistry, serology and thyroid function‬
‭Overall‬
‭Overall (N=)‬
‭Creatinine Value (mg/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Creatinine Clearing Value‬
‭(ml/min)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Bilirubin Value (mg/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Bilirubin Value < ULN‬
‭   Yes‬
‭ALT Value (U/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭ALT Value < ULN‬
‭   No‬
‭   Yes‬
‭AST Value (U/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭AST Value < ULN‬
‭   No‬
‭   Yes‬
‭GGT Value (U/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭GGT Value < ULN‬
‭   No‬
‭Page‬‭24‬‭of‬‭77‬


‭Overall‬
‭Overall (N=)‬
‭   Yes‬
‭   Unknown‬
‭Page‬‭25‬‭of‬‭77‬


‭5.7.‬ ‭O‬‭THER‬‭DETERMINATIONS‬
‭Table 27: Frequency other determinations‬
‭Overall‬
‭Overall (N=)‬
‭Urine Analysis ND‬
‭   Done‬
‭   Not done‬
‭Urine Analysis‬
‭   Missing data‬
‭   Negative‬
‭   Traces‬
‭   +1‬
‭   +2‬
‭   +3‬
‭   +4‬
‭Urine Analysis Blood‬
‭   NA‬
‭   Positive‬
‭   Negative‬
‭Urine Analysis‬
‭Glucose‬
‭   NA‬
‭   Normal‬
‭   Abnormal‬
‭Urine Analysis‬
‭Protein‬
‭   NA‬
‭   Positive‬
‭   Negative‬
‭Pregnancy Test Value‬
‭   NA‬
‭   Negative‬
‭   Unknown‬
‭Electrocardiogram‬
‭   Done‬
‭Ecg Value‬
‭   Normal‬
‭   Abnormal‬
‭FEVI‬
‭   Done‬
‭   Not done‬
‭FEVI Value‬
‭   NA‬
‭   Normal‬
‭   Abnormal‬
‭Page‬‭26‬‭of‬‭77‬


‭6.‬‭T‬‭REATMENT‬‭COMPLIANCE‬
‭The‬‭following‬‭analyses‬‭in‬‭this‬‭section‬‭are‬‭carried‬‭out‬‭in‬‭the‬‭safety‬‭population‬‭(N‬‭=‬
‭XX patients).‬
‭6.1.‬ ‭I‬‭NITIAL‬‭PHASE‬‭: C‬‭OMBINED‬‭TREATMENT‬‭(C1-C6)‬
‭ATEZOLIZUMAB‬‭,‬‭CISPLATIN‬‭AND‬‭GEMCITABINE‬
‭Table 28: Adherence to atezolizumab, cisplatin and gemcitabine‬
‭Overall‬
‭Overall (N=)‬
‭Number of cycles administered (Initial phase) - Atezolizumab‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles administered (Initial phase) - Atezolizumab‬
‭   1‬
‭   2‬
‭   3‬
‭   4‬
‭   5‬
‭   6‬
‭Atezolizumab treatment duration (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles administered (partial/complete) - Cisplatin‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles administered (complete) - Cisplatin‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles administered (partial/complete) - Cisplatin‬
‭   1‬
‭   2‬
‭   3‬
‭   4‬
‭   5‬
‭   6‬
‭Number of cycles administered (complete) - Cisplatin‬
‭   0‬
‭Page‬‭27‬‭of‬‭77‬


‭Overall‬
‭Overall (N=)‬
‭   1‬
‭   2‬
‭   3‬
‭   4‬
‭   5‬
‭   6‬
‭Cisplatin treatment duration (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles administered (partial/complete) - Gemcitabine‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles administered (complete) - Gemcitabine‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles administered (partial/complete) - Gemcitabine‬
‭   1‬
‭   2‬
‭   3‬
‭   4‬
‭   5‬
‭   6‬
‭Number of cycles administered (complete) - Gemcitabine‬
‭   0‬
‭   1‬
‭   2‬
‭   3‬
‭   4‬
‭   5‬
‭   6‬
‭Gemcitabine treatment duration (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Page‬‭28‬‭of‬‭77‬


‭Table 29: Atezolizumab, cisplatin and gemcitabine omissions‬
‭Overall‬
‭Overall (N=)‬
‭Omission (Initial phase) - Atezolizumab‬
‭   No‬
‭   Yes‬
‭Number of patients with omission (Initial phase) - Atezolizumab‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of patients with omissions (Initial phase) - Atezolizumab‬
‭   0‬
‭   1‬
‭Omission - Cisplatin‬
‭   No‬
‭   Yes‬
‭Number of patients with an omission - Cisplatin‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of patients with two omissions - Cisplatin‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of patients with an omission - Cisplatin‬
‭   0‬
‭   1‬
‭   2‬
‭   3‬
‭   5‬
‭Number of patients with two omissions - Cisplatin‬
‭   0‬
‭   1‬
‭Omission - Gemcitabine‬
‭   No‬
‭   Yes‬
‭Number of patients with an omission - Gemcitabine‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of patients with two omissions - Gemcitabine‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭Page‬‭29‬‭of‬‭77‬


‭Overall‬
‭Overall (N=)‬
‭   Range‬
‭Number of patients with an omission - Gemcitabine‬
‭   0‬
‭   1‬
‭   2‬
‭   3‬
‭   5‬
‭Number of patients with two omissions - Gemcitabine‬
‭   0‬
‭   1‬
‭Table 30: List of omissions reasons‬
‭Atezolizumab - Omission reason‬
‭N‬
‭%‬
‭Other‬
‭Cisplatin - Omission reason‬
‭N‬
‭%‬
‭AE‬
‭Other‬
‭Gemcitabine - Omission reason‬
‭N‬
‭%‬
‭AE‬
‭Other‬
‭Table 31: List of other omissions reasons specify‬
‭Atezolizumab - Omission reason‬
‭N‬
‭%‬
‭Cisplatin - Omission reason‬
‭N‬
‭%‬
‭Gemcitabine - Omission reason‬
‭N‬
‭%‬
‭Page‬‭30‬‭of‬‭77‬


