Conditions: Neuroendocrine Tumors Neuroendocrine Neoplasm Gastroenteropancreatic Neuroendocrine Tumor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 37
Healthy volunteers: no

Brief summary:
This is a prospective, multi-centre, open label, non-randomized phase II study evaluating the efficacy and safety of nivolumab plus platinum-based chemotherapy in patients with advanced G3 NENs of the GEP tract or of UK origin.

Detailed description:

Arms:
arm 1: 1. Induction Phase: Nivolumab 360 mg IV plus Carboplatin IV (AUC=5) plus Etoposide 10mg/m2/day on days 1-3D, all every 3 weeks up to 6 cycles followed by Nivolumab 480mg for 24 months or until progression of the disease (PD), death or toxicity.

   Order of administration: Nivolumab, Carboplatin, Etoposide
2. Maintenance Phase Nivolumab 480 mg IV will be administered every 4 weeks (±3 days) for 2 years.

Interventions: intervention 1: Nivolumab intervention 2: Carboplatin intervention 3: Etoposide
Intervention descriptions: intervention 1: Subjects will receive Nivolumab 360 mg every 3 weeks (Q3W) first day of each cycle plus Carboplatin area under the curve (AUC5) Q3W first day of each cycle plus Etoposide 100 day 1-3 of each cycle up to 6 cycles of combined therapy (Induction Phase).

At the time of completion of 6 cycles of chemotherapy and nivolumab, participants who have not experienced disease progression will continue to receive nivolumab at a dose of 480 mg as 30 minute infusion every 4 weeks for up to 2 years (24 months) (maintenance phase).

Cycles are defined by 4 weeks or 28 days. intervention 2: Subjects will receive Nivolumab 360 mg every 3 weeks (Q3W) first day of each cycle plus Carboplatin AUC5 Q3W first day of each cycle plus Etoposide 100 day 1-3 of each cycle up to 6 cycles of combined therapy (Induction Phase).

At the time of completion of 6 cycles of chemotherapy and nivolumab, participants who have not experienced disease progression will continue to receive nivolumab at a dose of 480 mg as 30 minute infusion every 4 weeks for up to 2 years (24 months) (maintenance phase).

Cycles are defined by 4 weeks or 28 days. intervention 3: Subjects will receive Nivolumab 360 mg every 3 weeks (Q3W) first day of each cycle plus Carboplatin AUC5 Q3W first day of each cycle plus Etoposide 100 day 1-3 of each cycle up to 6 cycles of combined therapy (Induction Phase).

At the time of completion of 6 cycles of chemotherapy and nivolumab, participants who have not experienced disease progression will continue to receive nivolumab at a dose of 480 mg as 30 minute infusion every 4 weeks for up to 2 years (24 months) (maintenance phase).

Cycles are defined by 4 weeks or 28 days.

Protocol document:
Prot_000.pdf: 
‭A phase II study of Platinum-doublet‬
‭chemotherapy in combination with nivolumab as‬
‭first-line treatment, in subjects with unresectable,‬
‭locally advanced or metastatic G3 Neuroendocrine‬
‭Neoplasms (NENs) of the gastroenteropancreatic‬
‭(GEP) tract or of unknown (UK) origin.‬
‭Protocol identification number / code / Registration n°:  CA209-73D‬
‭Sponsor code:‬‭GETNE-T1913‬
‭EudraCT number:‬ ‭2019-001546-18‬
‭Acronym:‬‭NICE-NEC‬
‭Study Coordinator or Chair:‬
‭Rocío García-Carbonero, MD, PhD‬
‭Maria del Carmen Riesco-Martínez, MD, PhD‬
‭Phone: +34-913908003/+34 913908926‬
‭e-mail: rgcarbonero@gmail.com/ m.carmen.riesco@gmail.com‬
‭(date)‬
‭Protocol approval‬
‭(date)‬
‭Amendment x‬
‭Version: (3.1) / 17 June, 2019‬
‭Study Protocol CA209- 73D (GETNE-T1913) v3.1 17 June 2019‬
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‭SYNOPSIS‬
‭Clinical Protocol‬‭CA209- 73D‬
‭Sponsor code:‬‭GETNE-T1913‬
‭EudraCT number:‬ ‭2019-001546-18‬
‭Protocol‬‭Title:‬‭A‬‭phase‬‭II‬‭study‬‭of‬‭platinum-doublet‬‭chemotherapy‬‭in‬‭combination‬‭with‬‭nivolumab‬‭as‬
‭first-line‬‭treatment‬‭in‬‭subjects‬‭with‬‭unresectable,‬‭locally‬‭advanced‬‭or‬‭metastatic‬‭G3‬‭neuroendocrine‬
‭neoplasms (NENs) of the gastroenteropancreatic (GEP) tract or of unknown (UK) origin.‬
‭Sponsor:‬‭Grupo Español de Tumores Neuroendocrinos‬‭y Endocrinos (GETNE)‬
‭Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with‬
‭Investigational Product(s):‬
‭INDUCTION PHASE‬
‭●‬ ‭Nivolumab 360 mg IV will be administered every 3 weeks (±3 days)‬
‭●‬ ‭Carboplatin‬ ‭(AUC=5)‬ ‭IV‬ ‭will‬ ‭be‬ ‭administered‬ ‭every‬ ‭3‬ ‭weeks‬ ‭(±3‬ ‭days)‬ ‭following‬ ‭the‬
‭administration of nivolumab.‬
‭●‬ ‭Etoposide‬‭100‬‭mg/m‬‭2‬‭/day‬‭IV‬‭will‬‭be‬‭administered‬‭on‬‭D1-3‬‭every‬‭3‬‭weeks‬‭(±3‬‭days)‬‭following‬
‭the administration of carboplatin.‬
‭MAINTENANCE PHASE‬
‭●‬ ‭Nivolumab 480 mg IV will be administered every 4 weeks (±3 days) for 2 years‬
‭Study Phase:‬‭Non-randomized phase II‬
‭Study Population:‬
‭●‬ ‭Patients with histologically confirmed non-resectable or stage IV G3 (Ki-67>20%)‬
‭neuroendocrine neoplasms of the GEP tract or of UK origin.‬
‭●‬
‭No prior systemic therapy.‬
‭●‬ ‭Available tumor sample for translational research.‬
‭Research Hypothesis:‬
‭●‬ ‭The‬‭addition‬‭of‬‭Nivolumab‬‭to‬‭platinum-based‬‭chemotherapy‬‭doublet‬‭will‬‭induce‬‭deeper‬‭and‬
‭more‬‭durable‬‭tumor‬‭responses‬‭and‬‭prolong‬‭overall‬‭survival‬‭(OS)‬‭of‬‭patients‬‭with‬‭advanced‬
‭G3‬‭NENs‬‭of‬‭gastroenteropancreatic‬‭(GEP)‬‭or‬‭unknown‬‭(UK)‬‭origin,‬‭as‬‭compared‬‭to‬‭historical‬
‭cohorts of patients treated with standard chemotherapy alone.‬
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‭Objectives:‬
‭Objectives‬
‭Endpoints‬
‭Primary‬
‭●‬ ‭To‬ ‭determine‬ ‭the‬ ‭overall‬ ‭survival‬
‭patients‬ ‭with‬ ‭advanced‬ ‭G3‬ ‭NENs‬
‭treated‬
‭with‬
‭nivolumab‬
‭+‬
‭platinum-based chemotherapy.‬
‭●‬
‭1 year-OS rate‬
‭Secondary‬
‭●‬ ‭To‬ ‭determine‬ ‭other‬ ‭efficacy‬ ‭outcomes‬
‭of‬
‭nivolumab‬
‭+‬
‭platinum-based‬
‭chemotherapy‬
‭in‬
‭patients‬
‭with‬
‭advanced G3 NENs.‬
‭●‬
‭ORR‬
‭●‬
‭Duration of response‬
‭●‬
‭PFS‬
‭●‬
‭OS‬
‭●‬ ‭To‬ ‭evaluate‬ ‭the‬ ‭safety‬ ‭and‬ ‭tolerability‬
‭of‬
‭nivolumab‬
‭+‬
‭platinum-based‬
‭chemotherapy‬
‭in‬
‭this‬
‭patient‬
‭population.‬
‭●‬ ‭Incidence‬ ‭of‬ ‭AEs,‬ ‭SAEs‬ ‭and‬ ‭selected‬
‭AEs‬
‭●‬ ‭To‬ ‭evaluate‬ ‭biochemical‬ ‭response‬ ‭as‬
‭predictive‬ ‭biomarker‬ ‭of‬ ‭efficacy‬ ‭of‬
‭nivolumab‬ ‭+‬ ‭chemotherapy‬ ‭in‬ ‭this‬
‭patient population.‬
‭●‬ ‭Chromogranin‬‭A‬‭and‬‭enolase‬‭values‬‭and‬
‭their‬ ‭association‬ ‭with‬ ‭ORR,‬ ‭PFS‬ ‭and‬
‭OS.‬
‭●‬ ‭To‬ ‭explore‬ ‭potential‬ ‭predictive‬ ‭and‬
‭prognostic biomarkers.‬
‭●‬ ‭Mutational‬ ‭burden,‬ ‭gene‬ ‭expression‬
‭signature,‬ ‭soluble‬ ‭factors‬ ‭and‬ ‭other‬
‭molecular‬ ‭markers‬ ‭in‬ ‭peripheral‬ ‭blood‬
‭and‬ ‭their‬ ‭association‬ ‭with‬ ‭clinical‬
‭outcomes.‬
‭Study Design:‬
‭Protocol‬‭CA209-‬‭73D‬‭is‬‭a‬‭non-randomized,‬‭open-label,‬‭phase‬‭2‬‭trial‬‭that‬‭will‬‭enroll‬‭38‬‭≥‬‭18‬‭years‬‭old‬
‭with‬‭untreated‬‭metastatic‬‭or‬‭unresectable‬‭G3‬‭NENs‬‭of‬‭gastroenteropancreatic‬‭or‬‭UK‬‭origin,‬‭evaluating‬
‭the‬ ‭efficacy‬ ‭of‬ ‭nivolumab‬ ‭combined‬ ‭with‬ ‭platinum-based‬ ‭doublet‬ ‭chemotherapy‬ ‭as‬ ‭first-line‬
‭treatment,‬‭followed‬‭by‬‭maintenance‬‭treatment‬‭with‬‭nivolumab‬‭in‬‭patients‬‭who‬‭have‬‭not‬‭progressed‬
‭after 6 months of first line platinum-based induction chemotherapy.‬
‭Tumor‬‭progression‬‭and‬‭response‬‭endpoints‬‭will‬‭be‬‭assessed‬‭using‬‭RECIST‬‭1.1‬‭criteria.‬‭If‬‭there‬‭is‬‭no‬
‭evidence‬ ‭of‬ ‭disease‬ ‭progression‬ ‭after‬‭the‬‭induction‬‭phase,‬‭treatment‬‭with‬‭nivolumab‬‭will‬‭continue‬
‭until‬ ‭RECIST‬ ‭1.1‬ ‭defined‬ ‭progression‬ ‭or‬ ‭death,‬ ‭unacceptable‬ ‭toxicity,‬ ‭24‬ ‭months‬‭of‬‭treatment‬‭or‬
‭withdrawal of consent.‬
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‭Dose‬ ‭reductions‬ ‭will‬‭not‬‭be‬‭allowed‬‭for‬‭nivolumab.‬‭Treatment‬‭beyond‬‭initial‬‭investigator-assessed‬
‭progression‬ ‭(either‬ ‭clinical‬ ‭or‬ ‭radiological)‬ ‭is‬ ‭permitted‬ ‭for‬ ‭nivolumab‬ ‭if‬ ‭the‬ ‭subject‬ ‭has‬ ‭an‬
‭investigator-assessed clinical benefit and is tolerating well study drug.‬
‭The‬‭study‬‭period‬‭will‬‭include‬‭18‬‭months‬‭of‬‭accrual‬‭plus‬‭12‬‭months‬‭of‬‭follow-up.‬‭The‬‭study‬‭will‬‭end‬
‭once survival follow-up has concluded.‬
‭Study Treatment‬
‭Medication‬
‭Potency‬
‭IP/Non-IP‬
‭Nivolumab‬
‭100 mg/vial‬
‭IP‬
‭Carboplatin‬
‭450 mg/vial‬
‭IP‬
‭Etoposide‬
‭100 mg/vial‬
‭IP‬
‭Figure-1. Study Schema‬
‭Study Population:‬
‭For study entry all the following criteria MUST be met:‬
‭Key Inclusion Criteria (See Protocol Section 4.1 for full list of criteria)‬
‭●‬ ‭Histologically‬ ‭confirmed‬ ‭G3‬ ‭NENs‬ ‭originated‬ ‭in‬ ‭the‬ ‭gastroenteropancreatic‬ ‭tract‬ ‭(WHO‬
‭2015/2019‬‭classification).‬‭Patients‬‭with‬‭a‬‭G3‬‭NEN‬‭of‬‭unknown‬‭primary‬‭will‬‭also‬‭be‬‭eligible‬
‭for this trial.‬
‭●‬
‭Ki-67 >20% or mitotic rate > 20 per 10 HPF.‬
‭●‬ ‭Metastatic‬‭or‬‭locally‬‭advanced‬‭unresectable‬‭disease‬‭not‬‭amenable‬‭to‬‭treatment‬‭with‬‭curative‬
‭intent.‬
‭●‬ ‭No prior systemic treatment for advanced disease nor as adjuvant therapy permitted.‬
‭●‬ ‭Availability‬‭of‬‭fresh‬‭or‬‭archive‬‭formalin-fixed,‬‭paraffin-embedded‬‭tumor‬‭tissue‬‭for‬‭biomarker‬
‭assessment.‬
‭●‬ ‭Patients must have clinically and/or radiographically documented measurable disease.‬
‭●‬ ‭Adequate organ function as defined by the following criteria‬
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‭○‬ ‭Absolute neutrophil count (ANC) ≥1500 cells/mm3;‬
‭○‬ ‭Platelets ≥100,000 cells/mm3;‬
‭○‬ ‭Hemoglobin ≥9.0 g/dL;‬
‭○‬ ‭AST‬‭and‬‭ALT‬‭≤2.5‬‭x‬‭upper‬‭limit‬‭of‬‭normal‬‭(ULN);‬‭in‬‭patients‬‭with‬‭liver‬‭metastases‬
‭AST and ALT ≤5.0 x ULN;‬
‭○‬ ‭Total bilirubin ≤1.5 x ULN;‬
‭○‬ ‭Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min.‬
‭●‬ ‭ECOG performance status of 0-2.‬
‭Key Exclusion Criteria (See Protocol Section 4.2 for full list of criteria)‬
‭●‬ ‭The‬‭following‬‭endocrine‬‭tumor‬‭types‬‭may‬‭not‬‭be‬‭included:‬‭paraganglioma,‬‭adrenal,‬‭thyroid‬
‭parathyroid‬‭or‬‭pituitary‬‭endocrine‬‭tumors.‬‭Large‬‭or‬‭small‬‭cell‬‭lung‬‭neuroendocrine‬‭carcinoma‬
‭of the lung will also be excluded.‬
‭●‬ ‭Prior therapy with any immune checkpoint inhibitor.‬
‭●‬ ‭Prior organ transplantation, including allogeneic stem-cell transplantation.‬
‭●‬ ‭Systemic‬ ‭chronic‬ ‭steroid‬ ‭therapy‬ ‭(‬‭>‬ ‭10‬ ‭mg/day‬ ‭prednisone‬ ‭or‬ ‭equivalent)‬ ‭or‬ ‭other‬
‭immunosuppressive‬‭agents‬‭or‬‭use‬‭of‬‭any‬‭investigational‬‭drug‬‭within‬‭28‬‭days‬‭before‬‭the‬‭start‬
‭of trial treatment.‬
‭●‬ ‭Known‬ ‭history‬ ‭of‬ ‭positive‬ ‭testing‬ ‭for‬ ‭Human‬ ‭Immunodeficiency‬ ‭Virus‬ ‭(HIV)‬ ‭infection,‬
‭known‬‭history‬‭of‬‭positive‬‭tests‬‭for‬‭Hepatitis‬‭B‬‭virus‬‭surface‬‭antigen‬‭(HBVsAg)‬‭or‬‭Hepatitis‬‭C‬
‭ribonucleic‬‭acid‬‭(HCV‬‭RNA)‬‭indicating‬‭acute‬‭or‬‭chronic‬‭infection‬‭or‬‭other‬‭significant‬‭acute‬
‭or chronic infections requiring medication at study entry.‬
‭Study Assessments:‬
‭The‬ ‭primary‬ ‭objective‬ ‭is‬ ‭to‬ ‭determine‬ ‭one-year‬ ‭OS‬ ‭rate‬ ‭of‬ ‭nivolumab‬ ‭in‬ ‭combination‬ ‭with‬
‭platinum-doublet‬‭chemotherapy‬‭in‬‭treatment-naïve‬‭patients‬‭with‬‭unresectable‬‭G3‬‭NENs.‬‭This‬‭will‬‭be‬
‭calculated‬ ‭from‬ ‭the‬ ‭date‬ ‭of‬ ‭treatment‬‭initiation‬‭with‬‭platinum-based‬‭chemotherapy‬‭and‬‭nivolumab‬
‭until‬‭the‬‭date‬‭of‬‭death‬‭from‬‭any‬‭cause.‬‭Subjects‬‭will‬‭be‬‭assessed‬‭for‬‭response‬‭every‬‭8‬‭weeks‬‭(±‬‭7‬‭days)‬
‭after‬ ‭the‬ ‭date‬ ‭of‬ ‭administration‬ ‭of‬ ‭the‬ ‭first‬ ‭dose‬ ‭for‬ ‭12‬ ‭months‬ ‭and‬ ‭every‬ ‭12‬ ‭weeks‬ ‭(±‬ ‭7‬ ‭days)‬
‭thereafter‬‭until‬‭disease‬‭progression.‬‭Patients‬‭that‬‭stop‬‭therapy‬‭due‬‭to‬‭toxicity‬‭in‬‭the‬‭absence‬‭of‬‭disease‬
‭progression‬ ‭shall‬ ‭continue‬ ‭to‬ ‭be‬ ‭assessed‬ ‭with‬ ‭CT‬ ‭scans‬ ‭with‬ ‭the‬ ‭same‬ ‭frequency‬ ‭until‬ ‭disease‬
‭progression‬‭or‬‭initiation‬‭of‬‭a‬‭new‬‭line‬‭of‬‭therapy.‬‭Upon‬‭treatment‬‭discontinuation,‬‭subjects‬‭will‬‭be‬
‭followed‬‭for‬‭survival‬‭every‬‭3‬‭months‬‭(via‬‭telephone‬‭contact‬‭allowed)‬‭until‬‭death.‬‭All‬‭patients‬‭included‬
‭will be followed.‬
‭Statistical Considerations:‬
‭Sample Size‬
‭A‬‭sample‬‭size‬‭of‬‭38‬‭subjects‬‭will‬‭provide‬‭80%‬‭power‬‭to‬‭test‬‭the‬‭null‬‭hypothesis‬‭(H‬‭0‬‭)‬‭that‬‭one-year‬‭OS‬
‭rate‬ ‭for‬ ‭advanced‬ ‭G3‬ ‭NENs‬ ‭treated‬ ‭with‬ ‭nivolumab‬ ‭in‬ ‭combination‬ ‭with‬ ‭platinum-doublet‬
‭chemotherapy‬‭is‬‭0.5‬‭against‬‭a‬‭two-sided‬‭alternative.‬‭This‬‭design‬‭yields‬‭a‬‭two-sided‬‭type‬‭I‬‭error‬‭rate‬‭of‬
‭5% when the true one-year OS rate is 0.72.‬
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‭Study Calendar:‬
‭-‬
‭Study start (estimated)‬
‭3Q 2019‬
‭-‬
‭First patient First visit (estimated)‬
‭4Q 2019‬
‭-‬
‭End or recruitment (estimated)‬
‭2Q 2021‬
‭-‬
‭Last patient Last visit (estimated)‬
‭2Q 2022‬
‭-‬
‭End of study (estimation)‬
‭4Q 2022‬
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‭Table of contents‬
‭1. Background and introduction‬
‭12‬
‭1.1. Background Disease Information‬
‭12‬
‭1.2.         Background Therapeutic Information‬
‭13‬
‭1.2.1.  Nivolumab: mechanism of action‬
‭13‬
‭1.2.2. Preclinical experience with Nivolumab‬
‭13‬
‭1.2.3. Clinical experience with Nivolumab in SCLC‬
‭13‬
‭1.2.4. Immune checkpoint inhibitors in other high grade NENs‬
‭15‬
‭1.2.5. Chemotherapy in combination with immune checkpoint inhibitors‬
‭15‬
‭1.2.6. Potential for drug-drug interactions‬
‭17‬
‭2. Objectives and Endpoints of the trial‬
‭17‬
‭2.1.  Primary objective‬
‭17‬
‭2.2. Secondary Objectives‬
‭17‬
‭3. Study Design‬
‭18‬
‭3.1. Overall Design‬
‭18‬
‭3.1.1. Data Monitoring Committee and Other External Committees‬
‭19‬
‭3.2. Number of participants‬
‭19‬
‭3.3. End of Study Definition‬
‭20‬
‭3.4. Study Calendar‬
‭20‬
‭4. Patient selection criteria‬
‭20‬
‭4.1. Inclusion Criteria‬
‭20‬
‭4.2. Exclusion Criteria‬
‭21‬
‭4.3. Screening Failures‬
‭22‬
‭4.3.1. Retesting during Screening Period‬
‭22‬
‭5. Therapeutic Regimens, Expected Toxicity, Dose Modifications‬
‭22‬
‭5.1. Treatments Administered‬
‭23‬
‭5.1.1. Dosing‬
‭24‬
‭5.1.1.1. Nivolumab‬
‭24‬
‭5.1.1.2 Chemotherapy dosing‬
‭24‬
‭5.1.1.3 Premedication‬
‭25‬
‭5.1.2. Patient Monitoring‬
‭25‬
‭5.1.3. Treatment of Nivolumab Infusion Reactions‬
‭26‬
‭5.2. Dose Adjustments‬
‭28‬
‭5.2.1. Dose modifications for Nivolumab‬
‭28‬
‭5.2.2. Dose modifications for Chemotherapy‬
‭32‬
‭5.2.2.1 Dose Reductions for Hematologic Adverse Events‬
‭32‬
‭5.2.2.2. Dose Reductions for Non-Hematologic Adverse Events‬
‭33‬
‭5.2.3. Dose Delay Criteria‬
‭34‬
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‭5.2.3.1. Dose delay Criteria for Nivolumab‬
‭34‬
‭5.2.3.2. Dose delay Criteria for Chemotherapy‬
‭35‬
‭5.2.4. Criteria to Resume Dosing‬
‭35‬
‭5.2.4.1. Criteria to Resume Nivolumab Dosing‬
‭35‬
‭5.2.4.2. Criteria to Resume Treatment with Chemotherapy‬
‭36‬
‭5.3. Duration of Therapy‬
‭36‬
‭5.3.1. Treatment Beyond Disease Progression‬
‭36‬
‭5.4. Preparation/Handling/Storage/ Accountability‬
‭37‬
‭5.5. Concomitant therapy‬
‭38‬
‭5.5.1. Prohibited and/or Restricted Therapy‬
‭38‬
‭5.5.2. Permitted Therapy‬
‭38‬
‭5.5.3. Palliative Local Therapy‬
‭39‬
‭5.5.4. Imaging Restrictions and Precautions‬
‭39‬
‭6. Discontinuation Criteria‬
‭40‬
‭6.1. Discontinuation from Study Treatment‬
‭40‬
‭6.1.1. Nivolumab Dose Discontinuation‬
‭40‬
‭6.1.2. Chemotherapy Dose Discontinuation‬
‭41‬
‭6.2. Discontinuation from Study‬
‭42‬
‭6.2.1. Post Study Treatment Study Follow-up‬
‭43‬
‭6.3. Lost to Follow-up‬
‭43‬
‭7. Clinical evaluation, laboratory tests, follow-up‬
‭43‬
‭7.1. Before treatment start‬
‭44‬
‭7.1.1. Informed Consent‬
‭44‬
‭7.1.1.1. General Informed Consent‬
‭44‬
‭7.1.1.2. Consent and Collection of Specimens for Future Biomedical Research‬
‭44‬
‭7.1.2. Inclusion/Exclusion Criteria Assessment‬
‭44‬
‭7.1.3. Medical History‬
‭45‬
‭7.1.4. Prior and concomitant medications review‬
‭45‬
‭7.1.4.1. Prior Medications‬
‭45‬
‭7.1.4.2. Concomitant Medications‬
‭45‬
‭7.1.5. Assignment of Screening Number‬
‭45‬
‭7.1.6. Subject Identification Card‬
‭45‬
‭7.1.7. Submitting Tumor Sample‬
‭45‬
‭7.1.8. Tumor Imaging‬
‭46‬
‭7.1.8.1. Computed  (CT) with IV contrast or Magnetic Resonance Imaging (MRI) of‬
‭chest, abdomen and pelvis.‬
‭46‬
‭7.1.8.2. Brain CT with IV contrast or MRI scan‬
‭46‬
‭7.1.8.3. Whole body bone scan‬
‭46‬
‭7.1.9. Laboratory Assessments‬
‭46‬
‭7.1.10. 12-Lead Electrocardiogram (ECG)‬
‭47‬
‭7.2. During treatment‬
‭47‬
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‭7.2.1. Adverse Event (AE) Monitoring‬
‭47‬
‭7.2.2. Physical Exam‬
‭47‬
‭7.2.3. Vital Signs‬
‭47‬
‭7.2.4. 12-Lead Electrocardiogram (ECG)‬
‭47‬
‭7.2.5. Eastern Cooperative Oncology Group (ECOG) Performance Status‬
‭47‬
‭7.2.6. Tumor Imaging and Assessment of Disease‬
‭48‬
‭7.2.7. Laboratory Assessments‬
‭48‬
‭7.2.8. Serum/Urine β-hCG‬
‭49‬
‭7.3. After the end of treatment (Follow-up)‬
‭49‬
‭7.4. Summary table‬
‭49‬
‭8.  Evaluation criteria‬
‭50‬
‭8.1. Definitions‬
‭50‬
‭8.2. Evaluation of efficacy‬
‭51‬
‭8.2.1. Measurability of tumour lesions at baseline‬
‭51‬
‭8.2.1.1. Definitions‬
‭51‬
‭8.2.1.2. Methods of measurements‬
‭52‬
‭8.2.2. Tumor response evaluation‬
‭52‬
‭8.2.2.1. Response evaluation according RECIST 1.1 [xliv]‬
‭52‬
‭8.2.2.2. Response evaluation according irRECIST [xlvi]‬
‭54‬
‭8.2.2.3. Frequency of tumor re-evaluation‬
‭55‬
‭8.2.3. Reporting of tumor response‬
‭56‬
‭8.2.3.1. Response duration‬
‭56‬
‭8.2.3.2. Stable disease duration‬
‭56‬
‭8.2.3.3. Progression Free Survival‬
‭56‬
‭8.2.3.4. Overall Survival‬
‭56‬
‭9. Statistical considerations‬
‭56‬
‭9.1. Statistical design‬
‭56‬
‭9.1.1. Sample Size Determination‬
‭56‬
‭9.2. Populations for Analysis‬
‭57‬
‭9.3. Statistical Analysis‬
‭57‬
‭9.3.1. Efficacy Analysis‬
‭57‬
‭9.3.1.1. Methods for Primary Endpoint‬
‭58‬
‭9.3.1.2. Methods for Secondary Endpoints‬
‭58‬
‭9.3.2. Safety Analysis‬
‭58‬
‭10. Translational research‬
‭59‬
‭11. Patient registration  procedure‬
‭59‬
‭12. Reporting adverse events‬
‭59‬
‭12.1. Definitions for adverse event reporting‬
‭59‬
‭12.2. Reporting procedure‬
‭60‬
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‭13. Quality assurance‬
‭63‬
‭13.1. Control of data consistency‬
‭63‬
‭13.2. On-site quality control (for multi-centre studies only when data are sent to a Data Centre or‬
‭similar)‬
‭64‬
‭13.3. Audits (for multi-centre studies only when data are sent to Data Centre or similar)‬
‭64‬
‭13.4. Central review of pathology‬
‭65‬
‭14. Ethical considerations‬
‭65‬
‭14.1. Patient protection‬
‭65‬
‭14.2. Subject identification‬
‭65‬
‭14.3. Informed consent‬
‭65‬
‭15. Publication policy‬
‭66‬
‭APPENDICES‬
‭67‬
‭Appendix A. Performance Status Criteria‬
‭67‬
‭Appendix B. References‬
‭68‬
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‭Schema:‬
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‭1.‬
‭Background and introduction‬
‭1.1.‬
‭Background Disease Information‬
‭NENs‬‭comprise‬‭a‬‭heterogeneous‬‭family‬‭of‬‭neoplasms‬‭with‬‭a‬‭wide‬‭and‬‭complex‬‭spectrum‬‭of‬‭clinical‬
‭behaviour.‬‭They‬‭are‬‭uncommon‬‭tumours‬‭with‬‭an‬‭estimated‬‭incidence‬‭per‬‭year‬‭that‬‭ranges‬‭from‬‭5‬‭to‬‭7‬
‭cases‬‭per‬‭100,000‬‭in‬‭the‬‭Caucasian‬‭population.‬ ‭The‬‭reported‬‭incidence‬‭has‬‭substantially‬‭increased‬
‭over‬ ‭the‬ ‭last‬ ‭decades,‬ ‭al‬ ‭least‬ ‭partially‬ ‭due‬ ‭to‬ ‭improved‬ ‭diagnostic‬ ‭techniques‬ ‭and‬ ‭clinical‬
‭awareness.‬‭[i],[ii]‬
‭G3‬‭NENs‬‭are‬‭defined‬‭according‬‭to‬‭the‬‭World‬‭Health‬‭Organization‬‭(WHO)‬‭as‬‭those‬‭with‬‭high‬
‭proliferative‬‭index‬‭(Ki-67‬‭index‬‭greater‬‭than‬‭20%‬‭or‬‭a‬‭mitotic‬‭rate‬‭greater‬‭than‬‭20‬‭per‬‭10‬‭high‬‭power‬
‭fields (HPF)), which are generally, but not always, poorly differentiated tumors‬‭[iii]‬‭.‬
‭The‬ ‭gastroenteropancreatic‬ ‭tract‬ ‭is‬ ‭the‬ ‭most‬ ‭common‬ ‭site‬ ‭for‬ ‭extra-pulmonary‬ ‭G3‬ ‭NENs‬
‭accounting‬‭for‬‭35-55%‬‭of‬‭all‬‭NENs‬‭outside‬‭the‬‭lung.‬‭Approximately‬‭50-60%‬‭of‬‭patients‬‭present‬‭with‬
‭metastatic‬‭disease‬‭at‬‭the‬‭time‬‭of‬‭diagnosis‬‭and‬‭have‬‭a‬‭fateful‬‭prognosis.‬‭Median‬‭OS‬‭of‬‭patients‬‭with‬
‭advanced‬‭disease‬‭is‬‭5‬‭months,‬‭ranging‬‭from‬‭less‬‭than‬‭a‬‭month‬‭for‬‭patients‬‭receiving‬‭best‬‭supportive‬
‭care‬ ‭only,‬ ‭up‬ ‭to‬ ‭11‬ ‭months‬ ‭with‬ ‭best‬ ‭available‬ ‭therapy‬‭[iv]‬‭,‬‭[v]‬‭.‬ ‭Historically,‬ ‭treatment‬ ‭strategies‬ ‭for‬
‭extra-pulmonary‬‭G3‬‭NENs‬‭have‬‭been‬‭often‬‭extrapolated‬‭from‬‭the‬‭treatment‬‭paradigm‬‭for‬‭small‬‭cell‬
‭lung‬ ‭cancer‬ ‭(SCLC)‬ ‭given‬ ‭the‬ ‭histologic‬ ‭similarities‬ ‭between‬ ‭both‬ ‭entities.‬ ‭Therefore,‬ ‭standard‬
‭front-line‬ ‭therapy‬ ‭involves‬ ‭the‬ ‭administration‬ ‭of‬ ‭a‬ ‭platinum‬ ‭agent‬ ‭(cisplatin‬ ‭or‬ ‭carboplatin)‬ ‭and‬
‭etoposide,‬‭with‬‭response‬‭rates‬‭in‬‭the‬‭largest‬‭recent‬‭western‬‭series‬‭of‬‭~‬‭30%‬‭and‬‭median‬‭survival‬‭of‬
‭about‬‭one‬‭year‬‭[vi],[vii],[viii],[ix],[x]‬‭.‬‭The‬‭optimal‬‭duration‬‭of‬‭first‬‭line‬‭(1L)‬‭treatment‬‭is‬‭unclear.‬‭However,‬‭in‬
‭the‬‭absence‬‭of‬‭progression,‬‭chemotherapy‬‭is‬‭usually‬‭stopped‬‭after‬‭4‬‭to‬‭6‬‭cycles‬‭due‬‭to‬‭cumulative‬
‭toxicity‬ ‭and‬ ‭the‬ ‭lack‬ ‭of‬ ‭evidence‬ ‭demonstrating‬ ‭greater‬ ‭clinical‬ ‭benefit‬ ‭with‬ ‭extended‬ ‭treatment.‬
‭Progression-free‬‭survival‬‭after‬‭this‬‭induction‬‭period‬‭remains‬‭poor,‬‭lasting‬‭2-‬‭3‬‭months.‬‭Therefore,‬‭new‬
‭therapeutic‬‭strategies‬‭are‬‭needed‬‭in‬‭this‬‭setting‬‭to‬‭improve‬‭response‬‭rates‬‭and‬‭prolong‬‭progression‬‭free‬
‭survival‬‭without‬‭increasing‬‭toxicity‬‭in‬‭these‬‭patients.‬‭The‬‭addition‬‭of‬‭an‬‭immune‬‭checkpoint‬‭inhibitor‬
‭to‬ ‭1L‬ ‭chemotherapy,‬ ‭followed‬ ‭by‬ ‭maintenance‬ ‭immunotherapy‬ ‭could‬ ‭be‬‭a‬‭valuable‬‭option‬‭in‬‭this‬
‭scenario.‬
‭More‬‭recently,‬‭a‬‭better‬‭understanding‬‭of‬‭the‬‭role‬‭of‬‭the‬‭immunological‬‭system‬‭in‬‭tumor‬‭control‬
‭has‬ ‭opened‬ ‭multiple‬ ‭doors‬ ‭to‬ ‭implement‬ ‭different‬ ‭strategies‬ ‭to‬ ‭enhance‬ ‭immune‬‭response‬‭against‬
‭cancer‬‭cells‬‭[xi]‬‭.‬‭It‬‭is‬‭well‬‭known‬‭that‬‭tumor‬‭cells‬‭elude‬‭immune‬‭response‬‭by‬‭several‬‭mechanisms.‬‭The‬
‭programmed‬ ‭death-1‬ ‭receptor‬ ‭(PD-1)‬ ‭and‬ ‭its‬ ‭ligand‬ ‭(PD-L1)‬ ‭are‬ ‭key‬ ‭therapeutic‬ ‭targets‬ ‭in‬ ‭the‬
‭reactivation‬ ‭of‬ ‭the‬ ‭immune‬ ‭response‬ ‭against‬ ‭multiple‬ ‭cancers.‬ ‭PD-1‬ ‭receptor‬ ‭is‬ ‭expressed‬ ‭on‬
‭activated‬‭T‬‭cells‬‭and‬‭interacts‬‭with‬‭its‬‭ligand‬‭(PD-L1),‬‭which‬‭is‬‭expressed‬‭in‬‭tumor‬‭and‬‭immune‬‭cells,‬
‭to‬‭down-regulate‬‭T-cell‬‭activation‬‭and‬‭promote‬‭tumor‬‭immune‬‭escape‬‭,‬‭a‬‭mechanism‬‭by‬‭which‬‭tumor‬
‭cells‬‭avoid‬‭recognition‬‭and‬‭elimination‬‭by‬‭the‬‭immune‬‭system‬‭[xii]‬‭.‬‭The‬‭development‬‭of‬‭monoclonal‬
‭antibodies‬ ‭against‬ ‭the‬ ‭PD-1/‬ ‭PD-L1‬ ‭pathway,‬ ‭that‬ ‭disrupt‬ ‭PD-1–mediated‬ ‭signalling‬ ‭and‬ ‭restore‬
‭thereby‬‭antitumor‬‭immunity,‬‭has‬‭led‬‭to‬‭significant‬‭antitumor‬‭activity‬‭in‬‭a‬‭wide‬‭spectrum‬‭of‬‭neoplastic‬
‭diseases,‬‭inducing‬‭increased‬‭progression-free-survival‬‭(PFS),‬‭overall‬‭survival‬‭(OS)‬‭and‬‭long‬‭lasting‬
‭responses in different tumor types such as melanoma or lung cancer‬‭[xiii],[xiv],[xv],[xvi]‬‭.‬
‭On‬‭the‬‭other‬‭hand,‬‭an‬‭increasing‬‭body‬‭of‬‭evidence‬‭has‬‭demonstrated‬‭that‬‭mutational‬‭burden‬‭is‬
‭strongly‬‭associated‬‭with‬‭increased‬‭response‬‭to‬‭immunotherapy.‬‭In‬‭this‬‭regard,‬‭high‬‭grade‬‭NENs‬‭are‬
‭suitable‬‭candidates‬‭for‬‭these‬‭treatment‬‭strategies‬‭as‬‭they‬‭are‬‭highly‬‭mutated‬‭tumours‬‭with‬‭high‬‭PD-L1‬
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‭expression.‬ ‭For‬ ‭example,‬ ‭some‬ ‭authors‬ ‭have‬ ‭shown‬ ‭that‬ ‭virus-negative‬ ‭Merkel‬ ‭Cell‬ ‭Carcinomas‬
‭(MCCs),‬‭a‬‭type‬‭of‬‭high‬‭grade‬‭NEN,‬‭harbour‬‭more‬‭tumor‬‭neoantigens‬‭than‬‭melanomas‬‭or‬‭non-small‬
