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
Phase: PHASE2
Conditions: Locally Advanced or Metastatic Urothelial Carcinoma
Sponsor: Spanish Oncology Genito-Urinary Group

‭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
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‭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
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‭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
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‭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
‭AUREA -  SOGUG-2020-IEC(VEJ)-1 - Protocol version 3.0 22AUG2023‬
‭Page‬‭9‬‭of‬‭315‬

‭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.‬
‭AUREA -  SOGUG-2020-IEC(VEJ)-1 - Protocol version 3.0 22AUG2023‬
‭Page‬‭80‬‭of‬‭315‬

‭13.3.‬ ‭Fecal‬‭samples‬
‭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 3.0 22AUG2023‬
‭Page‬‭81‬‭of‬‭315‬

‭14.‬
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‭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.‬
‭AUREA -  SOGUG-2020-IEC(VEJ)-1 - Protocol version 2.0 08MAR2022‬
‭Page‬‭109‬‭of‬‭315‬

‭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 2.0 08MAR2022‬
‭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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‭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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‭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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‭Page‬‭114‬‭of‬‭315‬

‭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.‬
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‭14.‬
‭REFERENCES‬
‭Adashek‬ ‭ML,‬ ‭Feldman‬ ‭M.‬ ‭Cytokine‬ ‭release‬ ‭syndrome‬ ‭resulting‬ ‭from‬ ‭anti‬ ‭programmed‬
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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.‬
‭AUREA -  SOGUG-2020-IEC(VEJ)-1 - Protocol version 1.1 6.NOV.2020‬
‭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)‬
‭AUREA -  SOGUG-2020-IEC(VEJ)-1 - Protocol version 1.1 6.NOV.2020‬
‭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:‬‭__________________________________‬
‭AUREA -  SOGUG-2020-IEC(VEJ)-1 - Protocol version 1.1 6.NOV.2020‬
‭Page‬‭215‬‭of‬‭315‬

‭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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‭Page‬‭264‬‭of‬‭315‬

‭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
‭AUREA -  SOGUG-2020-IEC(VEJ)-1 - Protocol version 1.1 6.NOV.2020‬
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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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‭Accelerated‬ ‭methotrexate,‬ ‭vinblastine,‬ ‭doxorubicin,‬ ‭and‬ ‭cisplatin‬ ‭is‬ ‭safe,‬ ‭effective,‬ ‭and‬
‭efficient‬‭neoadjuvant‬‭treatment‬‭for‬‭muscle-invasive‬‭bladder‬‭cancer:‬‭results‬‭of‬‭a‬‭multicenter‬
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‭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 ‭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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‭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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‭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
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