‭Table 32: Atezolizumab, cisplatin and gemcitabine delays‬
‭Overall‬
‭Overall (N=)‬
‭Delay (Initial phase) - Atezolizumab‬
‭   No‬
‭   Yes‬
‭Number of cycles with delay (Initial phase) - Atezolizumab‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with delay (Initial phase) - Atezolizumab‬
‭   0‬
‭   2‬
‭   1‬
‭   3‬
‭   4‬
‭Delay‬
‭   No‬
‭   Yes‬
‭Number of cycles with a delay - Cisplatin‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with two delays - Cisplatin‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with a delay - Cisplatin‬
‭   0‬
‭   1‬
‭   2‬
‭   3‬
‭   4‬
‭Number of cycles with two delays - Cisplatin‬
‭   0‬
‭   1‬
‭   2‬
‭Delay - Gemcitabine‬
‭   No‬
‭   Yes‬
‭Number of cycles with a delay - Gemcitabine‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with two delays - Gemcitabine‬
‭Page‬‭31‬‭of‬‭77‬


‭Overall‬
‭Overall (N=)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with a delay - Gemcitabine‬
‭   0‬
‭   1‬
‭   2‬
‭   3‬
‭   4‬
‭Number of cycles with two delays - Gemcitabine‬
‭   0‬
‭   1‬
‭   2‬
‭Table 33: List of delay reasons‬
‭Atezolizumab - Delay reason‬
‭N‬
‭%‬
‭AE‬
‭Other‬
‭Cisplatin - Delay reason‬
‭N‬
‭%‬
‭AE‬
‭Other‬
‭Gemcitabine - Delay reason‬
‭N‬
‭%‬
‭AE‬
‭Other‬
‭Table 34: List of other delay reasons‬
‭Atezolizumab - Delay reason‬
‭N‬
‭%‬
‭Cisplatin - Delay reason‬
‭N‬
‭%‬
‭Gemcitabine - Delay reason‬
‭N‬
‭%‬
‭Table 35: Cisplatin and gemcitabine dose decrease‬
‭Overall‬
‭Overall (N=)‬
‭Dose reduction‬
‭   No‬
‭   Yes‬
‭Number of cycles with a dose reduction - Cisplatin‬
‭   N‬
‭Page‬‭32‬‭of‬‭77‬


‭Overall‬
‭Overall (N=)‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with two dose reductions - Cisplatin‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with a dose reduction - Cisplatin‬
‭   0‬
‭   1‬
‭   2‬
‭Number of cycles with two dose reductions - Cisplatin‬
‭   0‬
‭Minimum dose in dose reductions - Cisplatin‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Dose reduction - Gemcitabine‬
‭   No‬
‭   Yes‬
‭Number of cycles with a dose reduction - Gemcitabine‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with two dose reductions - Gemcitabine‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with a dose reduction - Gemcitabine‬
‭   0‬
‭   1‬
‭   2‬
‭Number of cycles with two dose reductions - Gemcitabine‬
‭   0‬
‭Minimum dose in dose reductions - Gemcitabine‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Page‬‭33‬‭of‬‭77‬


‭Table 36: List of dose decrease reasons‬
‭Cisplatin - Dose reduction reason‬
‭N‬
‭%‬
‭AE‬
‭Gemcitabine - Dose reduction reason‬
‭N‬
‭%‬
‭AE‬
‭Other‬
‭Table 37: List of other dose decrease reasons (AEs)‬
‭Cisplatin - Dose reduction reason‬
‭N‬
‭%‬
‭Gemcitabine - Dose reduction reason‬
‭N‬
‭%‬
‭Table 38: Cisplatin and gemcitabine re-scalation after dose reduction‬
‭Overall‬
‭Overall (N=)‬
‭Dose re-scalation after dose reduction‬
‭   No‬
‭   Yes‬
‭Number of cycles with a re-scalation after dose reduction - Cisplatin‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with two re-scalation after dose reduction - Cisplatin‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with a re-scalation after dose reduction - Cisplatin‬
‭   0‬
‭   1‬
‭Number of cycles with two re-scalation after dose reduction - Cisplatin‬
‭   0‬
‭Minimum dose in dose re-scalation after dose reduction - Cisplatin‬
‭   N‬
‭   Mean‬
‭   SD‬
‭   Median‬
‭   Range‬
‭Dose re-scalation after dose reduction - Gemcitabine‬
‭   No‬
‭   Yes‬
‭Number of cycles with a re-scalation after dose reduction - Gemcitabine‬
‭Page‬‭34‬‭of‬‭77‬


‭Overall‬
‭Overall (N=)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with two re-scalation after dose reduction -‬
‭Gemcitabine‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with a re-scalation after dose reduction - Gemcitabine‬
‭   0‬
‭   1‬
‭Number of cycles with two re-scalation after dose reduction -‬
‭Gemcitabine‬
‭   0‬
‭Minimum dose in dose re-scalation after dose reduction - Gemcitabine‬
‭   N‬
‭   Mean‬
‭   SD‬
‭   Median‬
‭   Range‬
‭Table 39: List of re-scalation after dose reduction reasons‬
‭Cisplatin - Re-scalation after dose reduction reason‬
‭N‬
‭%‬
‭Gemcitabine - Re-scalation after dose reduction reason‬
‭N‬
‭%‬
‭Page‬‭35‬‭of‬‭77‬