‭cell‬ ‭lung‬ ‭cancers‬ ‭(median‬ ‭of‬ ‭173,‬ ‭65,‬ ‭and‬ ‭111‬ ‭neoantigens/sample,‬‭respectively),‬‭two‬‭cancers‬‭for‬
‭which immune checkpoint blockade can produce durable clinical responses‬‭[xvii]‬‭.‬
‭In‬‭summary,‬‭the‬‭addition‬‭of‬‭a‬‭checkpoint‬‭inhibitor‬‭could‬‭be‬‭a‬‭valuable‬‭treatment‬‭option‬‭in‬‭these‬
‭patients.‬‭The‬‭objective‬‭of‬‭this‬‭trial‬‭is‬‭to‬‭determine‬‭the‬‭one-year‬‭overall‬‭survival‬‭rate‬‭of‬‭nivolumab‬‭in‬
‭addition to platinum-doublet chemotherapy in advanced G3 NENs without prior therapy.‬
‭1.2.         Background Therapeutic Information‬
‭1.2.1.‬ ‭Nivolumab: mechanism of action‬
‭Nivolumab‬‭(BMS-936558)‬‭is‬‭a‬‭fully‬‭human,‬‭IgG4‬‭mAb‬‭that‬‭binds‬‭PD-1‬‭on‬‭activated‬‭immune‬‭cells‬
‭and‬ ‭disrupts‬ ‭engagement‬ ‭of‬ ‭the‬‭receptor‬‭with‬‭its‬‭ligands‬‭PD-L1‬‭and‬‭PD-L2,‬‭abrogating‬‭inhibitory‬
‭signals‬‭and‬‭augmenting‬‭the‬‭host‬‭antitumor‬‭response.‬‭The‬‭PD-1‬‭receptor-ligand‬‭interaction‬‭is‬‭a‬‭major‬
‭pathway‬‭hijacked‬‭by‬‭tumors‬‭to‬‭suppress‬‭immune‬‭control.‬‭The‬‭normal‬‭function‬‭of‬‭PD-1,‬‭expressed‬‭on‬
‭the‬‭cell‬‭surface‬‭of‬‭activated‬‭T‬‭cells‬‭under‬‭physiological‬‭conditions,‬‭is‬‭to‬‭down-modulate‬‭unwanted‬‭or‬
‭excessive‬‭immune‬‭responses,‬‭including‬‭autoimmune‬‭reactions.‬‭PD-1‬‭has‬‭been‬‭shown‬‭to‬‭negatively‬
‭regulate‬‭antigen‬‭receptor‬‭signaling‬‭upon‬‭engagement‬‭of‬‭its‬‭ligands‬‭(PD-L1‬‭and/or‬‭PD‬‭L2)‬‭[xviii]‬‭.‬‭These‬
‭ligands‬ ‭are‬‭constitutively‬‭expressed‬‭or‬‭can‬‭be‬‭induced‬‭in‬‭a‬‭variety‬‭of‬‭cell‬‭types,‬‭including‬‭various‬
‭tumors‬‭[xix],[xx],[xxi]‬‭.‬‭Binding‬‭of‬‭PD-1‬‭to‬‭its‬‭ligands‬‭inhibits‬‭T‬‭cell‬‭activation‬‭triggered‬‭through‬‭the‬‭T-cell‬
‭receptor.‬ ‭PD-L2‬‭is‬‭thought‬‭to‬‭control‬‭immune‬‭T-cell‬‭activation‬‭in‬‭lymphoid‬‭organs,‬‭whereas‬‭PD-L1‬
‭serves‬‭to‬‭dampen‬‭unwarranted‬‭T-cell‬‭function‬‭in‬‭peripheral‬‭tissues.‬‭A‬‭variety‬‭of‬‭cancers‬‭have‬‭been‬
‭shown‬‭to‬‭express‬‭abundant‬‭levels‬‭of‬‭this‬‭PD-L1.‬‭This‬‭suggests‬‭that‬‭the‬‭PD-1/PD-L1‬‭pathway‬‭plays‬‭a‬
‭critical role in tumor immune evasion and can be an attractive target for therapeutic intervention.‬
‭1.2.2.‬ ‭Preclinical experience with Nivolumab‬
‭In‬ ‭vitro,‬ ‭nivolumab‬ ‭(BMS-936558)‬ ‭binds‬ ‭to‬ ‭PD-1‬ ‭with‬‭high‬‭affinity‬‭(EC50‬‭0.39‬‭-‬‭2.62‬‭nM),‬‭and‬
‭inhibits‬ ‭the‬ ‭binding‬ ‭of‬ ‭PD-1‬ ‭to‬ ‭its‬ ‭ligands‬ ‭PD-L1‬ ‭and‬ ‭PD-L2‬ ‭(IC50:‬ ‭1‬ ‭nM).‬ ‭Nivolumab‬ ‭binds‬
‭specifically‬‭to‬‭PD-1‬‭and‬‭not‬‭to‬‭related‬‭members‬‭of‬‭the‬‭CD28‬‭family‬‭such‬‭as‬‭CD28,‬‭ICOS,‬‭CTLA-4,‬
‭and‬‭BTLA.‬‭Blockade‬‭of‬‭the‬‭PD-1‬‭pathway‬‭by‬‭nivolumab‬‭results‬‭in‬‭a‬‭reproducible‬‭enhancement‬‭of‬
‭both‬ ‭proliferation‬ ‭and‬ ‭IFN-γ‬ ‭release‬ ‭in‬ ‭the‬ ‭mixed‬ ‭lymphocyte‬ ‭reaction‬ ‭(MLR).‬ ‭Using‬ ‭a‬ ‭CMV‬
‭re-stimulation‬‭assay‬‭with‬‭human‬‭PBMC,‬‭the‬‭effect‬‭of‬‭nivolumab‬‭on‬‭antigen‬‭specific‬‭recall‬‭response‬
‭indicates‬ ‭that‬ ‭nivolumab‬ ‭augmented‬ ‭IFN-γ‬ ‭secretion‬ ‭from‬ ‭CMV‬ ‭specific‬ ‭memory‬ ‭T‬ ‭cells‬ ‭in‬ ‭a‬
‭dose-dependent‬‭manner‬‭versus‬‭isotype-matched‬‭control.‬‭In‬‭vivo‬‭blockade‬‭of‬‭PD-1‬‭by‬‭a‬‭murine‬‭analog‬
‭of‬ ‭nivolumab‬ ‭enhances‬ ‭the‬ ‭anti-tumor‬ ‭immune‬ ‭response‬ ‭and‬ ‭result‬ ‭in‬ ‭tumor‬ ‭rejection‬ ‭in‬ ‭several‬
‭immunocompetent mouse tumor models (MC38, SA1/N, and PAN02)‬‭[xxii]‬‭.‬
‭1.2.3.‬ ‭Clinical experience with Nivolumab in SCLC‬
‭In‬ ‭early‬ ‭clinical‬ ‭trials,‬ ‭nivolumab‬ ‭has‬ ‭demonstrated‬ ‭activity‬ ‭in‬ ‭several‬ ‭tumor‬ ‭types,‬ ‭including‬
‭melanoma, renal cell cancer (RCC), and NSCLC‬‭[xxiii]‬‭.‬
‭Nivolumab‬‭is‬‭now‬‭approved‬‭in‬‭the‬‭U.S.‬‭and‬‭Europe‬‭to‬‭treat‬‭different‬‭tumor‬‭types‬‭including:‬
‭melanoma‬‭(both‬‭adjuvant‬‭and‬‭metastatic‬‭setting),‬‭metastatic‬‭NSCLC‬‭in‬‭patients‬‭with‬‭progression‬‭on‬
‭or‬ ‭after‬ ‭platinum-based‬ ‭chemotherapy,‬ ‭advanced‬ ‭SCLC‬ ‭with‬ ‭progression‬ ‭after‬ ‭platinum-based‬
‭chemotherapy,‬‭advanced‬‭renal‬‭cell‬‭carcinoma,‬‭metastatic‬‭urothelial‬‭cancer‬‭and‬‭advanced‬‭squamous‬
‭cell carcinoma of head and neck‬‭[xxiv]‬‭.‬
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‭The‬ ‭approval‬ ‭in‬ ‭SCLC‬ ‭was‬ ‭based‬ ‭on‬ ‭the‬ ‭results‬ ‭of‬ ‭Checkmate-032‬ ‭[xxv]‬‭,‬ ‭This‬ ‭was‬ ‭a‬ ‭phase‬ ‭I/II‬
‭multicentre,‬‭multi-arm,‬‭open-label‬‭trial‬‭that‬‭included‬‭a‬‭cohort‬‭of‬‭216‬‭patients‬‭with‬‭SCLC.‬ ‭Patients‬
‭progressing‬ ‭after‬ ‭at‬ ‭least‬ ‭one‬ ‭platinum-containing‬ ‭therapy‬ ‭were‬‭allocated‬‭to‬‭three‬‭treatment‬‭arms:‬
‭nivolumab‬‭plus‬‭ipilimumab‬‭[1‬‭mg/kg‬‭+‬‭1‬‭mg/kg‬‭iv‬‭(n‬‭=‬‭3),‬‭1‬‭mg/kg‬‭+‬‭3‬‭mg/kg‬‭iv‬‭(n‬‭=‬‭61),‬‭and‬‭3‬
‭mg/kg‬‭+‬‭1‬‭mg/kg‬‭iv‬‭(n‬‭=‬‭54)]‬‭versus‬‭nivolumab‬‭monotherapy‬‭(3‬‭mg/kg‬‭iv)‬‭(n‬‭=‬‭98).‬‭Nivolumab‬‭plus‬
‭ipilimumab‬‭was‬‭administered‬‭every‬‭3‬‭weeks‬‭for‬‭four‬‭cycles‬‭followed‬‭by‬‭nivolumab‬‭3‬‭mg/kg‬‭iv‬‭every‬
‭other‬‭week.‬‭The‬‭primary‬‭endpoint‬‭was‬‭objective‬‭response‬‭per‬‭RECIST‬‭v1.1.‬‭Objective‬‭response‬‭was‬
‭achieved‬ ‭in‬ ‭14/61‬ ‭(23%)‬ ‭receiving‬ ‭nivolumab‬ ‭1‬ ‭mg/kg‬ ‭plus‬ ‭ipilimumab‬ ‭3‬ ‭mg/kg;‬ ‭10/54‬ ‭(19%)‬
‭receiving‬‭nivolumab‬‭3‬‭mg/kg‬‭plus‬‭ipilimumab‬‭1‬‭mg/kg,‬‭1/3‬‭(33%)‬‭receiving‬‭nivolumab‬‭1‬‭mg/kg‬‭plus‬
‭ipilimumab‬ ‭1‬ ‭mg/kg,‬ ‭and‬ ‭10/98‬ ‭(10%)‬ ‭patients‬ ‭in‬ ‭the‬ ‭nivolumab‬ ‭monotherapy‬ ‭arm.‬ ‭The‬ ‭median‬
‭duration‬‭of‬‭response‬‭was‬‭17.9‬‭months‬‭for‬‭nivolumab‬‭monotherapy,‬‭and‬‭14.2‬‭months‬‭with‬‭nivolumab‬‭1‬
‭mg/kg‬‭plus‬‭ipilimumab‬‭3‬‭mg/kg.‬‭Patients‬‭with‬‭ongoing‬‭responses‬‭at‬‭2‬‭years‬‭were‬‭45%‬‭for‬‭nivolumab‬
‭monotherapy‬ ‭and‬ ‭36%‬ ‭in‬ ‭the‬ ‭combination.‬ ‭Responses‬ ‭were‬ ‭observed‬ ‭regardless‬ ‭of‬ ‭platinum‬
‭sensitivity,‬‭line‬‭of‬‭therapy,‬‭or‬‭PD-L1‬‭status.‬‭Two-year‬‭OS‬‭rates‬‭were‬‭14%‬‭for‬‭nivolumab‬‭monotherapy‬
‭and‬ ‭26%‬ ‭in‬ ‭the‬ ‭combination‬ ‭arm,‬ ‭with‬ ‭a‬ ‭median‬ ‭OS‬ ‭of‬ ‭4.1‬ ‭(95%‬ ‭CI‬ ‭3.0–6.8)‬ ‭and‬ ‭7.8‬‭(95%‬‭CI‬
‭3.6–14.2),‬ ‭respectively.‬ ‭In‬ ‭a‬ ‭randomized,‬‭phase‬‭II‬‭cohort‬‭from‬‭CheckMate‬‭032‬‭to‬‭further‬‭evaluate‬
‭nivolumab‬ ‭±‬ ‭ipilimumab,‬ ‭the‬ ‭initial‬ ‭efficacy‬ ‭of‬ ‭242‬ ‭patients‬ ‭was‬ ‭consistent‬ ‭with‬ ‭that‬ ‭in‬ ‭the‬
‭non-randomized‬‭cohort‬‭[xxvi]‬‭.‬‭Grade‬‭≥‬‭3‬‭toxicities‬‭occurred‬‭in‬‭18/61‬‭(30%)‬‭in‬‭the‬‭nivolumab‬‭1‬‭mg/kg‬
‭plus‬‭ipilimumab‬‭3‬‭mg/kg‬‭group,‬‭10/54‬‭(19%)‬‭in‬‭the‬‭nivolumab‬‭3‬‭mg/kg‬‭plus‬‭ipilimumab‬‭1‬‭mg/kg,‬‭and‬
‭13/98‬‭(13%)‬‭in‬‭the‬‭nivolumab‬‭monotherapy.‬‭Six‬‭(6%)‬‭patients‬‭in‬‭the‬‭nivolumab‬‭3‬‭mg/kg‬‭group,‬‭seven‬
‭(11%)‬‭in‬‭the‬‭nivolumab‬‭1‬‭mg/kg‬‭plus‬‭ipilimumab‬‭3‬‭mg/kg‬‭group,‬‭and‬‭four‬‭(7%)‬‭in‬‭the‬‭nivolumab‬‭3‬
‭mg/kg‬ ‭plus‬ ‭ipilimumab‬ ‭1‬ ‭mg/kg‬ ‭group‬ ‭discontinued‬ ‭treatment‬ ‭due‬ ‭to‬ ‭treatments‬ ‭related‬ ‭adverse‬
‭events‬ ‭(TRAEs).‬ ‭Four‬ ‭patients‬ ‭who‬ ‭received‬ ‭nivolumab‬ ‭plus‬ ‭ipilimumab‬ ‭died‬ ‭from‬ ‭TRAEs‬
‭(myasthenia‬‭gravis,‬‭pneumonitis,‬‭encephalitis‬‭and‬‭hepatitis),‬‭and‬‭one‬‭patient‬‭who‬‭received‬‭nivolumab‬
‭monotherapy died from treatment-related pneumonitis.‬
‭Several‬ ‭trials‬ ‭are‬ ‭currently‬ ‭evaluating‬ ‭nivolumab‬ ‭±‬ ‭ipilimumab.‬ ‭Initial‬ ‭results‬ ‭from‬ ‭the‬
‭randomized‬ ‭phase‬‭III‬‭clinical‬‭trial‬‭Checkmate‬‭331(NCT02481830)‬‭evaluating‬‭the‬‭role‬‭of‬‭nivolumab‬
‭versus‬ ‭chemotherapy‬ ‭(topotecan‬ ‭or‬‭amrubicin)‬‭in‬‭patients‬‭with‬‭relapsed‬‭SCLC‬‭have‬‭been‬‭recently‬
‭presented‬‭showing‬‭no‬‭statistically‬‭significant‬‭improvement‬‭in‬‭OS‬‭with‬‭nivolumab‬‭vs‬‭chemotherapy‬
‭(HR,‬‭0.86‬‭[95%‬‭CI,‬‭0.72–1.04]);‬‭however‬‭OS‬‭curves‬‭showed‬‭delayed‬‭separation‬‭after‬‭month‬‭12.‬‭HR‬
‭for‬‭OS‬‭with‬‭nivolumab‬‭vs‬‭chemotherapy‬‭in‬‭patients‬‭with‬‭platinum-resistant‬‭SCLC‬‭was‬‭0.71‬‭(95%‬‭CI,‬
‭0.54–0.94)‬‭[xxvii]‬‭.‬
‭Checkmate‬ ‭451‬ ‭evaluated‬ ‭the‬ ‭role‬ ‭of‬ ‭nivolumab‬ ‭alone,‬ ‭nivolumab‬ ‭1‬ ‭mg/kg‬ ‭in‬ ‭combination‬ ‭with‬
‭ipilimumab‬ ‭3‬ ‭mg/kg,‬ ‭or‬ ‭placebo‬ ‭as‬ ‭consolidation/maintenance‬ ‭therapy‬ ‭after‬ ‭completion‬ ‭of‬
‭platinum-based‬ ‭first-line‬ ‭chemotherapy‬ ‭in‬ ‭patients‬ ‭with‬ ‭extended‬ ‭disease‬ ‭SCLC.‬ ‭The‬ ‭primary‬
‭endpoint‬‭of‬‭OS‬‭has‬‭not‬‭been‬‭met‬‭[xxviii]‬‭.‬ ‭Results‬‭from‬‭a‬‭phase‬‭II‬‭trial‬‭of‬‭consolidation‬‭with‬‭nivolumab‬
‭and‬
‭ipilimumab‬
‭in‬ ‭localized‬ ‭SCLC‬ ‭after‬ ‭chemo-radiotherapy‬ ‭are‬ ‭pending‬ ‭(STIMULI,‬
‭NCT02046733)‬‭[xxix]‬‭.‬
‭In‬ ‭general,‬ ‭nivolumab‬ ‭has‬ ‭been‬ ‭well‬ ‭tolerated‬ ‭to‬ ‭date,‬ ‭with‬ ‭a‬ ‭favorable‬ ‭safety‬ ‭profile‬ ‭relative‬‭to‬
‭anticipated toxicities based on an immunostimulatory mechanism of action.‬
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‭1.2.4.‬ ‭Immune checkpoint inhibitors in other high grade NENs‬
‭Further‬‭research‬‭of‬‭these‬‭therapeutic‬‭strategies‬‭in‬‭other‬‭types‬‭of‬‭high‬‭grade‬‭NENs,‬‭such‬‭as‬
‭Merkel‬ ‭cell‬ ‭carcinomas‬ ‭(MCC),‬ ‭has‬ ‭also‬ ‭proven‬ ‭to‬ ‭be‬ ‭highly‬ ‭effective‬ ‭both‬ ‭in‬ ‭chemonaive‬ ‭and‬
‭pretreated‬‭patients.‬‭In‬‭a‬‭multicenter‬‭phase‬‭2‬‭trial,‬‭patients‬‭with‬‭advanced‬‭MCC‬‭who‬‭had‬‭received‬‭no‬
‭previous‬‭systemic‬‭therapy‬‭were‬‭assigned‬‭to‬‭receive‬‭pembrolizumab‬‭at‬‭a‬‭dose‬‭of‬‭2‬‭mg‬‭per‬‭kilogram‬
‭every‬ ‭3‬ ‭weeks.‬ ‭The‬ ‭primary‬‭endpoint‬‭was‬‭the‬‭objective‬‭response‬‭rate‬‭(ORR).‬‭Twenty-six‬‭patients‬
‭were‬‭treated‬‭with‬‭pembrolizumab,‬‭with‬‭an‬‭ORR‬‭of‬‭56%‬‭(95%‬‭confidence‬‭interval‬‭[CI],‬‭35‬‭–‬‭76%)‬‭and‬
‭a‬‭rate‬‭of‬‭progression‬‭free‬‭survival‬‭at‬‭6‬‭months‬‭of‬‭67%‬ ‭[xxx]‬‭.‬‭Avelumab,‬‭an‬‭anti-PD-L1‬‭monoclonal‬
‭antibody,‬‭also‬‭showed‬‭efficacy‬‭in‬‭MCC‬‭refractory‬‭to‬‭chemotherapy‬‭in‬‭a‬‭phase‬‭II‬‭trial‬‭that‬‭enrolled‬‭88‬
‭patients‬ ‭with‬ ‭advanced‬ ‭disease.‬‭Responses‬‭were‬‭achieved‬‭in‬‭32%‬‭of‬‭patients,‬‭82%‬‭of‬‭which‬‭were‬
‭maintained‬‭at‬‭10‬‭months‬‭of‬‭follow-up‬‭time.‬‭Grade‬‭3‬‭treatment-related‬‭events‬‭occurred‬‭in‬‭only‬‭5%‬‭of‬
‭patients‬‭with‬‭no‬‭grade‬‭4‬‭events‬‭described‬ ‭[xxxi]‬‭.‬‭These‬‭promising‬‭results‬‭represent‬‭a‬‭new‬‭therapeutic‬
‭option‬‭for‬‭advanced‬‭MCC‬‭and‬‭open‬‭a‬‭new‬‭path‬‭for‬‭future‬‭clinical‬‭trials‬‭in‬‭G3‬‭NENs.‬‭In‬‭SCLC,‬‭which‬
‭shares‬ ‭many‬ ‭histopathological‬ ‭and‬ ‭biological‬ ‭features‬ ‭with‬ ‭extrapulmonary‬ ‭high‬ ‭grade‬ ‭NEN,‬
‭Nivolumab‬ ‭has‬ ‭recently‬ ‭shown‬ ‭clinical‬ ‭activity‬ ‭in‬‭a‬‭phase‬‭I/II‬‭study‬‭of‬‭SCLC‬‭patients‬‭previously‬
‭treated‬‭with‬‭platinum-based‬‭chemotherapy‬‭[xxxii]‬‭.‬‭An‬‭objective‬‭response‬‭rate‬‭of‬‭18%‬‭was‬‭documented‬
‭in‬ ‭40‬ ‭patients‬ ‭treated‬ ‭with‬ ‭nivolumab‬ ‭monotherapy.‬ ‭Pembrolizumab‬ ‭has‬ ‭also‬ ‭recently‬ ‭showed‬
‭promising‬ ‭activity‬ ‭in‬ ‭a‬ ‭phase‬ ‭IB‬ ‭study‬ ‭of‬ ‭20‬ ‭patients‬ ‭who‬ ‭had‬ ‭received‬ ‭prior‬ ‭platinum-based‬
‭combination‬ ‭chemotherapy‬ ‭[xxxiii]‬‭.‬ ‭Preliminary‬ ‭results‬ ‭reported‬ ‭objective‬ ‭responses‬ ‭in‬ ‭35%‬ ‭of‬ ‭the‬
‭treated‬‭patients.‬‭Nivolumab‬‭has‬‭also‬‭been‬‭tested‬‭in‬‭a‬‭cohort‬‭of‬‭25‬‭patients‬‭with‬‭advanced‬‭MCC‬‭within‬
‭the‬‭CheckMate‬‭358‬‭trial‬‭(NCT02488759)‬‭[xxxiv]‬‭.‬‭Preliminary‬‭results‬‭have‬‭reported‬‭an‬‭overall‬‭response‬
‭rate‬ ‭of‬ ‭68%‬ ‭in‬ ‭22‬ ‭evaluable‬ ‭patients.‬ ‭Responses‬ ‭occurred‬ ‭in‬ ‭both‬ ‭treatment-naïve‬ ‭(71%)‬ ‭and‬
‭-experienced‬‭(63%)‬‭patients,‬‭regardless‬‭of‬‭tumor‬‭MCPyV‬‭or‬‭PD-L1‬‭expression.‬‭Expansion‬‭cohorts‬
‭will evaluate combinations of nivolumab with ipilimumab or anti-LAG-3.‬
‭More‬‭recently,‬‭initial‬‭results‬‭from‬‭an‬‭open-label,‬‭phase‬‭1b‬‭trial‬‭evaluating‬‭the‬‭efficacy‬‭and‬
‭safety‬ ‭of‬ ‭JS001‬ ‭on‬ ‭advanced‬ ‭NENs‬ ‭with‬ ‭high‬ ‭proliferative‬ ‭index‬ ‭(Ki67>10%)‬ ‭who‬‭had‬‭failed‬‭to‬
‭standard‬‭therapy,‬‭have‬‭been‬‭presented.‬‭JS001‬‭is‬‭a‬‭monoclonal‬‭humanized‬‭IgG4‬‭PD-1‬‭antibody‬‭with‬‭a‬
‭hinge‬‭S228P‬‭mutation‬‭that‬‭completely‬‭blocks‬‭PD-1‬‭interactions‬‭with‬‭PD-L1‬‭and‬‭PD-L2.‬‭A‬‭total‬‭of‬‭35‬
‭patients‬‭were‬‭enrolled,‬‭with‬‭a‬‭majority‬‭of‬‭NECs‬‭(n=28).‬‭An‬‭encouraging‬‭18%‬‭overall‬‭response‬‭rate‬
‭and‬ ‭25%‬ ‭disease‬ ‭control‬ ‭rate‬ ‭was‬ ‭achieved‬ ‭in‬ ‭NECs,‬ ‭with‬ ‭a‬ ‭50%‬ ‭response‬ ‭rate‬ ‭in‬ ‭patients‬ ‭with‬
‭PD1-positive‬‭tumors,‬ ‭and‬‭the‬‭median‬‭OS‬‭had‬‭not‬‭been‬‭reached.‬‭JS001‬‭was‬‭tolerable‬‭in‬‭patients‬‭with‬
‭NENs‬ ‭with‬ ‭<3%‬ ‭of‬ ‭severe‬ ‭adverse‬ ‭events‬ ‭[xxxv]‬‭.‬ ‭Other‬ ‭checkpoint‬ ‭inhibitors‬ ‭have‬ ‭not‬ ‭shown‬
‭significant‬ ‭activity‬ ‭as‬ ‭monotherapy‬ ‭in‬ ‭G3‬‭heavily‬‭pretreated‬‭NEN‬‭(i.e.‬‭pembrolizumab,‬‭PDR001).‬
‭Currently,‬‭ongoing‬‭trials‬‭are‬‭evaluating‬‭the‬‭role‬‭of‬‭these‬‭immunomodulating‬‭agents‬‭as‬‭maintenance‬
‭treatment‬ ‭at‬ ‭earlier‬ ‭stages‬ ‭of‬ ‭disease,‬ ‭and‬ ‭in‬ ‭combination‬ ‭with‬ ‭different‬ ‭therapeutic‬ ‭strategies‬
‭including chemotherapy.‬
‭1.2.5.‬ ‭Chemotherapy in combination with immune checkpoint inhibitors‬
‭There‬ ‭is‬ ‭increasing‬ ‭evidence‬ ‭suggesting‬ ‭that‬ ‭chemotherapy‬‭not‬‭only‬‭has‬‭antitumor‬‭activity‬‭due‬‭to‬
‭cytotoxic‬‭effects,‬‭but‬‭also‬‭through‬‭immunological‬‭effects,‬‭including‬‭reducing‬‭T-regulatory‬‭cell‬‭activity‬
‭and‬‭enhancing‬‭cross-presentation‬‭of‬‭tumour‬‭antigens‬‭[xxxvi],[xxxvii]‬‭.‬‭Chemotherapy‬‭has‬‭also‬‭been‬‭shown‬
‭to‬ ‭induce‬ ‭PD-L1‬ ‭expression‬ ‭on‬ ‭tumour‬ ‭cells.‬ ‭Therefore,‬ ‭combining‬ ‭immunotherapy‬ ‭and‬
‭chemotherapy‬ ‭could‬ ‭synergistically‬ ‭improve‬ ‭the‬ ‭anticancer‬ ‭activity‬ ‭of‬ ‭anti-PD-1‬ ‭and‬ ‭anti-PD-L1‬
‭monotherapy.‬
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‭Results‬‭from‬‭PD-1‬‭inhibitors‬‭in‬‭combination‬‭with‬‭platinum-based‬‭chemotherapy‬‭in‬‭first‬‭line‬
‭phase‬‭Ib/II‬‭trials‬‭have‬‭shown‬‭promising‬‭results‬‭in‬‭NSCLC.‬‭A‬‭phase‬‭I‬‭multicohort‬‭study‬‭was‬‭conducted‬
‭to‬ ‭explore‬ ‭the‬ ‭efficacy‬ ‭and‬ ‭safety‬ ‭of‬ ‭nivolumab‬ ‭in‬ ‭combination‬ ‭with‬ ‭standard‬ ‭chemotherapy‬ ‭in‬
‭first-line‬‭NSCLC‬ ‭[xxxviii]‬‭.‬‭56‬‭patients‬‭were‬‭assigned‬‭by‬‭histology‬‭to‬‭receive‬‭nivolumab‬‭10‬‭mg/kg‬‭iv‬
‭every‬ ‭3‬ ‭weeks‬ ‭plus‬ ‭gemcitabine‬ ‭and‬ ‭cisplatin‬ ‭(squamous)‬ ‭or‬ ‭pemetrexed‬ ‭plus‬ ‭cisplatin‬
‭(non-squamous)‬ ‭or‬ ‭nivolumab‬ ‭5‬ ‭or‬ ‭10‬ ‭mg/kg‬ ‭plus‬‭carboplatin-paclitaxel‬‭(all‬‭histologies).‬‭Patients‬
‭received‬‭the‬‭combination‬‭treatment‬‭for‬‭four‬‭cycles‬‭followed‬‭by‬‭nivolumab‬‭alone‬‭until‬‭progression‬‭or‬
‭unacceptable‬ ‭toxicity.‬ ‭No‬ ‭dose-limiting‬ ‭toxicities‬ ‭(DLTs)‬ ‭occurred‬ ‭during‬ ‭the‬ ‭first‬ ‭6‬ ‭weeks‬ ‭of‬
‭treatment.‬‭Consistent‬‭with‬‭previous‬‭reports‬‭for‬‭immune‬‭checkpoint‬‭inhibitors‬‭monotherapy,‬‭grade‬‭3-4‬
‭treatment-related‬‭adverse‬‭events‬‭were‬‭reported‬‭in‬‭45%‬‭of‬‭patients.‬‭ORR‬‭were‬‭33%,‬‭47%,‬‭47%‬‭and‬
‭43%‬
‭for‬
‭nivolumab‬ ‭10‬ ‭mg/kg‬ ‭plus‬ ‭gemcitabine-cisplatin,‬ ‭nivolumab‬ ‭10‬ ‭mg/kg‬ ‭plus‬
‭pemetrexed-cisplatin,‬‭nivolumab‬‭10‬‭mg/kg‬‭plus‬‭paclitaxel-carboplatin,‬‭and‬‭nivolumab‬‭5‬‭mg/kg‬‭plus‬
‭paclitaxel-carboplatin‬‭respectively.‬‭Responses‬‭were‬‭achieved‬‭regardless‬‭of‬‭tumor‬‭programmed‬‭death‬
‭ligand-1‬‭expression.‬‭The‬‭safety‬‭profile‬‭of‬‭nivolumab‬‭was‬‭consistent‬‭with‬‭that‬‭expected‬‭for‬‭individual‬
‭agents with no particular concerns.‬
‭Recently,‬‭the‬‭international,‬‭multicohort,‬‭phase‬‭1/2‬‭KEYNOTE-021‬‭study‬‭assessed‬‭the‬‭safety‬
‭and‬ ‭anti-tumour‬ ‭activity‬ ‭of‬ ‭pembrolizumab‬ ‭added‬ ‭to‬ ‭three‬‭different‬‭platinum-based‬‭chemotherapy‬
‭doublets‬‭in‬‭patients‬‭with‬‭advanced‬‭NSCLC‬ ‭[xxxix]‬‭.‬‭Chemotherapy-naïve‬‭NSCLC‬‭pts‬‭were‬‭randomly‬
‭assigned‬‭to‬‭pembrolizumab‬‭2‬‭or‬‭10‬‭mg/kg‬‭every‬‭3‬‭weeks‬‭plus‬‭carboplatin‬‭(AUC‬‭6)‬‭+‬‭paclitaxel‬‭200‬
‭mg/m2‬ ‭(any‬ ‭histology)‬‭or‬‭carboplatin‬‭(AUC‬‭6)‬‭+‬‭paclitaxel‬‭200‬‭mg/m2‬‭+‬‭bevacizumab‬‭15‬‭mg/kg‬
‭(non-squamous)‬ ‭or‬ ‭carboplatin‬ ‭(AUC‬ ‭5)‬‭plus‬‭pemetrexed‬‭500‬‭mg/m2‬‭(nonsquamous)‬‭for‬‭4‬‭cycles‬
‭followed‬ ‭by‬ ‭maintenance‬ ‭treatment‬ ‭with‬ ‭pembrolizumab,‬ ‭pembrolizumab‬ ‭+‬ ‭bevacizumab‬ ‭or‬
‭pembrolizumab‬ ‭plus‬ ‭pemetrexed‬ ‭respectively.‬ ‭Seventy-four‬ ‭pts‬ ‭were‬ ‭included‬ ‭in‬ ‭the‬ ‭study.‬ ‭All‬
‭combinations‬‭showed‬‭promising‬‭anti-tumour‬‭activity‬‭irrespective‬‭of‬‭tumour‬‭PD-L1‬‭expression,‬‭with‬
‭manageable‬‭safety‬‭profiles.‬‭One‬‭DLT‬‭occurred‬‭in‬‭cycle‬‭1‬‭(grade‬‭3‬‭rash).‬‭Grade‬‭3-4‬‭treatment-related‬
‭AEs‬‭occurred‬‭in‬‭36%,‬‭46%‬‭and‬‭42%‬‭of‬‭pts‬‭in‬‭each‬‭cohort‬‭respectively.‬‭Most‬‭common‬‭AEs‬‭were‬‭AST‬
‭elevation‬ ‭(n=3),‬ ‭anemia‬ ‭(n=2),‬ ‭neutropenia‬ ‭(n=2)‬ ‭and‬ ‭febrile‬ ‭neutropenia‬ ‭(n=2).‬ ‭Based‬ ‭on‬ ‭these‬
‭results,‬ ‭123‬ ‭patients‬ ‭with‬ ‭advanced‬ ‭chemotherapy-naïve‬ ‭NSCLC‬ ‭were‬ ‭randomized‬ ‭(1:1)‬ ‭in‬ ‭an‬
‭open-label‬‭phase‬‭II‬‭trial‬‭to‬‭four‬‭cycles‬‭of‬‭carboplatin‬‭(AUC‬‭5)‬‭plus‬‭pemetrexed‬‭500‬‭mg/m2‬‭iv‬‭every‬
‭three‬‭weeks‬‭alone‬‭or‬‭in‬‭combination‬‭with‬‭pembrolizumab‬‭200‬‭mg‬‭iv,‬‭flat‬‭dose,‬‭every‬‭three‬‭weeks,‬
‭followed‬ ‭by‬ ‭maintenance‬ ‭with‬ ‭pembrolizumab‬ ‭for‬ ‭24‬ ‭months‬ ‭and‬ ‭pemetrexed‬ ‭until‬ ‭progressive‬
‭disease‬‭or‬‭unacceptable‬‭toxicity.‬‭Patients‬‭were‬‭stratified‬‭according‬‭to‬‭PD-L1‬‭expression‬‭(<1%‬‭vs‬‭≥‬
‭1%).‬ ‭55%‬‭of‬‭patients‬‭in‬‭the‬‭pembrolizumab‬‭plus‬‭chemotherapy‬‭group‬‭achieved‬‭an‬‭objective‬‭response‬
‭compared‬‭with‬‭29%‬‭in‬‭the‬‭chemotherapy‬‭alone‬‭group‬‭(p=0.0016).‬‭The‬‭incidence‬‭of‬‭grade‬‭3‬‭or‬‭worse‬
‭treatment-related‬ ‭adverse‬ ‭events‬ ‭was‬ ‭similar‬ ‭between‬ ‭both‬ ‭arms‬‭occurring‬‭in‬‭23‬‭pts‬‭(39%)‬‭in‬‭the‬
‭pembrolizumab‬‭plus‬‭chemotherapy‬‭arm‬‭and‬‭16‬‭(26%)‬‭in‬‭the‬‭chemotherapy‬‭alone‬‭arm.‬ ‭Most‬‭common‬
‭grade‬ ‭3‬ ‭or‬ ‭worse‬‭treatment-related‬‭adverse‬‭events‬‭were‬‭anaemia‬‭(12%‬‭in‬‭the‬‭pembrolizumab‬‭plus‬
‭chemotherapy‬‭group‬‭vs‬‭15%‬‭in‬‭the‬‭chemotherapy‬‭alone‬‭group),‬‭decreased‬‭neutrophil‬‭count‬‭(5%‬‭vs‬
‭3%),‬‭thrombocytopenia‬‭(3%‬‭in‬‭both‬‭arms)‬‭and‬‭decreased‬‭lymphocyte‬‭count,‬‭neutropenia,‬‭and‬‭sepsis‬
‭(3%‬‭vs‬‭2%‬‭each).‬‭The‬‭incidence‬‭of‬‭adverse‬‭events‬‭based‬‭on‬‭a‬‭presumed‬‭immunological‬‭mechanism‬‭of‬
‭action,‬‭was‬‭22%‬‭in‬‭the‬‭pembrolizumab‬‭plus‬‭chemotherapy‬‭group‬‭and‬‭11%‬‭in‬‭the‬‭chemotherapy‬‭group.‬
‭The‬ ‭only‬ ‭events‬ ‭of‬ ‭grade‬ ‭3‬ ‭or‬ ‭worse‬ ‭were‬ ‭one‬ ‭infusion‬‭reaction‬‭(2%‬‭in‬‭the‬‭pembrolizumab‬‭plus‬
‭chemotherapy‬‭group‬‭vs‬‭none‬‭in‬‭the‬‭chemotherapy‬‭alone‬‭group),‬‭grade‬‭3‬‭skin‬‭reaction‬‭(one‬‭[2%]‬‭in‬‭the‬
‭pembrolizumab‬ ‭plus‬ ‭chemotherapy‬ ‭group‬ ‭vs‬ ‭one‬ ‭[2%]‬ ‭in‬ ‭the‬ ‭chemotherapy‬ ‭group,‬ ‭and‬ ‭grade‬ ‭3‬
‭pneumonitis‬‭(one‬‭[2%]‬‭in‬‭the‬‭pembrolizumab‬‭plus‬‭chemotherapy‬‭group).‬‭Deaths‬‭attributed‬‭to‬‭study‬
‭treatment‬‭occurred‬‭in‬‭one‬‭patient‬‭(1%)‬‭in‬‭the‬‭pembrolizumab‬‭plus‬‭chemotherapy‬‭group‬‭due‬‭to‬‭sepsis‬
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‭and‬‭two‬‭patients‬‭(3%)‬‭in‬‭the‬‭chemotherapy‬‭alone‬‭group‬‭(pancytopenia‬‭and‬‭sepsis).‬‭This‬‭study‬‭showed‬
‭that‬ ‭the‬ ‭combination‬ ‭of‬ ‭pembrolizumab‬ ‭and‬ ‭platinum‬ ‭chemotherapy‬ ‭could‬ ‭be‬ ‭an‬ ‭effective‬ ‭and‬
‭tolerable first-line treatment option for patients with NSCLC‬‭[xl]‬‭.‬
‭Furthermore,‬‭a‬‭recently‬‭published‬‭clinical‬‭trial‬‭assessing‬‭atezolizumab‬‭in‬‭combination‬‭with‬
‭different‬‭platinum-doublets‬‭in‬‭patients‬‭with‬‭newly‬‭diagnosed‬‭metastatic‬‭NSCLC‬‭showed‬‭encouraging‬
‭efficacy.‬‭Seventy-six‬‭NSCLC‬‭patients‬‭were‬‭enrolled‬‭and‬‭assigned‬‭to‬‭three‬‭different‬‭treatment‬‭arms:‬
‭atezolizumab‬‭plus‬‭carboplatin‬‭and‬‭paclitaxel‬‭(Arm‬‭C),‬‭atezolizumab‬‭plus‬‭carboplatin‬‭and‬‭pemetrexed‬
‭(Arm‬ ‭D)‬ ‭or‬ ‭atezolizumab‬‭plus‬‭carboplatin‬‭and‬‭nab-paclitaxel‬‭(Arm‬‭E).‬‭Common‬‭treatment-related‬
‭grade‬ ‭3-4‬‭adverse‬‭events‬‭were‬‭neutropenia‬‭(36%‬‭Arm‬‭C,‬‭36%‬‭Arm‬‭D,‬‭42%‬‭Arm‬‭E)‬‭and‬‭anaemia‬
‭(16%‬‭Arm‬‭C,‬‭16%‬‭Arm‬‭D,‬‭31%‬‭Arm‬‭E).‬‭Confirmed‬‭ORRs‬‭were‬‭36%‬‭Arm‬‭C,‬‭68%‬‭Arm‬‭D‬‭(one‬‭CR)‬
‭and‬‭46%‬‭Arm‬‭E‬‭(four‬‭CRs).‬‭Median‬‭PFS‬‭was‬‭7.1‬‭months,‬‭(95%‬‭CI:‬‭4.2-8.3),‬‭8.4‬‭months‬‭(95%‬‭CI:‬
‭4.7-11)‬ ‭and‬ ‭5.7‬ ‭months‬ ‭(95%‬ ‭CI:‬ ‭4.4-14.8),‬ ‭respectively.‬ ‭Median‬ ‭OS‬ ‭was‬‭12.9‬‭months‬‭(95%‬‭CI:‬
‭8.8-21.3),‬ ‭18.9‬ ‭months‬ ‭(95%‬ ‭CI:‬ ‭9.9-27.4)‬ ‭and‬ ‭17.0‬ ‭months‬ ‭(95%‬ ‭CI:‬ ‭12.7-not‬ ‭evaluable),‬
‭respectively.‬ ‭Atezolizumab‬ ‭was‬ ‭well‬ ‭tolerated‬ ‭in‬ ‭combination‬ ‭with‬ ‭all‬ ‭chemotherapy‬ ‭regimens‬
‭tested‬‭[xli],[xlii]‬‭.‬
‭Currently‬ ‭several‬ ‭phase‬ ‭Ib/II‬ ‭trials‬ ‭evaluating‬ ‭the‬ ‭combination‬ ‭of‬ ‭immune‬ ‭checkpoint‬
‭inhibitors plus chemotherapy are ongoing.‬
‭1.2.6.‬ ‭Potential for drug-drug interactions‬
‭Given‬‭nivolumab‬‭is‬‭a‬‭therapeutic‬‭monoclonal‬‭antibody,‬‭it‬‭is‬‭not‬‭anticipated‬‭to‬‭be‬‭directly‬‭eliminated‬
‭through‬‭hepatic/renal‬‭metabolism‬‭to‬‭compete‬‭with‬‭the‬‭elimination‬‭of‬‭platinum-doublet‬‭chemotherapy‬
‭agents, which are mainly eliminated through metabolism and renal excretion.‬
‭As‬‭nivolumab‬‭is‬‭not‬‭considered‬‭a‬‭cytokine‬‭modulator,‬‭it‬‭is‬‭unlikely‬‭to‬‭have‬‭an‬‭effect‬‭on‬‭drug‬
‭metabolizing‬‭enzymes‬‭or‬‭transporters‬‭in‬‭terms‬‭of‬‭inhibition‬‭or‬‭induction‬‭such‬‭as‬‭cytochrome‬‭P450‬
‭(CYP)‬ ‭enzymes.‬ ‭Therefore‬ ‭the‬ ‭risk‬ ‭of‬ ‭drug-drug‬ ‭interactions‬ ‭between‬ ‭nivolumab‬ ‭and‬
‭platinum-doublet chemotherapy agents is anticipated to be low.‬
‭2.‬
‭Objectives and Endpoints of the trial‬
‭The objectives and endpoints of the trial are summarized in Table 2-1.‬
‭2.1.‬
‭Primary objective‬
‭●‬ ‭To‬ ‭determine‬ ‭the‬ ‭efficacy‬ ‭of‬ ‭nivolumab‬ ‭in‬ ‭combination‬ ‭with‬ ‭platinum-chemotherapy‬ ‭in‬
‭patients‬ ‭with‬ ‭high‬‭grade‬‭neuroendocrine‬‭neoplasms,‬‭evaluated‬‭as‬‭one-year‬‭overall‬‭survival‬
‭(OS)‬ ‭rate‬ ‭calculated‬ ‭from‬ ‭the‬‭date‬‭of‬‭treatment‬‭initiation‬‭until‬‭the‬‭date‬‭of‬‭death‬‭from‬‭any‬
‭cause.‬
‭2.2.‬
‭Secondary Objectives‬
‭●‬ ‭To‬ ‭determine‬ ‭overall‬ ‭response‬ ‭rate‬ ‭(ORR)‬ ‭as‬ ‭per‬ ‭Response‬ ‭Evaluation‬ ‭Criteria‬ ‭in‬ ‭Solid‬
‭Tumors version 1.1 (RECIST v1.1) and the immune-related RECIST (irRECIST).‬
‭●‬ ‭To‬‭determine‬‭progression‬‭free‬‭survival‬‭(PFS)‬‭calculated‬‭from‬‭the‬‭date‬‭of‬‭treatment‬‭initiation‬
‭with‬ ‭first-line‬ ‭chemotherapy‬ ‭and‬ ‭nivolumab‬ ‭until‬ ‭the‬ ‭date‬ ‭of‬ ‭first‬ ‭documentation‬ ‭of‬
‭progressive disease as per RECIST v1.1 or death.‬
‭●‬ ‭To‬ ‭determine‬ ‭the‬ ‭OS‬ ‭calculated‬ ‭from‬ ‭the‬ ‭date‬ ‭of‬‭treatment‬‭initiation‬‭with‬‭nivolumab‬‭and‬
‭platinum-based chemotherapy until the date of death from any cause.‬
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‭●‬ ‭To‬‭assess‬‭biochemical‬‭response‬‭in‬‭patients‬‭with‬‭baseline‬‭elevation‬‭of‬‭chromogranin‬‭A‬‭and/or‬
‭enolase, and correlate it with clinical outcome.‬
‭●‬ ‭To‬‭assess‬‭the‬‭safety‬‭and‬‭toxicity‬‭profile‬‭of‬‭nivolumab‬‭in‬‭combination‬‭with‬‭platinum-doublets‬
‭in‬‭this‬‭patient‬‭population‬‭according‬‭to‬‭the‬‭Common‬‭Terminology‬‭Criteria‬‭for‬‭Adverse‬‭Events‬
‭v.5.0 (CTCAE).‬
‭●‬ ‭To explore potential predictive or prognostic blood or tissue biomarkers.‬
‭Objectives‬
‭Endpoints‬
‭Primary‬
‭●‬ ‭To‬ ‭determine‬ ‭the‬ ‭overall‬ ‭survival‬
‭patients‬ ‭with‬ ‭advanced‬ ‭G3‬ ‭NENs‬
‭treated‬
‭with‬
‭nivolumab‬
‭+‬
‭platinum-based chemotherapy.‬
‭●‬ ‭1 year-OS rate‬
‭Secondary‬
‭●‬ ‭To‬
‭determine‬
‭other‬
‭efficacy‬
‭outcomes‬
‭of‬
‭nivolumab‬
‭+‬
‭platinum-based‬ ‭chemotherapy‬ ‭in‬
‭patients with advanced G3 NENs.‬
‭●‬ ‭ORR‬
‭●‬ ‭Duration of response‬
‭●‬ ‭PFS‬
‭●‬ ‭OS‬
‭●‬ ‭To‬
‭evaluate‬
‭the‬
‭safety‬
‭and‬
‭tolerability‬
‭of‬
‭nivolumab‬
‭+‬
‭platinum-based‬ ‭chemotherapy‬ ‭in‬
‭this patient population.‬
‭●‬ ‭Incidence‬ ‭of‬ ‭AEs,‬ ‭SAEs‬ ‭and‬ ‭selected‬
‭AEs‬
‭●‬ ‭To‬‭evaluate‬‭biochemical‬‭response‬‭as‬
‭predictive‬ ‭biomarker‬ ‭of‬‭efficacy‬‭of‬
‭nivolumab‬ ‭+‬ ‭chemotherapy‬ ‭in‬ ‭this‬
‭patient population..‬
‭●‬ ‭Chromogranin‬ ‭A‬ ‭and‬ ‭enolase‬ ‭values‬