‭6.2.‬ ‭M‬‭ONOTHERAPY‬‭PHASE‬‭: A‬‭DHERENCE‬‭TO‬‭ATEZOLIZUMAB‬‭AND‬
‭ENTIRE‬‭TREATMENT‬
‭Table 40: Adherence to atezolizumab, monotherapy phase and entire treatment‬
‭Overall‬
‭Overall (N=)‬
‭Number of cycles administered (Monotherapy phase) - Atezolizumab‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles administered (Monotherapy phase) - Atezolizumab‬
‭   0‬
‭   1‬
‭   2‬
‭   3‬
‭   …‬
‭Atezolizumab treatment duration (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles administered (Entire treatment) - Atezolizumab‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles administered (Entire treatment) - Atezolizumab‬
‭   1‬
‭   2‬
‭   3‬
‭ …‬
‭Atezolizumab treatment duration (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Page‬‭36‬‭of‬‭77‬


‭Table 41: Atezolizumab omissions, monotherapy phase and entire treatment‬
‭Overall‬
‭Overall (N=)‬
‭Omission (Monotherapy phase) - Atezolizumab‬
‭   No‬
‭   Yes‬
‭Number of cycles with omission (Monotherapy phase) - Atezolizumab‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with omissions (Monotherapy phase) - Atezolizumab‬
‭   0‬
‭   1‬
‭Omission (Entire treatment) - Atezolizumab‬
‭   No‬
‭   Yes‬
‭Number of cycles with omission (Entire treatment) - Atezolizumab‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with omissions (Entire treatment) - Atezolizumab‬
‭   0‬
‭   1‬
‭Table 42: List of omissions reasons‬
‭Atezolizumab - Omission reason (Monotherapy)‬
‭N‬
‭%‬
‭Atezolizumab - Omission reason (Entire treatment)‬
‭N‬
‭%‬
‭Table 43: List of omissions reasons specify‬
‭Atezolizumab - Omission reason (Entire treatment)‬
‭N‬
‭%‬
‭Page‬‭37‬‭of‬‭77‬


‭Table 44: Atezolizumab delays, monotherapy phase and entire treatment‬
‭Overall‬
‭Overall (N=)‬
‭Delay (Monotherapy phase) - Atezolizumab‬
‭   No‬
‭   Yes‬
‭Number of cycles with delay (Monotherapy phase) - Atezolizumab‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with delay (Monotherapy phase) - Atezolizumab‬
‭   0‬
‭   1‬
‭   2‬
‭Delay (Entire treatment) - Atezolizumab‬
‭   No‬
‭   Yes‬
‭Number of cycles with delay (Entire treatment) - Atezolizumab‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Number of cycles with delay (Entire treatment) - Atezolizumab‬
‭   0‬
‭   1‬
‭   2‬
‭Table 45: List of delay reasons‬
‭Atezolizumab - Delay reason (Monotherapy)‬
‭N‬
‭%‬
‭Atezolizumab - Delay reason (Entire treatment)‬
‭N‬
‭%‬
‭Page‬‭38‬‭of‬‭77‬


‭Table 46: List of other delay reasons‬
‭Atezolizumab - Delay reason (Monotherapy)‬
‭N‬
‭%‬
‭Atezolizumab - Delay reason (Entire Treatment)‬
‭N‬
‭%‬
‭Page‬‭39‬‭of‬‭77‬


‭7.‬‭E‬‭ND‬‭OF‬‭TREATMENT‬
‭The‬‭following‬‭analyses‬‭in‬‭this‬‭section‬‭are‬‭carried‬‭out‬‭in‬‭the‬‭safety‬‭population‬‭(N‬‭=‬
‭XX patients).‬
‭Table 47: End of treatment‬
‭Overall‬
‭Overall (N=)‬
‭End of Atezolizumab Treatment Reason‬
‭   Progression according RECIST 1.1‬
‭   Death‬
‭   Study treatment completion‬
‭   AE not related to the treatment study‬
‭   Unnacceptable toxicity‬
‭   Investigator decision‬
‭   Withdraw consent‬
‭   Other‬
‭End of Atezolizumab Treatment Reason Specify‬
‭End of Cisplatin Treatment Reason‬
‭   Study treatment completion‬
‭   Unnacceptable toxicity‬
‭   Progression according RECIST 1.1‬
‭   Death‬
‭   AE not related to the treatment study‬
‭   Investigator decision‬
‭   Withdraw consent‬
‭   Other‬
‭End of Gemcitabine Treatment Reason‬
‭   Study treatment completion‬
‭   Unnacceptable toxicity‬
‭   Progression according RECIST 1.1‬
‭   Death‬
‭   AE not related to the treatment study‬
‭   Investigator decision‬
‭   Withdraw consent‬
‭   Other‬
‭Note‬‭:‬ ‭the‬ ‭following‬ ‭reasons‬ ‭have‬ ‭been‬ ‭recoded‬ ‭to‬ ‭minimize‬ ‭categories‬ ‭-‬ ‭Kidney‬
‭function impairment/Urinary tract infection/: AE not related to the treatment study‬
‭Table 48: End of treatment (Grouped to minimize categories)‬
‭Treatment‬
‭Atezolizumab‬
‭(N=)‬
‭Cisplatin‬
‭(N=)‬
‭Gemcitabine‬
‭(N=)‬
‭Total (N=)‬
‭End of treatment reason‬
‭   Study treatment‬
‭completion‬
‭   Progression disease‬
‭   Unnacceptable toxicity‬
‭Page‬‭40‬‭of‬‭77‬


‭Treatment‬
‭Atezolizumab‬
‭(N=)‬
‭Cisplatin‬
‭(N=)‬
‭Gemcitabine‬
‭(N=)‬
‭Total (N=)‬
‭   Death‬
‭   AE not related to the‬
‭treatment study‬
‭   Investigator decision‬
‭   Withdraw consent‬
‭   Other‬
‭Note‬‭:‬ ‭the‬ ‭following‬ ‭reasons‬ ‭have‬ ‭been‬ ‭recoded‬ ‭to‬ ‭minimize‬ ‭categories‬ ‭-‬
‭Symptomatic‬
‭deterioration/Progression‬
‭according‬
‭RECIST‬
‭1.1/Clinical‬
‭Progression: Progression disease‬
‭Page‬‭41‬‭of‬‭77‬