‭and‬ ‭their‬ ‭association‬ ‭with‬ ‭ORR,‬ ‭PFS‬
‭and OS.‬
‭●‬ ‭To‬ ‭explore‬ ‭potential‬‭predictive‬‭and‬
‭prognostic biomarkers.‬
‭●‬ ‭Mutational‬ ‭burden,‬ ‭gene‬ ‭expression‬
‭signature,‬ ‭soluble‬ ‭factors‬ ‭and‬ ‭other‬
‭molecular‬ ‭markers‬‭in‬‭peripheral‬‭blood‬
‭and‬ ‭their‬ ‭association‬ ‭with‬ ‭clinical‬
‭outcomes.‬
‭3.‬
‭Study Design‬
‭3.1.‬
‭Overall Design‬
‭This‬ ‭is‬ ‭a‬ ‭multi-center‬ ‭phase‬ ‭II‬ ‭non-randomized,‬ ‭open-label‬ ‭trial‬ ‭investigating‬ ‭platinum-doublet‬
‭chemotherapy‬‭in‬‭combination‬‭with‬‭nivolumab‬‭in‬‭patients‬‭with‬‭advanced‬‭G3‬‭NENs‬‭of‬‭GEP‬‭or‬‭UK‬
‭origin‬ ‭followed‬ ‭by‬ ‭maintenance‬ ‭treatment‬ ‭with‬‭nivolumab‬‭for‬‭up‬‭to‬‭2‬‭years‬‭in‬‭patients‬‭who‬‭have‬
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‭achieved‬‭complete‬‭response‬‭(CR),‬‭partial‬‭response‬‭(PR)‬‭or‬‭stable‬‭disease‬‭(SD)‬‭after‬‭6‬‭months‬‭of‬‭first‬
‭line platinum-based induction chemotherapy with nivolumab.‬
‭All participants will be treated as described below:‬
‭●‬ ‭6‬‭cycles‬‭of‬‭chemotherapy‬‭(carboplatin‬‭(AUC=‬‭5)‬‭iv‬‭on‬‭day‬‭1‬‭and‬‭etoposide‬‭100‬‭mg/m2/day‬‭iv‬
‭on‬‭days‬‭1-3,‬‭administered‬‭every‬‭3‬‭weeks)‬‭in‬‭combination‬‭with‬‭nivolumab‬‭360‬‭mg‬‭iv‬‭q3w‬‭(flat‬
‭dose).‬
‭●‬ ‭In‬ ‭the‬‭absence‬‭of‬‭disease‬‭progression,‬‭nivolumab‬‭treatment‬‭will‬‭be‬‭continued‬‭until‬‭disease‬
‭progression,‬ ‭unacceptable‬ ‭toxicity,‬ ‭death,‬ ‭withdrawal‬ ‭of‬‭consent,‬‭or‬‭a‬‭maximum‬‭treatment‬
‭duration‬ ‭of‬ ‭2‬ ‭years,‬ ‭whichever‬ ‭occurs‬ ‭first.‬ ‭Participants‬ ‭will‬ ‭be‬ ‭permitted‬ ‭to‬ ‭continue‬‭on‬
‭nivolumab‬‭beyond‬‭initial‬‭RECIST‬‭1.1‬‭defined‬‭progression,‬‭as‬‭long‬‭as‬‭they‬‭meet‬‭the‬‭criteria‬
‭described in‬‭section 5.3.1‬
‭The study design schematic is presented in Figure‬‭3.1-1‬
‭Figure 3.1-1‬
‭3.1.1.‬ ‭Data Monitoring Committee and Other External Committees‬
‭A Data Monitoring Committee (DMC) will not be required for this study, considering the following:‬
‭1.‬ ‭This study is an open-label study.‬
‭2.‬ ‭Data‬‭from‬‭the‬‭Checkmate-012‬‭study‬‭has‬‭demonstrated‬‭a‬‭favourable‬‭and‬‭manageable‬‭safety‬
‭profile that is consistent with prior experience with these agents.‬
‭3.‬ ‭Safety‬‭data‬‭will‬‭be‬‭closely‬‭monitored‬‭by‬‭BMS‬‭and‬‭the‬‭pharmacovigilance‬‭team‬‭of‬‭MFAR,‬
‭with‬‭real‬‭time‬‭review‬‭and‬‭assessment‬‭of‬‭SAEs‬‭as‬‭they‬‭are‬‭received,‬‭and‬‭periodic‬‭review‬‭of‬‭all‬
‭adverse events data for potential new safety signals.‬
‭3.2.‬
‭Number of participants‬
‭The‬‭planned‬‭sample‬‭size‬‭is‬‭38‬‭patients‬‭with‬‭G3‬‭NENs‬‭of‬‭gastroenteropancreatic‬‭or‬‭unknown‬‭primary‬
‭origin.‬
‭Participating‬‭centres‬‭will‬‭include‬‭10‬‭academic‬‭hospitals‬‭selected‬‭from‬‭the‬‭GETNE‬‭Spanish‬‭network‬
‭(Please see‬‭Section 9,‬‭statistical considerations,‬‭for specific details).‬
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‭3.3.‬
‭End of Study Definition‬
‭The‬‭duration‬‭of‬‭the‬‭study‬‭from‬‭start‬‭of‬‭enrollment‬‭to‬‭the‬‭last‬‭participant‬‭inclusion‬‭is‬‭expected‬‭to‬‭be‬‭18‬
‭months. The study will end once additional survival follow-up of 12 months has concluded.‬
‭3.4.‬
‭Study Calendar‬
‭-‬
‭Study start (estimated)‬
‭3Q 2019‬
‭-‬
‭First patient First visit (estimated)‬
‭4Q 2019‬
‭-‬
‭End or recruitment (estimated)‬
‭2Q 2021‬
‭-‬
‭Last patient Last visit (estimated)‬
‭2Q 2022‬
‭-‬
‭End of study (estimation)‬
‭4Q 2022‬
‭4.‬
‭Patient selection criteria‬
‭The‬ ‭following‬ ‭eligibility‬ ‭criteria‬ ‭are‬ ‭designed‬ ‭to‬ ‭select‬ ‭subjects‬ ‭for‬ ‭whom‬ ‭protocol‬ ‭treatment‬ ‭is‬
‭considered‬ ‭appropriate.‬ ‭All‬ ‭relevant‬ ‭medical‬ ‭and‬ ‭non-medical‬ ‭conditions‬ ‭should‬ ‭be‬ ‭taken‬ ‭into‬
‭consideration when deciding whether this protocol is suitable for a particular subject.‬
‭4.1.‬
‭Inclusion Criteria‬
‭Patients should meet all of the following inclusion criteria:‬
‭1.‬ ‭Histologically‬‭confirmed‬‭G3‬‭NENs‬‭originated‬‭in‬‭the‬‭gastroenteropancreatic‬‭tract‬‭(WHO‬‭2010‬
‭classification). Patients with a G3 NEN of unknown primary will also be eligible for this trial.‬
‭2.‬ ‭Ki-67 >20% or mitotic rate > 20 per 10 HPF.‬
‭3.‬ ‭Metastatic‬‭or‬‭locally‬‭advanced‬‭unresectable‬‭disease‬‭not‬‭amenable‬‭to‬‭treatment‬‭with‬‭curative‬
‭intent.‬
‭4.‬ ‭No prior systemic treatment for advanced disease‬‭nor as adjuvant therapy.‬
‭5.‬ ‭Availability‬‭of‬‭fresh‬‭or‬‭archive‬‭formalin-fixed,‬‭paraffin-embedded‬‭tumor‬‭tissue‬‭for‬‭biomarker‬
‭assessment.‬
‭6.‬ ‭Patients‬‭must‬‭have‬‭clinically‬‭and/or‬‭radiographically‬‭documented‬‭measurable‬‭disease.‬‭At‬‭least‬
‭one site of disease must be unidimensionally measurable as per RECIST 1.1.‬
‭7.‬ ‭Adequate‬ ‭organ‬ ‭function‬ ‭as‬ ‭defined‬ ‭by‬ ‭the‬ ‭following‬ ‭criteria‬ ‭(within‬ ‭7‬ ‭days‬ ‭prior‬ ‭to‬
‭enrollment):‬
‭a.‬ ‭absolute neutrophil count (ANC) ≥1500 cells/mm3‬
‭b.‬ ‭platelets ≥100,000 cells/mm3‬
‭c.‬ ‭hemoglobin ≥9.0 g/dL‬
‭d.‬ ‭AST‬‭and‬‭ALT‬‭≤2.5‬‭x‬‭upper‬‭limit‬‭of‬‭normal‬‭(ULN);‬‭in‬‭patients‬‭with‬‭liver‬‭metastases‬
‭AST and ALT ≤5.0 x ULN‬
‭e.‬ ‭total bilirubin ≤1.5 x ULN‬
‭f.‬
‭serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min.‬
‭8.‬ ‭Male or female, age ≥18 years.‬
‭9.‬ ‭ECOG performance status of 0-2.‬
‭10.‬‭Life expectancy of ≥12 weeks.‬
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‭11.‬ ‭Women‬‭of‬‭childbearing‬‭potential‬‭must‬‭have‬‭a‬‭negative‬‭serum‬‭or‬‭urine‬‭pregnancy‬‭test‬‭within‬‭7‬
‭days prior to treatment initiation.‬
‭12.‬‭Highly‬‭effective‬‭contraception‬‭(i.e.‬‭methods‬‭with‬‭a‬‭failure‬‭rate‬‭of‬‭less‬‭than‬‭1‬‭%‬‭per‬‭year)‬‭for‬
‭both‬‭fertile,‬‭sexually‬‭active‬‭male‬‭and‬‭female‬‭subjects.‬‭Highly‬‭effective‬‭contraception‬‭must‬‭be‬
‭used‬‭28‬‭days‬‭prior‬‭to‬‭first‬‭trial‬‭treatment‬‭administration,‬‭for‬‭the‬‭duration‬‭of‬‭trial‬‭treatment,‬
‭and at least for 60 days after stopping trial treatment.‬
‭13.‬‭Signed‬ ‭and‬ ‭dated‬ ‭informed‬ ‭consent‬ ‭document‬ ‭must‬ ‭be‬ ‭given‬ ‭according‬ ‭to‬‭ICH/GCP,‬‭and‬
‭national/local‬‭regulations‬‭indicating‬‭that‬‭the‬‭patient‬‭(or‬‭legally‬‭acceptable‬‭representative)‬‭has‬
‭been informed of all pertinent aspects of the trial prior to enrolment.‬
‭4.2.‬
‭Exclusion Criteria‬
‭Subjects shall not meet any of the following exclusion criteria:‬
‭1.‬ ‭The‬‭following‬‭endocrine‬‭tumor‬‭types‬‭may‬‭not‬‭be‬‭included:‬‭paraganglioma,‬‭adrenal,‬‭thyroid‬
‭parathyroid‬‭or‬‭pituitary‬‭endocrine‬‭tumors.‬‭Large‬‭or‬‭small‬‭cell‬‭lung‬‭neuroendocrine‬‭carcinoma‬
‭of the lung will also be excluded.‬
‭2.‬ ‭Prior therapy with any immune checkpoint inhibitor.‬
‭3.‬ ‭Major‬‭surgery,‬‭except‬‭diagnostic‬‭biopsy,‬‭in‬‭<4‬‭weeks‬‭or‬‭radiation‬‭therapy‬‭<2‬‭weeks‬‭prior‬‭to‬
‭starting‬ ‭study‬ ‭treatment.‬ ‭Prior‬ ‭palliative‬ ‭radiotherapy‬ ‭to‬ ‭metastatic‬ ‭lesion(s)‬ ‭is‬ ‭permitted,‬
‭provided there is at least one measurable lesion that has not been irradiated.‬
‭4.‬ ‭Prior organ transplantation, including allogeneic stem-cell transplantation.‬
‭5.‬ ‭Prior history of non-infectious pneumonitis requiring steroids or current pneumonitis.‬
‭6.‬ ‭Systemic‬ ‭chronic‬ ‭steroid‬ ‭therapy‬ ‭(>‬ ‭10‬ ‭mg/day‬ ‭prednisone‬ ‭or‬ ‭equivalent)‬ ‭or‬ ‭other‬
‭immunosuppressive‬‭agents‬‭or‬‭use‬‭of‬‭any‬‭investigational‬‭drug‬‭within‬‭28‬‭days‬‭before‬‭the‬‭start‬
‭of‬‭trial‬‭treatment.‬‭Short-term‬‭administration‬‭of‬‭steroids‬‭for‬‭allergic‬‭reactions‬‭or‬‭management‬
‭of‬‭immune-related‬‭adverse‬‭events‬‭is‬‭allowed.‬‭Topical,‬‭inhaled,‬‭nasal‬‭and‬‭ophthalmic‬‭steroids‬
‭are also allowed.‬
‭7.‬ ‭Use‬ ‭of‬ ‭any‬ ‭live‬ ‭vaccines‬ ‭against‬ ‭infectious‬ ‭diseases‬‭within‬‭4‬‭weeks‬‭of‬‭initiation‬‭of‬‭study‬
‭treatment.‬
‭8.‬ ‭Known‬ ‭history‬ ‭of‬ ‭positive‬ ‭testing‬ ‭for‬ ‭Human‬ ‭Immunodeficiency‬ ‭Virus‬ ‭(HIV)‬ ‭infection,‬
‭known‬‭history‬‭of‬‭or‬‭positive‬‭tests‬‭for‬‭Hepatitis‬‭B‬‭virus‬‭surface‬‭antigen‬‭(HBVsAg)‬‭or‬‭Hepatitis‬
‭C‬‭ribonucleic‬‭acid‬‭(HCV‬‭RNA)‬‭indicating‬‭acute‬‭or‬‭chronic‬‭infection‬‭or‬‭other‬‭significant‬‭acute‬
‭or chronic infections requiring medication at study entry.‬
‭9.‬ ‭Active,‬ ‭known‬ ‭or‬ ‭suspected‬ ‭autoimmune‬ ‭disease‬ ‭or‬ ‭a‬‭documented‬‭history‬‭of‬‭autoimmune‬
‭disease,‬ ‭including‬ ‭ulcerative‬ ‭colitis‬ ‭and‬ ‭Crohn’s‬ ‭disease.‬ ‭(Patients‬ ‭with‬ ‭vitiligo,‬ ‭type‬ ‭I‬
‭diabetes‬ ‭mellitus,‬ ‭residual‬ ‭hypothyroidism‬ ‭due‬ ‭to‬ ‭autoimmune‬ ‭condition‬ ‭only‬ ‭requiring‬
‭hormone‬‭replacement,‬‭psoriasis‬‭not‬‭requiring‬‭systemic‬‭treatment,‬‭or‬‭conditions‬‭not‬‭expected‬
‭to recur in the absence of an external trigger are permitted to enroll).‬
‭10.‬‭Active‬ ‭seizure‬ ‭disorder‬ ‭or‬ ‭evidence‬ ‭of‬ ‭brain‬ ‭metastases,‬ ‭spinal‬ ‭cord‬ ‭compression,‬ ‭or‬
‭carcinomatous meningitis.‬
‭11.‬ ‭A‬‭serious‬‭uncontrolled‬‭medical‬‭disorder‬‭or‬‭active‬‭infection‬‭that‬‭would‬‭impair‬‭their‬‭ability‬‭to‬
‭receive‬‭study‬‭treatment‬‭will‬‭not‬‭be‬‭allowed‬‭to‬‭enter‬‭the‬‭study.‬‭Any‬‭of‬‭the‬‭following‬‭within‬‭the‬
‭12‬ ‭months‬ ‭prior‬ ‭to‬ ‭study‬ ‭drug‬ ‭administration:‬ ‭myocardial‬ ‭infarction,‬‭uncontrolled‬‭angina,‬
‭coronary/peripheral‬ ‭artery‬ ‭bypass‬ ‭graft,‬ ‭NYHA‬ ‭class‬ ‭>‬ ‭III‬ ‭congestive‬ ‭heart‬ ‭failure,‬
‭cerebrovascular‬‭accident‬‭or‬‭transient‬‭ischemic‬‭attack‬‭and‬‭6‬‭months‬‭for‬‭deep‬‭vein‬‭thrombosis‬
‭or pulmonary embolism.‬
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‭12.‬‭Known‬ ‭hypersensitivity‬ ‭reactions‬ ‭to‬ ‭monoclonal‬ ‭antibodies‬ ‭(≥‬ ‭grade‬ ‭3‬ ‭according‬ ‭to‬ ‭NCI‬
‭Common‬‭Terminology‬‭Criteria‬‭for‬‭Adverse‬‭Events‬‭(CTCAE)‬‭v‬‭5.0‬‭[xliii]‬ ‭or‬‭any‬‭past‬‭medical‬
‭history‬‭of‬‭anaphylaxis‬‭or‬‭uncontrolled‬‭asthma‬‭(i.e.,‬‭3‬‭or‬‭more‬‭asthma‬‭characteristics‬‭partially‬
‭controlled).‬
‭13.‬‭Any‬‭other‬‭prior‬‭malignancy‬‭within‬‭5‬‭years‬‭of‬‭study‬‭entry,‬‭with‬‭the‬‭exception‬‭of‬‭adequately‬
‭treated in-situ carcinoma of the cervix, breast or uteri, or non-melanomatous skin cancer.‬
‭14.‬‭Any‬ ‭psychological,‬ ‭familial,‬ ‭sociological‬ ‭or‬ ‭geographical‬ ‭condition‬ ‭potentially‬ ‭hampering‬
‭compliance‬ ‭with‬ ‭the‬ ‭study‬ ‭protocol‬ ‭and‬ ‭follow-up‬ ‭schedule;‬ ‭those‬ ‭conditions‬ ‭should‬ ‭be‬
‭discussed with the patient before registration in the trial.‬
‭15.‬‭Dementia‬ ‭or‬ ‭significantly‬ ‭altered‬ ‭mental‬ ‭status‬ ‭that‬ ‭would‬ ‭prohibit‬ ‭the‬ ‭understanding‬ ‭or‬
‭rendering of informed consent and compliance with the requirements of this protocol.‬
‭16.‬‭Female‬‭patients‬‭who‬‭are‬‭pregnant‬‭or‬‭lactating,‬‭or‬‭men‬‭and‬‭women‬‭of‬‭reproductive‬‭potential‬
‭not‬‭willing‬‭or‬‭not‬‭able‬‭to‬‭employ‬‭an‬‭effective‬‭method‬‭of‬‭birth‬‭control/contraception‬‭to‬‭prevent‬
‭pregnancy‬ ‭during‬ ‭treatment‬ ‭and‬ ‭for‬ ‭6‬ ‭months‬ ‭after‬ ‭discontinuing‬ ‭study‬ ‭treatment‬ ‭The‬
‭definition‬‭of‬‭effective‬‭contraception‬‭should‬‭be‬‭in‬‭agreement‬‭with‬‭local‬‭regulation‬‭and‬‭based‬
‭on the judgment of the principal investigator or a designated associate.‬
‭17.‬‭Other‬‭severe‬‭acute‬‭or‬‭chronic‬‭medical‬‭or‬‭psychiatric‬‭condition,‬‭or‬‭laboratory‬‭abnormality‬‭that‬
‭may‬‭increase‬‭the‬‭risk‬‭associated‬‭with‬‭study‬‭participation‬‭or‬‭study‬‭drug‬‭administration,‬‭or‬‭may‬
‭interfere‬‭with‬‭the‬‭interpretation‬‭of‬‭study‬‭results,‬‭and‬‭in‬‭the‬‭judgment‬‭of‬‭the‬‭investigator‬‭would‬
‭make the patient inappropriate for study entry.‬
‭4.3.‬
‭Screening Failures‬
‭Screening‬‭failures‬‭are‬‭defined‬‭as‬‭participants‬‭who‬‭consent‬‭to‬‭participate‬‭in‬‭the‬‭clinical‬‭study‬‭but‬‭are‬
‭not‬ ‭subsequently‬ ‭randomized.‬ ‭A‬ ‭minimal‬ ‭set‬ ‭of‬ ‭screen‬ ‭failure‬ ‭information‬ ‭is‬ ‭required‬ ‭to‬ ‭ensure‬
‭transparent‬‭reporting‬‭of‬‭screen‬‭failure‬‭participants,‬‭to‬‭meet‬‭the‬‭Consolidated‬‭Standards‬‭of‬‭Reporting‬
‭Trials‬‭(CONSORT)‬‭publishing‬‭requirements,‬‭and‬‭to‬‭respond‬‭to‬‭queries‬‭from‬‭regulatory‬‭authorities.‬
‭Minimal‬‭information‬‭includes‬‭date‬‭of‬‭consent,‬‭demography,‬‭screen‬‭failure‬‭details,‬‭eligibility‬‭criteria,‬
‭and any serious AEs.‬
‭4.3.1.‬ ‭Retesting during Screening Period‬
‭This‬‭study‬‭permits‬‭the‬‭re-enrollment‬‭of‬‭a‬‭participant‬‭that‬‭has‬‭discontinued‬‭the‬‭study‬‭as‬‭a‬‭pre-treatment‬
‭failure‬ ‭(ie,‬ ‭participant‬ ‭has‬ ‭not‬ ‭been‬ ‭treated).‬ ‭If‬ ‭re-enrolled,‬ ‭the‬ ‭participant‬ ‭must‬ ‭be‬ ‭re-consented.‬
‭Retesting‬ ‭of‬ ‭laboratory‬ ‭parameters‬ ‭and/or‬ ‭other‬ ‭assessments‬ ‭within‬ ‭any‬ ‭single‬ ‭screening‬ ‭will‬ ‭be‬
‭permitted (in addition to any parameters that require a confirmatory value).‬
‭5.‬
‭Therapeutic Regimens, Expected Toxicity, Dose Modifications‬
‭Study‬ ‭treatment‬ ‭is‬ ‭defined‬ ‭as‬ ‭any‬ ‭investigational‬ ‭treatment(s),‬ ‭marketed‬ ‭product(s),‬ ‭placebo‬ ‭or‬
‭medical‬‭device‬‭intended‬‭to‬‭be‬‭administered‬‭to‬‭a‬‭study‬‭participant‬‭according‬‭to‬‭the‬‭study‬‭treatment‬
‭allocation.‬
‭Study‬‭treatment‬‭includes‬‭both‬‭Investigational‬‭[Medicinal]‬‭Product‬‭(IP/IMP)‬‭and‬‭Non-investigational‬
‭[Medicinal] Product (Non-IP/Non-IMP) and consist of the following:‬
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‭●‬ ‭Nivolumab‬
‭●‬ ‭Carboplatin‬
‭●‬ ‭Etoposide‬
‭Other‬‭medications‬‭used‬‭as‬‭support‬‭or‬‭escape‬‭medication‬‭for‬‭preventative,‬‭diagnostic,‬‭or‬‭therapeutic‬
‭reasons,‬ ‭as‬ ‭components‬ ‭of‬ ‭the‬ ‭standard‬ ‭of‬ ‭care‬ ‭for‬ ‭a‬ ‭given‬ ‭diagnosis,‬ ‭may‬ ‭be‬ ‭considered‬ ‭as‬
‭non-investigational products.‬
‭Study Treatments for Study CA209- 73D‬
‭Product‬
‭description and‬
‭dosage Form‬
‭Potency‬
‭IP/Non-‬
‭IP‬
‭Blinded or‬
‭Open‬
‭Label‬
‭Primary‬
‭Packaging‬
‭(Volume)/Label‬
‭Type and‬
‭Secondary‬
‭Packaging‬
‭(Qty)/Label Type‬
‭Appearance‬
‭Storage‬
‭Conditions‬
‭(per label)‬
‭BMS-936558-01‬
‭Nivolumab‬
‭Solution for‬
‭Injection‬‭a‬
‭100‬
‭mg/vial‬
‭(10‬
‭mg/mL)‬
‭IP‬
‭Open Label‬
‭10 mL per vial and‬
‭5 or 10 vials per‬
‭carton‬
‭Clear to‬
‭opalescent‬
‭colorless to pale‬
‭yellow liquid.‬
‭May contain‬
‭particles‬
‭2 to 8 C.‬
‭Protect from‬
‭light and‬
‭freezing‬
‭Carboplatin‬
‭Solution for‬
‭injection‬‭b‬
‭450‬
‭mg/vial‬
‭(10‬
‭mg/mL)‬
‭IP‬
‭Open Label‬
‭Various packaging‬
‭configuration‬
‭Clear, colorless‬
‭or slightly‬
‭yellow solution.‬
‭Product should‬
‭be stored as‬
‭per market‬
‭product‬
‭conditions.‬
‭Etoposide‬
‭100 mg/‬
‭vial‬
‭(20mg/‬
‭mL)‬
‭IP‬
‭Open Label‬
‭Various packaging‬
‭configuration‬
‭Powder, white‬
‭to white with a‬
‭yellow cast.‬
‭Product should‬
‭be stored as‬
‭per market‬
‭product‬
‭conditions.‬
‭NOTES:‬‭a‬‭May be labeled as either “BMS-936558-01”‬‭or “Nivolumab”‬
‭5.1.‬
‭Treatments Administered‬
‭The‬‭treatments‬‭that‬‭will‬‭be‬‭used‬‭in‬‭this‬‭trial‬‭are‬‭outlined‬‭below‬‭(Table-5.1).‬‭They‬‭will‬‭be‬‭administered‬
‭in the order presented.‬
‭All trial treatments may be administered on an outpatient basis.‬
‭Table-5.1. Trial treatments‬
‭Drug‬
‭Drug‬
‭Frequency‬
‭Administration‬
‭Treatment‬
‭period‬
‭Use‬
‭Nivolumab‬
‭360 mg‬
‭Q3W‬
‭IV infusion‬
‭Day 1 of each‬
‭cycle‬
‭Experimental‬
‭Carboplatin‬
‭AUC5‬
‭Q3W‬
‭IV infusion‬
‭Day 1 of each‬
‭cycle‬
‭Standard‬
‭Etoposide‬
‭100‬
‭mg/m‬‭2‬‭/day‬
‭Q3W‬
‭IV infusion‬
‭Days 1-3 of‬
‭each cycle‬
‭Standard‬
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‭Nivolumab‬‭will‬‭be‬‭administered‬‭first‬‭as‬‭a‬‭30‬‭minute‬‭IV‬‭infusion,‬‭followed‬‭by‬‭the‬‭carboplatin‬‭infusion‬
‭and‬‭then‬‭the‬‭etoposide‬‭infusion.‬‭Platinum-doublet‬‭will‬‭start‬‭at‬‭least‬‭30‬‭minutes‬‭after‬‭completion‬‭of‬‭the‬
‭nivolumab‬‭infusion.‬‭At‬‭the‬‭investigator’s‬‭discretion,‬‭nivolumab‬‭may‬‭be‬‭administered‬‭over‬‭a‬‭longer‬
‭infusion time (60 minutes) if the participant developed a prior infusion reaction.‬
‭Nivolumab‬ ‭treatment‬ ‭will‬ ‭continue‬ ‭until‬ ‭disease‬ ‭progression,‬ ‭discontinuation‬ ‭due‬ ‭to‬‭unacceptable‬
‭toxicity,‬ ‭or‬ ‭withdrawal‬ ‭of‬ ‭consent.‬ ‭Participants‬ ‭will‬ ‭be‬‭treated‬‭up‬‭to‬‭24‬‭months‬‭in‬‭the‬‭absence‬‭of‬
‭disease progression or unacceptable toxicity.‬
‭All‬‭participants‬‭will‬‭be‬‭monitored‬‭continuously‬‭for‬‭adverse‬‭events‬‭(AEs)‬‭while‬‭on‬‭study‬‭treatment.‬
‭Treatment‬‭modifications‬‭(eg,‬‭dose‬‭delay,‬‭reduction,‬‭retreatment,‬‭or‬‭discontinuation)‬‭will‬‭be‬‭based‬‭on‬
‭specific laboratory and adverse event criteria, as described in‬‭sections 5.2-5.3.‬
‭5.1.1.‬ ‭Dosing‬
‭5.1.1.1.‬‭Nivolumab‬
‭Participants‬‭will‬‭receive‬‭nivolumab,‬‭followed‬‭by‬‭chemotherapy‬‭on‬‭day‬‭1‬‭of‬‭every‬‭3‬‭weeks‬
‭cycle‬ ‭for‬ ‭6‬ ‭cycles‬ ‭(‬‭induction‬ ‭phase‬‭).‬ ‭At‬‭the‬‭time‬‭of‬‭completion‬‭of‬‭6‬‭cycles‬‭of‬‭chemotherapy‬‭and‬
‭nivolumab,‬ ‭participants‬ ‭who‬ ‭have‬ ‭not‬ ‭experienced‬ ‭disease‬ ‭progression‬ ‭will‬ ‭continue‬ ‭to‬ ‭receive‬
‭nivolumab‬‭at‬‭a‬‭dose‬‭of‬‭480‬‭mg‬‭as‬‭30‬‭minute‬‭infusion‬‭every‬‭4‬‭weeks‬‭for‬‭up‬‭to‬‭2‬‭years‬‭(‬‭maintenance‬
‭phase‬‭).‬
‭Drug‬
‭Dose‬
‭Frequency‬
‭Administration‬
‭Treatment period‬
‭Use‬
‭Induction phase‬
‭Nivolumab‬
‭360 mg‬
‭Q3W‬
‭IV infusion‬
‭Day 1 of each cycle‬
‭Experimental‬
‭Maintenance phase‬
‭Nivolumab‬
‭480 mg‬
‭Q4W‬
‭IV infusion‬
‭Day 1 of each cycle‬
‭Experimental‬
‭Treatment‬ ‭will‬ ‭continue‬ ‭until‬ ‭progression,‬ ‭unacceptable‬ ‭toxicity,‬ ‭withdrawal‬ ‭of‬ ‭consent,‬
‭whichever‬‭occurs‬‭first.‬‭Treatment‬‭with‬‭nivolumab‬‭will‬‭be‬‭given‬‭for‬‭up‬‭to‬‭24‬‭months‬‭including‬‭the‬
‭induction phase (a total of 34 cycles) in the absence of disease progression or unacceptable toxicity.‬
‭The‬ ‭assessment‬ ‭for‬ ‭discontinuation‬ ‭of‬ ‭nivolumab‬ ‭should‬ ‭be‬ ‭made‬ ‭separately‬ ‭from‬
‭chemotherapy.‬ ‭If‬ ‭criteria‬ ‭for‬ ‭discontinuation‬ ‭for‬ ‭nivolumab‬ ‭are‬ ‭met,‬ ‭platinum-based‬ ‭doublet‬
‭chemotherapy‬ ‭may‬‭continue‬‭until‬‭6‬‭cycles‬‭have‬‭been‬‭completed.‬‭If‬‭a‬‭participant‬‭meets‬‭criteria‬‭for‬
‭discontinuation‬‭and‬‭investigator‬‭is‬‭unable‬‭to‬‭determine‬‭whether‬‭the‬‭event‬‭is‬‭related‬‭to‬‭all‬‭or‬‭one‬‭study‬
‭drug, the participant should discontinue all study drugs and be taken off the study.‬
‭5.1.1.2 Chemotherapy dosing‬
‭6‬ ‭cycles‬ ‭of‬‭carboplatin‬‭in‬‭combination‬‭with‬‭etoposide‬‭will‬‭be‬‭administered‬‭every‬‭3‬‭weeks‬
‭(Q3W).‬
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‭All‬‭chemotherapy‬‭agents’‬‭preparation,‬‭premedication,‬‭administration,‬‭monitoring,‬‭and‬‭management‬‭of‬
‭complications‬‭are‬‭to‬‭follow‬‭local‬‭prescription‬‭guidelines‬‭and‬‭regulations.‬‭The‬‭dose‬‭of‬‭chemotherapy‬
‭may be capped per local standards.‬
‭❏‬ ‭Carboplatin:‬
‭Carboplatin‬‭(AUC=5)‬‭will‬‭be‬‭administered‬‭as‬‭a‬‭15-60‬‭minute‬‭IV‬‭infusion‬‭per‬‭site’s‬‭standard‬‭practice‬
‭Q3W‬‭on‬‭day‬‭1‬‭of‬‭each‬‭treatment‬‭cycle.‬‭Carboplatin‬‭will‬‭be‬‭administered‬‭to‬‭participants‬‭at‬‭least‬‭30‬
‭minutes following the end of the nivolumab infusion.‬
‭The dose of carboplatin will be calculated using the‬‭Calvert formula‬‭as follows:‬
‭Carboplatin dose (mg)= AUC target x ([CrCl (ml/min) + 25]‬
‭Creatinine‬‭clearance‬‭(CrCl)‬‭calculation‬‭is‬‭based‬‭on‬‭the‬‭Cockcroft-Gault‬‭formula‬‭and‬‭should‬‭include‬
‭the most recent serum creatinine and the most recent weight.‬
‭NOTE‬‭:‬‭If‬‭calculation‬‭of‬‭the‬‭CrCl‬‭by‬‭the‬‭Cockcroft-Gault‬‭formula‬‭yields‬‭a‬‭result‬‭of‬‭>‬‭125‬‭mL/min,‬
‭then‬‭a‬‭CrCl‬‭should‬‭be‬‭calculated‬‭by‬‭an‬‭alternative‬‭formula‬‭per‬‭institutional‬‭standards‬‭or‬‭capped‬‭at‬‭125‬
‭mL/min.‬
‭The dose of carboplatin may be capped per local standards.‬
‭❏‬ ‭Etoposide:‬
‭Etoposide‬ ‭100‬ ‭mg/m‬‭2‬‭/day‬‭will‬ ‭be‬ ‭administered‬ ‭as‬ ‭a‬ ‭30-60‬ ‭minute‬ ‭IV‬ ‭infusion‬‭per‬‭site’s‬‭standard‬
‭practice‬‭Q3W‬‭on‬‭days‬‭1,‬‭2‬‭and‬‭3‬‭of‬‭each‬‭treatment‬‭cycle.‬‭Etoposide‬‭will‬‭be‬‭administered‬‭following‬
‭the end of carboplatin infusion.‬
‭5.1.1.3 Premedication‬
‭❏‬ ‭Nivolumab‬
‭Patients‬ ‭should‬ ‭not‬ ‭receive‬‭pre-medication‬‭to‬‭prevent‬‭infusion‬‭reaction‬‭before‬‭the‬‭first‬‭infusion‬‭of‬
‭nivolumab.‬‭If‬‭a‬‭patient‬‭experiences‬‭an‬‭infusion‬‭reaction,‬‭he/she‬‭may‬‭receive‬‭premedication‬‭prior‬‭to‬
‭subsequent dosing days  (‬‭Table 5.1.3).‬
‭❏‬ ‭Carboplatin and Etoposide:‬
‭Antiemetic‬ ‭premedication‬ ‭will‬ ‭be‬ ‭administered‬ ‭according‬ ‭to‬ ‭local‬ ‭standards.‬ ‭Recommended‬
‭antiemetic treatments are:‬
‭❏‬ ‭Dexamethasone‬‭(dosing‬‭according‬‭to‬‭local‬‭standards;‬‭an‬‭equivalent‬‭dose‬‭of‬‭another‬
‭corticosteroid may be administered).‬
‭❏‬ ‭A‬ ‭5-HT3‬ ‭receptor‬ ‭antagonist‬ ‭(type‬ ‭per‬ ‭investigator‬ ‭discretion‬ ‭and‬ ‭local‬
‭standards-of-care).‬
‭Additional‬‭use‬‭of‬‭antiemetic‬‭premedications‬‭may‬‭be‬‭employed‬‭at‬‭the‬‭discretion‬‭of‬‭the‬‭Investigator.‬
‭Please‬‭refer‬‭to‬‭the‬‭product‬‭label‬‭or‬‭local‬‭standards‬‭of‬‭care‬‭for‬‭carboplatin‬‭and‬‭etoposide‬‭supportive‬
‭measures.‬
‭5.1.2.‬ ‭Patient Monitoring‬
‭Vital‬ ‭signs‬ ‭including‬ ‭temperature,‬ ‭pulse,‬ ‭respiratory‬ ‭rate,‬ ‭weight‬ ‭and‬ ‭blood‬ ‭pressure‬ ‭prior‬ ‭to‬ ‭the‬
‭administration of each dose of trial treatment will be measured as specified in‬‭section 7.4.‬
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‭5.1.3.‬ ‭Treatment of Nivolumab Infusion Reactions‬
‭Since‬‭nivolumab‬‭contains‬‭only‬‭human‬‭immunoglobulin‬‭protein‬‭sequences,‬‭it‬‭is‬‭unlikely‬‭to‬‭be‬
‭immunogenic‬‭and‬‭induce‬‭infusion‬‭or‬‭hypersensitivity‬‭reactions.‬‭However,‬‭if‬‭such‬‭a‬‭reaction‬‭were‬‭to‬
‭occur,‬ ‭it‬ ‭might‬ ‭manifest‬ ‭with‬ ‭fever,‬ ‭chills,‬ ‭rigors,‬ ‭headache,‬ ‭rash,‬ ‭pruritus,‬ ‭arthralgias,‬ ‭hypo-‬ ‭or‬
‭hypertension,‬ ‭bronchospasm,‬ ‭or‬ ‭other‬ ‭symptoms.‬ ‭All‬ ‭Grade‬ ‭3‬ ‭or‬ ‭4‬ ‭infusion‬ ‭reactions‬ ‭should‬ ‭be‬
‭reported‬ ‭within‬ ‭24‬ ‭hours‬ ‭to‬ ‭the‬‭BMS‬‭Medical‬‭Monitor‬‭and‬‭reported‬‭as‬‭a‬‭SAE‬‭if‬‭criteria‬‭are‬‭met.‬
‭Infusion reactions should be graded according to NCI CTCAE (Version 5.0) guidelines.‬
‭Treatment‬ ‭recommendations‬ ‭are‬ ‭provided‬ ‭below‬ ‭and‬ ‭may‬ ‭be‬ ‭modified‬ ‭based‬ ‭on‬ ‭local‬ ‭treatment‬
‭standards and guidelines, as appropriate:‬
‭For‬ ‭Grade‬ ‭1‬ ‭symptoms:‬‭(mild‬‭reaction;‬‭infusion‬‭interruption‬‭not‬‭indicated;‬‭intervention‬‭not‬
‭indicated)‬
‭●‬ ‭Remain‬ ‭at‬ ‭bedside‬ ‭and‬ ‭monitor‬ ‭the‬ ‭patient‬ ‭until‬ ‭recovery‬ ‭from‬‭symptoms.‬‭The‬‭following‬
‭prophylactic‬‭premedications‬‭are‬‭recommended‬‭for‬‭future‬‭infusions:‬‭diphenhydramine‬‭50‬‭mg‬
‭(or‬‭equivalent)‬‭and/or‬‭acetaminophen/paracetamol‬‭325‬‭to‬‭1000‬‭mg‬‭at‬‭least‬‭30‬‭minutes‬‭before‬
‭additional nivolumab administration.‬
‭For‬ ‭Grade‬ ‭2‬ ‭symptoms:‬ ‭(moderate‬ ‭reaction‬ ‭requires‬ ‭therapy‬ ‭or‬ ‭infusion‬ ‭interruption‬ ‭but‬
‭responds‬
‭promptly‬
‭to‬
‭symptomatic‬
‭treatment‬
‭[eg,‬
‭antihistamines,‬
‭non-steroidal‬
‭anti-inflammatory‬ ‭drugs,‬ ‭narcotics,‬ ‭corticosteroids,‬ ‭bronchodilators,‬ ‭IV‬ ‭fluids];‬ ‭prophylactic‬
‭medications indicated for < 24 hours)‬
‭●‬ ‭Stop‬‭the‬‭nivolumab‬‭infusion,‬‭begin‬‭an‬‭IV‬‭infusion‬‭of‬‭normal‬‭saline,‬‭and‬‭treat‬‭the‬‭participant‬
‭with‬ ‭diphenhydramine‬‭50‬‭mg‬‭IV‬‭(or‬‭equivalent)‬‭and/or‬‭acetaminophen/paracetamol‬‭325‬‭to‬
‭1000‬ ‭mg;‬ ‭remain‬ ‭at‬ ‭bedside‬ ‭and‬ ‭monitor‬ ‭participant‬ ‭until‬ ‭resolution‬ ‭of‬ ‭symptoms.‬
‭Corticosteroid‬‭and/or‬‭bronchodilator‬‭therapy‬‭may‬‭also‬‭be‬‭administered‬‭as‬‭appropriate.‬‭If‬‭the‬
‭infusion‬ ‭is‬ ‭interrupted,‬ ‭then‬ ‭restart‬ ‭the‬‭infusion‬‭at‬‭50%‬‭of‬‭the‬‭original‬‭infusion‬‭rate‬‭when‬
‭symptoms‬ ‭resolve;‬ ‭if‬ ‭no‬ ‭further‬ ‭complications‬ ‭ensue‬ ‭after‬ ‭30‬ ‭minutes,‬ ‭the‬ ‭rate‬ ‭may‬ ‭be‬
‭increased‬ ‭to‬ ‭100%‬ ‭of‬ ‭the‬ ‭original‬ ‭infusion‬ ‭rate.‬ ‭Monitor‬ ‭participant‬ ‭closely.‬‭If‬‭symptoms‬
‭recur,‬ ‭then‬ ‭no‬ ‭further‬ ‭nivolumab‬ ‭will‬ ‭be‬ ‭administered‬ ‭at‬ ‭that‬ ‭visit.‬ ‭Administer‬
‭diphenhydramine‬‭50‬‭mg‬‭IV,‬‭and‬‭remain‬‭at‬‭bedside‬‭and‬‭monitor‬‭the‬‭participant‬‭until‬‭resolution‬