‭Figure 1: Atezolizumab treatment discontinuation‬
‭Page‬‭42‬‭of‬‭77‬


‭Figure 2: Cisplatin treatment discontinuation‬
‭Page‬‭43‬‭of‬‭77‬


‭Figure 3: Gemcitabine treatment discontinuation‬
‭Page‬‭44‬‭of‬‭77‬


‭8.‬‭E‬‭FFICACY‬‭ANALYSIS‬
‭The‬‭following‬‭analyses‬‭in‬‭this‬‭section‬‭are‬‭carried‬‭out‬‭in‬‭the‬‭Per‬‭Protocol‬‭population‬
‭(N = XX patients).‬
‭8.1.‬ ‭P‬‭RIMARY‬‭OBJECTIVE‬
‭8.1.1.‬‭O‬‭VERALL‬‭RESPONSE‬‭RATE‬‭(ORR)‬
‭To‬ ‭evaluate‬ ‭the‬ ‭preliminary‬ ‭efficacy‬ ‭of‬ ‭atezolizumab‬ ‭plus‬‭split-dose‬‭gemcitabine‬
‭and‬‭cisplatin‬‭(GC)‬‭for‬‭the‬‭first-line‬‭setting,‬‭in‬‭patients‬‭with‬‭histologically‬‭confirmed‬
‭advanced‬ ‭(locally‬ ‭advanced‬ ‭and‬ ‭metastatic)‬ ‭urothelial‬‭cancer‬‭in‬‭terms‬‭of‬‭overall‬
‭response‬‭rate‬‭(ORR)‬‭assessed‬‭by‬‭the‬‭investigator‬‭using‬‭the‬‭Response‬‭Evaluation‬
‭Criteria in Solid Tumors (RECIST) v1.1.‬
‭Overall‬‭Response‬‭Rate‬‭(ORR)‬‭:‬‭Assessed‬‭by‬‭the‬‭investigator‬‭using‬‭the‬‭Response‬
‭Evaluation‬‭Criteria‬‭in‬‭Solid‬‭Tumors‬‭(RECIST)‬‭v1.1.‬‭This‬‭will‬‭be‬‭considered‬‭as‬‭the‬
‭percentage/proportion‬‭of‬‭patients‬‭with‬‭confirmed‬‭complete‬‭response‬‭(CR)‬‭or‬‭partial‬
‭response (PR) as their overall best response throughout the study period.‬
‭Table 49: Frequency best overall response‬
‭Best OR Confirmed‬
‭N‬
‭%‬
‭95%CI‬
‭CR‬
‭PR‬
‭SD‬
‭PD‬
‭NE/UK‬
‭UK‬
‭Total‬
‭Table 50: List of patients with NE/UK as best overall response‬
‭Patient‬
‭number‬
‭Best OR‬
‭Confirmed‬
‭Resp. 1.1‬
‭Tumor‬
‭Assessment‬
‭Target Sum‬
‭Status‬
‭EOS Date‬
‭End of Trial‬
‭Reason‬
‭Exitus Reason‬
‭Exitus Reason‬
‭Specify‬
‭Table 51: Frequency best overall response without UK/NE‬
‭Best OR Confirmed‬
‭N‬
‭%‬
‭95%CI‬
‭CR‬
‭Page‬‭45‬‭of‬‭77‬


‭Best OR Confirmed‬
‭N‬
‭%‬
‭95%CI‬
‭PR‬
‭SD‬
‭PD‬
‭NE‬
‭UK‬
‭Total‬
‭Table 52: List of patients with CR/PR as best overall response‬
‭Patient number‬
‭Hospital‬
‭Best OR Confirmed‬
‭Table 53: Frequency overall response rate‬
‭Overall Response Rate (confirmed)‬
‭N‬
‭%‬
‭95%CI‬
‭Yes (CR/PR)‬
‭No‬
‭Total‬
‭Table 54: Frequency overall response rate without UK/NE‬
‭Overall Response Rate (confirmed)‬
‭N‬
‭%‬
‭95%CI‬
‭Yes (CR/PR)‬
‭No‬
‭Total‬
‭Figure 4: Waterfall plot‬
‭Page‬‭46‬‭of‬‭77‬


‭8.1.1.1.‬
‭ORR‬‭VS‬‭A‬‭GE‬‭>70‬
‭Table 1: Age>70 by Overall response rate‬
‭Age > 70 years‬
‭No (N=)‬
‭Yes (N=)‬
‭Total (N=)‬
‭p-value
‭Overall Response Rate (confirmed)‬
‭N‬
‭No‬
‭Yes (CR/PR)‬
‭(1) Fisher's exact test‬
‭(*) The percentages take into account missing data, the p-values do not‬
‭Table 2: Age>70 by Overall response rate without UK/NE‬
‭Age > 70 years‬
‭No (N=)‬
‭Yes (N=)‬
‭Total (N=)‬
‭p-value
‭Overall Response Rate (confirmed)‬
‭N‬
‭Yes (CR/PR)‬
‭No‬
‭(1) Fisher's exact test‬
‭(*) The percentages take into account missing data, the p-values do not‬
‭Page‬‭47‬‭of‬‭77‬


‭8.1.1.2.‬
‭ORR‬‭VS‬‭R‬‭ENAL‬‭I‬‭MPAIRMENT‬
‭Table 3: Renal Impairment by Overall response rate‬
‭Creatinine clearance >30 µmol/L  and <60 µmol/L‬
‭No (N=)‬
‭Yes (N=)‬
‭Total (N=)‬
‭p-value
‭Overall Response Rate (confirmed)‬
‭N‬
‭No‬
‭Yes (CR/PR)‬
‭(1) Fisher's exact test‬
‭(*) The percentages take into account missing data, the p-values do not‬
‭Table 4: Renal Impairment by Overall response rate without UK/NE‬
‭Creatinine clearance >30 µmol/L  and <60 µmol/L‬
‭No (N=)‬
‭Yes (N=)‬
‭Total (N=)‬
‭p-value
‭Overall Response Rate (confirmed)‬
‭N‬
‭Yes (CR/PR)‬
‭No‬
‭(1) Fisher's exact test‬
‭(*) The percentages take into account missing data, the p-values do not‬
‭Page‬‭48‬‭of‬‭77‬