‭of‬ ‭symptoms.‬ ‭The‬ ‭amount‬ ‭of‬ ‭study‬ ‭drug‬ ‭infused‬ ‭must‬‭be‬‭recorded‬‭on‬‭the‬‭electronic‬‭case‬
‭report form (eCRF).‬
‭●‬ ‭For‬ ‭future‬ ‭infusions,‬ ‭the‬ ‭following‬ ‭prophylactic‬ ‭premedications‬ ‭are‬ ‭recommended:‬
‭diphenhydramine‬‭50‬‭mg‬‭(or‬‭equivalent)‬‭and/or‬‭acetaminophen/paracetamol‬‭325‬‭to‬‭1000‬‭mg‬
‭should‬ ‭be‬ ‭administered‬ ‭at‬ ‭least‬ ‭30‬ ‭minutes‬ ‭before‬ ‭nivolumab‬ ‭infusion.‬ ‭If‬ ‭necessary,‬
‭corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.‬
‭For‬‭Grade‬‭3‬‭or‬‭4‬‭symptoms:‬‭(severe‬‭reaction,‬‭Grade‬‭3:‬‭prolonged‬‭[ie,‬‭not‬‭rapidly‬‭responsive‬‭to‬
‭symptomatic‬ ‭medication‬ ‭and/or‬ ‭brief‬ ‭interruption‬ ‭of‬ ‭infusion];‬ ‭recurrence‬ ‭of‬ ‭symptoms‬
‭following‬ ‭initial‬ ‭improvement;‬ ‭hospitalization‬ ‭indicated‬ ‭for‬ ‭other‬ ‭clinical‬‭sequelae‬‭[eg,‬‭renal‬
‭impairment,‬ ‭pulmonary‬ ‭infiltrates].‬ ‭Grade‬ ‭4:‬‭Life‬‭threatening;‬‭pressor‬‭or‬‭ventilator‬‭support‬
‭indicated)‬
‭●‬ ‭Immediately‬‭discontinue‬‭infusion‬‭of‬‭nivolumab.‬‭Begin‬‭an‬‭IV‬‭infusion‬‭of‬‭normal‬‭saline‬‭and‬
‭treat‬ ‭the‬ ‭participant‬ ‭as‬ ‭follows:‬ ‭Recommend‬‭bronchodilators,‬‭epinephrine‬‭0.2‬‭to‬‭1mg‬‭of‬‭a‬
‭1:1000‬ ‭solution‬ ‭for‬ ‭subcutaneous‬ ‭administration‬ ‭or‬ ‭0.1‬ ‭to‬‭0.25‬‭mg‬‭of‬‭a‬‭1:10.000‬‭solution‬
‭injected‬ ‭slowly‬ ‭for‬ ‭IV‬ ‭administration,‬ ‭and/or‬ ‭diphenhydramine‬ ‭50‬ ‭mg‬ ‭IV‬ ‭with‬
‭methylprednisolone‬‭100‬‭mg‬‭IV‬‭(or‬‭equivalent),‬‭as‬‭needed.‬‭Participant‬‭should‬‭be‬‭monitored‬
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‭until‬ ‭the‬ ‭investigator‬ ‭is‬ ‭comfortable‬ ‭that‬ ‭the‬ ‭symptoms‬ ‭will‬‭not‬‭recur.‬‭Nivolumab‬‭will‬‭be‬
‭permanently‬ ‭discontinued.‬ ‭Investigators‬ ‭should‬ ‭follow‬ ‭their‬‭institutional‬‭guidelines‬‭for‬‭the‬
‭treatment‬ ‭of‬ ‭anaphylaxis.‬ ‭Remain‬ ‭at‬ ‭bedside‬‭and‬‭monitor‬‭participant‬‭until‬‭recovery‬‭of‬‭the‬
‭symptoms.‬
‭In‬ ‭case‬ ‭of‬ ‭late-occurring‬ ‭hypersensitivity‬ ‭symptoms‬ ‭(eg,‬ ‭appearance‬ ‭of‬‭a‬‭localized‬‭or‬‭generalized‬
‭pruritus‬‭within‬‭1‬‭week‬‭after‬‭treatment),‬‭symptomatic‬‭treatment‬‭may‬‭be‬‭given‬‭(eg,‬‭oral‬‭antihistamine‬
‭or corticosteroids).‬
‭Table 5.1.3 Infusion reaction guidelines‬
‭Grade‬
‭Treatment‬
‭Premedication at subsequent dosing‬
‭Grade 1‬
‭Increase monitoring of vital signs‬
‭until the subject is deemed medically‬
‭stable in the opinion of the investigator.‬
‭Subject‬ ‭may‬ ‭be‬ ‭premedicated‬ ‭at‬ ‭least‬ ‭30‬
‭minutes prior to nivolumab infusion with:‬
‭●‬
‭Diphenhydramine‬
‭50‬
‭mg‬ ‭po‬ ‭(or‬
‭equivalent dose of antihistamine).‬
‭●‬
‭Acetaminophen 325-1000 mg po.‬
‭Grade 2‬
‭Stop Infusion and monitor symptoms.‬
‭Treat the participant with:‬
‭●‬
‭IV infusion of normal saline‬
‭●‬
‭Diphenhydramine 50 mg IV‬
‭●‬
‭Acetaminophen/‬
‭paracetamol‬
‭325-1000mg.‬
‭●‬
‭Increase‬ ‭monitoring‬ ‭of‬ ‭vital‬ ‭signs‬ ‭as‬
‭medically‬‭indicated‬‭until‬‭the‬‭subject‬‭is‬
‭deemed‬
‭medically‬
‭stable‬
‭in‬ ‭the‬
‭opinion of the investigator.‬
‭●‬
‭If‬ ‭symptoms‬ ‭resolve‬ ‭within‬ ‭one‬‭hour‬
‭of‬‭stopping‬‭drug‬‭infusion,‬‭the‬‭infusion‬
‭may‬‭be‬‭restarted‬‭at‬‭50%‬‭of‬‭the‬‭original‬
‭infusion‬‭rate‬‭(e.g.,‬‭from‬‭100‬‭mL/hr‬‭to‬
‭50‬ ‭mL/hr).‬ ‭Otherwise‬ ‭dosing‬ ‭will‬ ‭be‬
‭held‬ ‭until‬ ‭symptoms‬ ‭resolve‬ ‭and‬ ‭the‬
‭subject‬‭should‬‭be‬‭premedicated‬‭for‬‭the‬
‭next scheduled dose.‬
‭Subject should be premedicated at least 30‬
‭minutes prior to nivolumab infusion with:‬
‭●‬
‭Diphenhydramine‬
‭50‬
‭mg‬ ‭po‬ ‭(or‬
‭equivalent dose of antihistamine).‬
‭●‬
‭Acetaminophen 325-1000 mg po.‬
‭●‬
‭If‬ ‭necessary‬ ‭corticosteroids‬ ‭may‬ ‭be‬
‭used‬‭(up‬‭to‬‭25‬‭mg‬‭of‬‭hydrocortisone‬‭or‬
‭equivalent).‬
‭Grade 3-4‬
‭Stop Infusion.‬
‭Treat the participant with:‬
‭●‬
‭IV infusion of normal saline.‬
‭●‬
‭Bronchodilators if required.‬
‭●‬
‭Epinephrine‬ ‭0.2‬ ‭to‬ ‭1‬ ‭mg‬ ‭of‬‭a‬‭1:1000‬
‭solution sc.‬
‭●‬
‭Diphenhydramine 50 mg IV.‬
‭●‬
‭Methylprednisolone‬ ‭100‬ ‭mg‬ ‭IV‬ ‭(or‬
‭equivalent).‬
‭●‬
‭Remain‬
‭at‬ ‭bedside‬ ‭and‬ ‭monitor‬
‭participant‬ ‭until‬ ‭recovery‬ ‭of‬ ‭the‬
‭symptoms‬‭and‬‭stable‬‭in‬‭the‬‭opinion‬‭of‬
‭the investigator.‬
‭●‬
‭Hospitalization may be indicated.‬
‭Nivolumab permanently discontinued‬
‭No subsequent dosing‬
‭Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug‬
‭administration.‬
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‭5.2.‬
‭Dose Adjustments‬
‭●‬ ‭The‬ ‭Investigator‬ ‭may‬ ‭attribute‬ ‭each‬ ‭toxicity‬ ‭event‬ ‭to‬ ‭carboplatin,‬ ‭etoposide‬‭or‬‭nivolumab‬
‭alone‬ ‭and‬ ‭use‬ ‭a‬ ‭dose‬ ‭reduction‬ ‭according‬ ‭to‬ ‭Tables‬ ‭5.2,‬ ‭5.1.3.‬ ‭For‬ ‭individual‬ ‭subjects‬
‭requiring‬‭a‬‭dose‬‭modification,‬‭treatment‬‭for‬‭each‬‭new‬‭cycle‬‭may‬‭be‬‭delayed‬‭if‬‭the‬‭scheduled‬
‭off-drug‬‭periods‬‭are‬‭not‬‭adequate‬‭to‬‭allow‬‭for‬‭recovery‬‭to‬‭Grade‬‭≤1‬‭or‬‭the‬‭baseline‬‭status‬‭of‬
‭the subject.‬
‭●‬ ‭Nivolumab‬ ‭dose‬ ‭reductions‬ ‭are‬ ‭not‬‭permitted.‬‭Nivolumab‬‭treatment‬‭may‬‭be‬‭interrupted‬‭or‬
‭discontinued‬‭due‬‭to‬‭toxicity‬‭for‬‭up‬‭to‬‭6‬‭weeks‬‭(longer‬‭interruptions‬‭shall‬‭be‬‭discussed‬‭and‬
‭approved‬‭by‬‭the‬‭medical‬‭monitor‬‭on‬‭an‬‭individual‬‭basis).‬‭If‬‭toxicity‬‭has‬‭not‬‭recovered‬‭to‬‭at‬
‭least‬ ‭a‬ ‭grade‬ ‭1‬‭the‬‭patient‬‭shall‬‭be‬‭permanently‬‭discontinued‬‭from‬‭the‬‭study.‬‭Longer‬‭dose‬
‭interruptions.‬
‭●‬ ‭If‬ ‭a‬ ‭dose‬ ‭reduction‬ ‭for‬ ‭toxicity‬ ‭occurs‬ ‭with‬ ‭any‬ ‭agent,‬ ‭the‬ ‭dose‬‭may‬‭not‬‭be‬‭re-escalated.‬
‭Subjects‬‭can‬‭have‬‭a‬‭maximum‬‭of‬‭2‬‭dose‬‭modifications‬‭to‬‭each‬‭of‬‭the‬‭components‬‭of‬‭study‬
‭therapy‬ ‭throughout‬ ‭the‬ ‭course‬ ‭of‬ ‭the‬ ‭study‬ ‭for‬ ‭toxicities.‬ ‭If‬ ‭a‬‭subject‬‭experiences‬‭several‬
‭toxicities‬‭and‬‭there‬‭are‬‭conflicting‬‭recommendations,‬‭dose‬‭reduction‬‭will‬‭be‬‭done‬‭according‬
‭to‬‭the‬‭most‬‭severe‬‭toxicity.‬‭Subjects‬‭who‬‭require‬‭a‬‭3rd‬‭dose‬‭modification‬‭to‬‭any‬‭particular‬
‭component will have that agent discontinued.‬
‭●‬ ‭Reduction‬‭of‬‭one‬‭chemotherapy‬‭agent‬‭and‬‭not‬‭the‬‭other‬‭agent‬‭is‬‭appropriate‬‭if,‬‭in‬‭the‬‭opinion‬
‭of‬‭the‬‭investigator,‬‭the‬‭toxicity‬‭is‬‭clearly‬‭related‬‭to‬‭one‬‭of‬‭the‬‭treatments.‬‭If,‬‭in‬‭the‬‭opinion‬‭of‬
‭the‬‭investigator,‬‭the‬‭toxicity‬‭is‬‭related‬‭to‬‭the‬‭combination‬‭of‬‭both‬‭chemotherapy‬‭agents,‬‭both‬
‭drugs‬ ‭should‬ ‭be‬ ‭reduced‬ ‭according‬ ‭to‬ ‭recommended‬ ‭dose‬ ‭modifications.‬‭If‬‭the‬‭toxicity‬‭is‬
‭related‬‭to‬‭the‬‭combination‬‭of‬‭three‬‭agents,‬‭chemotherapy‬‭should‬‭be‬‭reduced,‬‭interrupted‬‭or‬
‭discontinued‬ ‭and‬ ‭nivolumab‬ ‭should‬ ‭be‬ ‭interrupted‬ ‭or‬ ‭discontinued‬ ‭according‬ ‭to‬ ‭the‬
‭recommended dose modifications.‬
‭Table 5.2. Dose modifications for trial medications‬
‭Drug‬
‭Dose level 0‬
‭Dose level -1‬
‭Dose level -2‬
‭Dose level -3‬
‭Carboplatin‬
‭AUC 5‬
‭AUC 4‬
‭AUC 3‬
‭Discontinue‬
‭Etoposide‬
‭100 mg/m2‬
‭80 mg/m2‬
‭60 mg/m2‬
‭Discontinue‬
‭Nivolumab‬
‭360 mg/m2‬
‭Dose reductions not permitted‬
‭5.2.1.‬ ‭Dose modifications for Nivolumab‬
‭There‬‭will‬‭be‬‭no‬‭dose‬‭reductions‬‭for‬‭nivolumab.‬‭Adverse‬‭events‬‭(AEs),‬‭both‬‭non-serious‬‭and‬‭serious,‬
‭associated‬‭with‬‭nivolumab‬‭exposure‬‭may‬‭represent‬‭an‬‭immunologic‬‭etiology.‬‭These‬‭adverse‬‭events‬
‭may‬‭occur‬‭shortly‬‭after‬‭the‬‭first‬‭dose‬‭or‬‭several‬‭months‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭treatment.‬‭AEs‬‭can‬‭differ‬
‭in‬ ‭severity‬ ‭and‬ ‭duration‬ ‭from‬ ‭AEs‬ ‭caused‬ ‭by‬ ‭other‬ ‭therapeutic‬ ‭classes.‬ ‭Early‬ ‭recognition‬ ‭and‬
‭management‬ ‭of‬ ‭AEs‬ ‭associated‬ ‭with‬ ‭immune-oncology‬ ‭agents‬ ‭may‬ ‭mitigate‬ ‭severe‬ ‭toxicity.‬
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‭Nivolumab‬ ‭must‬ ‭be‬ ‭withheld‬ ‭for‬ ‭drug-related‬ ‭toxicities‬ ‭and‬ ‭severe‬‭or‬‭life-threatening‬‭AEs‬‭as‬‭per‬
‭Table 5.2.1‬‭below.‬
‭Table 5.2.1 Nivolumab guidelines for drug-related adverse events.‬
‭Toxicity‬
‭Grade‬
‭of event‬
‭Management‬
‭Follow-up‬
‭Diarrhea/Colitis‬
‭1‬
‭Continue immunotherapy per‬
‭protocol.‬
‭Symptomatic treatment‬
‭-Close monitoring for worsening‬
‭symptoms.‬
‭-Educate patient to report worsening‬
‭immediately.‬
‭If worsens:‬
‭-Treat as Grade 2 or 3/4.‬
‭2‬
‭Hold treatment until toxicity resolves‬
‭to grade 0-1.‬
‭Symptomatic treatment.‬
‭If improves to grade 1‬‭:‬
‭-resume therapy per protocol‬
‭If persists> 5-7 days or recur‬‭:‬
‭-0.5-1.0 mg/kg/day methylprednisolone‬
‭or equivalent.‬
‭-When symptoms improve to grade 1,‬
‭taper steroids over at least 1 month,‬
‭consider prophylactic antibiotic for‬
‭opportunistic infections, and resume‬
‭immunotherapy per protocol.‬
‭If worsens or persists>3-5 days with oral‬
‭steroids:‬
‭-Treat as grade 3-4.‬
‭3-4‬
‭-Discontinue treatment.‬
‭-1.0 to 2.0 mg/kg/day‬
‭methylprednisolone IV or equivalent.‬
‭- Add prophylactic antibiotics for‬
‭opportunistic infections.‬
‭-Consider lower endoscopy‬
‭If improves:‬
‭-Continue steroids until grade 1, then‬
‭taper over at least 1 month.‬
‭If persists >3-5 days or recurs after‬
‭improvement:‬
‭-Add infliximab 5mg/kg (if no‬
‭contraindication).‬
‭Note: infliximab should not be used in‬
‭cases of perforation or sepsis.‬
‭AST, ALT,‬
‭Bilirubin‬
‭1‬
‭Continue treatment per protocol‬
‭Continue LFT monitoring per protocol.‬
‭If worsens:‬
‭-Treat as Grade 2 or 3-4.‬
‭2‬
‭-Hold treatment until toxicity resolves‬
‭to grade 0-1‬
‭-Increase frequency of monitoring to‬
‭every 3 days.‬
‭If returns to baseline:‬
‭-Resume routine monitoring, resume‬
‭therapy per protocol.‬
‭If elevations persist >5-7 days or worsen:‬
‭-0.5-1 mg/kg/day methylprednisolone or‬
‭oral equivalent and when LFT returns to‬
‭grade 1 or baseline, taper steroids over at‬
‭least 1 month, consider prophylactic‬
‭antibiotics for opportunistic infections‬
‭and resumen therapy per protocol.‬
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‭Toxicity‬
‭Grade‬
‭of event‬
‭Management‬
‭Follow-up‬
‭AST, ALT,‬
‭Bilirubin‬
‭3-4‬
‭-Discontinue nivolumab‬‭1‬
‭-Increase frequency of monitoring to‬
‭every 1-2 days.‬
‭-1.0 to 2.0 mg/kg/day‬
‭methylprednisolone IV or IV‬
‭equivalent‬‭2‬
‭If returns to grade 2‬‭:‬
‭-Taper steroids over at least 1 month.‬
‭If does not improve in >3-5 days, worsens‬
‭or rebounds:‬
‭-Add mycophenolate mofetil 1 g BID.‬
‭-If no response within an additional 3-5‬
‭days, consider other immunosuppressants‬
‭per local guidelines.‬
‭Skin Rash‬
‭1-2‬
‭-Symptomatic therapy (eg.‬
‭antihistamines, topical steroids).‬
‭-Continue nivolumab per protocol.‬
‭If persists >1-2 weeks or recurs:‬
‭-Consider skin biopsy.‬
‭-Delay nivolumab per protocol.‬
‭-Consider 0.5-1.0 mg/kg/day‬
‭methylprednisolone IV or oral equivalent.‬
‭Once improving, taper steroids over at‬
‭least 1 month, consider prophylactic‬
‭antibiotics for opportunistic infections,‬
‭and resume nivolumab per protocol.‬
‭If worsens:‬
‭-Treat as Grade 3-4.‬
‭3-4‬
‭-Hold or discontinue nivolumab per‬
‭protocol.‬
‭-Consider skin biopsy.‬
‭-Dermatology consult.‬
‭-1.0 to 2.0 mg/kg/day‬
‭methylprednisolone IV or IV‬
‭equivalent.‬
‭If it improves to Grade 1:‬
‭-Taper steroids over at least 1 month and‬
‭add prophylactic antibiotics for‬
‭opportunistic infections.‬
‭- Resume nivolumab per protocol.‬
‭Pneumonitis‬
‭1‬
‭-Consider delay of nivolumab.‬
‭-Monitor for symptoms every 2-3‬
‭days.‬
‭-Consider Pulmonary and ID consults.‬
‭-Re-image at least every 3 weeks.‬
‭If worsens:‬
‭-Treat as Grade 2 or 3-4‬
‭2‬
‭-Delay of nivolumab per protocol.‬
‭-Monitor for symptoms daily,consider‬
‭hospitalization.‬
‭- Pulmonary and ID consults.‬
‭-1.0 mg/kg/day methylprednisolone‬
‭IV or oral equivalent.‬
‭- Consider bronchoscopy, lung biopsy.‬
‭-Re-image every 1-3 days.‬
‭If improves:‬
‭-When symptoms return to near baseline,‬
‭taper steroids over at least 1 month and‬
‭then resume nivolumab per protocol and‬
‭consider prophylactic antibiotics.‬
‭If not improving after 2 weeks or‬
‭worsening:‬
‭-Treat as Grade 3-4.‬
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‭Toxicity‬
‭Grade‬
‭of event‬
‭Management‬
‭Follow-up‬
‭Pneumonitis‬
‭3-4‬
‭-Discontinue nivolumab per protocol.‬
‭-Hospitalize.‬
‭-Pulmonary and ID consults.‬
‭-2-4 mg/kg/day methylprednisolone‬
‭IV or equivalent.‬
‭-Add prophylactic antibiotics for‬
‭opportunistic infections.‬
‭- Consider bronchoscopy, lung biopsy.‬
‭If improves to baseline:‬
‭-Taper steroids over at least 6 weeks.‬
‭If not improving after 48 hours or‬
‭worsening‬‭:‬
‭-Add additional immunosuppression.‬
‭Renal failure or‬
‭nephritis‬
‭1‬
‭-Continue nivolumab per protocol.‬
‭-Monitor creatinine weekly‬
‭If returns to baseline:‬
‭-Resume routine creatinine monitoring‬
‭per protocol.‬
‭If worsens:‬
‭-Treat as Grade 2 or 3-4.‬
‭2-3‬
‭-Hold nivolumab per protocol.‬
‭-Monitor creatinine every 2-3 days.‬
‭0.5-1 mg/kg/day methylprednisolone‬
‭IV or equivalent.‬
‭-Consider renal biopsy with‬
‭nephrology consult.‬
‭If returns to Grade 1‬‭:‬
‭-Taper steroids over at least 1 month,‬
‭consider prophylactic antibiotics for‬
‭opportunistic infections, and resume‬
‭nivolumab and routine creatinine‬
‭monitoring per protocol.‬
‭If elevations persist >7 days or worsen:‬
‭-Treat as Grade 4.‬
‭4‬
‭-Discontinue nivolumab per protocol.‬
‭-Monitor creatinine daily.‬
‭-1.0-2.0mg/kg/day‬
‭methylprednisolone IV or IV‬
‭equivalent.‬
‭-Consider renal biopsy.‬
‭- Consult nephrologist.‬
‭If returns to Grade 1‬‭:‬
‭-Taper steroids over at least 1 month,‬
‭consider prophylactic antibiotics for‬
‭opportunistic infections.‬
‭Management‬
‭Follow-up‬
‭Asymptomatic‬
‭TSH elevation‬
‭-Continue nivolumab per protocol.‬
‭-If TSH<0.5 X LLN, or TSH>2 x ULN, or consistently out of range in 2 subsequent‬
‭measurements :include fT4 at subsequent cycles as clinically indicated; consider endocrinology‬
‭consult.‬
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‭Toxicity‬
‭Management‬
‭Follow-up‬
‭Symptomatic‬
‭endocrinopathy‬
‭-Evaluate endocrine function.‬
‭-Consider pituitary scan.‬
‭Symptomatic with abnormal lab/pituitary scan:‬
‭-Delay nivolumab per protocol.‬
‭-1-2 mg/kg/day methylprednisolone or PO‬
‭equivalent.‬
‭-Initiate appropriate hormone therapy.‬
‭No abnormal lab/pituitary MRI scan but‬
‭symptoms persist:‬
‭-Repeat labs in 1-3 weeks/MRI in 1 month.‬
‭If improves (with or without hormone‬
‭replacement):‬
‭-Taper steroids over at least 1 month,‬
‭consider prophylactic antibiotics for‬
‭opportunistic infections.‬
‭-Resume nivolumab per protocol.‬
‭- Patients with adrenal insufficiency may‬
‭need to continue steroids with‬
‭mineralocorticoid component.‬
‭Suspicion of‬
‭adrenal crisis (e.g.‬
‭severe‬
‭dehydration,‬
‭hypotension, shock‬
‭out of proportion‬
‭to current illness)‬
‭-Delay or Discontinue nivolumab therapy per protocol.‬
‭-Rule out sepsis.‬
‭-Stress dose of IV steroids with mineralocorticoid activity.‬
‭-IV fluids.‬
‭-Consult endocrinologist.‬
‭-If adrenal crisis ruled out, then trat as above for symptomatic endocrinopathy.‬
‭1‬‭Nivolumab may be delayed rather than discontinued‬‭if AST/ALT ≤ 8 X ULN or Total Bilirubin ≤ 5 x ULN.‬
‭2‬‭The recommended starting dose for grade 4 hepatitis‬‭is 2 mg/kg/day methylprednisolone IV.‬
‭3‬‭Patients with intolerable or persistent Grade 2‬‭drug-related AE may hold study medication at physician discretion.‬
‭Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has‬
‭been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.‬
‭5.2.2.‬ ‭Dose modifications for Chemotherapy‬
‭Dose‬‭reductions‬‭of‬‭chemotherapy‬‭may‬‭be‬‭required,‬‭and‬‭will‬‭be‬‭performed‬‭according‬‭to‬‭Table‬‭5.2.2.‬
‭Chemotherapy‬‭dose‬‭reductions‬‭are‬‭permanent;‬‭once‬‭the‬‭dose‬‭of‬‭any‬‭chemotherapy‬‭agent‬‭is‬‭reduced,‬‭it‬
‭may‬ ‭not‬ ‭be‬ ‭re-escalated‬ ‭in‬ ‭subsequent‬ ‭cycles.‬ ‭The‬ ‭dose‬ ‭reductions‬ ‭for‬ ‭each‬ ‭agent‬ ‭in‬ ‭the‬
‭platinum-based‬‭doublet‬‭chemotherapy‬‭regimen‬‭are‬‭not‬‭linked‬‭and‬‭may‬‭be‬‭adjusted‬‭independently‬‭as‬
‭summarized below.‬
‭Table 5.2.2 Dose modifications for Chemotherapeutic Agents‬
‭Drug‬
‭Dose level 0‬
‭Dose level -1‬
‭Dose level -2‬
‭Dose level -3‬
‭Carboplatin‬
‭AUC 5‬
‭AUC 4‬
‭AUC 3‬
‭Discontinue‬
‭Etoposide‬
‭100 mg/m2‬
‭80 mg/m2‬
‭60 mg/m2‬
‭Discontinue‬
‭Any‬‭participants‬‭with‬‭two‬‭prior‬‭dose‬‭reductions‬‭for‬‭one‬‭agent‬‭who‬‭experiences‬‭a‬‭toxicity‬‭that‬‭would‬
‭cause a third dose reduction must be discontinued from that agent.‬
‭5.2.2.1 Dose Reductions for Hematologic Adverse Events‬
‭Dose‬‭modifications‬‭for‬‭hematologic‬‭toxicities‬‭(according‬‭to‬‭CTCAE‬‭version‬‭5.0)‬‭are‬‭summarized‬‭in‬
‭Table-5.2.2.1‬‭.‬
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‭Dose‬ ‭adjustments‬ ‭are‬ ‭based‬ ‭on‬ ‭nadir‬ ‭blood‬ ‭counts‬ ‭(assessed‬ ‭as‬ ‭per‬ ‭local‬ ‭standards)‬ ‭since‬ ‭the‬
‭preceding‬‭drug‬‭administration.‬‭Dose‬‭level‬‭adjustments‬‭for‬‭platinum-based‬‭doublet‬‭chemotherapy‬‭are‬
‭relative‬ ‭to‬ ‭that‬ ‭of‬ ‭the‬ ‭preceding‬ ‭administration.‬ ‭Generally,‬ ‭both‬ ‭chemotherapy‬ ‭agents‬ ‭in‬ ‭the‬
‭platinum-based‬ ‭doublet‬ ‭chemotherapy‬ ‭regimen‬ ‭should‬ ‭be‬ ‭dose‬ ‭reduced‬ ‭together‬ ‭for‬ ‭hematologic‬
‭toxicity.‬‭After‬‭the‬‭first‬‭cycle,‬‭growth‬‭factors‬‭may‬‭be‬‭used‬‭to‬‭assist‬‭hematologic‬‭recovery.‬‭Use‬‭local‬
‭standards‬‭of‬‭care‬‭in‬‭the‬‭use‬‭of‬‭these‬‭supportive‬‭measures.‬‭Additionally,‬‭prophylactic‬‭antibiotics‬‭may‬
‭be‬‭used‬‭according‬‭to‬‭local‬‭standards‬‭of‬‭care.‬‭Please‬‭report‬‭any‬‭antibiotic‬‭or‬‭growth‬‭factor‬‭use‬‭on‬‭the‬
‭eCRF.‬
‭Table 5.2.2.1 Dose modifications for carboplatin/etoposide hematologic adverse events‬
‭Toxicity‬
‭Grade‬
‭Action‬
‭Treatment Restart‬
‭Treatment discontinuation‬
‭Neutropenia‬
‭3‬
‭Hold treatment until‬
‭Neutrophil count resolves‬
‭to >1,500/mm3‬
‭No dose reduction‬
‭required if‬
‭neutropenia does not‬
‭induce treatment‬
‭delay. If neutropenia‬
‭induces treatment‬
‭delay consider G-CSF‬
‭support. If already con‬
‭G-CSF support reduce‬
‭by 1 DL (at the‬
‭discretion of the‬
‭investigator)‬
‭Toxicity does not resolve‬
‭within 6 weeks of last‬
‭infusion‬
‭or if > 2 Dose Level‬
‭reductions are‬
‭exceeded‬
‭4‬
‭Hold treatment until‬
‭neutrophil count resolves‬
‭to >1,500/mm‬‭3‬
‭Reduce by 1 DL‬
‭*consider G-CSF‬
‭Febrile Neutropenia‬
‭3-4‬
‭Hold treatment until‬
‭toxicity resolves to‬
‭Grade 0-1‬
‭Reduce by 1 DL‬
‭Toxicity does not resolve‬
‭within 6 weeks of last‬
‭infusion‬
‭or if > 2 Dose Level‬
‭reductions are‬
‭exceeded‬
‭Thrombocytopenia‬
‭3-4‬
‭Platelet count resolves‬
‭to >100,000/mm3‬
‭Reduce by 1 DL‬
‭Toxicity does not resolve‬
‭within 6 weeks of last‬
‭infusion or if > 2 Dose Level‬
‭reductions‬
‭exceeded‬
‭5.2.2.2.‬‭Dose Reductions for Non-Hematologic Adverse Events‬
‭Dose‬‭adjustments‬‭for‬‭chemotherapy‬‭for‬‭non-hematologic‬‭toxicities‬‭during‬‭treatment‬‭are‬‭described‬‭in‬
‭Section‬‭5.2.2.‬‭All‬‭dose‬‭reductions‬‭should‬‭be‬‭made‬‭based‬‭on‬‭the‬‭worst‬‭grade‬‭toxicity‬‭during‬‭the‬‭prior‬
‭cycle.‬ ‭Participants‬ ‭experiencing‬ ‭any‬ ‭toxicity‬ ‭during‬ ‭the‬ ‭previous‬ ‭cycle‬ ‭should‬ ‭have‬ ‭their‬
‭chemotherapy‬ ‭delayed‬ ‭up‬ ‭to‬ ‭3‬ ‭weeks‬ ‭(6‬ ‭weeks‬ ‭since‬‭the‬‭administration‬‭of‬‭the‬‭last‬‭chemotherapy‬
‭infusion)‬‭until‬‭retreatment‬‭criteria‬‭are‬‭met‬‭and‬‭then‬‭reduced‬‭for‬‭all‬‭subsequent‬‭cycles‬‭by‬‭1‬‭dose‬‭level‬
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‭or‬‭discontinued‬‭as‬‭appropriate.‬‭Dose‬‭levels‬‭for‬‭the‬‭two‬‭drugs‬‭in‬‭the‬‭platinum-doublet‬‭chemotherapy‬
‭regimen are not linked and may be reduced independently, as summarized in‬‭Table-5.2.2.2.‬
‭Table 5.2.2.2. Dose modifications for non-hematologic adverse events‬
‭Toxicity‬
‭Grade‬
‭Action‬
‭Treatment Restart‬
‭Creatinine increased‬
‭2‬
‭Hold treatment until toxicity resolves to‬
‭Grade 0-1‬
‭Reduce cisplatin by 1‬
‭DL‬
‭3-4‬‭1‬
‭Discontinue carboplatin if creatinine‬
‭clearance <20 ml/min‬
‭Discontinue treatment‬
‭Ototoxicity or sensory‬
‭neuropathy‬
‭2‬
‭Hold treatment  until toxicity resolves to‬
‭Grade 0-1‬
‭Reduce cisplatin by 1‬
‭DL‬
‭≥ 3‬
‭Discontinue chemotherapy‬
‭Discontinue‬
‭chemotherapy‬
‭Allergic reaction‬‭a‬
‭≥ 3‬
‭Discontinue chemotherapy‬
‭Discontinue‬
‭chemotherapy‬
‭All other non-hematological‬
‭toxicities‬
‭3-4‬
‭Hold treatment until toxicity resolves to‬
‭Grade 0-1.‬
‭Reduce by 1 DL‬
‭a‬ ‭Only‬ ‭the‬ ‭drug(s)‬ ‭causing‬ ‭the‬ ‭hypersensitivity‬ ‭reaction‬ ‭or‬ ‭acute‬ ‭infusion‬ ‭reaction‬ ‭(≥‬ ‭Grade‬ ‭3)‬ ‭require‬
‭discontinuation. All other drugs may be continued.‬
‭5.2.3.‬ ‭Dose Delay Criteria‬
‭5.2.3.1.‬‭Dose delay Criteria for Nivolumab‬
‭Tumor assessments for all participants should continue as per protocol even if dosing is delayed.‬
‭Nivolumab administration should be delayed for the following:‬
‭●‬ ‭Any‬ ‭Grade‬ ‭≥‬ ‭2‬ ‭non-skin,‬ ‭drug-related‬ ‭adverse‬ ‭event,‬ ‭except‬ ‭for‬ ‭fatigue‬ ‭and‬ ‭laboratory‬
‭abnormalities.‬
‭●‬ ‭Any Grade ≥ 3 skin drug-related AE.‬
‭●‬ ‭Any‬ ‭Grade‬ ‭≥‬ ‭3‬ ‭drug-related‬ ‭laboratory‬ ‭abnormality‬ ‭with‬ ‭the‬ ‭following‬ ‭exceptions‬ ‭for‬
‭lymphopenia, AST, ALT, or total bilirubin or asymptomatic amylase or lipase:‬
‭○‬ ‭Grade 3 lymphopenia does not require a dose delay‬
‭If‬‭a‬‭participant‬‭has‬‭a‬‭baseline‬‭AST,‬‭ALT,‬‭or‬‭total‬‭bilirubin‬‭that‬‭is‬‭within‬‭normal‬‭limits,‬‭delay‬‭dosing‬
‭for drug-related Grade 2 toxicity.‬
‭If‬‭a‬‭participant‬‭has‬‭baseline‬‭AST,‬‭ALT,‬‭or‬‭total‬‭bilirubin‬‭within‬‭the‬‭Grade‬‭1‬‭toxicity‬‭range,‬‭delay‬
‭dosing for drug-related Grade ≥ 3 toxicity.‬
‭●‬ ‭Any‬ ‭Grade‬ ‭≥‬ ‭3‬ ‭drug-related‬ ‭amylase‬ ‭or‬ ‭lipase‬ ‭abnormality‬ ‭that‬ ‭is‬ ‭not‬ ‭associated‬ ‭with‬
‭symptoms or clinical manifestations of pancreatitis does not require dose delay.‬
‭●‬ ‭Any‬ ‭AE,‬ ‭laboratory‬ ‭abnormality‬ ‭or‬ ‭intercurrent‬ ‭illness,‬ ‭which,‬ ‭in‬ ‭the‬ ‭judgment‬ ‭of‬ ‭the‬
‭investigator, warrants delaying the dose of study medication.‬
‭Participants‬ ‭who‬ ‭require‬ ‭delay‬ ‭should‬ ‭be‬ ‭re-evaluated‬ ‭weekly‬ ‭or‬ ‭more‬ ‭frequently‬ ‭if‬ ‭clinically‬
‭indicated. Participants should resume dosing when re-treatment criteria are met.‬
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‭5.2.3.2.‬‭Dose delay Criteria for Chemotherapy‬
‭Chemotherapy drugs should be delayed for any of the following on the Day 1 of each cycle:‬
‭●‬ ‭Absolute neutrophil count (ANC) < 1500/L‬
‭●‬ ‭Platelets < 100,000/mm3‬
‭●‬ ‭Any‬ ‭Grade‬ ‭≥‬ ‭2‬‭non-skin,‬‭non-hematologic,‬‭drug-related‬‭adverse‬‭event‬‭(excluding‬‭Grade‬‭2‬
‭alopecia, Grade 2 fatigue, and Grade 2 laboratory abnormalities)‬
‭●‬ ‭Any Grade ≥ 3 skin, drug-related adverse event‬
‭●‬ ‭Any‬ ‭Grade‬ ‭≥‬ ‭3‬ ‭drug-related‬ ‭laboratory‬ ‭abnormality,‬ ‭with‬ ‭the‬ ‭following‬ ‭exceptions‬ ‭for‬
‭lymphopenia, AST, ALT, or total bilirubin:‬
‭○‬ ‭Grade 3 lymphopenia does not require dose delay.‬
‭○‬ ‭If‬‭a‬‭participant‬‭has‬‭a‬‭baseline‬‭AST,‬‭ALT‬‭or‬‭total‬‭bilirubin‬‭that‬‭is‬‭within‬‭normal‬‭limits,‬
‭delay dosing for drug-related Grade ≥ 2 toxicity.‬
‭o‬ ‭If‬‭a‬‭participant‬‭has‬‭baseline‬‭AST,‬‭ALT,‬‭or‬‭total‬‭bilirubin‬‭within‬‭the‬‭Grade‬‭1‬‭toxicity‬‭range,‬
‭delay dosing for drug-related Grade ≥ 3 toxicity.‬
‭●‬ ‭Any‬‭adverse‬‭event,‬‭laboratory‬‭abnormality,‬‭or‬‭intercurrent‬‭illness,‬‭which,‬‭in‬‭the‬‭judgment‬‭of‬
‭the investigator, warrants delaying the dose of study medication.‬
‭Investigators‬ ‭should‬ ‭consult‬ ‭local‬ ‭labeling‬ ‭for‬ ‭the‬ ‭chemotherapy‬ ‭drugs‬ ‭being‬‭administered‬‭to‬‭any‬
‭given participant for additional guidance on dose delays.‬
‭If‬‭any‬‭non-hematologic‬‭adverse‬‭event‬‭meeting‬‭the‬‭dose‬‭delay‬‭criteria‬‭above‬‭is‬‭felt‬‭to‬‭be‬‭related‬‭to‬‭only‬
‭one‬‭particular‬‭agent‬‭in‬‭the‬‭platinum-based‬‭doublet‬‭chemotherapy‬‭regimen,‬‭then‬‭that‬‭agent‬‭alone‬‭may‬