‭8.1.1.3.‬
‭ORR‬‭VS‬‭ECOG 2‬
‭Table 5: ECOG 2 by Overall response rate‬
‭ECOG 2‬
‭No (N=)‬
‭Yes (N=)‬
‭Total (N=)‬
‭p-value
‭Overall Response Rate (confirmed)‬
‭N‬
‭51‬
‭15‬
‭66‬
‭No‬
‭26 (51.0%)‬
‭8 (53.3%)‬
‭34 (51.5%)‬
‭Yes (CR/PR)‬
‭25 (49.0%)‬
‭7 (46.7%)‬
‭32 (48.5%)‬
‭(1) Fisher's exact test‬
‭(*) The percentages take into account missing data, the p-values do not‬
‭Table 6: ECOG 2 by Overall response rate without UK/NE‬
‭ECOG 2‬
‭No (N=)‬
‭Yes (N=)‬
‭Total (N=)‬
‭p-value
‭Overall Response Rate (confirmed)‬
‭N‬
‭Yes (CR/PR)‬
‭No‬
‭(1) Fisher's exact test‬
‭(*) The percentages take into account missing data, the p-values do not‬
‭Page‬‭49‬‭of‬‭77‬


‭8.1.1.4.‬
‭ORR‬‭VS‬‭HEMOGLOBIN‬
‭Table 7: HEMOGLOBIN by Overall response rate‬
‭Hemoglobin (g/dL)‬
‭<10 (N=)‬
‭>=10 (N=)‬
‭Total (N=)‬
‭p-value
‭Overall Response Rate (confirmed)‬
‭N‬
‭No‬
‭Yes (CR/PR)‬
‭(1) Fisher's exact test‬
‭(*) The percentages take into account missing data, the p-values do not‬
‭Table 8: HEMOGLOBIN by Overall response rate without UK/NE‬
‭Hemoglobin (g/dL)‬
‭<10 (N=)‬
‭>=10 (N=)‬
‭Total (N=)‬
‭p-value
‭Overall Response Rate (confirmed)‬
‭N‬
‭Yes (CR/PR)‬
‭No‬
‭(1) Fisher's exact test‬
‭(*) The percentages take into account missing data, the p-values do not‬
‭Page‬‭50‬‭of‬‭77‬


‭8.1.1.5.‬
‭ORR‬‭VS‬‭LIVER METASTASIS‬
‭Table 9: LIVER METASTASIS by Overall response rate‬
‭Liver metastasis at baseline‬
‭No (N=)‬
‭Yes (N=)‬
‭Total (N=)‬
‭p-value
‭Overall Response Rate (confirmed)‬
‭N‬
‭No‬
‭Yes (CR/PR)‬
‭(1) Fisher's exact test‬
‭(*) The percentages take into account missing data, the p-values do not‬
‭Table 10: LIVER METASTASIS by Overall response rate without UK/NE‬
‭Liver metastasis at baseline‬
‭No (N=)‬
‭Yes (N=)‬
‭Total (N=)‬
‭p-value
‭Overall Response Rate (confirmed)‬
‭N‬
‭Yes (CR/PR)‬
‭No‬
‭(1) Fisher's exact test‬
‭(*) The percentages take into account missing data, the p-values do not‬
‭Page‬‭51‬‭of‬‭77‬


‭8.2.‬ ‭S‬‭ECONDARY‬‭OBJECTIVES‬
‭8.2.1.‬‭T‬‭IME‬‭TO‬‭RESPONSE‬
‭To‬ ‭evaluate‬ ‭the‬ ‭time‬ ‭to‬ ‭response‬ ‭(TtR)‬ ‭associated‬ ‭with‬ ‭the‬ ‭study‬ ‭treatment,‬
‭understood‬‭as‬‭the‬‭time‬‭from‬‭the‬‭first‬‭dose‬‭of‬‭the‬‭study‬‭treatment‬‭to‬‭the‬‭confirmed‬
‭response (CR or PR) based on RECIST 1.1 criteria.‬
‭Time‬‭to‬‭response‬‭(TtR)‬‭:‬‭Time‬‭from‬‭first‬‭dosing‬‭date‬‭to‬‭the‬‭date‬‭of‬‭the‬‭documented‬
‭ORR as determined using RECIST 1.1 criteria.‬
‭Table 55: Time to response‬
‭Overall‬
‭Overall (N=)‬
‭Time to response‬
‭(months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭8.2.2.‬‭D‬‭URATION‬‭OF‬‭RESPONSE‬
‭Duration‬‭of‬‭response‬‭(DoR)‬‭:‬‭Time‬‭from‬‭first‬‭confirmed‬‭response‬‭(CR‬‭or‬‭PR)‬‭to‬
‭the‬‭date‬‭of‬‭the‬‭documented‬‭PD‬‭as‬‭determined‬‭using‬‭RECIST‬‭1.1‬‭criteria‬‭or‬‭death‬
‭due to any cause, whichever occurs first.‬
‭Table 56: Duration of response‬
‭Overall‬
‭Overall (N=)‬
‭Duration of response‬
‭(months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Table 57: Duration of response of responders (Best Overall Response CR or PR)‬
‭Best Overall Response (Recist 1.1)‬
‭CR (N=)‬
‭PR (N=)‬
‭Total (N=)‬
‭Duration of response (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Page‬‭52‬‭of‬‭77‬