‭be‬‭omitted‬‭for‬‭that‬‭cycle‬‭while‬‭the‬‭other‬‭agent‬‭is‬‭given.‬‭In‬‭order‬‭to‬‭maintain‬‭synchronized‬‭dosing‬‭of‬
‭the‬ ‭regimen,‬‭the‬‭omitted‬‭agent‬‭should‬‭be‬‭resumed‬‭with‬‭the‬‭next‬‭scheduled‬‭cycle‬‭once‬‭the‬‭AE‬‭has‬
‭improved‬‭and‬‭retreatment‬‭criteria‬‭are‬‭met.‬‭Please‬‭refer‬‭to‬‭Section‬‭5.2.2‬‭to‬‭determine‬‭if‬‭dose‬‭reduction‬
‭of the resumed agent is required.‬
‭If‬‭both‬‭drugs‬‭in‬‭the‬‭platinum-based‬‭doublet‬‭chemotherapy‬‭regimen‬‭are‬‭delayed,‬‭then‬‭the‬‭participant‬
‭should‬‭be‬‭re-evaluated‬‭weekly‬‭or‬‭more‬‭frequently‬‭if‬‭clinically‬‭indicated‬‭until‬‭retreatment‬‭criteria‬‭are‬
‭met (as per‬‭Section 5.2.4‬‭).‬
‭5.2.4.‬ ‭Criteria to Resume Dosing‬
‭5.2.4.1.‬‭Criteria to Resume Nivolumab Dosing‬
‭Participants‬‭may‬‭resume‬‭treatment‬‭with‬‭nivolumab‬‭when‬‭the‬‭drug-related‬‭AE(s)‬‭resolve(s)‬‭to‬‭Grade‬‭≤‬
‭1 or baseline, with the following exceptions:‬
‭●‬ ‭Participants may resume treatment in the presence of Grade 2 fatigue.‬
‭●‬ ‭Participants‬‭who‬‭have‬‭not‬‭experienced‬‭a‬‭Grade‬‭3‬‭drug-related‬‭skin‬‭AE‬‭may‬‭resume‬‭treatment‬
‭in the presence of Grade 2 skin toxicity.‬
‭●‬ ‭Participants‬‭with‬‭baseline‬‭Grade‬‭1‬‭AST/ALT‬‭or‬‭total‬‭bilirubin‬‭who‬‭require‬‭dose‬‭delays‬‭for‬
‭reasons‬‭other‬‭than‬‭a‬‭2-grade‬‭shift‬‭in‬‭AST/ALT‬‭or‬‭total‬‭bilirubin‬‭may‬‭resume‬‭treatment‬‭in‬‭the‬
‭presence of Grade 2 AST/ALT OR total bilirubin.‬
‭●‬ ‭Participants‬ ‭with‬ ‭combined‬ ‭Grade‬ ‭2‬ ‭AST/ALT‬ ‭and‬ ‭total‬ ‭bilirubin‬ ‭values‬ ‭meeting‬
‭discontinuation parameters (‬‭Section 6.1.1‬‭) should‬‭have treatment permanently discontinued.‬
‭●‬ ‭Drug-related‬ ‭pulmonary‬ ‭toxicity,‬ ‭diarrhea,‬‭or‬‭colitis‬‭must‬‭have‬‭resolved‬‭to‬‭baseline‬‭before‬
‭treatment‬‭is‬‭resumed.‬‭Participants‬‭with‬‭persistent‬‭Grade‬‭1‬‭pneumonitis‬‭after‬‭completion‬‭of‬‭a‬
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‭steroid‬ ‭taper‬ ‭over‬ ‭at‬ ‭least‬ ‭1‬ ‭month‬ ‭may‬ ‭be‬ ‭eligible‬ ‭for‬ ‭retreatment‬ ‭if‬‭discussed‬‭with‬‭and‬
‭approved by the BMS Medical Monitor.‬
‭●‬ ‭Participants‬ ‭who‬ ‭received‬ ‭systemic‬ ‭corticosteroids‬ ‭for‬ ‭management‬ ‭of‬ ‭any‬ ‭drug-related‬
‭toxicity‬‭must‬‭be‬‭off‬‭corticosteroids‬‭or‬‭have‬‭tapered‬‭down‬‭to‬‭an‬‭equivalent‬‭dose‬‭of‬‭prednisone‬
‭≤ 10 mg/day.‬
‭●‬ ‭Drug-related‬ ‭endocrinopathies‬ ‭adequately‬ ‭controlled‬ ‭with‬ ‭only‬ ‭physiologic‬ ‭hormone‬
‭replacement may resume treatment.‬
‭●‬ ‭Dose‬ ‭delay‬ ‭of‬ ‭nivolumab‬ ‭which‬ ‭results‬ ‭in‬ ‭treatment‬ ‭interruption‬ ‭of‬ ‭>‬ ‭6‬ ‭weeks‬ ‭requires‬
‭treatment discontinuation, with exceptions as noted in‬‭Section 6.1.1‬
‭5.2.4.2.‬‭Criteria to Resume Treatment with Chemotherapy‬
‭●‬ ‭Participants‬‭may‬‭resume‬‭treatment‬‭with‬‭chemotherapy‬‭when‬‭the‬‭ANC‬‭returns‬‭to‬‭1500/μl,‬‭the‬
‭platelet‬‭count‬‭returns‬‭to‬‭100,000/mm3,‬‭and‬‭all‬‭other‬‭drug-related‬‭toxicities‬‭have‬‭returned‬‭to‬
‭baseline or Grade 1 (or Grade 2 for alopecia and fatigue).‬
‭●‬ ‭If‬‭a‬‭participant‬‭fails‬‭to‬‭meet‬‭criteria‬‭for‬‭re-treatment,‬‭then‬‭re-treatment‬‭should‬‭be‬‭delayed,‬‭and‬
‭the‬‭participant‬‭should‬‭be‬‭re-evaluated‬‭weekly‬‭or‬‭more‬‭frequently‬‭as‬‭clinically‬‭indicated.‬‭Any‬
‭participant‬ ‭who‬ ‭fails‬ ‭to‬ ‭recover‬ ‭from‬ ‭toxicity‬ ‭attributable‬ ‭to‬ ‭chemotherapy‬ ‭to‬ ‭baseline‬‭or‬
‭Grade‬‭1‬‭(except‬‭Grade‬‭2‬‭alopecia‬‭and‬‭fatigue)‬‭within‬‭6‬‭weeks‬‭from‬‭the‬‭last‬‭dose‬‭given‬‭should‬
‭discontinue the drug(s) that caused the delay.‬
‭●‬ ‭When‬‭resuming‬‭chemotherapy‬‭treatment,‬‭please‬‭follow‬‭the‬‭dose‬‭reduction‬‭recommendations‬
‭in‬‭Section 5.2.2.‬
‭5.3.‬
‭Duration of Therapy‬
‭●‬ ‭During‬‭the‬‭“induction‬‭phase”‬‭six‬‭cycles‬‭of‬‭chemotherapy‬‭in‬‭combination‬‭with‬‭nivolumab‬‭will‬
‭be‬ ‭given‬ ‭unless‬ ‭disease‬‭progression‬‭(see‬‭definition‬‭Section‬‭7)‬‭or‬‭unacceptable‬‭toxicity‬‭are‬
‭encountered.‬
‭●‬ ‭If‬‭no‬‭progression‬‭or‬‭unacceptable‬‭toxicity‬‭are‬‭observed‬‭after‬‭the‬‭induction‬‭phase,‬‭the‬‭patient‬
‭will‬‭continue‬‭to‬‭receive‬‭nivolumab‬‭480‬‭mg‬‭every‬‭4‬‭weeks.‬‭The‬‭maximum‬‭treatment‬‭duration‬
‭is 24 months or 34 cycles including the induction phase.‬
‭●‬ ‭End of treatment‬
‭Patients‬ ‭will‬ ‭continue‬ ‭study‬ ‭treatment‬ ‭until‬ ‭disease‬ ‭progression‬ ‭per‬ ‭RECIST‬ ‭1.1‬ ‭or,‬
‭unacceptable‬‭toxicity,‬‭withdrawal‬‭of‬‭consent,‬‭physician’s‬‭decision,‬‭subject/guardian‬‭decision,‬
‭lost‬‭to‬‭follow-up,‬‭death,‬‭study‬‭treatment‬‭completion‬‭(24‬‭months)‬‭or‬‭the‬‭study‬‭is‬‭terminated‬‭by‬
‭the Sponsor.‬
‭5.3.1.‬ ‭Treatment Beyond Disease Progression‬
‭Accumulating‬‭evidence‬‭indicates‬‭a‬‭minority‬‭of‬‭participants‬‭treated‬‭with‬‭immunotherapy‬‭may‬‭derive‬
‭clinical benefit despite initial evidence of PD.‬
‭Participants‬ ‭will‬ ‭be‬ ‭permitted‬ ‭to‬ ‭continue‬ ‭on‬ ‭nivolumab‬ ‭for‬‭treatment‬‭beyond‬‭initial‬‭RECIST‬‭1.1‬
‭defined PD as long as they meet the following criteria:‬
‭●‬ ‭Investigator-assessed clinical benefit and no rapid disease progression.‬
‭●‬ ‭Participant is tolerating study treatment.‬
‭●‬ ‭Stable performance status.‬
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‭●‬ ‭Treatment‬ ‭beyond‬ ‭progression‬ ‭will‬ ‭not‬ ‭delay‬ ‭an‬ ‭imminent‬ ‭intervention‬ ‭to‬‭prevent‬‭serious‬
‭complications of disease progression (eg, CNS metastases).‬
‭●‬ ‭Participant‬ ‭provides‬ ‭written‬ ‭informed‬ ‭consent‬ ‭prior‬ ‭to‬ ‭receiving‬ ‭additional‬ ‭nivolumab‬
‭treatment,‬‭using‬‭an‬‭ICF‬‭describing‬‭any‬‭reasonably‬‭foreseeable‬‭risks‬‭or‬‭discomforts,‬‭or‬‭other‬
‭alternative treatment options.‬
‭The‬‭decision‬‭to‬‭continue‬‭treatment‬‭beyond‬‭initial‬‭investigator-assessed‬‭progression‬‭should‬‭be‬
‭discussed‬‭with‬‭the‬‭BMS‬‭Medical‬‭Monitor‬‭and‬‭documented‬‭in‬‭the‬‭study‬‭records.‬‭A‬‭follow-up‬‭scan‬
‭should‬‭be‬‭performed‬‭within‬‭six‬‭weeks‬‭+/-‬‭7‬‭days‬‭of‬‭original‬‭PD‬‭to‬‭determine‬‭whether‬‭there‬‭has‬‭been‬‭a‬
‭decrease‬ ‭in‬ ‭the‬ ‭tumor‬ ‭size,‬ ‭or‬ ‭continued‬ ‭progression‬ ‭of‬ ‭disease.‬ ‭Subsequent‬ ‭scans‬ ‭should‬ ‭be‬
‭performed per protocol defined schedule +/- 7 days until further progression is determined.‬
‭If‬ ‭the‬ ‭investigator‬ ‭feels‬ ‭that‬ ‭the‬ ‭participant‬ ‭continues‬ ‭to‬ ‭achieve‬ ‭clinical‬ ‭benefit‬ ‭by‬ ‭continuing‬
‭treatment,‬‭the‬‭participant‬‭should‬‭remain‬‭on‬‭the‬‭trial‬‭and‬‭continue‬‭to‬‭receive‬‭monitoring‬‭according‬‭to‬
‭the Time and Events Schedule in Section‬‭7.2.‬
‭For‬‭the‬‭participants‬‭who‬‭continue‬‭study‬‭therapy‬‭beyond‬‭progression,‬‭further‬‭progression‬‭is‬
‭defined‬ ‭as‬ ‭an‬ ‭additional‬ ‭10%‬ ‭increase‬ ‭in‬ ‭tumor‬ ‭burden‬‭from‬‭time‬‭of‬‭initial‬‭PD.‬‭This‬‭includes‬‭an‬
‭increase‬‭in‬‭the‬‭sum‬‭of‬‭diameters‬‭of‬‭all‬‭target‬‭lesions‬‭and/or‬‭the‬‭diameters‬‭of‬‭new‬‭measurable‬‭lesions‬
‭compared‬‭to‬‭the‬‭time‬‭of‬‭initial‬‭PD.‬‭Nivolumab‬‭treatment‬‭should‬‭be‬‭discontinued‬‭permanently‬‭upon‬
‭documentation of further progression.‬
‭New‬ ‭lesions‬ ‭are‬ ‭considered‬ ‭measurable‬ ‭at‬ ‭the‬ ‭time‬ ‭of‬ ‭initial‬ ‭progression‬ ‭if‬ ‭the‬ ‭longest‬
‭diameter‬‭is‬‭at‬‭least‬‭10‬‭mm‬‭(except‬‭for‬‭pathological‬‭lymph‬‭nodes‬‭which‬‭must‬‭have‬‭a‬‭short‬‭axis‬‭of‬‭at‬
‭least 15 mm).‬
‭Any‬‭new‬‭lesion‬‭considered‬‭non-measurable‬‭at‬‭the‬‭time‬‭of‬‭initial‬‭progression‬‭may‬‭become‬‭measurable‬
‭and‬‭therefore‬‭included‬‭in‬‭the‬‭tumor‬‭burden‬‭if‬‭the‬‭longest‬‭diameter‬‭increases‬‭to‬‭at‬‭least‬‭10‬‭mm‬‭(except‬
‭for‬‭pathological‬‭lymph‬‭nodes‬‭which‬‭must‬‭have‬‭a‬‭short‬‭axis‬‭of‬‭at‬‭least‬‭15‬‭mm).‬‭In‬‭situations‬‭where‬‭the‬
‭relative‬‭increase‬‭in‬‭total‬‭tumor‬‭burden‬‭by‬‭10%‬‭is‬‭solely‬‭due‬‭to‬‭inclusion‬‭of‬‭new‬‭lesions‬‭which‬‭become‬
‭measurable, these new lesions must demonstrate an absolute increase of at least 5 mm.‬
‭5.4.‬
‭Preparation/Handling/Storage/ Accountability‬
‭The‬‭investigational‬‭product‬‭should‬‭be‬‭stored‬‭in‬‭a‬‭secure‬‭area‬‭according‬‭to‬‭local‬‭regulations.‬‭It‬
‭is‬‭the‬‭responsibility‬‭of‬‭the‬‭investigator‬‭to‬‭ensure‬‭that‬‭investigational‬‭product‬‭is‬‭only‬‭dispensed‬‭to‬‭study‬
‭participants.‬ ‭The‬ ‭investigational‬ ‭product‬ ‭must‬ ‭be‬ ‭dispensed‬ ‭only‬ ‭from‬ ‭official‬ ‭study‬ ‭sites‬ ‭by‬
‭authorized personnel according to local regulations.‬
‭The‬‭product‬‭storage‬‭manager‬‭should‬‭ensure‬‭that‬‭the‬‭study‬‭treatment‬‭is‬‭stored‬‭in‬‭accordance‬
‭with‬ ‭the‬ ‭environmental‬ ‭conditions‬ ‭(temperature,‬ ‭light,‬ ‭and‬ ‭humidity)‬ ‭as‬ ‭determined‬ ‭by‬ ‭BMS.‬ ‭If‬
‭concerns‬‭regarding‬‭the‬‭quality‬‭or‬‭appearance‬‭of‬‭the‬‭study‬‭treatment‬‭arise,‬‭the‬‭study‬‭treatment‬‭should‬
‭not be dispensed and contact BMS immediately.‬
‭Study treatment not supplied by BMS will be stored in accordance with the package insert.‬
‭Investigational‬‭product‬‭documentation‬‭(whether‬‭supplied‬‭by‬‭BMS‬‭or‬‭not)‬‭must‬‭be‬‭maintained‬
‭that‬ ‭includes‬ ‭all‬ ‭processes‬ ‭required‬ ‭to‬ ‭ensure‬ ‭drug‬ ‭is‬ ‭accurately‬ ‭administered.‬ ‭This‬ ‭includes‬
‭documentation‬‭of‬‭drug‬‭storage,‬‭administration‬‭and,‬‭as‬‭applicable,‬‭storage‬‭temperatures,‬‭reconstitution,‬
‭and use of required processes (eg, required diluents, administration sets).‬
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‭5.5.‬
‭Concomitant therapy‬
‭5.5.1.‬
‭Prohibited and/or Restricted Therapy‬
‭Subjects‬ ‭are‬ ‭prohibited‬ ‭from‬ ‭receiving‬ ‭the‬ ‭following‬ ‭therapies‬ ‭during‬ ‭screening‬ ‭to‬ ‭the‬ ‭end‬ ‭of‬
‭treatment of this trial:‬
‭●‬ ‭Antineoplastic systemic chemotherapy or biological therapy not specified in the protocol‬
‭●‬ ‭Immunotherapy not specified in this protocol.‬
‭●‬ ‭Investigational agents other than nivolumab.‬
‭●‬ ‭Radiation‬‭therapy;‬‭palliative‬‭radiation‬‭therapy‬‭to‬‭a‬‭symptomatic‬‭lesion‬‭(e.g.‬‭bony‬‭metastasis),‬
‭or to the brain may be permitted.‬
‭●‬ ‭Live‬‭vaccines‬‭within‬‭30‬‭days‬‭prior‬‭to‬‭the‬‭first‬‭dose‬‭of‬‭trial‬‭treatment‬‭and‬‭while‬‭participating‬‭in‬
‭the‬‭trial.‬‭Live‬‭vaccines‬‭include,‬‭but‬‭are‬‭not‬‭limited‬‭to,‬‭the‬‭following:‬‭measles,‬‭mumps,‬‭rubella,‬
‭chicken‬‭pox,‬‭yellow‬‭fever,‬‭rabies,‬‭BCG,‬‭and‬‭typhoid‬‭(oral)‬‭vaccine.‬‭The‬‭killed‬‭virus‬‭vaccines‬
‭used‬ ‭for‬ ‭seasonal‬ ‭influenza‬ ‭vaccines‬ ‭for‬ ‭injection‬ ‭are‬ ‭allowed;‬ ‭however‬ ‭live‬ ‭attenuated‬
‭intranasal influenza vaccines (e.g. Flu - Mist®) are not allowed.‬
‭●‬ ‭The‬‭use‬‭of‬‭systemic‬‭steroid‬‭therapy‬‭and‬‭other‬‭immunosuppressive‬‭drugs‬‭is‬‭not‬‭allowed‬‭except‬
‭for‬‭the‬‭treatment‬‭of‬‭infusion‬‭reaction,‬‭irAEs,‬‭and‬‭for‬‭prophylaxis‬‭against‬‭imaging‬‭contrast‬‭dye‬
‭allergy‬‭or‬‭replacement-dose‬‭steroids‬‭in‬‭the‬‭setting‬‭of‬‭adrenal‬‭insufficiency‬‭(providing‬‭this‬‭is‬
‭<10‬‭mg/day‬‭prednisone‬‭or‬‭equivalent),‬‭or‬‭transient‬‭exacerbations‬‭of‬‭other‬‭underlying‬‭diseases‬
‭such‬‭as‬‭COPD‬‭requiring‬‭treatment‬‭for‬‭≤‬‭3‬‭weeks.‬‭If‬‭systemic‬‭corticosteroids‬‭are‬‭required‬‭for‬
‭the‬ ‭control‬ ‭of‬ ‭infusion‬ ‭reactions‬ ‭or‬ ‭irAEs,‬ ‭it‬ ‭must‬ ‭be‬ ‭tapered‬ ‭and‬ ‭be‬ ‭at‬ ‭non‬
‭immunosuppressive‬ ‭doses‬ ‭(<‬ ‭10‬ ‭mg/day‬ ‭of‬ ‭prednisone‬ ‭or‬ ‭equivalent)‬ ‭before‬ ‭the‬ ‭next‬
‭administration‬‭of‬‭study‬‭treatment.‬‭If‬‭the‬‭dose‬‭of‬‭prednisone‬‭or‬‭equivalent‬‭cannot‬‭be‬‭reduced‬
‭to‬ ‭less‬ ‭than‬ ‭10‬ ‭mg/day‬ ‭before‬ ‭the‬ ‭administration‬ ‭of‬ ‭next‬ ‭dose‬ ‭of‬ ‭study‬ ‭treatment‬ ‭then‬
‭nivolumab must be discontinued.‬
‭Caution‬‭should‬‭be‬‭used‬‭regarding‬‭the‬‭use‬‭of‬‭herbal‬‭medications‬‭as‬‭there‬‭may‬‭be‬‭yet‬‭unknown‬
‭interactions‬ ‭with‬ ‭nivolumab.‬ ‭Discontinuation‬ ‭of‬ ‭the‬ ‭use‬ ‭of‬ ‭herbal‬ ‭medications‬ ‭prior‬ ‭to‬ ‭study‬
‭enrollment‬‭is‬‭encouraged.‬‭Except‬‭for‬‭the‬‭permitted‬‭procedures‬‭specified‬‭as‬‭palliative‬‭local‬‭therapies‬
‭(Section‬‭5.5.3),‬‭all‬‭other‬‭radiation‬‭therapy‬‭or‬‭surgery‬‭to‬‭any‬‭tumor‬‭lesion‬‭is‬‭not‬‭permitted‬‭during‬‭study‬
‭treatment.‬
‭There are no prohibited therapies during the post-treatment follow-up phase.‬
‭5.5.2.‬ ‭Permitted Therapy‬
‭All‬‭treatments‬‭that‬‭the‬‭investigator‬‭considers‬‭necessary‬‭for‬‭a‬‭subject’s‬‭welfare‬‭may‬‭be‬‭administered‬
‭at the discretion of the investigator in keeping with the standards of medical care.‬
‭Participants‬ ‭are‬ ‭permitted‬ ‭the‬ ‭use‬ ‭of‬ ‭topical,‬ ‭ocular,‬ ‭intra-articular,‬ ‭intranasal,‬‭and‬‭inhalational‬
‭corticosteroids‬‭(with‬‭minimal‬‭systemic‬‭absorption).‬‭Adrenal‬‭replacement‬‭steroid‬‭doses‬‭>10‬‭mg‬‭daily‬
‭prednisone‬‭are‬‭permitted.‬‭A‬‭brief‬‭(less‬‭than‬‭3‬‭weeks)‬‭course‬‭of‬‭corticosteroids‬‭for‬‭prophylaxis‬‭(eg,‬
‭contrast‬ ‭dye‬ ‭allergy)‬ ‭or‬ ‭for‬ ‭treatment‬ ‭of‬ ‭non-autoimmune‬ ‭conditions‬ ‭(eg,‬ ‭delayed-type‬
‭hypersensitivity reaction caused by a contact allergen) is permitted.‬
‭All‬ ‭concomitant‬ ‭medication‬ ‭will‬ ‭be‬ ‭recorded‬ ‭on‬ ‭the‬ ‭case‬ ‭report‬ ‭form‬ ‭(CRF)‬ ‭including‬ ‭all‬
‭prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids.‬
‭If‬‭changes‬‭occur‬‭during‬‭the‬‭trial‬‭period,‬‭documentation‬‭of‬‭drug‬‭dosage,‬‭frequency,‬‭route,‬‭and‬‭date‬
‭may also be included on the CRF.‬
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‭All‬‭concomitant‬‭medications‬‭received‬‭during‬‭the‬‭trial‬‭through‬‭30‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭trial‬
‭treatment should be recorded.‬
‭5.5.3.‬ ‭Palliative Local Therapy‬
‭Palliative‬‭local‬‭therapy,‬‭including‬‭palliative‬‭radiation‬‭therapy‬‭and‬‭palliative‬‭surgical‬‭resection,‬
‭to‬ ‭symptomatic‬ ‭non-target‬ ‭bone‬ ‭lesions,‬ ‭skin‬ ‭lesions,‬ ‭or‬ ‭CNS‬ ‭lesions‬ ‭is‬ ‭permitted‬ ‭prior‬ ‭to‬
‭discontinuation‬‭of‬‭study‬‭treatment‬‭for‬‭participants‬‭who‬‭do‬‭not‬‭have‬‭evidence‬‭of‬‭overall‬‭clinical‬‭or‬
‭radiographic progression per RECIST 1.1.‬
‭Palliative‬ ‭local‬ ‭therapy‬ ‭to‬ ‭lesions‬ ‭causing‬ ‭gastrointestinal‬ ‭bleeding‬‭may‬‭also‬‭be‬‭permitted‬
‭prior‬‭to‬‭discontinuation‬‭of‬‭study‬‭treatment‬‭in‬‭participants‬‭who‬‭do‬‭not‬‭have‬‭evidence‬‭of‬‭overall‬‭clinical‬
‭or‬ ‭radiographic‬ ‭progression‬ ‭per‬ ‭RECIST‬ ‭1.1,‬‭provided‬‭that‬‭the‬‭lesions‬‭undergoing‬‭palliative‬‭local‬
‭therapy‬‭are‬‭not‬‭the‬‭only‬‭sites‬‭of‬‭measurable‬‭disease‬‭and‬‭the‬‭case‬‭is‬‭discussed‬‭with‬‭and‬‭approved‬‭by‬
‭the BMS Medical Monitor.‬
‭Participants‬‭requiring‬‭palliative‬‭local‬‭therapy‬‭should‬‭be‬‭evaluated‬‭for‬‭objective‬‭evidence‬‭of‬
‭disease‬ ‭progression‬ ‭prior‬ ‭to‬ ‭the‬ ‭initiation‬ ‭of‬ ‭such‬ ‭therapy,‬ ‭particularly‬ ‭if‬ ‭the‬ ‭most‬ ‭recent‬ ‭tumor‬
‭assessment‬‭was‬‭more‬‭than‬‭4‬‭weeks‬‭prior‬‭to‬‭the‬‭start‬‭of‬‭local‬‭therapy.‬‭If‬‭progression‬‭per‬‭RECIST‬‭1.1‬‭is‬
‭identified‬‭on‬‭any‬‭tumor‬‭assessments‬‭prior‬‭to‬‭the‬‭initiation‬‭of‬‭palliative‬‭local‬‭therapy,‬‭then‬‭participants‬
‭must‬‭either‬‭discontinue‬‭study‬‭drug‬‭treatment‬‭or‬‭they‬‭must‬‭meet‬‭criteria‬‭to‬‭continue‬‭treatment‬‭beyond‬
‭progression (‬‭Section 5.3.1‬‭) in order to resume immunotherapy‬‭after palliative local therapy.‬
‭The‬ ‭potential‬ ‭for‬ ‭overlapping‬ ‭toxicities‬ ‭with‬ ‭radiotherapy‬ ‭and‬ ‭nivolumab‬ ‭currently‬ ‭is‬ ‭not‬
‭known;‬ ‭however,‬ ‭anecdotal‬ ‭data‬ ‭suggests‬ ‭that‬ ‭it‬ ‭is‬ ‭tolerable.‬ ‭As‬ ‭concurrent‬ ‭radiotherapy‬ ‭and‬
‭nivolumab‬‭have‬‭not‬‭been‬‭formally‬‭evaluated,‬‭in‬‭cases‬‭where‬‭palliative‬‭radiotherapy‬‭is‬‭required‬‭for‬‭a‬
‭tumor‬‭lesion,‬‭then‬‭nivolumab‬‭should‬‭be‬‭withheld‬‭for‬‭at‬‭least‬‭1‬‭week‬‭before,‬‭during,‬‭and‬‭1‬‭week‬‭after‬
‭radiation.‬ ‭Participants‬ ‭should‬ ‭be‬ ‭closely‬ ‭monitored‬ ‭for‬ ‭any‬ ‭potential‬ ‭toxicity‬ ‭during‬ ‭and‬ ‭after‬
‭receiving radiotherapy, and AEs should resolve to Grade ≤ 1 prior to resuming nivolumab.‬
‭5.5.4.‬ ‭Imaging Restrictions and Precautions‬
‭It‬‭is‬‭the‬‭local‬‭imaging‬‭facility’s‬‭responsibility‬‭to‬‭determine,‬‭based‬‭on‬‭participant‬‭attributes‬‭(eg,‬
‭allergy‬ ‭history,‬ ‭diabetic‬ ‭history‬ ‭and‬ ‭renal‬ ‭status),‬ ‭the‬ ‭appropriate‬ ‭imaging‬ ‭modality‬ ‭and‬ ‭contrast‬
‭regimen‬‭for‬‭each‬‭participant.‬‭Imaging‬‭contraindications‬‭and‬‭contrast‬‭risks‬‭should‬‭be‬‭considered‬‭in‬‭this‬
‭assessment.‬‭Participants‬‭with‬‭renal‬‭insufficiency‬‭should‬‭be‬‭assessed‬‭as‬‭to‬‭whether‬‭or‬‭not‬‭they‬‭should‬
‭receive‬‭contrast‬‭and‬‭if‬‭so,‬‭what‬‭type‬‭and‬‭dose‬‭of‬‭contrast‬‭is‬‭appropriate.‬‭Should‬‭a‬‭participant‬‭have‬‭a‬
‭contraindication‬‭for‬‭CT‬‭IV‬‭contrast,‬‭a‬‭non-contrast‬‭CT‬‭of‬‭the‬‭chest‬‭and‬‭a‬‭contrast‬‭enhanced‬‭MRI‬‭of‬
‭the abdomen and pelvis may be obtained.‬
‭Specific‬ ‭to‬ ‭MRI,‬ ‭participants‬ ‭with‬ ‭severe‬ ‭renal‬ ‭insufficiency‬ ‭(ie,‬ ‭estimated‬ ‭glomerular‬
‭filtration‬‭rate‬‭(eGFR)‬‭<‬‭30‬‭mL/min/1.73‬‭m2)‬‭are‬‭at‬‭increased‬‭risk‬‭of‬‭nephrogenic‬‭systemic‬‭fibrosis.‬
‭MRI‬‭contrast‬‭should‬‭not‬‭be‬‭given‬‭to‬‭this‬‭participant‬‭population.‬‭In‬‭addition,‬‭participants‬‭are‬‭excluded‬
‭from‬‭MRI‬‭if‬‭they‬‭have‬‭tattoos,‬‭metallic‬‭implants,‬‭pacemakers,‬‭etc.‬‭The‬‭ultimate‬‭decision‬‭to‬‭perform‬
‭MRI‬‭in‬‭an‬‭individual‬‭participant‬‭in‬‭this‬‭study‬‭rests‬‭with‬‭the‬‭site‬‭radiologist,‬‭the‬‭investigator‬‭and‬‭the‬
‭standard set by the local Ethics Committee.‬
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‭6.‬
‭Discontinuation Criteria‬
‭6.1.‬
‭Discontinuation from Study Treatment‬
‭For‬‭all‬‭participants,‬‭global‬‭deterioration‬‭of‬‭health‬‭status‬‭requiring‬‭discontinuation‬‭of‬‭treatment‬
‭without‬ ‭objective‬‭evidence‬‭of‬‭disease‬‭progression‬‭at‬‭that‬‭time‬‭should‬‭be‬‭reported‬‭as‬‭‘symptomatic‬
‭deterioration’ in the source data and in the case report form.‬
‭Tumor‬ ‭assessments‬ ‭for‬ ‭participants,‬ ‭who‬ ‭discontinue‬ ‭study‬ ‭treatment‬ ‭without‬ ‭radiographic‬
‭progression, should continue as per protocol until radiographic progression is determined.‬
‭Chemotherapy‬‭dose‬‭reduction‬‭is‬‭allowed‬‭on‬‭study.‬‭Any‬‭participant‬‭with‬‭two‬‭prior‬‭dose‬‭reductions‬
‭to‬‭one‬‭agent‬‭who‬‭experiences‬‭a‬‭toxicity‬‭that‬‭would‬‭cause‬‭a‬‭third‬‭dose‬‭reduction‬‭must‬‭be‬‭discontinued‬
‭from‬‭that‬‭agent.‬‭A‬‭participant‬‭who‬‭is‬‭discontinued‬‭from‬‭the‬‭chemotherapy‬‭treatment‬‭will‬‭remain‬‭on‬
‭the study and receive nivolumab.‬
‭6.1.1.‬ ‭Nivolumab Dose Discontinuation‬
‭Treatment with nivolumab should be permanently discontinued for any of the following:‬
‭●‬ ‭Any‬ ‭Grade‬ ‭≥‬‭2‬‭drug-related‬‭uveitis‬‭or‬‭eye‬‭pain‬‭or‬‭blurred‬‭vision‬‭that‬‭does‬‭not‬‭respond‬‭to‬
‭topical‬‭therapy‬‭and‬‭does‬‭not‬‭improve‬‭to‬‭Grade‬‭1‬‭severity‬‭within‬‭the‬‭re-treatment‬‭period‬‭OR‬
‭requires systemic treatment.‬
‭●‬ ‭Any‬‭Grade‬‭≥‬‭2‬‭drug-related‬‭pneumonitis‬‭or‬‭interstitial‬‭lung‬‭disease‬‭that‬‭does‬‭not‬‭resolve‬‭after‬
‭a dose delay and systemic steroids (also see‬‭Table‬‭5.2.1).‬
‭●‬ ‭Any‬ ‭Grade‬ ‭3‬ ‭drug-related‬ ‭bronchospasm,‬ ‭hypersensitivity‬ ‭reaction,‬ ‭or‬ ‭infusion‬ ‭reaction,‬
‭regardless of duration;‬
‭●‬ ‭Any‬ ‭Grade‬ ‭3‬ ‭non-skin,‬ ‭drug-related‬ ‭adverse‬ ‭event‬ ‭lasting‬ ‭>‬ ‭7‬ ‭days,‬ ‭with‬ ‭the‬ ‭following‬
‭exceptions‬ ‭for‬ ‭uveitis,‬ ‭pneumonitis,‬ ‭bronchospasm,‬ ‭diarrhea,‬ ‭colitis,‬ ‭neurologic‬ ‭toxicity,‬
‭hypersensitivity reactions, infusion reactions, endocrinopathies, and laboratory abnormalities:‬
‭○‬ ‭Grade‬‭3‬‭drug-related‬‭uveitis,‬‭pneumonitis,‬‭bronchospasm,‬‭diarrhea,‬‭colitis,‬‭neurologic‬
‭toxicity,‬ ‭hypersensitivity‬ ‭reaction,‬ ‭or‬ ‭infusion‬ ‭reaction‬ ‭of‬ ‭any‬ ‭duration‬ ‭requires‬
‭discontinuation.‬
‭○‬ ‭Grade‬ ‭3‬ ‭drug-related‬‭endocrinopathies‬‭adequately‬‭controlled‬‭with‬‭only‬‭physiologic‬
‭hormone replacement do not require discontinuation.‬
‭○‬ ‭Grade‬
‭3‬
‭drug-related‬
‭laboratory‬ ‭abnormalities‬ ‭do‬ ‭not‬ ‭require‬ ‭treatment‬
‭discontinuation except:‬
‭■‬ ‭Grade‬‭3‬‭drug-related‬‭thrombocytopenia‬‭>‬‭7‬‭days‬‭or‬‭associated‬‭with‬‭bleeding‬
‭requires discontinuation.‬
‭■‬ ‭Any‬ ‭drug-related‬ ‭liver‬ ‭function‬ ‭test‬ ‭(LFT)‬ ‭abnormality‬ ‭that‬ ‭meets‬ ‭the‬
‭following‬‭criteria‬‭require‬‭discontinuation:‬‭Grade‬‭≥‬‭3‬‭drug-related‬‭AST,‬‭ALT‬
‭or Total Bilirubin requires discontinuation.*‬
‭*‬ ‭In‬ ‭most‬ ‭cases‬ ‭of‬ ‭Grade‬ ‭3‬ ‭AST‬ ‭or‬ ‭ALT‬ ‭elevation,‬ ‭study‬ ‭drugs(s)‬ ‭will‬ ‭be‬ ‭permanently‬
‭discontinued.‬ ‭If‬ ‭the‬ ‭investigator‬ ‭determines‬ ‭a‬ ‭possible‬ ‭favorable‬ ‭benefit/risk‬ ‭ratio‬ ‭that‬
‭warrants‬‭continuation‬‭of‬‭study‬‭drugs(s),‬‭a‬‭discussion‬‭between‬‭the‬‭investigator‬‭and‬‭the‬‭BMS‬
‭medical monitor or designee must occur.‬
‭Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN‬
‭●‬ ‭Any‬‭Grade‬‭4‬‭drug-related‬‭adverse‬‭event‬‭or‬‭laboratory‬‭abnormality,‬‭except‬‭for‬‭the‬‭following‬
‭events, which do not require discontinuation:‬
‭○‬ ‭Grade 4 neutropenia ≤ 7 days.‬
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‭○‬ ‭Grade 4 lymphopenia or leukopenia.‬
‭○‬ ‭Isolated‬ ‭Grade‬ ‭4‬ ‭amylase‬ ‭or‬ ‭lipase‬ ‭abnormalities‬ ‭that‬ ‭are‬ ‭not‬ ‭associated‬ ‭with‬
‭symptoms‬ ‭or‬‭clinical‬‭manifestations‬‭of‬‭pancreatitis‬‭and‬‭decrease‬‭to‬‭<‬‭Grade‬‭4‬‭within‬
‭1 week of onset.‬
‭○‬ ‭Isolated‬ ‭Grade‬ ‭4‬ ‭electrolyte‬ ‭imbalances/abnormalities‬ ‭that‬ ‭are‬ ‭not‬ ‭associated‬‭with‬
‭clinical‬ ‭sequelae‬ ‭and‬ ‭are‬ ‭corrected‬ ‭with‬ ‭supplementation/appropriate‬ ‭management‬
‭within 72 hours of their onset.‬
‭●‬ ‭Grade‬ ‭4‬ ‭drug-related‬ ‭endocrinopathy‬ ‭adverse‬ ‭events‬ ‭such‬ ‭as‬‭adrenal‬‭insufficiency,‬‭ACTH‬
‭deficiency,‬‭hyper-‬‭or‬‭hypothyroidism,‬‭or‬‭glucose‬‭intolerance,‬‭which‬‭resolve‬‭or‬‭are‬‭adequately‬
‭controlled‬ ‭with‬ ‭physiologic‬ ‭hormone‬ ‭replacement‬ ‭(corticosteroids,‬ ‭thyroid‬ ‭hormones)‬ ‭or‬
‭glucose‬‭controlling‬‭agents,‬‭respectively,‬‭may‬‭not‬‭require‬‭discontinuation‬‭after‬‭discussion‬‭with‬
‭and approval from the BMS Medical Monitor.‬
‭●‬ ‭Dosing‬ ‭delays‬ ‭lasting‬ ‭>‬ ‭6‬ ‭weeks‬ ‭from‬ ‭the‬ ‭previous‬ ‭dose‬ ‭that‬ ‭occur‬ ‭for‬ ‭non-drug-related‬
‭reasons‬ ‭may‬ ‭be‬ ‭allowed‬ ‭if‬ ‭approved‬ ‭by‬ ‭the‬ ‭BMS‬ ‭medical‬ ‭monitor.‬ ‭Prior‬ ‭to‬ ‭re-initiating‬
‭treatment‬‭in‬‭a‬‭participant‬‭with‬‭a‬‭dosing‬‭delay‬‭lasting‬‭>‬‭6‬‭weeks,‬‭the‬‭BMS‬‭medical‬‭monitor‬
‭must‬ ‭be‬ ‭consulted.‬ ‭Tumor‬ ‭assessments‬ ‭should‬ ‭continue‬ ‭as‬ ‭per‬ ‭protocol‬ ‭even‬ ‭if‬ ‭dosing‬‭is‬
‭delayed.‬ ‭Periodic‬ ‭study‬ ‭visits‬ ‭to‬ ‭assess‬ ‭safety‬ ‭and‬‭laboratory‬‭studies‬‭should‬‭also‬‭continue‬
‭every 6 weeks or more frequently if clinically indicated during such dosing delays.‬
‭●‬ ‭Any‬‭adverse‬‭event,‬‭laboratory‬‭abnormality,‬‭or‬‭intercurrent‬‭illness‬‭which,‬‭in‬‭the‬‭judgment‬‭of‬
‭the‬ ‭Investigator,‬ ‭presents‬ ‭a‬ ‭substantial‬ ‭clinical‬ ‭risk‬ ‭to‬ ‭the‬ ‭participant‬ ‭with‬ ‭continued‬
‭nivolumab dosing.‬
‭The‬ ‭assessment‬ ‭for‬ ‭discontinuation‬ ‭of‬ ‭nivolumab‬ ‭should‬ ‭be‬ ‭made‬ ‭separately‬ ‭from‬ ‭the‬
‭assessment made for discontinuation of chemotherapy.‬
‭If‬ ‭a‬ ‭participant‬ ‭meets‬ ‭criteria‬ ‭for‬ ‭discontinuation‬ ‭and‬ ‭investigator‬ ‭is‬ ‭unable‬ ‭to‬ ‭determine‬
‭whether‬ ‭the‬ ‭event‬ ‭is‬ ‭related‬ ‭to‬ ‭nivolumab‬ ‭or‬‭chemotherapy,‬‭the‬‭participant‬‭should‬‭discontinue‬‭all‬
‭treatment.‬
‭The‬ ‭assessment‬ ‭for‬ ‭discontinuation‬ ‭of‬ ‭nivolumab‬ ‭should‬ ‭be‬ ‭made‬ ‭separately‬ ‭from‬ ‭the‬
‭assessment‬ ‭made‬ ‭for‬ ‭discontinuation‬ ‭of‬ ‭chemotherapy‬ ‭doublet.‬ ‭If‬ ‭criteria‬ ‭for‬ ‭discontinuation‬ ‭for‬
‭nivolumab‬‭are‬‭met‬‭before‬‭the‬‭nivolumab‬‭plus‬‭platinum-based‬‭doublet‬‭chemotherapy‬‭cycles‬‭have‬‭been‬
‭completed, platinum-based doublet chemotherapy may continue until 6 cycles have been completed.‬
‭6.1.2.‬ ‭Chemotherapy Dose Discontinuation‬
‭Except‬ ‭where‬ ‭specified‬ ‭below,‬ ‭chemotherapy‬ ‭drugs‬ ‭in‬ ‭the‬ ‭platinum-based‬ ‭doublet‬ ‭chemotherapy‬