‭Table 11: Patients with duration of response greater than 24 months‬
‭Patient‬
‭number‬
‭Hospital‬
‭Duration of response‬
‭(months)‬
‭Best Overall Response‬
‭(Recist 1.1)‬
‭Figure 5: Spider plot‬
‭Page‬‭53‬‭of‬‭77‬


‭8.2.3.‬‭C‬‭LINICAL‬‭BENEFIT‬‭RATE‬
‭To‬‭evaluate‬‭the‬‭clinical‬‭benefit‬‭rate‬‭(CBR),‬‭defined‬‭as‬‭the‬‭percentage‬‭of‬‭patients‬
‭who‬ ‭have‬ ‭achieved‬ ‭complete‬ ‭response,‬ ‭partial‬ ‭response‬ ‭and‬ ‭stable‬ ‭disease.‬
‭Stable‬ ‭disease‬ ‭should‬ ‭be‬ ‭maintained‬ ‭for‬ ‭at‬ ‭least‬ ‭6‬‭months‬‭to‬‭be‬‭considered‬‭as‬
‭CBR‬‭event,‬‭from‬‭baseline‬‭(treatment‬‭start)‬‭to‬‭last‬‭tumor‬‭assessment‬‭with‬‭SD‬‭(or‬
‭PR/CR in patients with non-confirmed response).‬
‭Table 58: Clinical benefit rate‬
‭ClinicalBenefitRate‬
‭N‬
‭%‬
‭95%CI‬
‭No‬
‭Yes (CR/PR/Manteined SD)‬
‭Total‬
‭8.2.4.‬‭F‬‭OLLOW‬‭-‬‭UP‬‭TIME‬
‭Table 59: Follow-up time in months (since study inclusion until death or last FU)‬
‭Overall‬
‭Overall (N=)‬
‭Follow-up time‬
‭(months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Page‬‭54‬‭of‬‭77‬


‭8.2.5.‬‭PFS‬
‭Progression-free‬ ‭Survival‬ ‭(PFS):‬ ‭Median‬ ‭Progression‬ ‭free‬ ‭survival‬ ‭(mPFS)‬ ‭is‬
‭defined‬‭as‬‭the‬‭time‬‭from‬‭the‬‭date‬‭of‬‭inclusion‬‭to‬‭the‬‭date‬‭of‬‭the‬‭first‬‭documented‬
‭disease‬‭progression‬‭or‬‭death‬‭due‬‭to‬‭any‬‭cause,‬‭whichever‬‭occurs‬‭first.‬‭PFS‬‭will‬‭be‬
‭determined‬‭based‬‭on‬‭tumour‬‭assessment‬‭(RECIST‬‭version‬‭1.1‬‭criteria).‬‭The‬‭local‬
‭Investigator’s‬‭assessments‬‭will‬‭be‬‭used‬‭for‬‭analyses.‬‭Patients‬‭who‬‭are‬‭alive‬‭and‬
‭have‬‭not‬‭progressed‬‭at‬‭the‬‭last‬‭follow-up‬‭will‬‭be‬‭censored‬‭at‬‭the‬‭date‬‭of‬‭the‬‭last‬
‭available‬‭image‬‭determination‬‭(CT‬‭scan‬‭or‬‭MRI).‬‭Patients‬‭with‬‭no‬‭additional‬‭image‬
‭test‬‭other‬‭than‬‭that‬‭at‬‭baseline‬‭will‬‭be‬‭censored‬‭to‬‭the‬‭day‬‭after‬‭inclusion.‬‭Patients‬
‭initiating‬‭new‬‭anticancer‬‭therapy‬‭(without‬‭progression‬‭to‬‭the‬‭study‬‭treatment)‬‭will‬
‭be censored to the date of new anticancer therapy initiation.‬
‭Table 60: Progression information‬
‭Progression‬
‭N‬
‭%‬
‭95%CI‬
‭No‬
‭Yes‬
‭Total‬
‭Table 61: Progression status‬
‭Overall‬
‭Overall (N=)‬
‭PFS status‬
‭   Alive without‬
‭progression‬
‭   Death‬
‭   Progression‬
‭Page‬‭55‬‭of‬‭77‬


‭Figure 6: PFS‬
‭Table 62: Median/mean PFS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭RMST‬
‭CI 95%‬
‭Progression Free Survival‬
‭Table 63: PFS estimated survival ratio‬
‭Progression Free‬
‭Survival‬
‭Events (%, total N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭Page‬‭56‬‭of‬‭77‬


‭8.2.5.1.‬
‭PFS‬‭VS‬‭A‬‭GE‬‭>70‬
‭Figure 7: PFS vs Age>70‬
‭Table 64: Median/mean PFS (estimated by Kaplan-Meier) vs Age>70‬
‭Median (months)‬
‭CI 95%‬
‭RMST‬
‭CI 95%‬
‭Yes‬
‭No‬
‭Table 65: PFS estimated survival ratio vs Age>70‬
‭PFS‬
‭Events (%, total N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭Yes‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭No‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭Page‬‭57‬‭of‬‭77‬


‭8.2.5.2.‬
‭PFS‬‭VS‬‭R‬‭ENAL‬‭I‬‭MPAIRMENT‬
‭Figure 8: PFS vs Renal Impairment‬
‭Table 66: Median/mean PFS (estimated by Kaplan-Meier) vs Renal Impairment‬
‭Median (months)‬
‭CI 95%‬
‭RMST‬
‭CI 95%‬
‭Yes‬
‭No‬
‭Table 67: PFS estimated survival ratio vs Renal Impairment‬
‭PFS‬
‭Events (%, total N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭Yes‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭No‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭Page‬‭58‬‭of‬‭77‬


‭8.2.5.3.‬
‭PFS‬‭VS‬‭ECOG 2‬
‭Figure 9: PFS vs ECOG 2‬
‭Table 68: Median/mean PFS (estimated by Kaplan-Meier) vs ECOG 2‬
‭Median (months)‬
‭CI 95%‬
‭RMST‬
‭CI 95%‬
‭Yes‬
‭No‬
‭Table 69: PFS estimated survival ratio vs ECOG 2‬
‭PFS‬
‭Events (%, total N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭Yes‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭No‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭Page‬‭59‬‭of‬‭77‬