‭regimen should be discontinued for any of the following:‬
‭●‬ ‭Any Grade  ≥ 3 peripheral neuropathy‬
‭●‬ ‭Any‬ ‭drug-related‬ ‭liver‬ ‭function‬ ‭test‬ ‭(LFT)‬ ‭abnormality‬ ‭that‬ ‭meets‬ ‭the‬ ‭following‬ ‭criteria‬
‭requires discontinuation:‬
‭○‬ ‭AST or ALT > 5-10 x ULN for > 2 weeks‬
‭○‬ ‭AST or ALT > 10 x ULN‬
‭○‬ ‭Total bilirubin > 5 x ULN‬
‭○‬ ‭Concurrent AST or ALT > 3x ULN and total bilirubin > 2 x ULN‬
‭●‬ ‭Any‬ ‭drug-related‬ ‭adverse‬ ‭event‬ ‭which‬‭recurs‬‭after‬‭two‬‭prior‬‭dose‬‭reductions‬‭for‬‭the‬‭same‬
‭drug-related‬‭adverse‬‭event‬‭requires‬‭discontinuation‬‭of‬‭the‬‭drug(s)‬‭which‬‭was/were‬‭previously‬
‭dose reduced.‬
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‭●‬ ‭Any‬ ‭Grade‬ ‭≥‬ ‭3‬ ‭drug-related‬ ‭hypersensitivity‬ ‭reaction‬ ‭or‬ ‭infusion‬ ‭reaction‬ ‭requires‬
‭discontinuation‬‭of‬‭the‬‭drug(s)‬‭felt‬‭to‬‭be‬‭causing‬‭the‬‭reaction.‬‭The‬‭drug‬‭not‬‭felt‬‭to‬‭be‬‭related‬‭to‬
‭the hypersensitivity reaction or infusion reaction may be continued.‬
‭●‬ ‭Any‬‭Grade‬‭4‬‭drug-related‬‭adverse‬‭event‬‭which‬‭the‬‭investigator‬‭deems‬‭is‬‭inappropriate‬‭to‬‭be‬
‭managed‬‭by‬‭dose‬‭reduction(s)‬‭requires‬‭discontinuation‬‭of‬‭the‬‭drug(s)‬‭felt‬‭to‬‭be‬‭causing‬‭the‬
‭event. The drug not felt to be related to the event may be continued.‬
‭●‬ ‭Any‬‭event‬‭that‬‭leads‬‭to‬‭delay‬‭in‬‭dosing‬‭of‬‭any‬‭study‬‭drug(s)‬‭for‬‭>‬‭6‬‭weeks‬‭from‬‭the‬‭previous‬
‭dose requires discontinuation of that drug(s) with the following exception:‬
‭○‬ ‭Dosing‬ ‭delays‬ ‭lasting‬ ‭>‬ ‭6‬ ‭weeks‬ ‭from‬ ‭the‬ ‭previous‬ ‭dose‬ ‭that‬ ‭occur‬ ‭for‬
‭non-drug-related‬‭reasons‬‭may‬‭be‬‭allowed‬‭if‬‭approved‬‭by‬‭the‬‭BMS‬‭medical‬‭monitor.‬
‭Prior‬‭to‬‭re-initiating‬‭treatment‬‭in‬‭a‬‭participant‬‭with‬‭a‬‭dosing‬‭delay‬‭lasting‬‭>‬‭6‬‭weeks,‬
‭the‬‭BMS‬‭medical‬‭monitor‬‭must‬‭be‬‭consulted.‬‭Periodic‬‭study‬‭visits‬‭to‬‭assess‬‭safety‬
‭and‬ ‭laboratory‬ ‭studies‬ ‭should‬ ‭also‬ ‭continue‬ ‭every‬ ‭6‬ ‭weeks‬ ‭or‬ ‭more‬ ‭frequently‬ ‭if‬
‭clinically indicated during such dosing delays.‬
‭●‬ ‭Any‬‭adverse‬‭event,‬‭laboratory‬‭abnormality,‬‭or‬‭intercurrent‬‭illness‬‭which,‬‭in‬‭the‬‭judgment‬‭of‬
‭the‬ ‭Investigator,‬ ‭presents‬ ‭a‬ ‭substantial‬ ‭clinical‬ ‭risk‬ ‭to‬ ‭the‬ ‭participant‬ ‭with‬ ‭continued‬
‭platinum-based‬‭doublet‬‭chemotherapy‬‭dosing.‬‭Investigators‬‭should‬‭consult‬‭local‬‭labeling‬‭for‬
‭the‬‭chemotherapy‬‭drugs‬‭being‬‭administered‬‭to‬‭any‬‭given‬‭participant‬‭for‬‭additional‬‭guidance‬
‭on dose discontinuation.‬
‭6.2.‬
‭Discontinuation from Study‬
‭Participants‬ ‭who‬ ‭request‬ ‭to‬‭discontinue‬‭study‬‭treatment‬‭will‬‭remain‬‭in‬‭the‬‭study‬‭and‬‭must‬
‭continue‬ ‭to‬‭be‬‭followed‬‭for‬‭protocol‬‭specified‬‭follow-up‬‭procedures.‬‭The‬‭only‬‭exception‬‭to‬‭this‬‭is‬
‭when‬ ‭a‬ ‭participant‬ ‭specifically‬ ‭withdraws‬‭consent‬‭for‬‭any‬‭further‬‭contact‬‭with‬‭him/her‬‭or‬‭persons‬
‭previously authorized by participant to provide this information.‬
‭●‬ ‭Participants‬ ‭should‬‭notify‬‭the‬‭investigator‬‭of‬‭the‬‭decision‬‭to‬‭withdraw‬‭consent‬‭from‬‭future‬
‭follow-up in writing, whenever possible.‬
‭●‬ ‭The‬ ‭withdrawal‬ ‭of‬ ‭consent‬ ‭should‬ ‭be‬ ‭explained‬ ‭in‬ ‭detail‬ ‭in‬ ‭the‬ ‭medical‬ ‭records‬ ‭by‬ ‭the‬
‭investigator,‬‭as‬‭to‬‭whether‬‭the‬‭withdrawal‬‭is‬‭from‬‭further‬‭treatment‬‭with‬‭study‬‭treatment‬‭only‬
‭or‬ ‭also‬ ‭from‬ ‭study‬ ‭procedures‬ ‭and/or‬ ‭post‬ ‭treatment‬ ‭study‬ ‭follow-up,‬ ‭and‬ ‭entered‬ ‭on‬‭the‬
‭appropriate CRF page.‬
‭●‬ ‭In‬ ‭the‬ ‭event‬ ‭that‬ ‭vital‬ ‭status‬ ‭(whether‬ ‭the‬‭participant‬‭is‬‭alive‬‭or‬‭dead)‬‭is‬‭being‬‭measured,‬
‭publicly‬‭available‬‭information‬‭should‬‭be‬‭used‬‭to‬‭determine‬‭vital‬‭status‬‭only‬‭as‬‭appropriately‬
‭directed in accordance with local law.‬
‭●‬ ‭If‬ ‭the‬ ‭participant‬ ‭withdraws‬ ‭consent‬‭for‬‭disclosure‬‭of‬‭future‬‭information,‬‭the‬‭sponsor‬‭may‬
‭retain and continue to use any data collected before such a withdrawal of consent.‬
‭In‬ ‭the‬ ‭case‬ ‭of‬ ‭pregnancy,‬ ‭the‬ ‭investigator‬ ‭must‬ ‭immediately‬ ‭notify‬ ‭the‬ ‭BMS‬ ‭Medical‬
‭Monitor/designee‬‭of‬‭this‬‭event.‬‭In‬‭the‬‭event‬‭a‬‭normal‬‭healthy‬‭female‬‭participant‬‭becomes‬‭pregnant‬
‭during‬‭a‬‭clinical‬‭trial,‬‭the‬‭study‬‭treatment‬‭must‬‭be‬‭discontinued‬‭immediately.‬‭In‬‭most‬‭cases,‬‭the‬‭study‬
‭treatment‬‭will‬‭be‬‭permanently‬‭discontinued‬‭in‬‭an‬‭appropriate‬‭manner‬‭(eg,‬‭dose‬‭tapering‬‭if‬‭necessary‬
‭for‬ ‭participant‬ ‭safety).‬‭Please‬‭call‬‭the‬‭BMS‬‭Medical‬‭Monitor‬‭within‬‭24‬‭hours‬‭of‬‭awareness‬‭of‬‭the‬
‭pregnancy.‬ ‭If‬ ‭the‬ ‭investigator‬ ‭determines‬ ‭a‬ ‭possible‬ ‭favorable‬ ‭benefit/risk‬ ‭ratio‬ ‭that‬ ‭warrants‬
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‭continuation‬ ‭of‬ ‭study‬ ‭treatment,‬ ‭a‬ ‭discussion‬ ‭between‬ ‭the‬ ‭investigator‬ ‭and‬ ‭the‬ ‭BMS‬ ‭Medical‬
‭Monitor/designee must occur.‬
‭All‬ ‭participants‬ ‭who‬ ‭discontinue‬ ‭study‬ ‭treatment‬ ‭should‬ ‭comply‬ ‭with‬ ‭protocol‬ ‭specified‬
‭follow-up‬ ‭procedures‬ ‭as‬ ‭outlined‬ ‭in‬ ‭Section‬ ‭7‬‭.‬ ‭The‬ ‭only‬ ‭exception‬ ‭to‬ ‭this‬‭requirement‬‭is‬‭when‬‭a‬
‭participant‬ ‭withdraws‬‭consent‬‭for‬‭all‬‭study‬‭procedures‬‭including‬‭post-treatment‬‭study‬‭follow-up‬‭or‬
‭loses‬‭the‬‭ability‬‭to‬‭consent‬‭freely‬‭(ie,‬‭is‬‭imprisoned‬‭or‬‭involuntarily‬‭incarcerated‬‭for‬‭the‬‭treatment‬‭of‬
‭either a psychiatric or physical illness).‬
‭If‬‭study‬‭treatment‬‭is‬‭discontinued‬‭prior‬‭to‬‭the‬‭participant’s‬‭completion‬‭of‬‭the‬‭study,‬‭the‬‭reason‬
‭for‬‭the‬‭discontinuation‬‭must‬‭be‬‭documented‬‭in‬‭the‬‭participant’s‬‭medical‬‭records‬‭and‬‭entered‬‭on‬‭the‬
‭appropriate case report form (CRF) page.‬
‭6.2.1.‬ ‭Post Study Treatment Study Follow-up‬
‭In‬‭this‬‭study,‬‭OS‬‭is‬‭a‬‭key‬‭endpoint‬‭of‬‭the‬‭study.‬‭Post‬‭study‬‭follow-up‬‭is‬‭of‬‭critical‬‭importance‬
‭and‬ ‭is‬ ‭essential‬ ‭to‬ ‭preserving‬ ‭participant‬ ‭safety‬ ‭and‬ ‭the‬ ‭integrity‬ ‭of‬ ‭the‬ ‭study.‬ ‭Participants‬ ‭who‬
‭discontinue‬‭study‬‭treatment‬‭must‬‭continue‬‭to‬‭be‬‭followed‬‭for‬‭collection‬‭of‬‭outcome‬‭and/or‬‭survival‬
‭follow-up data as required and in line with‬‭Section‬‭7‬‭until death or the conclusion of the study.‬
‭6.3.‬
‭Lost to Follow-up‬
‭All‬ ‭reasonable‬ ‭efforts‬ ‭must‬ ‭be‬ ‭made‬ ‭to‬ ‭locate‬ ‭participants‬ ‭to‬ ‭determine‬ ‭and‬ ‭report‬ ‭their‬
‭ongoing status. This includes follow-up with persons authorized by the participant.‬
‭Lost‬‭to‬‭follow-up‬‭is‬‭defined‬‭by‬‭the‬‭inability‬‭to‬‭reach‬‭the‬‭participant‬‭after‬‭a‬‭minimum‬‭of‬‭three‬
‭documented‬‭phone‬‭calls,‬‭faxes,‬‭or‬‭emails‬‭as‬‭well‬‭as‬‭lack‬‭of‬‭response‬‭by‬‭participant‬‭to‬‭one‬‭registered‬
‭mail letter. All attempts should be documented in the participant’s medical records.‬
‭If‬‭it‬‭is‬‭determined‬‭that‬‭the‬‭participant‬‭has‬‭died,‬‭the‬‭site‬‭will‬‭use‬‭permissible‬‭local‬‭methods‬‭to‬
‭obtain date and cause of death.‬
‭If‬‭investigator’s‬‭use‬‭of‬‭third‬‭party‬‭representative‬‭to‬‭assist‬‭in‬‭the‬‭follow-up‬‭portion‬‭of‬‭the‬‭study‬
‭has‬ ‭been‬ ‭included‬ ‭in‬ ‭the‬ ‭participant’s‬ ‭informed‬ ‭consent,‬ ‭then‬ ‭the‬‭investigator‬‭may‬‭use‬‭a‬‭Sponsor‬
‭retained‬‭third‬‭party‬‭representative‬‭to‬‭assist‬‭site‬‭staff‬‭with‬‭obtaining‬‭participant’s‬‭contact‬‭information‬‭or‬
‭other public vital status data necessary to complete the follow-up portion of the study.‬
‭The‬‭site‬‭staff‬‭and‬‭representative‬‭will‬‭consult‬‭publicly‬‭available‬‭sources,‬‭such‬‭as‬‭public‬‭health‬
‭registries and databases, in order to obtain updated contact information.‬
‭If‬‭after‬‭all‬‭attempts,‬‭the‬‭participant‬‭remains‬‭lost‬‭to‬‭follow-up,‬‭then‬‭the‬‭last‬‭known‬‭alive‬‭date‬‭as‬
‭determined‬ ‭by‬ ‭the‬ ‭investigator‬ ‭should‬ ‭be‬ ‭reported‬ ‭and‬ ‭documented‬ ‭in‬ ‭the‬ ‭participant’s‬ ‭medical‬
‭records.‬
‭7.‬
‭Clinical evaluation, laboratory tests, follow-up‬
‭Study procedures and timing are summarized in the Schedule of Activities.‬
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‭●‬ ‭All‬ ‭immediate‬ ‭safety‬ ‭concerns‬ ‭must‬ ‭be‬ ‭discussed‬ ‭with‬ ‭the‬ ‭Sponsor‬ ‭immediately‬ ‭upon‬
‭occurrence‬ ‭or‬ ‭awareness‬ ‭to‬ ‭determine‬ ‭if‬ ‭the‬ ‭participant‬ ‭should‬ ‭continue‬ ‭or‬ ‭discontinue‬
‭treatment.‬
‭●‬ ‭Adherence‬ ‭to‬ ‭the‬ ‭study‬ ‭design‬ ‭requirements,‬ ‭including‬ ‭those‬ ‭specified‬‭in‬‭the‬‭Schedule‬‭of‬
‭Activities, is essential and required for study conduct.‬
‭●‬ ‭All‬ ‭screening‬ ‭evaluations‬ ‭must‬ ‭be‬ ‭completed‬ ‭and‬ ‭reviewed‬ ‭to‬ ‭confirm‬ ‭that‬ ‭potential‬
‭participants‬‭meet‬‭all‬‭eligibility‬‭criteria‬‭before‬‭randomization.‬‭The‬‭investigator‬‭will‬‭maintain‬‭a‬
‭screening‬‭log‬‭to‬‭record‬‭details‬‭of‬‭all‬‭participants‬‭screened‬‭and‬‭to‬‭confirm‬‭eligibility‬‭or‬‭record‬
‭reasons for screening failure, as applicable.‬
‭7.1.‬
‭Before treatment start‬
‭7.1.1.‬
‭Informed Consent‬
‭The‬‭investigator‬‭or‬‭qualified‬‭designee‬‭must‬‭obtain‬‭documented‬‭consent‬‭from‬‭each‬‭potential‬‭subject‬‭or‬
‭each‬ ‭subject’s‬ ‭legally‬ ‭acceptable‬ ‭representative‬ ‭prior‬ ‭to‬ ‭participating‬ ‭in‬ ‭a‬ ‭clinical‬ ‭trial‬ ‭or‬ ‭Future‬
‭Biomedical Research.‬
‭7.1.1.1.‬‭General Informed Consent‬
‭●‬ ‭Consent‬ ‭must‬ ‭be‬ ‭documented‬ ‭by‬ ‭the‬ ‭subject’s‬ ‭dated‬ ‭signature‬ ‭or‬ ‭by‬ ‭the‬ ‭subject’s‬‭legally‬
‭acceptable‬‭representative‬‭dated‬‭signature‬‭on‬‭a‬‭consent‬‭form‬‭along‬‭with‬‭the‬‭dated‬‭signature‬‭of‬
‭the person conducting the consent discussion.‬
‭●‬ ‭A‬ ‭copy‬ ‭of‬ ‭the‬ ‭signed‬ ‭and‬ ‭dated‬ ‭consent‬ ‭form‬ ‭should‬ ‭be‬ ‭given‬ ‭to‬ ‭the‬ ‭subject‬ ‭before‬
‭participation‬‭in‬‭the‬‭trial.‬‭The‬‭initial‬‭informed‬‭consent‬‭form,‬‭any‬‭subsequent‬‭revised‬‭written‬
‭informed‬‭consent‬‭form‬‭and‬‭any‬‭written‬‭information‬‭provided‬‭to‬‭the‬‭subject‬‭must‬‭receive‬‭the‬
‭IRB/ERC’s approval/favorable opinion in advance of use.‬
‭●‬ ‭The‬ ‭subject‬ ‭or‬ ‭his/her‬ ‭legally‬ ‭acceptable‬ ‭representative‬ ‭should‬ ‭be‬ ‭informed‬ ‭in‬ ‭a‬ ‭timely‬
‭manner‬ ‭if‬ ‭new‬ ‭information‬ ‭becomes‬ ‭available‬ ‭that‬ ‭may‬ ‭be‬ ‭relevant‬ ‭to‬ ‭the‬ ‭subject’s‬
‭willingness‬‭to‬‭continue‬‭participation‬‭in‬‭the‬‭trial.‬‭The‬‭communication‬‭of‬‭this‬‭information‬‭will‬
‭be‬‭provided‬‭and‬‭documented‬‭via‬‭a‬‭revised‬‭consent‬‭form‬‭or‬‭addendum‬‭to‬‭the‬‭original‬‭consent‬
‭form‬ ‭that‬ ‭captures‬ ‭the‬ ‭subject’s‬ ‭dated‬ ‭signature‬ ‭or‬ ‭by‬ ‭the‬ ‭subject’s‬ ‭legally‬ ‭acceptable‬
‭representative dated signature.‬
‭●‬ ‭The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations.‬
‭7.1.1.2. Consent and Collection of Specimens for Future Biomedical Research‬
‭●‬ ‭The‬‭investigator‬‭or‬‭qualified‬‭designee‬‭will‬‭explain‬‭the‬‭Future‬‭Biomedical‬‭Research‬‭consent‬‭to‬
‭the‬ ‭subject,‬ ‭answer‬ ‭all‬ ‭of‬ ‭his/her‬ ‭questions,‬ ‭and‬ ‭obtain‬ ‭written‬ ‭informed‬ ‭consent‬ ‭before‬
‭performing any procedure related to the Future Biomedical Research sub-trial.‬
‭●‬ ‭A copy of the informed consent will be given to the subject.‬
‭7.1.2.‬ ‭Inclusion/Exclusion Criteria Assessment‬
‭All‬ ‭inclusion‬ ‭and‬ ‭exclusion‬ ‭criteria‬ ‭will‬ ‭be‬ ‭reviewed‬ ‭by‬ ‭the‬ ‭investigator‬ ‭or‬ ‭qualified‬‭designee‬‭to‬
‭ensure‬‭that‬‭the‬‭subject‬‭qualifies‬‭for‬‭the‬‭trial.‬‭More‬‭details‬‭on‬‭criteria‬‭for‬‭patients‬‭eligibility‬‭section‬‭4.1‬
‭and 4.2.‬
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‭7.1.3.‬ ‭Medical History‬
‭●‬ ‭A‬‭medical‬‭history‬‭will‬‭be‬‭obtained‬‭by‬‭the‬‭investigator‬‭or‬‭qualified‬‭designee.‬‭Medical‬‭history‬
‭will‬‭include‬‭all‬‭active‬‭conditions,‬‭and‬‭any‬‭condition‬‭diagnosed‬‭within‬‭the‬‭prior‬‭10‬‭years‬‭that‬
‭are considered to be clinically significant by the Investigator.‬
‭●‬ ‭Any autoimmune disorders, regardless of onset date, should be recorded.‬
‭7.1.4.‬ ‭Prior and concomitant medications review‬
‭7.1.4.1.‬‭Prior Medications‬
‭The‬ ‭investigator‬ ‭or‬ ‭qualified‬ ‭designee‬ ‭will‬ ‭review‬ ‭prior‬ ‭medication‬ ‭use,‬ ‭including‬ ‭any‬
‭protocol-specified‬‭washout‬‭requirement,‬‭and‬‭record‬‭prior‬‭medication‬‭taken‬‭by‬‭the‬‭subject‬‭within‬‭30‬
‭days of first dose.‬
‭7.1.4.2.‬‭Concomitant Medications‬
‭●‬ ‭The‬ ‭investigator‬ ‭or‬ ‭qualified‬ ‭designee‬‭will‬‭record‬‭medication,‬‭if‬‭any,‬‭taken‬‭by‬‭the‬‭subject‬
‭during‬‭the‬‭trial‬‭from‬‭the‬‭time‬‭of‬‭signing‬‭the‬‭informed‬‭consent‬‭form‬‭until‬‭the‬‭Safety‬‭Follow-up‬
‭Visit.‬
‭●‬ ‭All medications related to reportable SAEs should be recorded.‬
‭7.1.5.‬ ‭Assignment of Screening Number‬
‭●‬ ‭All‬‭consented‬‭subjects‬‭will‬‭be‬‭given‬‭a‬‭unique‬‭screening‬‭number‬‭that‬‭will‬‭be‬‭used‬‭to‬‭identify‬
‭the subject for all procedures that occur.‬
‭●‬ ‭Each‬ ‭subject‬‭will‬‭be‬‭assigned‬‭only‬‭one‬‭screening‬‭number.‬‭Screening‬‭numbers‬‭must‬‭not‬‭be‬
‭re-used‬ ‭for‬ ‭different‬ ‭subjects.‬ ‭Any‬ ‭subject‬ ‭who‬ ‭is‬ ‭screened‬ ‭multiple‬ ‭times‬ ‭will‬‭retain‬‭the‬
‭original screening number assigned at the initial screening visit.‬
‭7.1.6.‬ ‭Subject Identification Card‬
‭●‬ ‭All‬‭subjects‬‭will‬‭be‬‭given‬‭a‬‭Subject‬‭Identification‬‭Card‬‭identifying‬‭them‬‭as‬‭participants‬‭in‬‭a‬
‭research‬‭trial.‬‭The‬‭card‬‭will‬‭contain‬‭trial‬‭site‬‭contact‬‭information‬‭(including‬‭direct‬‭telephone‬
‭numbers) to be utilized in the event of an emergency.‬
‭●‬ ‭The‬‭investigator‬‭or‬‭qualified‬‭designee‬‭will‬‭provide‬‭the‬‭subject‬‭with‬‭a‬‭Subject‬‭Identification‬
‭Card immediately after the subject provides written informed consent.‬
‭7.1.7.‬ ‭Submitting Tumor Sample‬
‭●‬ ‭Tumor tissue sample is mandatory to participate in this trial.‬
‭●‬ ‭Either‬ ‭pre-existing‬ ‭archived‬‭or‬‭newly-obtained‬‭(fresh‬‭tissue)‬‭biopsy‬‭specimens‬‭from‬‭either‬
‭primary or metastatic tumor, whichever is most recent.‬
‭○‬ ‭Newly-obtained‬‭(fresh‬‭tissue)‬‭is‬‭defined‬‭as‬‭a‬‭specimen‬‭obtained‬‭up‬‭to‬‭42‬‭days‬‭prior‬‭to‬
‭administration‬‭of‬‭study‬‭treatment‬‭on‬‭Day‬‭1‬‭of‬‭Cycle‬‭1,‬‭and‬‭no‬‭additional‬‭anti-cancer‬
‭treatment has been given after the specimen was obtained.‬
‭○‬ ‭Pre-existing,‬‭archived‬‭tissue‬‭must‬‭be‬‭obtained‬‭prior‬‭to‬‭time‬‭point‬‭that‬‭any‬‭anti-cancer‬
‭treatment was given.‬
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‭●‬ ‭A‬‭fine‬‭needle‬‭aspirate‬‭(FNA)‬‭or‬‭cytologic‬‭specimen‬‭will‬‭not‬‭be‬‭acceptable.‬‭In‬‭the‬‭event‬‭the‬
‭most‬ ‭recent‬ ‭available‬ ‭tumor‬‭tissue‬‭specimen‬‭is‬‭an‬‭FNA‬‭or‬‭cytologic‬‭specimen,‬‭a‬‭previous‬
‭specimen‬‭obtained‬‭prior‬‭to‬‭any‬‭anti-cancer‬‭therapy‬‭was‬‭given‬‭may‬‭be‬‭submitted‬‭(provided‬‭it‬
‭is not an FNA or cytologic specimen).‬
‭●‬ ‭Where‬ ‭available,‬ ‭both‬ ‭newly-obtained‬ ‭(fresh‬ ‭tissue)‬ ‭and‬ ‭pre-existing‬ ‭archived‬ ‭tissues‬ ‭are‬
‭requested.‬
‭●‬ ‭Tumor tissue specimen submitted in either formalin solution or FFPE block is acceptable.‬
‭7.1.8.‬ ‭Tumor Imaging‬
‭●‬ ‭To‬‭meet‬‭screening‬‭criteria,‬‭initial‬‭tumor‬‭imaging‬‭must‬‭be‬‭performed‬‭within‬‭28‬‭days‬‭prior‬‭to‬
‭the‬‭beginning‬‭of‬‭the‬‭treatment.‬‭This‬‭scan‬‭will‬‭be‬‭considered‬‭the‬‭baseline‬‭assessment‬‭for‬‭the‬
‭study.‬‭Scans‬‭performed‬‭as‬‭part‬‭of‬‭routine‬‭clinical‬‭management‬‭are‬‭acceptable‬‭for‬‭use‬‭as‬‭the‬
‭baseline‬‭scan‬‭if‬‭they‬‭are‬‭of‬‭diagnostic‬‭quality,‬‭include‬‭all‬‭required‬‭anatomy,‬‭and‬‭performed‬
‭within 28 days prior to the beginning of the treatment.‬
‭●‬ ‭The‬‭site‬‭study‬‭team‬‭must‬‭review‬‭pre-trial‬‭images‬‭to‬‭confirm‬‭the‬‭subject‬‭has‬‭at‬‭least‬‭one‬‭target‬
‭lesion (i.e. meets measurability requirements) per RECIST 1.1.‬
‭●‬ ‭The following assessments are required at screening:‬
‭7.1.8.1.‬‭Computed‬ ‭(CT)‬‭with‬‭IV‬‭contrast‬‭or‬‭Magnetic‬‭Resonance‬‭Imaging‬‭(MRI)‬‭of‬‭chest,‬‭abdomen‬
‭and pelvis.‬
‭●‬ ‭The‬‭preferred‬‭radiologic‬‭technique‬‭is‬‭CT‬‭with‬‭intravenous‬‭(IV)‬‭contrast.‬‭If‬‭a‬‭patient‬‭is‬‭known‬
‭to‬ ‭have‬‭a‬‭contraindication‬‭to‬‭CT‬‭contrast‬‭or‬‭develops‬‭a‬‭contraindication‬‭during‬‭the‬‭trial,‬‭a‬
‭non-contrast‬‭CT‬‭of‬‭the‬‭chest‬‭(MRI‬‭is‬‭not‬‭recommended‬‭due‬‭to‬‭respiratory‬‭artifacts)‬‭plus‬‭a‬
‭contrast-enhanced MRI (if possible) of the abdomen and pelvis should be performed.‬
‭7.1.8.2.‬‭Brain CT with IV contrast or MRI scan‬
‭Patients‬‭with‬‭known‬‭baseline‬‭brain‬‭lesions‬‭are‬‭not‬‭eligible‬‭for‬‭this‬‭study,‬‭but‬‭brain‬‭CT‬‭scan‬‭or‬‭MRI‬‭is‬
‭not required neither at baseline nor in the follow-up in the absence of neurological signs or symptoms.‬
‭7.1.8.3.‬‭Whole body bone scan‬
‭This is not required at any time point unless clinically indicated.‬
‭7.1.9.‬ ‭Laboratory Assessments‬
‭●‬ ‭Laboratory‬‭tests‬‭for‬‭screening‬‭should‬‭be‬‭performed‬‭within‬‭7‬‭days‬‭prior‬‭to‬‭study‬‭enrollment.‬‭If‬
‭performed‬‭<‬‭7‬‭days‬‭prior‬‭to‬‭the‬‭first‬‭dose‬‭of‬‭trial‬‭therapy‬‭the‬‭screening‬‭laboratory‬‭tests‬‭will‬
‭serve‬‭as‬‭cycle‬‭1‬‭day‬‭1‬‭laboratory‬‭tests.‬‭If‬‭not,‬‭laboratory‬‭tests‬‭will‬‭need‬‭to‬‭be‬‭performed‬‭again‬
‭on day 1 of cycle 1.‬
‭○‬ ‭Serum‬‭and‬‭plasma‬‭samples‬‭for‬‭optional‬‭biomarker‬‭studies‬‭will‬‭be‬‭collected‬‭prior‬‭to‬
‭the beginning of treatment.‬
‭A summary of the procedures required is summarized in Table 1 and flow chart- Section 7.4.‬
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‭7.1.10.‬ ‭12-Lead Electrocardiogram (ECG)‬
‭A‬ ‭standard‬ ‭12-lead‬ ‭ECG‬ ‭will‬ ‭be‬ ‭performed‬ ‭using‬ ‭local‬ ‭standard‬ ‭procedures‬ ‭once‬ ‭at‬ ‭screening.‬
‭Clinically‬ ‭significant‬ ‭abnormal‬ ‭findings‬ ‭should‬ ‭be‬ ‭recorded‬ ‭as‬ ‭medical‬ ‭history‬ ‭and‬ ‭monitored‬ ‭if‬
‭needed. No new ECGs will be performed unless clinically indicated.‬
‭7.2.‬
‭During treatment‬
‭7.2.1.‬ ‭Adverse Event (AE) Monitoring‬
‭●‬ ‭The‬‭investigator‬‭or‬‭qualified‬‭designee‬‭will‬‭assess‬‭each‬‭subject‬‭to‬‭evaluate‬‭for‬‭potential‬‭new‬‭or‬
‭worsening‬ ‭AEs‬ ‭as‬ ‭specified‬ ‭in‬ ‭the‬ ‭Trial‬ ‭Flow‬ ‭Chart‬ ‭and‬ ‭more‬ ‭frequently‬ ‭if‬ ‭clinically‬
‭indicated.‬
‭●‬ ‭Adverse‬ ‭events‬ ‭will‬ ‭be‬‭graded‬‭and‬‭recorded‬‭throughout‬‭the‬‭trial‬‭and‬‭during‬‭the‬‭follow-up‬
‭period‬ ‭according‬ ‭to‬ ‭NCI‬ ‭CTCAE‬ ‭Version‬ ‭5.0.‬ ‭Toxicities‬ ‭will‬ ‭be‬ ‭characterized‬ ‭in‬ ‭terms‬
‭regarding‬ ‭seriousness,‬ ‭causality,‬ ‭toxicity‬ ‭grading,‬ ‭and‬ ‭action‬ ‭taken‬ ‭with‬ ‭regard‬ ‭to‬ ‭trial‬
‭treatment.‬
‭●‬ ‭All‬ ‭AEs‬ ‭of‬ ‭unknown‬ ‭etiology‬‭associated‬‭with‬‭nivolumab‬‭exposure‬‭should‬‭be‬‭evaluated‬‭to‬
‭determine‬ ‭if‬ ‭it‬ ‭is‬ ‭possibly‬ ‭an‬ ‭ECI‬ ‭of‬ ‭a‬ ‭potentially‬ ‭immunologic‬ ‭etiology‬ ‭(termed‬
‭immune-related adverse events, or irAEs).‬
‭7.2.2.‬ ‭Physical Exam‬
‭The‬ ‭investigator‬ ‭or‬ ‭clinical‬ ‭designee‬ ‭will‬ ‭perform‬‭a‬‭complete‬‭physical‬‭exam‬‭during‬‭the‬‭screening‬
‭period. Clinically significant abnormal findings should be recorded as medical history.‬
‭Additional‬‭full‬‭physical‬‭exams‬‭should‬‭be‬‭performed‬‭as‬‭specified‬‭in‬‭the‬‭Trial‬‭Flow‬‭Chart-Section‬‭7.4.‬
‭After‬‭the‬‭first‬‭dose‬‭of‬‭trial‬‭treatment‬‭new‬‭clinically‬‭significant‬‭abnormal‬‭findings‬‭should‬‭be‬‭recorded‬
‭as AEs.‬
‭7.2.3.‬ ‭Vital Signs‬
‭●‬ ‭The‬ ‭investigator‬ ‭or‬ ‭qualified‬ ‭designee‬ ‭will‬ ‭take‬ ‭vital‬ ‭signs‬ ‭at‬ ‭screening,‬ ‭prior‬ ‭to‬ ‭the‬
‭administration‬‭of‬‭each‬‭dose‬‭of‬‭trial‬‭treatment‬‭and‬‭at‬‭treatment‬‭discontinuation‬‭as‬‭specified‬‭in‬
‭the Trial Flow Chart-Section 7.4.‬
‭●‬ ‭Vital‬ ‭signs‬ ‭should‬ ‭include‬ ‭temperature,‬ ‭pulse,‬ ‭respiratory‬‭rate,‬‭weight‬‭and‬‭blood‬‭pressure.‬
‭Height will be measured at screening only.‬
‭7.2.4.‬ ‭12-Lead Electrocardiogram (ECG)‬
‭No ECGs will be performed unless clinically indicated.‬
‭7.2.5.‬ ‭Eastern Cooperative Oncology Group (ECOG) Performance Status‬
‭The‬‭investigator‬‭or‬‭qualified‬‭designee‬‭will‬‭assess‬‭ECOG‬‭status‬‭(see‬‭appendix)‬‭at‬‭screening,‬‭prior‬‭to‬
‭dosing‬‭on‬‭day‬‭1‬‭of‬‭each‬‭treatment‬‭cycle‬‭and‬‭at‬‭discontinuation‬‭of‬‭trial‬‭treatment‬‭as‬‭specified‬‭in‬‭the‬
‭Trial Flow Chart.‬
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‭7.2.6.‬ ‭Tumor Imaging and Assessment of Disease‬
‭●‬ ‭Tumor‬‭imaging‬‭will‬‭be‬‭performed‬‭by‬‭whole‬‭body‬‭contrast-enhanced‬‭computed‬‭tomography‬
‭(CT; preferred).‬
‭●‬ ‭The‬‭first‬‭on-study‬‭imaging‬‭assessment‬‭should‬‭be‬‭performed‬‭at‬‭8‬‭weeks‬‭(±‬‭7‬‭days)‬‭after‬‭the‬
‭first‬ ‭dose‬ ‭of‬‭trial‬‭treatment.‬‭Subsequent‬‭imaging‬‭should‬‭be‬‭performed‬‭every‬‭8‬‭weeks‬‭(±‬‭7‬
‭days)‬ ‭during‬‭the‬‭first‬‭12‬‭months‬‭and‬‭every‬‭12‬‭weeks‬‭thereafter‬‭until‬‭PD.‬‭Imaging‬‭may‬‭be‬
‭more frequently performed if clinically indicated.‬
‭7.2.7.‬ ‭Laboratory Assessments‬
‭●‬ ‭After‬ ‭Cycle‬ ‭1,‬ ‭pre-dose‬ ‭laboratory‬ ‭procedures‬ ‭can‬ ‭be‬ ‭conducted‬ ‭within‬ ‭72‬‭hours‬‭prior‬‭to‬
‭dosing.‬‭Results‬‭must‬‭be‬‭reviewed‬‭by‬‭the‬‭investigator‬‭or‬‭qualified‬‭designee‬‭and‬‭found‬‭to‬‭be‬
‭acceptable prior to each dose of trial treatment.‬
‭●‬ ‭The main laboratory determinations are summarized in Table 7‬
‭Table 7. Laboratory determinations required during the study‬
‭Test category‬
‭Determinations‬
‭Hematology‬
‭Hematocrit,‬ ‭Hemoglobin,‬ ‭Platelets,‬ ‭Red‬ ‭blood‬ ‭cells,‬ ‭White‬ ‭blood‬ ‭cells,‬ ‭Differential‬
‭(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, Other).‬
‭Chemistry‬
‭Albumin,‬ ‭Alkaline‬ ‭phosphatase,‬ ‭ALT,‬ ‭AST,‬ ‭Gamma-glutamyl-transferase‬ ‭(GGT),‬
‭Lactate‬‭Dehydrogenase‬‭(LDH),‬‭Calcium,‬‭Magnesium,‬‭Phosphorus,,‬‭Sodium,‬‭Potassium,‬
‭Creatinine,‬ ‭Creatine‬‭kinase,‬‭Direct‬‭Bilirubin,‬‭Indirect‬‭Bilirubin,‬‭Total‬‭Bilirubin,,,‬‭Total‬
‭Protein, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose.‬
‭Coagulation‬
‭At‬‭Screening:‬‭Prothrombin‬‭time‬‭(PT),‬‭International‬‭normalized‬‭ratio‬‭(INR]),‬‭Activated‬
‭partial thromboplastin time (APTT).‬
‭Thyroid‬
‭At screening‬‭: TSH (Thyroid Stimulating Hormone), Free‬‭T3 and Free T4.‬
‭At the subsequent visits as indicated in the flow chart: TSH only.‬
‭If TSH is abnormal, Free T3 and T4 shall be tested.‬
‭Hepatitis markers‬
‭At screening‬‭: HBV-DNA, HBsAg, HBsAb, HBcAb, HCV RNA-PCR.‬
‭Cytokines‬
‭IFN-γ, IL-6, IL-1,TNF-α.‬
‭Tumor markers‬
‭At screening‬‭: NSE, CGA.‬
‭On treatment:‬‭every 2 cycles if elevated at baseline.‬
‭Urinalysis‬
‭At‬ ‭Screening‬‭:‬ ‭Macroscopic‬ ‭Panel‬ ‭(Dipstick)‬ ‭(Color,‬ ‭Bilirubin,‬ ‭Blood,‬ ‭Glucose,‬
‭Ketones, Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)‬
‭If‬ ‭dipstick‬ ‭is‬ ‭abnormal‬ ‭then‬ ‭perform‬ ‭local‬ ‭laboratory‬ ‭Microscopic‬ ‭Panel‬ ‭(Red‬ ‭Blood‬
‭Cells, White Blood Cells, Casts, Crystals, Bacteria, Epithelial cells).‬
‭Pregnancy test‬
‭A‬‭serum‬‭pregnancy‬‭test‬‭must‬‭be‬‭performed‬‭at‬‭screening‬‭(at‬‭the‬‭local‬‭laboratory)‬‭within‬
‭≤72 hours before first dose of study treatment.‬
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‭7.2.8.‬ ‭Serum/Urine β-hCG‬
‭●‬ ‭All‬‭women‬‭who‬‭are‬‭being‬‭considered‬‭for‬‭participation‬‭in‬‭the‬‭trial,‬‭and‬‭who‬‭are‬‭not‬‭surgically‬
‭sterilized‬‭or‬‭postmenopausal‬‭(defined‬‭as:‬‭a‬‭woman‬‭who‬‭is‬‭≥45‬‭years‬‭of‬‭age‬‭and‬‭has‬‭not‬‭had‬
‭menses‬‭for‬‭more‬‭than‬‭1‬‭year),‬‭will‬‭be‬‭tested‬‭for‬‭pregnancy‬‭within‬‭72‬‭hours‬‭prior‬‭to‬‭each‬‭cycle‬
‭of trial treatment and 30 days post treatment.‬
‭●‬ ‭Subjects‬‭must‬‭be‬‭excluded/discontinued‬‭in‬‭the‬‭event‬‭of‬‭a‬‭positive‬‭or‬‭borderline-positive‬‭test‬
‭result.‬‭If‬‭a‬‭urine‬‭test‬‭is‬‭positive‬‭or‬‭borderline‬‭a‬‭serum‬‭β-HCG‬‭test‬‭will‬‭be‬‭required.‬‭The‬‭results‬
‭of the pregnancy testing will not be recorded.‬
‭7.3.‬
‭After the end of treatment (Follow-up)‬
‭●‬ ‭After‬ ‭the‬ ‭end‬ ‭of‬ ‭the‬ ‭treatment‬ ‭clinical‬ ‭procedures‬ ‭and‬ ‭assessment‬ ‭will‬ ‭be‬ ‭performed‬ ‭as‬
‭previously explained and is reflected in the summary table (section 7.4).‬
‭●‬ ‭Serum and plasma samples for optional biomarker studies will also be collected at this point.‬
‭7.4.‬
‭Summary table‬
‭Table 7.4. Trial  flow chart‬
‭Screening‬
‭phase‬
‭Treatment cycles‬‭a‬
‭(chemotherapy +‬
‭nivolumab)‬
‭Maintenance‬
‭phase Cycles‬ ‭End of treatment‬
‭Post-treatment‬
‭Pre-Study‬
‭1‬
‭2‬
‭3‬
‭4‬
‭5‬
‭6‬
‭1‬
‭2 and‬
‭beyond‬
‭Time of treatment‬
‭discontinuation‬
‭Safety‬
‭follow up‬
‭Follow up‬
‭visits‬
‭Survival‬
‭follow up‬‭o‬
‭30 days‬
‭after last‬
‭dose‬
‭Every 12 w‬
‭after last‬
‭dose‬
‭Every 12w‬
‭Scheduling window (days)‬
‭-28 to -1‬
‭±3‬
‭±3‬
‭±3‬ ‭±3‬ ‭±3‬ ‭±3‬
‭±3‬
‭±3‬
‭±7‬
‭±7‬
‭±7‬
‭Study Drug Admin‬‭a‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Cycle of Chemotherapy‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Informed consent‬‭b‬
‭X‬
‭Informed consent for future‬
‭biomedical research‬‭b‬
‭X‬
‭History/Demographics‬‭c‬
‭X‬
‭Physical exam‬‭d‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Concomitant meds‬‭e‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭ECOG - Performance status‬‭f‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Vital signs, Weight‬‭g‬
‭X‬
‭X (when clinically indicated)‬
‭x‬
‭x‬
‭Adverse event evaluation‬‭h‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Tumor sample collection‬‭i‬
‭X‬
‭Hematology‬‭j‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Serum chemistry‬‭j‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭TSH, T3, FT4‬‭j‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Hepatitis testing‬‭j‬
‭X‬
‭If clinically indicated, perform test as needed.‬
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‭Screening‬
‭phase‬
‭Treatment cycles‬‭a‬
‭(chemotherapy +‬
‭nivolumab)‬
‭Maintenance‬
‭phase Cycles‬ ‭End of treatment‬
‭Post-treatment‬
‭Pre-Study‬
‭1‬
‭2‬
‭3‬
‭4‬
‭5‬
‭6‬
‭1‬
‭2 and‬
‭beyond‬
‭Time of treatment‬
‭discontinuation‬
‭Safety‬
‭follow up‬
‭Follow up‬
‭visits‬
‭Survival‬
‭follow up‬‭o‬
‭30 days‬
‭after last‬
‭dose‬
‭Every 12 w‬
‭after last‬
‭dose‬
‭Every 12w‬
‭Cytokines‬‭j‬
‭X‬
‭Anytime when a suspected cytokine release syndrome occurs, immediately after the AE, and one week‬
‭after occurrence of the AE‬
‭Optional serum and plasma‬
‭samples for biomedical‬
‭research‬‭K‬
‭X‬
‭X‬
‭Urinalysis‬‭j‬
‭X‬
‭Serum or urine pregnancy test‬‭l‬
‭X‬
‭EKG‬‭m‬
‭X‬
‭Radiologic evaluation‬‭n‬
‭X‬
‭Treatment‬ ‭Period:‬ ‭Every‬ ‭8‬ ‭weeks‬ ‭counting‬ ‭from‬ ‭Cycle‬ ‭1‬ ‭Day‬ ‭1‬ ‭for‬ ‭12‬ ‭months,‬ ‭and‬ ‭every‬ ‭12‬ ‭weeks‬
‭thereafter.‬
‭EOT: If a scan was not conducted within 30 days prior to end of study treatment‬
‭Efficacy‬ ‭follow-up:‬ ‭Continue‬ ‭same‬ ‭schedule‬ ‭as‬ ‭during‬ ‭treatment‬ ‭period‬‭until‬‭central‬‭review‬‭confirmed‬
‭irRECIST progression.‬
‭a) Unless otherwise specified, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle.‬
‭b)‬‭Informed‬‭consent‬‭must‬‭be‬‭obtained‬‭before‬‭conducting‬‭any‬‭study-specific‬‭procedures‬‭(i.e.‬‭all‬‭of‬‭the‬‭procedures‬‭described‬‭in‬‭the‬‭protocol).‬‭The‬‭process‬
‭of‬‭obtaining‬‭informed‬‭consent‬‭should‬‭be‬‭documented‬‭in‬‭the‬‭patient‬‭source‬‭documents.‬‭If‬‭a‬‭patient‬‭decides‬‭not‬‭to‬‭participate‬‭in‬‭the‬‭optional‬‭biomarker‬
‭study, this in no way will affect the patient’s ability to participate in the main research study.‬
‭c)‬‭All‬‭active‬‭conditions,‬‭and‬‭any‬‭condition‬‭diagnosed‬‭within‬‭the‬‭prior‬‭10‬‭years‬‭that‬‭are‬‭considered‬‭to‬‭be‬‭clinically‬‭significant‬‭by‬‭the‬‭Investigator.‬‭Any‬
‭autoimmune disorders, regardless of onset date, should be recorded‬
‭d)‬‭Complete‬‭physical‬‭exam‬‭during‬‭the‬‭screening‬‭period.‬‭Clinically‬‭significant‬‭abnormal‬‭findings‬‭should‬‭be‬‭recorded‬‭as‬‭medical‬‭history.‬‭After‬‭the‬‭first‬
‭dose of trial treatment new clinically significant abnormal findings should be recorded as AEs.‬
‭e)‬‭Site‬‭staff‬‭will‬‭review‬‭and‬‭record‬‭prior‬‭medication‬‭taken‬‭by‬‭the‬‭subject‬‭within‬‭30‬‭days‬‭of‬‭first‬‭dose.All‬‭concomitant‬‭medications‬‭received‬‭during‬‭the‬
‭trial through 30 days after the last dose of trial treatment should be recorded.‬
‭f)‬ ‭ECOG‬‭status‬‭should‬‭be‬‭measured‬‭and‬‭registered‬‭at‬‭patient‬‭records‬‭and‬‭eCRF‬‭at‬‭screening,‬‭prior‬‭to‬‭dosing‬‭on‬‭day‬‭1‬‭of‬‭each‬‭treatment‬‭cycle‬‭and‬‭at‬
‭discontinuation of trial treatment.‬
‭g) Vital signs should include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at screening only.‬
‭h)‬‭Adverse‬‭events‬‭will‬‭be‬‭graded‬‭and‬‭recorded‬‭throughout‬‭the‬‭trial‬‭and‬‭during‬‭the‬‭follow-up‬‭period‬‭according‬‭to‬‭NCI‬‭CTCAE‬‭Version‬‭5.0.‬ ‭Toxicities‬
‭will be characterized in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial treatment.‬
‭i)‬ ‭Tumor‬ ‭tissue‬ ‭sample‬ ‭is‬ ‭mandatory‬ ‭to‬ ‭participate‬ ‭in‬ ‭this‬ ‭trial.‬ ‭It‬ ‭is‬ ‭accepted‬ ‭either‬ ‭pre-existing‬ ‭archived‬ ‭or‬ ‭newly-obtained‬ ‭(fresh‬ ‭tissue)‬ ‭biopsy‬
‭specimens from either primary or metastatic tumor, whichever is most recent.‬
‭j)‬‭Laboratory‬‭tests‬‭for‬‭screening‬‭should‬‭be‬‭performed‬‭within‬‭7‬‭days‬‭prior‬‭to‬‭study‬‭enrollment.‬‭If‬‭performed‬‭<‬‭7‬‭days‬‭prior‬‭to‬‭the‬‭first‬‭dose‬‭of‬‭trial‬‭therapy‬
‭the‬‭screening‬‭laboratory‬‭tests‬‭will‬‭serve‬‭as‬‭cycle‬‭1‬‭day‬‭1‬‭laboratory‬‭tests.‬‭If‬‭not,‬‭laboratory‬‭tests‬‭will‬‭need‬‭to‬‭be‬‭performed‬‭again‬‭on‬‭day‬‭1‬‭of‬‭cycle‬‭1.‬
‭Biochemistry‬ ‭includes:‬ ‭Albumin,‬ ‭Alkaline‬ ‭phosphatase,‬ ‭ALT,‬ ‭AST,‬ ‭Gamma-glutamyl-transferase‬ ‭(GGT),‬ ‭Lactate‬ ‭Dehydrogenase‬ ‭(LDH),‬ ‭Calcium,‬
‭Magnesium,‬‭Phosphorus,‬‭Sodium,‬‭Potassium,‬‭Creatinine,‬‭Creatine‬‭kinase,‬‭Direct‬‭Bilirubin,‬‭Indirect‬‭Bilirubin,‬‭Total‬‭Bilirubin,‬‭Total‬‭Protein,‬‭Blood‬‭Urea‬
‭Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose. The main laboratory determinations are summarized in Table 7 of the protocol.‬
‭k) Serum and plasma samples for optional biomarker studies will be collected prior to the beginning of treatment and at end of treatment.‬
‭l) Serum/Urine β-hCG A serum pregnancy test must be performed at screening (at the local laboratory) and when clinically indicated.‬
‭m) A standard 12-Lead Electrocardiogram (ECG) using local procedures at screening, additional ECGs will be performed‬‭only‬‭if clinically indicated.‬
‭n)‬‭The‬‭preferred‬‭radiologic‬‭technique‬‭is‬‭CT‬‭with‬‭intravenous‬‭(IV)‬‭contrast.‬‭If‬‭a‬‭patient‬‭is‬‭known‬‭to‬‭have‬‭a‬‭contraindication‬‭to‬‭CT‬‭contrast‬‭or‬‭develops‬‭a‬
‭contraindication‬‭during‬‭the‬‭trial,‬‭a‬‭non-contrast‬‭CT‬‭of‬‭the‬‭chest‬‭(MRI‬‭is‬‭not‬‭recommended‬‭due‬‭to‬‭respiratory‬‭artifacts)‬‭plus‬‭a‬‭contrast-enhanced‬‭MRI‬‭(if‬
‭possible)‬‭of‬‭the‬‭abdomen‬‭and‬‭pelvis‬‭should‬‭be‬‭performed.‬‭Brain‬‭CT‬‭scan‬‭or‬‭MRI‬‭or‬‭Whole‬‭Body‬‭Bone‬‭Scan‬‭are‬‭not‬‭required‬‭neither‬‭at‬‭baseline‬‭nor‬‭in‬
‭the‬‭follow-up‬‭in‬‭the‬‭absence‬‭of‬‭neurological/bone‬‭signs‬‭or‬‭symptoms.‬‭Participants‬‭who‬‭discontinue‬‭study‬‭treatment‬‭in‬‭absence‬‭of‬‭disease‬‭progression,‬
‭must continue their follow-up every 12 weeks (+/-7 days) by imaging until disease progression.‬
‭o)‬ ‭In‬‭this‬‭study,‬‭OS‬‭is‬‭a‬‭key‬‭endpoint‬‭of‬‭the‬‭study.‬‭Post-study‬‭follow-up‬‭is‬‭of‬‭critical‬‭importance‬‭and‬‭is‬‭essential.‬‭Participants‬‭who‬‭discontinue‬‭study‬
‭treatment must continue their follow-up every 12 weeks (+/- 7 days), until death or the conclusion of the study (phone contacts are allowed).‬
‭8.‬
‭Evaluation criteria‬
‭8.1.‬
‭Definitions‬
‭●‬ ‭Evaluable‬‭for‬‭toxicity‬‭:‬‭All‬‭patients‬‭will‬‭be‬‭evaluable‬‭for‬‭toxicity‬‭from‬‭the‬‭time‬‭of‬‭their‬‭first‬
‭treatment with nivolumab in combination with platinum-doublet chemotherapy.‬
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‭●‬ ‭Evaluable‬‭for‬‭response‬‭:‬ ‭All‬‭eligible‬‭patients‬‭will‬‭be‬‭included‬‭in‬‭the‬‭response‬‭rate‬‭calculation.‬
‭The‬‭subset‬‭that‬‭will‬‭be‬‭assigned‬‭a‬‭response‬‭category‬‭(Complete‬‭Response,‬‭Partial‬‭Response,‬
‭Stable‬ ‭Disease‬ ‭or‬ ‭Progressive‬ ‭Disease;‬ ‭see‬ ‭definitions‬ ‭below)‬ ‭are‬ ‭all‬ ‭patients‬ ‭who‬ ‭have‬
‭received‬‭at‬‭least‬‭one‬‭treatment‬‭and‬‭have‬‭their‬‭disease‬‭re-evaluated.‬‭Patients‬‭will‬‭have‬‭their‬
‭response classified according to the definitions set out below‬‭(Eisenhauer E, 2009)‬‭.‬
‭8.2.‬
‭Evaluation of efficacy‬
‭●‬ ‭Study‬‭evaluations‬‭will‬‭take‬‭place‬‭in‬‭accordance‬‭with‬‭the‬‭Schedule‬‭of‬‭Activities‬‭described‬‭in‬
‭Section 7.4.‬
‭●‬ ‭Objective‬ ‭tumor‬ ‭response‬‭and‬‭time‬‭of‬‭progression‬‭will‬‭be‬‭measured‬‭according‬‭to‬‭RECIST‬
‭criteria v.1.1.‬
‭●‬ ‭Response‬‭criteria‬‭are‬‭essentially‬‭based‬‭on‬‭a‬‭set‬‭of‬‭measurable‬‭lesions‬‭identified‬‭at‬‭baseline‬‭as‬
‭target‬ ‭lesions,‬ ‭and‬ ‭–‬ ‭together‬ ‭with‬ ‭other‬ ‭lesions‬ ‭that‬ ‭are‬ ‭denoted‬ ‭as‬ ‭non-target‬ ‭lesions‬ ‭–‬
‭followed until disease progression.‬
‭8.2.1.‬ ‭Measurability of tumour lesions at baseline‬
‭●‬ ‭Chest-‬ ‭abdominal‬ ‭and‬ ‭pelvic‬ ‭CT‬ ‭scan‬ ‭will‬ ‭be‬ ‭used‬ ‭to‬ ‭measure‬ ‭the‬ ‭lesions‬ ‭according‬ ‭to‬
‭RECIST criteria.‬
‭●‬ ‭To‬‭meet‬‭screening‬‭criteria,‬‭initial‬‭tumor‬‭imaging‬‭must‬‭be‬‭performed‬‭within‬‭28‬‭days‬‭prior‬‭to‬
‭the‬‭beginning‬‭of‬‭treatment.‬‭This‬‭scan‬‭will‬‭be‬‭considered‬‭the‬‭baseline‬‭assessment‬‭for‬‭the‬‭study.‬
‭The‬‭site‬‭study‬‭team‬‭must‬‭review‬‭pre-trial‬‭images‬‭to‬‭confirm‬‭the‬‭subject‬‭has‬‭at‬‭least‬‭one‬‭target‬
‭lesion (i.e. meets measurability requirements) per RECIST 1.1.‬
‭●‬ ‭irRECIST criteria will be used to measure ORR as secondary endpoint.‬
‭8.2.1.1.‬‭Definitions‬
‭●‬ ‭Measurable‬‭disease‬‭:‬‭the‬‭presence‬‭of‬‭at‬‭least‬‭one‬‭measurable‬‭lesion.‬‭If‬‭the‬‭measurable‬‭disease‬
‭is‬ ‭restricted‬ ‭to‬ ‭a‬ ‭solitary‬ ‭lesion,‬ ‭its‬ ‭neoplastic‬ ‭nature‬ ‭should‬ ‭be‬ ‭confirmed‬ ‭by‬
‭cytology/histology.‬
‭●‬ ‭Measurable‬‭lesions‬‭:‬‭tumour‬‭lesions‬‭that‬‭can‬‭be‬‭accurately‬‭measured‬‭in‬‭at‬‭least‬‭one‬‭dimension‬
‭(longest‬‭diameter‬‭to‬‭be‬‭recorded)‬‭as‬‭≥‬‭20‬‭mm‬‭with‬‭chest‬‭x-ray,‬‭and‬‭as‬‭≥‬‭10‬‭mm‬‭with‬‭CT‬‭scan‬
‭or‬ ‭clinical‬ ‭examination‬ ‭[using‬ ‭calipers].‬ ‭Bone‬ ‭lesions‬ ‭are‬ ‭considered‬ ‭measurable‬ ‭only‬ ‭if‬
‭assessed‬ ‭by‬ ‭CT‬ ‭scan‬ ‭and‬ ‭have‬ ‭an‬ ‭identifiable‬ ‭soft‬ ‭tissue‬ ‭component‬ ‭that‬ ‭meets‬ ‭these‬
‭requirements‬‭(soft‬‭tissue‬‭component‬‭>‬‭10‬‭mm‬‭by‬‭CT‬‭scan).‬ ‭Malignant‬‭lymph‬‭nodes‬‭must‬‭be‬
‭≥‬‭15‬‭mm‬‭in‬‭the‬‭short‬‭axis‬‭to‬‭be‬‭considered‬‭measurable;‬‭only‬‭the‬‭short‬‭axis‬‭will‬‭be‬‭measured‬
‭and‬‭followed.‬‭All‬‭tumour‬‭measurements‬‭must‬‭be‬‭recorded‬‭in‬‭millimeters‬‭(or‬‭decimal‬‭fractions‬
‭of‬‭centimeters)‬‭by‬‭use‬‭of‬‭a‬‭ruler‬‭or‬‭calipers.‬‭Tumour‬‭lesions‬‭situated‬‭in‬‭a‬‭previously‬‭irradiated‬
‭area,‬ ‭or‬ ‭in‬ ‭an‬ ‭area‬ ‭subjected‬ ‭to‬ ‭other‬ ‭locoregional‬ ‭therapy,‬ ‭are‬ ‭usually‬ ‭not‬ ‭considered‬
‭measurable‬‭unless‬‭there‬‭has‬‭been‬‭demonstrated‬‭progression‬‭in‬‭the‬‭lesion.‬‭Provide‬‭detail‬‭on‬‭the‬
‭conditions under which such lesions would be considered measurable.‬
‭●‬ ‭Non-measurable‬ ‭lesions‬‭:‬ ‭all‬ ‭other‬ ‭lesions‬ ‭(or‬ ‭sites‬‭of‬‭disease),‬‭including‬‭small‬‭lesions‬‭are‬
‭considered‬‭non-measurable‬‭disease.‬‭Bone‬‭lesions‬‭without‬‭a‬‭measurable‬‭soft‬‭tissue‬‭component,‬
‭leptomeningeal‬ ‭disease,‬ ‭ascites,‬ ‭pleural/pericardial‬ ‭effusions,‬ ‭lymphangitis‬ ‭cutis/pulmonis,‬
‭inflammatory‬‭breast‬‭disease,‬‭lymphangitic‬‭involvement‬‭of‬‭lung‬‭or‬‭skin‬‭and‬‭abdominal‬‭masses‬
‭followed‬‭by‬‭clinical‬‭examination‬‭are‬‭all‬‭non-measurable.‬‭Nodes‬‭that‬‭have‬‭a‬‭short‬‭axis‬‭<10‬
‭mm at baseline are considered non-pathological and should not be recorded or followed.‬
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‭●‬ ‭Target‬‭Lesions:‬‭when‬‭more‬‭than‬‭one‬‭measurable‬‭tumour‬‭lesion‬‭or‬‭malignant‬‭lymph‬‭node‬‭is‬
‭present‬‭at‬‭baseline‬‭all‬‭lesions‬‭up‬‭to‬‭a‬‭maximum‬‭of‬‭5‬‭lesions‬‭total‬‭(and‬‭a‬‭maximum‬‭of‬‭2‬‭lesions‬
‭per‬‭organ‬‭)‬‭representative‬‭of‬‭all‬‭involved‬‭organs‬‭should‬‭be‬‭identified‬‭as‬‭target‬‭lesions‬‭and‬‭will‬
‭be‬‭recorded‬‭and‬‭measured‬‭at‬‭baseline.‬‭Target‬‭lesions‬‭should‬‭be‬‭selected‬‭on‬‭the‬‭basis‬‭of‬‭their‬
‭size‬ ‭(lesions‬ ‭with‬ ‭the‬ ‭longest‬ ‭diameter),‬ ‭be‬ ‭representative‬ ‭of‬ ‭all‬ ‭involved‬ ‭organs,‬ ‭but‬ ‭in‬
‭addition‬‭should‬‭be‬‭those‬‭that‬‭lend‬‭themselves‬‭to‬‭reproducible‬‭repeated‬‭measurements‬‭.‬‭Note‬
‭that‬‭pathological‬‭nodes‬‭must‬‭meet‬‭the‬‭criterion‬‭of‬‭a‬‭short‬‭axis‬‭of‬‭≥‬‭15‬‭mm‬‭by‬‭CT‬‭scan‬‭and‬
‭only‬‭the‬‭short‬‭axis‬‭of‬‭these‬‭nodes‬‭will‬‭contribute‬‭to‬‭the‬‭baseline‬‭sum.‬‭At‬‭baseline,‬‭the‬‭sum‬‭of‬
‭the‬‭target‬‭lesions‬‭(longest‬‭diameter‬‭of‬‭tumour‬‭lesions‬‭plus‬‭short‬‭axis‬‭of‬‭lymph‬‭nodes:‬‭overall‬
‭maximum of 5 ) is to be calculated and recorded.‬
‭●‬ ‭Non-target‬ ‭Lesions:‬ ‭all‬ ‭non-measurable‬ ‭lesions‬‭(or‬‭sites‬‭of‬‭disease)‬‭including‬‭pathological‬
‭nodes‬‭(those‬‭with‬‭short‬‭axis‬‭≥‬‭10‬‭mm‬‭but‬‭<‬‭15‬‭mm),‬‭plus‬‭any‬‭measurable‬‭lesions‬‭over‬‭and‬
‭above‬‭those‬‭listed‬‭as‬‭target‬‭lesions‬‭are‬‭considered‬‭non-target‬‭lesions‬‭.‬‭Measurements‬‭are‬‭not‬
‭required‬‭but‬‭these‬‭lesions‬‭should‬‭be‬‭noted‬‭at‬‭baseline‬‭and‬‭should‬‭be‬‭followed‬‭as‬‭“present”‬‭or‬
‭“absent”.‬
‭8.2.1.2.‬‭Methods of measurements‬
‭●‬ ‭Patient‬‭must‬‭have‬‭measurable‬‭lesions‬‭on‬‭CT‬‭according‬‭to‬‭RECIST‬‭1.1‬‭in‬‭order‬‭to‬‭enter‬‭the‬
‭study.‬
‭●‬ ‭The‬‭preferred‬‭radiologic‬‭technique‬‭is‬‭CT‬‭with‬‭IV‬‭contrast.‬‭If‬‭a‬‭patient‬‭is‬‭known‬‭to‬‭have‬‭a‬
‭contraindication‬‭to‬‭CT‬‭contrast‬‭or‬‭develops‬‭a‬‭contraindication‬‭during‬‭the‬‭trial,‬‭a‬‭non-contrast‬
‭CT‬ ‭of‬ ‭the‬ ‭chest‬ ‭(MRI‬ ‭is‬ ‭not‬ ‭recommended‬ ‭due‬ ‭to‬ ‭respiratory‬ ‭artifacts)‬ ‭plus‬ ‭a‬
‭contrast-enhanced MRI (if possible) of the abdomen and pelvis should be performed.‬
‭8.2.2.‬ ‭Tumor response evaluation‬
‭8.2.2.1.‬‭Response evaluation according RECIST 1.1‬‭[xliv]‬
‭●‬ ‭All‬‭patients‬‭will‬‭have‬‭their‬‭best‬‭response‬‭according‬‭to‬‭RECIST‬‭criteria‬‭1.1‬‭from‬‭the‬‭start‬‭of‬
‭study treatment until the end of treatment classified as outlined below:‬
‭○‬ ‭Complete‬‭or‬‭partial‬‭responses‬‭may‬‭be‬‭claimed‬‭only‬‭if‬‭the‬‭criteria‬‭for‬‭each‬‭are‬‭met‬‭at‬‭a‬
‭subsequent‬ ‭time‬ ‭point‬ ‭at‬ ‭least‬ ‭4‬ ‭weeks‬ ‭later.‬ ‭Refer‬ ‭to‬ ‭the‬ ‭table‬ ‭below‬ ‭(Table‬
‭8.2.2.1-a).‬
‭○‬ ‭Complete‬ ‭Response‬ ‭(CR):‬ ‭disappearance‬ ‭of‬ ‭all‬ ‭target‬ ‭and‬ ‭non-target‬ ‭lesions‬ ‭and‬
‭normalization‬ ‭of‬ ‭tumour‬ ‭markers.‬ ‭Pathological‬ ‭lymph‬ ‭nodes‬ ‭must‬ ‭have‬‭short‬‭axis‬
‭measures‬‭<‬‭10‬‭mm‬‭(‬‭Note‬‭:‬‭continue‬‭to‬‭record‬‭the‬‭measurement‬‭even‬‭if‬‭<‬‭10‬‭mm‬‭and‬
‭considered‬‭CR).‬‭Tumour‬‭markers‬‭must‬‭have‬‭normalized.‬‭Residual‬‭lesions‬‭(other‬‭than‬
‭nodes‬ ‭<‬ ‭10‬ ‭mm)‬ ‭thought‬ ‭to‬ ‭be‬ ‭non-malignant‬ ‭should‬ ‭be‬ ‭further‬ ‭investigated‬ ‭(by‬
‭cytology or PET scans) before CR can be accepted.‬
‭○‬ ‭Partial‬ ‭Response‬ ‭(PR):‬ ‭at‬ ‭least‬ ‭a‬ ‭30%‬ ‭decrease‬ ‭in‬ ‭the‬ ‭sum‬ ‭of‬ ‭measures‬ ‭(longest‬
‭diameter‬‭for‬‭tumour‬‭lesions‬‭and‬‭short‬‭axis‬‭measure‬‭for‬‭nodes)‬‭of‬‭target‬‭lesions,‬‭taking‬
‭as reference the baseline sum of diameters. Non target lesions must be non-PD.‬
‭○‬ ‭Stable‬ ‭Disease‬ ‭(SD):‬ ‭Neither‬ ‭sufficient‬ ‭shrinkage‬ ‭to‬ ‭qualify‬ ‭for‬ ‭PR‬ ‭nor‬‭sufficient‬
‭increase to qualify for PD taking as reference the smallest sum of diameters on study.‬
‭○‬ ‭Progressive‬ ‭Disease‬ ‭(PD):‬ ‭at‬ ‭least‬ ‭a‬ ‭20%‬ ‭increase‬ ‭in‬ ‭the‬ ‭sum‬ ‭of‬ ‭diameters‬ ‭of‬
‭measured‬ ‭lesions‬ ‭taking‬ ‭as‬ ‭references‬ ‭the‬ ‭smallest‬ ‭sum‬ ‭of‬ ‭diameters‬ ‭recorded‬ ‭on‬
‭study‬‭(including‬‭baseline)‬‭AND‬‭an‬‭absolute‬‭increase‬‭of‬‭≥‬‭5‬‭mm.‬‭Appearance‬‭of‬‭new‬
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‭lesions‬‭will‬‭also‬‭constitute‬‭PD‬‭(including‬‭lesions‬‭in‬‭previously‬‭unassessed‬‭areas).‬‭In‬
‭exceptional‬ ‭circumstances,‬ ‭unequivocal‬ ‭progression‬ ‭of‬ ‭non-target‬ ‭disease‬ ‭may‬ ‭be‬
‭accepted‬ ‭as‬ ‭evidence‬ ‭of‬ ‭disease‬‭progression,‬‭where‬‭the‬‭overall‬‭tumour‬‭burden‬‭has‬
‭increased‬ ‭sufficiently‬ ‭to‬‭merit‬‭discontinuation‬‭of‬‭treatment,‬‭for‬‭example‬‭where‬‭the‬
‭tumour‬ ‭burden‬‭appears‬‭to‬‭have‬‭increased‬‭by‬‭at‬‭least‬‭73%‬‭in‬‭volume‬‭(which‬‭is‬‭the‬
‭increase‬‭in‬‭volume‬‭when‬‭all‬‭dimensions‬‭of‬‭a‬‭single‬‭lesion‬‭increase‬‭by‬‭20%).‬‭Modest‬
‭increases‬ ‭in‬ ‭the‬ ‭size‬ ‭of‬ ‭one‬ ‭or‬ ‭more‬ ‭non-target‬ ‭lesions‬ ‭are‬ ‭NOT‬ ‭considered‬
‭unequivocal‬‭progression.‬ ‭If‬‭the‬‭evidence‬‭of‬‭PD‬‭is‬‭equivocal‬‭(target‬‭or‬‭non-target),‬
‭treatment‬‭may‬‭continue‬‭until‬‭the‬‭next‬‭assessment,‬‭but‬‭on‬‭further‬‭documentation,‬‭the‬
‭earlier date must be used‬‭[xlv]‬‭.‬
‭Table 8.2.2.1-a: Integration of target, non-target and new lesions into response assessment:‬
‭Target Lesions‬
‭Non-Target Lesions‬
‭New Lesions‬ ‭Overall Response‬ ‭Best Response for this category‬
‭also requires‬
‭Patients with Target lesions ± non target lesions‬
‭CR‬
‭CR‬
‭No‬
‭CR‬
‭Normalization of tumour‬
‭markers, tumour nodes < 10 mm‬
‭CR‬
‭Non-CR/Non-PD‬
‭No‬
‭PR‬
‭CR‬
‭Not all evaluated‬
‭No‬
‭PR‬
‭PR‬
‭Non-PD/ not all evaluated‬
‭No‬
‭PR‬
‭SD‬
‭Non-PD/ not all evaluated‬
‭No‬
‭SD‬
‭Documented at least once ≥‬‭4‬
‭weeks from baseline [note,‬
‭protocol may define;  6-8 weeks‬
‭is recommended]‬
‭Not all evaluated‬
‭Non-PD‬
‭No‬
‭NE‬
‭PD‬
‭Any‬
‭Any‬
‭PD‬
‭Any‬
‭PD‬
‭Any‬
‭PD‬
‭Any‬
‭Any‬
‭Yes‬
‭PD‬
‭Patients with Non target lesions ONLY‬
‭No Target‬
‭CR‬
‭No‬
‭CR‬
‭Normalization of tumour‬
‭markers, all tumour nodes‬
‭<10 mm‬
‭Non-CR/Non-PD‬
‭No‬
‭Non-CR/Non-PD‬
‭Not all evaluated‬
‭No‬
‭NE‬
‭Unequivocal PD‬
‭Any‬
‭PD‬
‭Any‬
‭Yes‬
‭PD‬
‭Note‬‭: Patients with a global deterioration of health‬‭status requiring discontinuation of treatment without objective evidence‬
‭of disease progression [or evidence of unequivocal disease progression] at that time should be reported as “‬‭symptomatic‬
‭deterioration”‬‭. This is a reason for stopping therapy,‬‭but is NOT objective PD.  Every effort should be made to document‬
‭the objective progression even after discontinuation of treatment.‬
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‭The best overall response can be interpreted as below‬‭(Table 8.2.2.1-b)‬‭:‬
‭Table 8.2.2.1-b. Response on confirmation‬
‭Response:‬
‭First time point‬
‭Subsequent time point‬
‭BEST overall response‬
‭Also requires‬
‭CR‬
‭CR‬
‭CR‬
‭Normalization of tumour‬
‭markers, tumour nodes < 10‬
‭mm‬
‭CR‬
‭PR‬
‭SD, PD or PR (see‬
‭comment*)‬
‭-‬
‭CR‬
‭SD‬
‭SD provided minimum‬
‭criteria for SD duration met,‬
‭otherwise, PD‬
‭-‬
‭CR‬
‭PD‬
‭SD provided minimum‬
‭criteria for SD duration met,‬
‭otherwise, PD‬
‭-‬
‭CR‬
‭NE‬
‭SD provided minimum‬
‭criteria for SD duration met,‬
‭otherwise NE‬
‭-‬
‭PR‬
‭CR‬
‭PR‬
‭-‬
‭PR‬
‭PR‬
‭PR‬
‭-‬
‭PR‬
‭SD‬
‭SD‬
‭-‬
‭PR‬
‭PD‬
‭SD provided minimum‬
‭criteria for SD duration met,‬
‭otherwise, PD‬
‭-‬
‭PR‬
‭NE‬
‭SD provide minimum‬
‭criteria for SD duration met,‬
‭otherwise, NE‬
‭-‬
‭NE‬
‭NE‬
‭NE‬
‭-‬
*‬‭May‬‭consider‬‭PR‬‭providing‬‭initial‬‭“CR”‬‭likely‬‭PR‬‭on‬‭subsequent‬‭review‬‭–‬‭then‬‭original‬‭CR‬‭should‬‭be‬‭corrected.‬ ‭Recurrence‬‭of‬‭lesion‬‭after‬
true CR is PD.‬
‭8.2.2.2.‬‭Response evaluation according irRECIST‬‭[xlvi]‬
‭●‬ ‭Following‬‭radiological‬‭assessment‬‭of‬‭PD‬‭by‬‭RECIST‬‭1.1,‬‭sites‬‭will‬‭assess‬‭tumor‬‭response‬‭and‬
‭progression per immune-related RECIST (irRECIST) for all subjects included in the trial.‬
‭●‬ ‭If‬‭imaging‬‭shows‬‭PD‬‭per‬‭RECIST‬‭1.1,‬‭tumor‬‭assessment‬‭may‬‭be‬‭repeated‬‭at‬‭the‬‭site‬‭at‬‭least‬‭4‬
‭weeks‬‭later‬‭to‬‭confirm‬‭PD‬‭(per‬‭irRECIST)‬‭with‬‭the‬‭option‬‭of‬‭continuing‬‭treatment‬‭until‬‭this‬
‭scan‬‭is‬‭obtained‬‭for‬‭clinically‬‭stable‬‭subjects‬‭(see‬‭Table‬‭11).‬‭Subjects‬‭who‬‭have‬‭unconfirmed‬
‭disease‬ ‭progression‬ ‭(per‬ ‭irRECIST)‬ ‭may‬ ‭continue‬ ‭on‬ ‭treatment‬ ‭and‬ ‭follow‬ ‭the‬ ‭regular‬
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‭imaging‬‭schedule‬‭intervals‬‭until‬‭documented‬‭disease‬‭progression,‬‭the‬‭start‬‭of‬‭new‬‭anti-cancer‬
‭treatment, withdrawal of consent, death, or the end of the trial, whichever occurs first.‬
‭●‬ ‭In‬ ‭determining‬ ‭whether‬ ‭or‬ ‭not‬ ‭the‬ ‭tumor‬ ‭burden‬‭has‬‭increased‬‭or‬‭decreased,‬‭investigators‬
‭should consider all target lesions as well as non-target lesions.‬
‭●‬ ‭Subjects‬ ‭that‬ ‭are‬ ‭deemed‬ ‭clinically‬ ‭unstable‬ ‭are‬ ‭not‬ ‭required‬ ‭to‬ ‭have‬ ‭repeat‬ ‭imaging‬ ‭for‬
‭confirmation.‬‭If‬‭radiologic‬‭progression‬‭is‬‭confirmed‬‭by‬‭subsequent‬‭scan,‬‭it‬‭is‬‭recommended‬
‭that‬‭the‬‭subject‬‭be‬‭discontinued‬‭from‬‭trial‬‭treatment‬‭unless,‬‭in‬‭the‬‭investigator’s‬‭opinion,‬‭the‬
‭subject‬‭is‬‭deriving‬‭benefit‬‭from‬‭treatment.‬‭Clinically‬‭stable‬‭subjects‬‭may‬‭continue‬‭to‬‭receive‬
‭trial therapy. Clinically stable is defined as follows:‬
‭○‬ ‭Absence of signs and symptoms indicating disease progression.‬
‭○‬ ‭No decline in ECOG performance status.‬
‭○‬ ‭Absence of rapid progression of disease.‬
‭○‬ ‭Absence‬‭of‬‭progressive‬‭tumor‬‭at‬‭critical‬‭anatomical‬‭sites‬‭requiring‬‭urgent‬‭alternative‬
‭medical intervention.‬
‭Table 8.2.2.2. Management after 1‬‭st‬‭radiological progression‬
‭Clinically stable‬
‭Clinically unstable‬
‭Imaging‬
‭Treatment‬
‭Imaging‬
‭Treatment‬
‭1‬‭st‬‭Radiological‬
‭evidence of PD per‬
‭RECIST 1.1‬
‭Repeat imaging at ≥‬
‭4 weeks to confirm‬
‭PD.‬
‭May continue‬
‭treatment at‬
‭investigator’s‬
‭discretion while‬
‭waiting for‬
‭confirmatory scan.‬
‭Repeat imaging at ≥‬
‭4 weeks to confirm‬
‭PD if possible.‬
‭Discontinue‬
‭treatment.‬
‭Repeat scan confirms‬
‭PD‬
‭No additional‬
‭imaging required‬
‭Discontinue‬
‭treatment.‬
‭No additional‬
‭imaging required‬
‭Repeat scan shows‬
‭SD, PR or CR.‬
‭Continue regularly‬
‭schedule imaging‬
‭every 8 weeks.‬
‭Continue study‬
‭treatment at‬
‭investigator’s‬
‭discretion.‬
‭Continue regularly‬
‭schedule imaging‬
‭every 8 weeks.‬
‭May restart study‬
‭treatment as per‬
‭investigator´s‬
‭discretion.‬
‭8.2.2.3.‬‭Frequency of tumor re-evaluation‬
‭●‬ ‭The‬‭first‬‭on-study‬‭imaging‬‭assessment‬‭should‬‭be‬‭performed‬‭at‬‭12‬‭weeks‬‭(±‬‭7‬‭days)‬‭after‬‭the‬
‭first‬‭dose‬‭of‬‭trial‬‭treatment.‬‭Subsequent‬‭imaging‬‭should‬‭be‬‭performed‬‭every‬‭12‬‭weeks‬‭(±‬‭7‬
‭days) until PD.‬
‭●‬ ‭Imaging‬‭should‬‭be‬‭repeated‬‭at‬‭least‬‭4‬‭weeks‬‭after‬‭the‬‭first‬‭observation‬‭of‬‭a‬‭complete‬‭or‬‭partial‬
‭response.‬
‭●‬ ‭Imaging‬ ‭may‬ ‭be‬ ‭more‬ ‭frequent‬ ‭if‬ ‭clinically‬ ‭indicated.‬ ‭Imaging‬ ‭should‬‭not‬‭be‬‭delayed‬‭for‬
‭delays in cycle starts.‬
‭●‬ ‭After‬ ‭discontinuation‬ ‭of‬ ‭protocol‬ ‭treatment,‬ ‭patients‬‭who‬‭have‬‭not‬‭progressed‬‭will‬‭still‬‭be‬
‭re-evaluated every 12 weeks.‬
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‭8.2.3.‬ ‭Reporting of tumor response‬
‭All‬‭patients‬‭included‬‭in‬‭the‬‭study‬‭must‬‭be‬‭assessed‬‭for‬‭response‬‭to‬‭treatment,‬‭even‬‭if‬‭there‬‭is‬‭a‬
‭major‬‭protocol‬‭treatment‬‭deviation‬‭or‬‭if‬‭they‬‭are‬‭ineligible,‬‭or‬‭not‬‭followed/re-evaluated.‬‭Each‬‭patient‬
‭will‬‭be‬‭assigned‬‭one‬‭of‬‭the‬‭following‬‭categories:‬‭complete‬‭response,‬‭partial‬‭response,‬‭stable‬‭disease,‬
‭progressive‬‭disease,‬‭early‬‭death‬‭from‬‭malignant‬‭disease,‬‭early‬‭death‬‭from‬‭toxicity,‬‭early‬‭death‬‭from‬
‭other cause or unknown (not assessable, insufficient data).‬
‭Early‬ ‭death‬ ‭is‬ ‭defined‬ ‭as‬ ‭any‬ ‭death‬ ‭occurring‬ ‭before‬ ‭the‬ ‭first‬ ‭per‬ ‭protocol‬ ‭time‬ ‭point‬ ‭of‬ ‭tumor‬
‭re-evaluation.‬ ‭The‬ ‭responsible‬ ‭investigator‬ ‭will‬ ‭decide‬ ‭if‬ ‭the‬ ‭cause‬ ‭of‬‭death‬‭is‬‭malignant‬‭disease,‬
‭toxicity or other cause.‬