‭8.2.5.4.‬
‭PFS‬‭VS‬‭HEMOGLOBIN‬
‭Figure 10: PFS vs HEMOGLOBIN‬
‭Table 70: Median/mean PFS (estimated by Kaplan-Meier) vs HEMOGLOBIN‬
‭Median (months)‬
‭CI 95%‬
‭RMST‬
‭CI 95%‬
‭<10‬
‭>=10‬
‭Table 71: PFS estimated survival ratio vs HEMOGLOBIN‬
‭PFS‬
‭Events (%, total N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭<10‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭>=10‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭Page‬‭60‬‭of‬‭77‬


‭8.2.5.5.‬
‭PFS‬‭VS‬‭LIVER METASTASIS‬
‭Figure 11: PFS vs LIVER METASTASIS‬
‭Table 72: Median/mean PFS (estimated by Kaplan-Meier) vs LIVER METASTASIS‬
‭Median (months)‬
‭CI 95%‬
‭RMST‬
‭CI 95%‬
‭No‬
‭Yes‬
‭Table 73: PFS estimated survival ratio vs LIVER METASTASIS‬
‭PFS‬
‭Events (%, total N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭No‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭Yes‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭Page‬‭61‬‭of‬‭77‬


‭8.2.6.‬‭OS‬
‭To‬ ‭determine‬ ‭the‬ ‭overall‬ ‭survival‬ ‭(OS)‬‭of‬‭patients‬‭with‬‭locally-advanced‬‭or‬‭mUC‬
‭treated‬ ‭with‬ ‭the‬ ‭intended‬ ‭treatment‬ ‭regimen,‬ ‭understood‬ ‭as‬ ‭the‬ ‭time‬ ‭from‬ ‭first‬
‭dosing‬‭date‬‭to‬‭the‬‭date‬‭of‬‭death.‬‭A‬‭subject‬‭who‬‭has‬‭not‬‭died‬‭will‬‭be‬‭censored‬‭at‬‭the‬
‭last known date alive.‬
‭Table 74: Current situation information‬
‭Status‬
‭N‬
‭%‬
‭95%CI‬
‭Alive‬
‭Death‬
‭Total‬
‭Table 75: Death reason‬
‭Overall‬
‭Overall (N=)‬
‭Exitus Reason‬
‭   NA‬
‭   Progression disease‬
‭   Toxicity due to study treatment‬
‭   Other‬
‭Exitus Reason Specify‬
‭Page‬‭62‬‭of‬‭77‬


‭Figure 12: OS‬
‭Table 76: Median/mean OS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭RMST‬
‭CI 95%‬
‭Overall Survival‬
‭Table 77: OS estimated survival ratio‬
‭Overall‬
‭Survival‬
‭Events (%, total N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭At 24 months‬
‭Page‬‭63‬‭of‬‭77‬


‭8.2.6.1.‬
‭OS‬‭VS‬‭A‬‭GE‬‭>70‬
‭Figure 13: OS vs Age>70‬
‭Table 78: Median/mean OS (estimated by Kaplan-Meier) vs Age>70‬
‭Median (months)‬
‭CI 95%‬
‭RMST‬
‭CI 95%‬
‭Yes‬
‭No‬
‭Table 79: OS estimated survival ratio vs Age>70‬
‭OS‬
‭Events (%, total N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭Yes‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭No‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭8.2.6.2.‬
‭OS‬‭VS‬‭R‬‭ENAL‬‭I‬‭MPAIRMENT‬
‭Figure 14: OS vs Renal Impairment‬
‭Table 80: Median/mean OS (estimated by Kaplan-Meier) vs Renal Impairment‬
‭Median (months)‬
‭CI 95%‬
‭RMST‬
‭CI 95%‬
‭Yes‬
‭No‬
‭Table 81: OS estimated survival ratio vs Renal Impairment‬
‭OS‬
‭Events (%, total N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭Yes‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭Page‬‭64‬‭of‬‭77‬


‭OS‬
‭Events (%, total N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭No‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭Page‬‭65‬‭of‬‭77‬


‭8.2.6.3.‬
‭OS‬‭VS‬‭ECOG 2‬
‭Figure 15: OS vs ECOG 2‬
‭Table 82: Median/mean OS (estimated by Kaplan-Meier) vs ECOG 2‬
‭Median (months)‬
‭CI 95%‬
‭RMST‬
‭CI 95%‬
‭Yes‬
‭No‬
‭Table 83: OS estimated survival ratio vs ECOG 2‬
‭OS‬
‭Events (%, total N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭Yes‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭No‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭Page‬‭66‬‭of‬‭77‬


‭8.2.6.4.‬
‭OS‬‭VS‬‭HEMOGLOBIN‬
‭Figure 16: OS vs HEMOGLOBIN‬
‭Table 84: Median/mean OS (estimated by Kaplan-Meier) vs HEMOGLOBIN‬
‭Median (months)‬
‭CI 95%‬
‭RMST‬
‭CI 95%‬
‭<10‬
‭>=10‬
‭Table 85: OS estimated survival ratio vs HEMOGLOBIN‬
‭OS‬
‭Events (%, total N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭<10‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭>=10‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭Page‬‭67‬‭of‬‭77‬


‭8.2.6.5.‬
‭OS‬‭VS‬‭LIVER METASTASIS‬
‭Figure 17: OS vs LIVER METASTASIS‬
‭Table 86: Median/mean OS (estimated by Kaplan-Meier) vs LIVER METASTASIS‬
‭Median (months)‬
‭CI 95%‬
‭RMST‬
‭CI 95%‬
‭No‬
‭Yes‬
‭Table 87: OS estimated survival ratio vs LIVER METASTASIS‬
‭OS‬
‭Events (%, total N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭No‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭Yes‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12 months‬
‭Page‬‭68‬‭of‬‭77‬


‭9.‬‭S‬‭AFETY‬‭ANALYSIS‬
‭The‬‭following‬‭analyses‬‭in‬‭this‬‭section‬‭are‬‭carried‬‭out‬‭in‬‭the‬‭safety‬‭population‬‭(N‬‭=‬
‭XX patients).‬
‭In‬ ‭the‬ ‭following‬ ‭tables,‬ ‭the‬‭adverse‬‭event‬‭which‬‭are‬‭not‬‭completely‬‭ruled‬‭out‬‭as‬
‭toxicities or serious are considered toxicities and SAEs respectively.‬
‭Table 12: Overall safety‬
‭Overall‬
‭Overall (N=)‬
‭Adverse Events‬
‭   No‬
‭   Yes‬
‭AE Grade >=3‬
‭   No‬
‭   Yes‬
‭Toxicity: AE related to Atezolizumab‬
‭   No‬
‭   Yes‬
‭Toxicity: AE related to Cisplatin‬
‭   No‬
‭   Yes‬
‭Toxicity: AE related to Gemcitabine‬
‭   No‬
‭   Yes‬
‭Toxicity: AE related to all treatments‬
‭   No‬
‭   Yes‬
‭Toxicity: AE related to any treatment‬
‭   No‬
‭   Yes‬
‭Toxicity grade >=3‬
‭   No‬
‭   Yes‬
‭Toxicity related to Atezolizumab grade‬
‭>=3‬
‭   No‬
‭   Yes‬
‭Toxicity related to Cisplatin grade >=3‬
‭   No‬
‭   Yes‬
‭Toxicity related to Gemcitabine grade‬
‭>=3‬
‭   No‬
‭   Yes‬
‭Toxicity related to all treatments grade‬
‭>=3‬
‭   No‬
‭   Yes‬
‭SAE‬
‭   No‬
‭Page‬‭69‬‭of‬‭77‬


‭Overall‬
‭Overall (N=)‬
‭   Yes‬
‭Table 13: Toxicities with 5% threshold‬
‭Toxicity‬
‭Frequency‬
‭Percentage (%)‬
‭Table 14: Grade of toxicities with 5% threshold overall‬
‭Toxicity‬
‭No‬
‭G-UK‬
‭G-1‬
‭G-2‬
‭G-3‬
‭G-4‬
‭G-5‬
‭Page‬‭70‬‭of‬‭77‬


‭Table 15: List of toxicities grade ≥ 3 in all patients‬
‭Patient‬
‭Number‬
‭AE CTCAE‬
‭AE‬
‭Grade‬
‭AE‬
‭Related‬
‭AE Related to‬
‭Page‬‭71‬‭of‬‭77‬


‭Table 16: AEs with 5% threshold‬
‭AE‬
‭Frequency‬
‭Percentage (%)‬
‭Page‬‭72‬‭of‬‭77‬


‭Table 17: Grade of AEs with 5% threshold overall‬
‭AE‬
‭No‬
‭G-UK‬
‭G-1‬
‭G-2‬
‭G-3‬
‭G-4‬
‭G-5‬
‭Page‬‭73‬‭of‬‭77‬


‭Table 18: List of all SAEs‬
‭Patient‬
‭Number‬
‭AE CTCAE‬
‭AE CTCAE‬
‭Other‬
‭AE‬
‭Grade‬
‭AE Start‬
‭Date‬
‭AE Stop‬
‭Date‬
‭AE‬
‭Related‬
‭AE Related‬
‭to‬
‭AE‬
‭SAE‬
‭AE‬
‭Intensity‬
‭9.1.‬ ‭A‬‭NNEX‬‭1‬
‭Table 19: List of all toxicities‬
‭Patient‬
‭Number‬
‭AE CTCAE‬
‭AE CTCAE‬
‭Other‬
‭AE‬
‭Grade‬
‭AE Start‬
‭Date‬
‭AE Stop‬
‭Date‬
‭AE‬
‭Related‬
‭AE Related‬
‭to‬
‭AE‬
‭SAE‬‭AE Intensity‬
‭Page‬‭74‬‭of‬‭77‬


‭Figure 18: Global Toxicities with a frequency greater than 5%‬
‭Page‬‭75‬‭of‬‭77‬


‭Figure 19: Global irAEs with a frequency as toxicity greater than 5%‬
‭Page‬‭76‬‭of‬‭77‬


‭Figure 20: Summary of adverse events.‬
‭All‬‭AEs‬‭have‬‭been‬‭grouped‬‭into‬‭blocks‬‭when‬‭the‬‭start‬‭date‬‭is‬‭consecutive‬‭to‬‭the‬
‭end‬ ‭of‬ ‭the‬ ‭same‬ ‭previous‬ ‭AE‬ ‭(no‬ ‭more‬ ‭than‬ ‭1‬ ‭day‬ ‭has‬ ‭passed)‬ ‭for‬ ‭the‬ ‭same‬
‭patient.‬‭The‬‭highest‬‭severity‬‭within‬‭the‬‭block‬‭is‬‭the‬‭one‬‭that‬‭remains.‬‭Additionally,‬‭if‬
‭one‬‭of‬‭the‬‭events‬‭was‬‭related‬‭to‬‭the‬‭medication,‬‭that‬‭relationship‬‭is‬‭maintained‬‭for‬
‭the entire block.‬
‭Events‬
‭SAE (N pts)‬
‭No SAE (= Total‬
‭AEs - SAEs)‬
‭N pts‬
‭SAE‬
‭N‬
‭eventos‬
‭SAE‬
‭N‬
‭eventos‬
‭muerte‬
‭N SAE‬
‭Rlt‬
‭N pts‬
‭N‬
‭eventos‬
‭A threshold of 5% was set for No SAEs.‬
‭Page‬‭77‬‭of‬‭77‬