‭Patients‬‭for‬‭whom‬‭response‬‭is‬‭not‬‭confirmed‬‭will‬‭be‬‭classified‬‭as‬‭"unknown",‬‭unless‬‭they‬‭meet‬‭the‬
‭criteria‬ ‭for‬ ‭stable‬ ‭disease‬ ‭(or‬ ‭the‬ ‭criteria‬ ‭for‬ ‭partial‬‭response‬‭in‬‭case‬‭of‬‭an‬‭unconfirmed‬‭complete‬
‭response).‬‭Patients’‬‭response‬‭will‬‭also‬‭be‬‭classified‬‭as‬‭"unknown"‬‭if‬‭insufficient‬‭data‬‭were‬‭collected‬‭to‬
‭allow evaluation per these criteria. Please refer to table‬‭8.2.2.1-b.‬
‭8.2.3.1.‬‭Response duration‬
‭Response‬‭duration‬‭will‬‭be‬‭measured‬‭from‬‭the‬‭time‬‭measurement‬‭criteria‬‭for‬‭CR/PR‬‭(whichever‬‭is‬‭first‬
‭recorded)‬ ‭are‬ ‭first‬ ‭met‬ ‭until‬ ‭the‬ ‭first‬ ‭date‬ ‭that‬ ‭recurrent‬ ‭or‬ ‭progressive‬ ‭disease‬ ‭is‬ ‭objectively‬
‭documented.‬
‭8.2.3.2.‬‭Stable disease duration‬
‭Stable‬‭disease‬‭duration‬‭will‬‭be‬‭measured‬‭from‬‭the‬‭time‬‭of‬‭start‬‭of‬‭treatment‬‭(or‬‭randomization‬‭for‬
‭randomized studies) until the criteria for progression are met.‬
‭8.2.3.3.‬‭Progression Free Survival‬
‭Progression‬‭free‬‭survival‬‭will‬‭be‬‭calculated‬‭from‬‭the‬‭date‬‭treatment‬‭with‬‭first-line‬‭chemotherapy‬‭and‬
‭nivolumab begins until the date of first progressive disease as per RECIST 1.1 or death.‬
‭8.2.3.4.‬‭Overall Survival‬
‭Overall‬ ‭survival‬ ‭will‬ ‭be‬ ‭calculated‬ ‭from‬ ‭the‬ ‭date‬ ‭treatment‬ ‭with‬ ‭first-line‬ ‭chemotherapy‬ ‭and‬
‭nivolumab begins until the date of death from any cause.‬
‭9.‬
‭Statistical considerations‬
‭9.1.‬
‭Statistical design‬
‭9.1.1.‬ ‭Sample Size Determination‬
‭This‬‭is‬‭a‬‭phase‬‭II‬‭open-label,‬‭single‬‭arm‬‭study.‬‭The‬‭primary‬‭endpoint‬‭is‬‭the‬‭one-year‬‭overall‬
‭survival rate.‬
‭The‬ ‭sample‬‭size‬‭of‬‭this‬‭study‬‭is‬‭driven‬‭by‬‭its‬‭primary‬‭objective‬‭which‬‭is‬‭to‬‭determine‬‭the‬
‭one-year‬ ‭OS‬ ‭rate‬ ‭calculated‬ ‭from‬ ‭the‬ ‭date‬ ‭treatment‬ ‭with‬ ‭nivolumab‬ ‭and‬ ‭platinum-based‬
‭chemotherapy‬‭begins,‬‭until‬‭the‬‭date‬‭of‬‭death‬‭from‬‭any‬‭cause‬‭in‬‭patients‬‭with‬‭advanced‬‭G3‬‭NENs‬‭of‬
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‭GEP‬ ‭tract‬ ‭or‬ ‭unknown‬ ‭primary‬ ‭site,‬ ‭who‬ ‭have‬ ‭not‬ ‭received‬ ‭any‬ ‭prior‬ ‭antineoplastic‬ ‭systemic‬
‭treatment.‬
‭Based‬‭on‬‭data‬‭derived‬‭from‬‭tumor‬‭registries‬‭[xlvii],[xlviii]‬‭,‬‭median‬‭OS‬‭for‬‭these‬‭patients‬‭is‬‭approximately‬
‭11-12‬ ‭months,‬ ‭with‬ ‭1-year‬ ‭overall‬ ‭survival‬ ‭rate‬ ‭of‬ ‭50%.‬ ‭The‬ ‭primary‬ ‭hypothesis‬ ‭(H1)‬ ‭is‬ ‭that‬
‭chemotherapy‬‭in‬‭combination‬‭with‬‭nivolumab‬‭is‬‭superior‬‭to‬‭chemotherapy‬‭in‬‭terms‬‭of‬‭OS,‬‭achieving‬
‭a‬ ‭median‬ ‭OS‬ ‭of‬ ‭14‬ ‭months,‬ ‭with‬ ‭72%‬ ‭patients‬ ‭alive‬‭at‬‭12‬‭months.‬‭The‬‭study‬‭will‬‭be‬‭considered‬
‭successful‬‭if‬‭the‬‭primary‬‭hypothesis‬‭is‬‭statistically‬‭significant.‬‭Considering‬‭the‬‭following‬‭assumptions:‬
‭a‬‭power‬‭of‬‭80%,‬‭alpha‬‭error‬‭of‬‭0.05,‬‭18‬‭months‬‭accrual‬‭time‬‭and‬‭12-month‬‭follow-up‬‭period,‬‭a‬‭total‬
‭number of 38 patients should be included in the study, considering a drop out rate of 10%.‬
‭9.2.‬
‭Populations for Analysis‬
‭For purpose of analysis, the following populations are defined:‬
‭Population‬
‭Description‬
‭Enrolled‬
‭All participants who signed informed consent and were registered.‬
‭Treated‬
‭All‬‭participants‬‭who‬‭received‬‭at‬‭least‬‭one‬‭dose‬‭of‬‭any‬‭study‬‭medication.‬‭This‬‭is‬‭the‬‭primary‬
‭dataset for dosing and safety analysis.‬
‭Response-Evaluable‬
‭All treated subjects who have a baseline and at least one‬
‭on-treatment‬‭imaging‬‭evaluation‬‭or‬‭had‬‭progression‬‭or‬‭death‬‭prior‬‭to‬‭the‬‭first‬‭on-treatment‬
‭scan.‬
‭9.3.‬
‭Statistical Analysis‬
‭9.3.1.‬ ‭Efficacy Analysis‬
‭Endpoint‬
‭Statistical Analysis Methods‬
‭Primary‬
‭Primary‬‭endpoint‬‭is‬‭one‬‭year‬‭OS‬‭rate‬‭with‬‭nivolumab‬‭plus‬‭chemotherapy.‬‭This‬‭is‬‭defined‬
‭as‬ ‭the‬ ‭proportion‬ ‭of‬ ‭patients‬ ‭that‬ ‭remain‬ ‭alive‬ ‭at‬ ‭12‬ ‭months‬ ‭since‬ ‭the‬ ‭beginning‬ ‭of‬
‭treatment. OS will be censored on the last date a participant was known to be alive.‬
‭Secondary‬
‭PFS and OS with nivolumab plus chemotherapy assessed by Central Review.‬
‭ORR with nivolumab plus chemotherapy assessed by Central Review.‬
‭Chromogranin A and enolase levels and their association with ORR, PFS,‬
‭and OS.‬
‭ORR‬ ‭is‬‭defined‬‭as‬‭the‬‭number‬‭of‬‭participants‬‭with‬‭a‬‭best‬‭overall‬‭response‬‭of‬‭confirmed‬
‭CR‬ ‭or‬ ‭PR‬ ‭divided‬ ‭by‬ ‭the‬ ‭number‬ ‭of‬ ‭enrolled‬ ‭participants.‬ ‭BOR‬ ‭is‬ ‭defined‬ ‭as‬ ‭the‬ ‭best‬
‭response‬ ‭designation,‬ ‭as‬‭determined‬‭by‬‭the‬‭central‬‭review,‬‭recorded‬‭between‬‭the‬‭date‬‭of‬
‭treatment‬‭start‬‭and‬‭the‬‭date‬‭of‬‭objectively‬‭documented‬‭progression‬‭per‬‭RECIST‬‭1.1‬‭or,‬‭the‬
‭date‬ ‭of‬ ‭initiation‬ ‭of‬ ‭subsequent‬ ‭anti-cancer‬ ‭therapy,‬ ‭whichever‬ ‭occurs‬ ‭first.‬ ‭For‬
‭participants without documented‬
‭progression‬ ‭or‬ ‭subsequent‬ ‭anti-cancer‬ ‭therapy,‬ ‭all‬ ‭available‬ ‭response‬ ‭designations‬ ‭will‬
‭contribute‬ ‭to‬ ‭the‬ ‭BOR‬ ‭determination.‬ ‭For‬ ‭participants‬ ‭who‬ ‭continue‬ ‭treatment‬ ‭beyond‬
‭progression,‬ ‭the‬‭BOR‬‭will‬‭be‬‭determined‬‭based‬‭on‬‭response‬‭designations‬‭recorded‬‭up‬‭to‬
‭the‬‭time‬‭of‬‭the‬‭initial‬‭RECIST‬‭1.1-defined‬‭progression.‬‭Complete‬‭or‬‭partial‬‭responses‬‭may‬
‭be‬ ‭claimed‬ ‭only‬‭if‬‭the‬‭criteria‬‭for‬‭each‬‭are‬‭met‬‭at‬‭a‬‭subsequent‬‭time‬‭point‬‭of‬‭≥‬‭4‬‭weeks‬
‭later.‬
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‭9.3.1.1.‬‭Methods for Primary Endpoint‬
‭The efficacy analysis will be performed for the treatment population.‬
‭For‬ ‭the‬ ‭primary‬ ‭endpoint,‬ ‭the‬ ‭OS‬ ‭rate‬ ‭at‬ ‭12‬ ‭months‬ ‭with‬ ‭95%‬ ‭CIs‬ ‭will‬ ‭be‬ ‭estimated‬ ‭using‬
‭Kaplan-Meier‬‭methodology‬‭if‬‭follow-up‬‭requirement‬‭is‬‭met.‬‭OS‬‭curves,‬‭medians‬‭with‬‭95%‬‭CIs‬‭and‬
‭OS‬‭rates‬‭at‬‭6,‬‭18‬‭and‬‭24‬‭months‬‭with‬‭95%‬‭CIs‬‭will‬‭be‬‭estimated‬‭if‬‭follow-up‬‭requirement‬‭is‬‭met.‬‭The‬
‭proportion‬ ‭will‬ ‭be‬ ‭calculated‬ ‭by‬ ‭the‬ ‭product‬ ‭limit‬ ‭method‬‭(Kaplan-Meier‬‭[K-M]‬‭estimate),‬‭which‬
‭takes into account censored data.‬
‭9.3.1.2.‬‭Methods for Secondary Endpoints‬
‭The efficacy analysis for secondary endpoints will be performed for all treated patients.‬
‭PFS‬‭is‬‭defined‬‭as‬‭the‬‭time‬‭from‬‭the‬‭randomization‬‭date‬‭to‬‭the‬‭date‬‭of‬‭the‬‭first‬‭documented‬
‭tumor progression per RECIST 1.1, or death due to any cause.‬
‭Participants‬‭who‬‭did‬‭not‬‭progress‬‭or‬‭die‬‭will‬‭be‬‭censored‬‭on‬‭the‬‭date‬‭of‬‭their‬‭last‬‭evaluable‬‭tumor‬
‭assessment.‬‭Participants‬‭who‬‭did‬‭not‬‭have‬‭any‬‭on‬‭study‬‭tumor‬‭assessments‬‭will‬‭be‬‭censored‬‭on‬‭the‬
‭beginning‬‭of‬‭treatment‬‭date.‬‭PFS‬‭curves,‬‭PFS‬‭medians‬‭with‬‭95%‬‭CIs,‬‭and‬‭PFS‬‭rates‬‭at‬‭6,‬‭12,‬‭18,‬‭24,‬
‭36,‬‭and‬‭48‬‭months‬‭with‬‭95%‬‭CIs‬‭will‬‭be‬‭estimated‬‭using‬‭Kaplan-Meier‬‭methodology‬‭if‬‭follow-up‬
‭requirements are met.‬
‭ORR‬ ‭is‬ ‭defined‬ ‭as‬ ‭the‬ ‭number‬ ‭of‬ ‭participants‬ ‭with‬ ‭a‬ ‭best‬ ‭overall‬ ‭response‬ ‭(BOR)‬ ‭of‬
‭confirmed‬ ‭CR‬ ‭or‬ ‭PR‬ ‭divided‬ ‭by‬ ‭the‬ ‭number‬ ‭of‬ ‭enrolled‬ ‭participants.‬‭BOR‬‭is‬‭defined‬‭as‬‭the‬‭best‬
‭response‬‭designation,‬‭as‬‭determined‬‭by‬‭central‬‭review,‬‭recorded‬‭between‬‭the‬‭date‬‭of‬‭treatment‬‭start‬
‭and‬ ‭the‬ ‭date‬ ‭of‬ ‭objectively‬ ‭documented‬ ‭progression‬ ‭per‬ ‭RECIST‬ ‭1.1‬ ‭or,‬ ‭the‬ ‭date‬ ‭of‬‭initiation‬‭of‬
‭subsequent‬ ‭anti-cancer‬ ‭therapy,‬ ‭whichever‬ ‭occurs‬ ‭first.‬ ‭For‬ ‭participants‬ ‭without‬ ‭documented‬
‭progression‬‭or‬‭subsequent‬‭anti-cancer‬‭therapy,‬‭all‬‭available‬‭response‬‭designations‬‭will‬‭contribute‬‭to‬
‭the‬‭BOR‬‭determination.‬‭For‬‭participants‬‭who‬‭continue‬‭treatment‬‭beyond‬‭progression,‬‭the‬‭BOR‬‭will‬‭be‬
‭determined‬‭based‬‭on‬‭response‬‭designations‬‭recorded‬‭up‬‭to‬‭the‬‭time‬‭of‬‭the‬‭initial‬‭RECIST‬‭1.1-defined‬
‭progression.‬‭Complete‬‭or‬‭partial‬‭responses‬‭may‬‭be‬‭claimed‬‭only‬‭if‬‭the‬‭criteria‬‭for‬‭each‬‭are‬‭met‬‭at‬‭a‬
‭subsequent time point of ≥ 4 weeks later.‬
‭An estimate of the response rate and an associated exact two-sided 95% CI will be presented.‬
‭9.3.2.‬ ‭Safety Analysis‬
‭Safety analysis will be performed in all treated participants.‬
‭Descriptive‬ ‭statistics‬ ‭of‬ ‭safety‬ ‭will‬ ‭be‬ ‭presented‬ ‭using‬ ‭National‬ ‭Cancer‬ ‭Institute‬ ‭(NCI)‬ ‭Common‬
‭Terminology‬‭Criteria‬‭for‬‭Adverse‬‭Events‬‭(CTCAE)‬‭version‬‭5.0.‬‭All‬‭on-study‬‭AEs,‬‭drug‬‭related‬‭AEs,‬
‭SAEs‬ ‭and‬ ‭drug-related‬ ‭SAEs,‬ ‭AEs‬ ‭and‬ ‭drug-related‬ ‭AEs‬ ‭leading‬ ‭to‬ ‭drug‬ ‭discontinuation‬ ‭will‬ ‭be‬
‭tabulated‬‭using‬‭worst‬‭grade‬‭per‬‭NCI‬‭CTCAE‬‭v‬‭5.0‬‭criteria‬‭by‬‭system‬‭organ‬‭class‬‭and‬‭preferred‬‭term,‬
‭based‬ ‭on‬ ‭MedDRA‬ ‭terminology.‬ ‭On-study‬ ‭lab‬ ‭parameters‬ ‭including‬ ‭hematology,‬ ‭coagulation,‬
‭chemistry,‬‭liver‬‭function‬‭and‬‭renal‬‭function‬‭will‬‭be‬‭summarized‬‭using‬‭worst‬‭grade‬‭per‬‭NCI‬‭CTCAE‬‭v‬
‭5.0 criteria.‬
‭A‬‭tabular‬‭summary‬‭of‬‭the‬‭incidence‬‭of‬‭overall‬‭immune-mediated‬‭adverse‬‭events‬‭(imAEs)‬‭and‬‭serious‬
‭imAEs‬‭will‬‭be‬‭performed.‬‭Frequency,‬‭management‬‭and‬‭resolution‬‭of‬‭imAEs‬‭will‬‭be‬‭analyzed‬‭and‬‭a‬
‭descriptive‬ ‭analysis‬ ‭including‬ ‭time-to-onset,‬ ‭severity,‬ ‭duration,‬ ‭action‬ ‭taken‬ ‭with‬ ‭the‬ ‭study‬ ‭drug,‬
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‭dosing‬‭delays‬‭of‬‭the‬‭study‬‭drug,‬‭corticosteroid‬‭details,‬‭re-challenge‬‭information‬‭and‬‭outcome‬‭of‬‭the‬
‭AE will be individually characterized by imAE category.‬
‭10.‬
‭Translational research‬
‭Baseline‬‭tumor‬‭samples‬‭will‬‭be‬‭mandatory‬‭prior‬‭to‬‭the‬‭beginning‬‭of‬‭the‬‭study.‬‭Serial‬‭blood‬‭samples‬
‭(including‬ ‭serum‬ ‭and‬ ‭plasma‬ ‭at‬‭baseline‬‭and‬‭at‬‭disease‬‭progression‬‭or‬‭EOT)‬‭will‬‭be‬‭collected‬‭for‬
‭additional‬ ‭biomarker‬ ‭research‬ ‭to‬ ‭identify‬ ‭prognostic‬ ‭and/or‬ ‭predictive‬ ‭factors‬ ‭of‬ ‭response‬ ‭to‬
‭nivolumab and carboplatin-etoposide chemotherapy.‬
‭Biological‬ ‭samples‬ ‭may‬‭undergo‬‭genomic,‬‭metabolomic,‬‭transcriptomic‬‭and‬‭proteomic‬‭analyses‬‭or‬
‭other‬ ‭molecular‬ ‭assessments‬ ‭related‬ ‭to‬ ‭the‬ ‭disease,‬ ‭the‬ ‭immunological‬ ‭landscape‬ ‭of‬ ‭tumors‬ ‭and‬
‭patients,‬‭or‬‭the‬‭mechanism‬‭of‬‭action‬‭of‬‭drugs‬‭tested‬‭with‬‭this‬‭purpose.‬‭Additional‬‭information‬‭on‬‭this‬
‭subject is available for all participants in the informed consent form.‬
‭The‬ ‭samples‬ ‭will‬ ‭be‬ ‭sent‬ ‭to‬ ‭and‬ ‭stored‬ ‭at‬ ‭the‬ ‭Gastrointestinal‬ ‭Tumors‬ ‭Research‬ ‭Unit‬ ‭from‬ ‭the‬
‭Research Institute at the Hospital Universitario 12 de Octubre, Madrid.‬
‭11.‬
‭Patient registration  procedure‬
‭●‬ ‭Each‬ ‭patient‬‭is‬‭identified‬‭in‬‭the‬‭study‬‭by‬‭a‬‭Subject‬‭Number‬‭(Subject‬‭No.)‬‭that‬‭is‬‭assigned‬
‭when‬‭the‬‭patient‬‭is‬‭first‬‭enrolled‬‭for‬‭screening‬‭and‬‭is‬‭retained‬‭as‬‭the‬‭primary‬‭identifier‬‭for‬‭the‬
‭patient‬ ‭throughout‬ ‭his/her‬ ‭entire‬ ‭participation‬ ‭in‬ ‭the‬ ‭trial.‬‭The‬‭Subject‬‭No.‬‭consists‬‭of‬‭the‬
‭Center‬ ‭Number‬ ‭(Center‬ ‭No.)‬ ‭with‬ ‭a‬ ‭sequential‬ ‭patient‬‭number‬‭suffixed‬‭to‬‭it,‬‭so‬‭that‬‭each‬
‭patient is numbered uniquely across the entire database.‬
‭●‬ ‭Upon‬‭signing‬‭the‬‭informed‬‭consent‬‭form,‬‭the‬‭patient‬‭is‬‭assigned‬‭to‬‭the‬‭next‬‭sequential‬‭Subject‬
‭No. available to the investigator.‬
‭●‬ ‭The‬‭investigator‬‭or‬‭designated‬‭staff‬‭will‬‭contact‬‭the‬‭IRT‬‭and‬‭provide‬‭the‬‭requested‬‭identifying‬
‭information‬‭for‬‭the‬‭patient‬‭to‬‭register‬‭them‬‭into‬‭the‬‭IRT.‬‭Once‬‭assigned,‬‭the‬‭Subject‬‭No.‬‭must‬
‭not‬ ‭be‬ ‭reused‬ ‭for‬ ‭any‬ ‭other‬ ‭patient‬ ‭and‬ ‭the‬ ‭Subject‬ ‭No.‬ ‭for‬ ‭that‬ ‭individual‬ ‭must‬ ‭not‬ ‭be‬
‭changed,‬‭even‬‭if‬‭the‬‭patient‬‭is‬‭re-screened.‬‭If‬‭the‬‭patient‬‭fails‬‭to‬‭start‬‭treatment‬‭for‬‭any‬‭reason,‬
‭the reason will be entered into the Screening Disposition page.‬
‭12.‬
‭Reporting adverse events‬
‭12.1.‬ ‭Definitions for adverse event reporting‬
‭●‬ ‭An‬‭Adverse‬‭Event‬‭(AE)‬‭is‬‭defined‬‭as‬‭any‬‭untoward‬‭medical‬‭occurrence‬‭or‬‭experience‬‭in‬‭a‬
‭patient‬‭or‬‭clinical‬‭investigation‬‭subject‬‭which‬‭occurs‬‭following‬‭the‬‭administration‬‭of‬‭the‬‭trial‬
‭medication‬‭regardless‬‭of‬‭the‬‭dose‬‭or‬‭causal‬‭relationship.‬‭This‬‭can‬‭include‬‭any‬‭unfavorable‬‭and‬
‭unintended‬‭signs‬‭(such‬‭as‬‭rash‬‭or‬‭enlarged‬‭liver),‬‭or‬‭symptoms‬‭(such‬‭as‬‭nausea‬‭or‬‭chest‬‭pain),‬
‭an‬ ‭abnormal‬ ‭laboratory‬ ‭finding‬ ‭(including‬ ‭blood‬ ‭tests,‬ ‭x-rays‬ ‭or‬ ‭scans)‬ ‭or‬ ‭a‬ ‭disease‬
‭temporarily associated with the use of the protocol treatment.‬‭(ICH-GCP).‬
‭●‬ ‭An‬‭Adverse‬‭Drug‬‭Reaction‬‭(ADR)‬‭is‬‭defined‬‭as‬‭any‬‭response‬‭to‬‭a‬‭medical‬‭product,‬‭that‬‭is‬
‭noxious‬‭and/or‬‭unexpected,‬‭related‬‭to‬‭any‬‭dose.‬‭(ICH-GCP).‬‭Response‬‭to‬‭a‬‭medicinal‬‭product‬
‭(used‬‭in‬‭the‬‭above‬‭definition)‬‭means‬‭that‬‭a‬‭causal‬‭relationship‬‭between‬‭the‬‭medicinal‬‭product‬
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‭and‬‭the‬‭adverse‬‭event‬‭is‬‭at‬‭least‬‭a‬‭reasonable‬‭possibility,‬‭i.e.‬‭the‬‭relationship‬‭cannot‬‭be‬‭ruled‬
‭out.‬
‭●‬ ‭An‬ ‭Unexpected‬ ‭Adverse‬ ‭Drug‬ ‭Reaction‬ ‭is‬ ‭any‬ ‭adverse‬‭reaction‬‭for‬‭which‬‭the‬‭nature‬‭or‬
‭severity‬ ‭is‬ ‭not‬ ‭consistent‬ ‭with‬ ‭the‬ ‭applicable‬ ‭product‬ ‭information‬ ‭(e.g.,‬ ‭Investigator’s‬
‭Brochure).‬‭(ICH-GCP).‬
‭●‬ ‭A‬ ‭Serious‬ ‭Adverse‬ ‭Event‬ ‭(SAE)‬‭is‬‭defined‬‭as‬‭any‬‭undesirable‬‭experience‬‭occurring‬‭to‬‭a‬
‭patient,‬‭whether‬‭or‬‭not‬‭considered‬‭related‬‭to‬‭the‬‭protocol‬‭treatment.‬‭A‬‭Serious‬‭Adverse‬‭Event‬
‭(SAE)‬‭which‬‭is‬‭considered‬‭related‬‭to‬‭the‬‭protocol‬‭treatment‬‭is‬‭defined‬‭as‬‭a‬‭Serious‬‭Adverse‬
‭Drug Reaction (SADR)‬‭.‬
‭●‬ ‭Adverse‬‭events‬‭and‬‭adverse‬‭drug‬‭reactions‬‭which‬‭are‬‭considered‬‭as‬‭serious‬‭are‬‭those‬‭which‬
‭result in:‬
‭○‬ ‭Death‬
‭○‬ ‭A‬‭life‬‭threatening‬‭event‬‭(i.e.‬‭the‬‭patient‬‭was‬‭at‬‭immediate‬‭risk‬‭of‬‭death‬‭at‬‭the‬‭time‬‭the‬
‭reaction was observed)‬
‭○‬ ‭hospitalization or prolongation of hospitalization‬
‭○‬ ‭persistent or significant disability/incapacity‬
‭○‬ ‭a congenital anomaly/birth defect‬
‭○‬ ‭any‬‭other‬‭medically‬‭important‬‭condition‬‭(i.e.‬‭important‬‭adverse‬‭reactions‬‭that‬‭are‬‭not‬
‭immediately‬ ‭life‬ ‭threatening‬ ‭or‬ ‭do‬ ‭not‬ ‭result‬ ‭in‬ ‭death‬ ‭or‬ ‭hospitalization‬ ‭but‬ ‭may‬
‭jeopardize‬ ‭the‬ ‭patient‬ ‭or‬ ‭may‬ ‭require‬ ‭intervention‬ ‭to‬ ‭prevent‬ ‭one‬ ‭of‬ ‭the‬ ‭other‬
‭outcomes listed above)‬
‭12.2.‬ ‭Reporting procedure‬
‭To‬‭ensure‬‭patient‬‭safety,‬‭every‬‭SAE,‬‭regardless‬‭of‬‭suspected‬‭causality,‬‭occurring‬‭after‬‭the‬‭patient‬‭has‬
‭provided informed consent must be reported within 24 hours of knowing of its occurrence and until:‬
‭●‬ ‭Suspected SAEs up to Day 150 safety follow-up.‬
‭●‬ ‭Non-suspected‬ ‭SAEs‬ ‭up‬ ‭to‬ ‭Day‬ ‭150‬ ‭safety‬ ‭follow-up‬ ‭or‬ ‭start‬ ‭of‬ ‭new‬ ‭post‬ ‭treatment‬
‭antineoplastic‬ ‭medication‬ ‭if‬ ‭administered‬ ‭during‬ ‭the‬ ‭period‬ ‭between‬ ‭the‬ ‭30-Day‬ ‭safety‬
‭follow-up and 150-Day safety follow-up, whichever is sooner.‬
‭●‬ ‭If‬‭a‬‭patient‬‭starts‬‭a‬‭post‬‭treatment‬‭antineoplastic‬‭therapy‬‭after‬‭the‬‭30-day‬‭safety‬‭follow-up,‬
‭then‬‭only‬‭SAEs‬‭suspected‬‭to‬‭be‬‭related‬‭to‬‭study‬‭treatment‬‭should‬‭be‬‭collected‬‭out‬‭to‬‭150‬‭days‬
‭after‬‭discontinuation‬‭of‬‭treatment.‬‭SAEs‬‭suspected‬‭to‬‭be‬‭related‬‭to‬‭nivolumab‬‭will‬‭continue‬‭to‬
‭be collected beyond the 150-Day safety visit.‬
‭●‬ ‭Any‬ ‭additional‬‭information‬‭for‬‭the‬‭SAE‬‭including‬‭complications,‬‭progression‬‭of‬‭the‬‭initial‬
‭SAE,‬‭and‬‭recurrent‬‭episodes‬‭must‬‭be‬‭reported‬‭as‬‭follow-up‬‭to‬‭the‬‭original‬‭episode‬‭within‬‭24‬
‭hours‬‭of‬‭the‬‭investigator‬‭receiving‬‭the‬‭follow-up‬‭information.‬‭A‬‭SAE‬‭occurring‬‭at‬‭a‬‭different‬
‭time‬ ‭interval‬ ‭or‬ ‭otherwise‬ ‭considered‬ ‭completely‬ ‭unrelated‬ ‭to‬ ‭a‬ ‭previously‬ ‭reported‬ ‭one‬
‭should be reported separately as a new event.‬
‭●‬ ‭Any‬‭SAEs‬‭experienced‬‭after‬‭the‬‭reporting‬‭period‬‭described‬‭above‬‭should‬‭only‬‭be‬‭reported‬‭if‬
‭the investigator suspects a causal relationship to the study treatment.‬
‭●‬ ‭Information‬‭about‬‭all‬‭SAEs‬‭is‬‭collected‬‭and‬‭recorded‬‭on‬‭the‬‭Serious‬‭Adverse‬‭Event‬‭Report‬
‭Form;‬‭all‬‭applicable‬‭sections‬‭of‬‭the‬‭form‬‭must‬‭be‬‭completed‬‭in‬‭order‬‭to‬‭provide‬‭a‬‭clinically‬
‭thorough‬‭report.‬‭The‬‭investigator‬‭must‬‭assess‬‭and‬‭record‬‭the‬‭relationship‬‭of‬‭each‬‭SAE‬‭to‬‭each‬
‭specific study treatment (if there is more than one study treatment).‬
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‭●‬ ‭Each‬‭reoccurrence,‬‭complication,‬‭or‬‭progression‬‭of‬‭the‬‭original‬‭event‬‭should‬‭be‬‭reported‬‭as‬‭a‬
‭follow-up‬ ‭to‬ ‭that‬ ‭event‬ ‭regardless‬ ‭of‬ ‭when‬ ‭it‬ ‭occurs.‬ ‭The‬ ‭follow-up‬ ‭information‬ ‭should‬
‭describe‬‭whether‬‭the‬‭event‬‭has‬‭resolved‬‭or‬‭continues,‬‭if‬‭and‬‭how‬‭it‬‭was‬‭treated,‬‭and‬‭whether‬
‭the patient continued or withdrew from study participation.‬
‭●‬ ‭Suspected‬‭Unexpected‬‭Serious‬‭Adverse‬‭Reactions‬‭(SUSARs)‬‭will‬‭be‬‭collected‬‭and‬‭reported‬
‭to‬ ‭the‬ ‭competent‬ ‭authorities‬ ‭and‬ ‭relevant‬ ‭ethics‬ ‭committees‬ ‭in‬ ‭accordance‬ ‭with‬ ‭Directive‬
‭2001/20/EC or as per national regulatory requirements in participating countries.‬
‭●‬ ‭SAEs,‬‭whether‬‭related‬‭or‬‭not‬‭related‬‭to‬‭study‬‭drug,‬‭and‬‭pregnancies‬‭must‬‭be‬‭reported‬‭to‬‭BMS‬
‭within‬‭24‬‭hours‬‭\‬‭1‬‭Business‬‭Day‬‭of‬‭becoming‬‭aware‬‭of‬‭the‬‭event.‬‭SAEs‬‭must‬‭be‬‭recorded‬‭on‬
‭either CIOMS, MedWatch, or approved site SAE form.‬
‭●‬ ‭Pregnancies‬ ‭must‬ ‭be‬ ‭reported‬ ‭and‬ ‭submitted‬ ‭to‬ ‭MFAR‬ ‭Clinical‬ ‭Research‬ ‭that‬‭will‬‭act‬‭on‬
‭behalf‬ ‭of‬ ‭GETNE‬ ‭transferring‬ ‭the‬ ‭information‬ ‭to‬ ‭BMS.‬ ‭BMS‬ ‭will‬ ‭perform‬ ‭due‬‭diligence‬
‭follow-up using the BMS Pregnancy Form which the investigator must complete.‬
‭○‬ ‭SAE Email Address:‬‭investigacion@mfar.net‬
‭○‬ ‭SAE Facsimile Number:  + 34 93 253 11 68‬
‭●‬ ‭If‬ ‭only‬ ‭limited‬ ‭information‬ ‭is‬ ‭initially‬ ‭available,‬ ‭follow-up‬ ‭reports‬ ‭are‬ ‭required.‬ ‭(Note:‬
‭Follow-up SAE reports should include the same investigator term(s) initially reported.).‬
‭●‬ ‭If‬‭an‬‭ongoing‬‭SAE‬‭changes‬‭in‬‭its‬‭intensity‬‭or‬‭relationship‬‭to‬‭study‬‭drug‬‭or‬‭if‬‭new‬‭information‬
‭becomes‬‭available,‬‭a‬‭follow-up‬‭SAE‬‭report‬‭should‬‭be‬‭sent‬‭within‬‭24‬‭hours‬‭\‬‭1‬‭Business‬‭Day‬
‭to BMS using the same procedure used for transmitting the initial SAE report.‬
‭●‬
‭All SAEs should be followed to resolution or stabilization.‬
‭SAEs,‬ ‭whether‬ ‭related‬ ‭or‬ ‭not‬ ‭related‬ ‭to‬ ‭study‬ ‭drug,‬ ‭and‬ ‭pregnancies‬ ‭must‬ ‭be‬ ‭reported‬‭to‬‭MFAR‬
‭Clinical‬ ‭Research‬ ‭that‬ ‭will‬ ‭manage,‬ ‭on‬ ‭behalf‬ ‭GETNE,‬‭the‬‭communications‬‭with‬‭BMS‬‭within‬‭24‬
‭hours‬‭\‬‭1‬‭Business‬‭Day‬‭of‬‭becoming‬‭aware‬‭of‬‭the‬‭event.‬‭SAEs‬‭must‬‭be‬‭recorded‬‭on‬‭either‬‭CIOMS,‬
‭MedWatch, or approved site SAE form.‬
‭The causal relationship to study drug is determined by a physician and should be used to assess all‬
‭adverse events (AE). The casual relationship can be one of the following:‬
‭●‬ ‭Related:‬‭There is a reasonable causal relationship‬‭between study drug administration and the‬
‭AE.‬
‭●‬ ‭Not related:‬‭There is not a reasonable causal relationship‬‭between study drug administration‬
‭and the AE.‬
‭The‬‭causal‬‭relationship‬‭to‬‭study‬‭drug‬‭is‬‭determined‬‭by‬‭a‬‭physician‬‭and‬‭should‬‭be‬‭used‬‭to‬‭assess‬‭all‬
‭adverse events (AE). The casual relationship can be one of the following:‬
‭●‬
‭Related:‬‭There‬‭is‬‭a‬‭reasonable‬‭causal‬‭relationship‬‭between‬‭study‬‭drug‬‭administration‬‭and‬‭the‬
‭AE.‬
‭●‬ ‭Not‬‭related:‬‭There‬‭is‬‭not‬‭a‬‭reasonable‬‭causal‬‭relationship‬‭between‬‭study‬‭drug‬‭administration‬
‭and the AE.‬
‭●‬ ‭The‬ ‭term‬ ‭"reasonable‬ ‭causal‬ ‭relationship"‬ ‭means‬ ‭there‬ ‭is‬ ‭evidence‬ ‭to‬ ‭suggest‬ ‭a‬ ‭causal‬
‭relationship.‬
‭●‬ ‭Adverse‬ ‭events‬ ‭can‬ ‭be‬ ‭spontaneously‬ ‭reported‬ ‭or‬ ‭elicited‬ ‭during‬ ‭open-ended‬‭questioning,‬
‭examination,‬‭or‬‭evaluation‬‭of‬‭a‬‭subject.‬‭(In‬‭order‬‭to‬‭prevent‬‭reporting‬‭bias,‬‭subjects‬‭should‬
‭not be questioned regarding the specific occurrence of one or more AEs.)‬
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‭NON SERIOUS ADVERSE EVENT‬
‭Non-serious‬‭Adverse‬‭Events‬‭(AE)‬‭are‬‭to‬‭be‬‭provided‬‭to‬‭BMS‬‭in‬‭aggregate‬‭via‬‭interim‬‭or‬‭final‬‭study‬
‭reports‬‭as‬‭specified‬‭in‬‭the‬‭agreement‬‭or,‬‭if‬‭a‬‭regulatory‬‭requirement‬‭[eg,‬‭IND‬‭US‬‭trial]‬‭as‬‭part‬‭of‬‭an‬
‭annual reporting requirement.‬
‭The‬ ‭Sponsor‬ ‭will‬ ‭reconcile‬ ‭the‬ ‭clinical‬ ‭database‬ ‭AE‬ ‭cases‬ ‭(case‬ ‭level‬ ‭only)‬ ‭transmitted‬ ‭to‬ ‭BMS‬
‭Global Pharmacovigilance‬‭(‬‭Worldwide.Safety@bms.com‬‭).‬
‭Non-serious Adverse Event Collection and Reporting‬
‭The‬‭collection‬‭of‬‭non-serious‬‭AE‬‭information‬‭should‬‭begin‬‭following‬‭the‬‭subject’s‬‭written‬‭consent‬‭to‬
‭participate‬‭in‬‭the‬‭study.‬‭All‬‭non‬‭serious‬‭adverse‬‭events‬‭(not‬‭only‬‭those‬‭deemed‬‭to‬‭be‬‭treatment-related)‬
‭should‬‭be‬‭collected‬‭continuously‬‭during‬‭the‬‭treatment‬‭period‬‭and‬‭for‬‭a‬‭minimum‬‭of‬‭(provide‬‭#‬‭of‬‭days‬
‭depending on the asset and study type)  days following the last dose of study treatment.‬
‭Non-serious‬‭AEs‬‭should‬‭be‬‭followed‬‭to‬‭resolution‬‭or‬‭stabilization,‬‭or‬‭reported‬‭as‬‭SAEs‬‭if‬‭they‬‭become‬
‭serious.‬‭Follow-up‬‭is‬‭also‬‭required‬‭for‬‭non-serious‬‭AEs‬‭that‬‭cause‬‭interruption‬‭or‬‭discontinuation‬‭of‬
‭study drug and for those present at the end of study treatment as appropriate.‬
‭Laboratory Test Abnormalities‬
‭All‬ ‭laboratory‬ ‭test‬ ‭results‬ ‭captured‬ ‭as‬ ‭part‬‭of‬‭the‬‭study‬‭should‬‭be‬‭recorded‬‭following‬‭institutional‬
‭procedures. Test results that constitute SAEs should be documented and reported to BMS as such.‬
‭The following laboratory abnormalities should be documented and reported appropriately:‬
‭●‬ ‭any laboratory test result that is clinically significant or meets the definition of an SAE.‬
‭●‬ ‭any‬‭laboratory‬‭abnormality‬‭that‬‭required‬‭the‬‭participant‬‭to‬‭have‬‭study‬‭drug‬‭discontinued‬‭or‬
‭interrupted.‬
‭●‬ ‭any laboratory abnormality that required the subject to receive specific corrective therapy.‬
‭It‬‭is‬‭expected‬‭that‬‭wherever‬‭possible,‬‭the‬‭clinical‬‭rather‬‭than‬‭laboratory‬‭term‬‭would‬‭be‬‭used‬‭by‬‭the‬
‭reporting investigator (eg, anemia versus low hemoglobin value).‬
‭Potential Drug Induced Liver Injury (DILI) Language required as noted below:‬
‭Definition‬ ‭of‬ ‭DILI‬ ‭criteria‬‭is‬‭mandatory‬‭for‬‭all‬‭pre-marketed‬‭asset‬‭protocols‬‭enrolling‬‭participants‬
‭without‬‭known‬‭abnormalities‬‭in‬‭liver‬‭function‬‭at‬‭baseline‬‭AND‬‭for‬‭protocols‬‭involving‬‭participants‬
‭with‬ ‭known‬ ‭liver‬ ‭abnormalities‬‭at‬‭baseline‬‭or‬‭with‬‭other‬‭clinical‬‭confounders‬‭where‬‭asset‬‭specific‬
‭criteria for potential drug induced liver injury have been defined. Use for marketed assets is optional.‬
‭For‬‭protocols‬‭without‬‭known‬‭abnormalities‬‭in‬‭liver‬‭function‬‭at‬‭baseline,‬‭use‬‭the‬‭mandatory‬‭standard‬
‭DILI‬‭definition‬‭listed‬‭below:‬‭Wherever‬‭possible,‬‭timely‬‭confirmation‬‭of‬‭initial‬‭liver‬‭related‬‭laboratory‬
‭abnormalities‬ ‭should‬ ‭occur‬ ‭prior‬ ‭to‬ ‭the‬ ‭reporting‬ ‭of‬ ‭a‬ ‭potential‬ ‭DILI‬ ‭event.‬ ‭All‬ ‭occurrences‬ ‭of‬
‭potential DILIs, meeting the defined criteria, must be reported as SAEs.‬
‭Potential drug induced liver injury is defined as:‬
‭1.‬ ‭AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) AND‬
‭2.‬ ‭Total‬‭bilirubin‬‭>‬‭2‬‭times‬‭ULN,‬‭without‬‭initial‬‭findings‬‭of‬‭cholestasis‬‭(elevated‬‭serum‬‭alkaline‬
‭phosphatase) AND‬
‭3.‬ ‭No‬ ‭other‬ ‭immediately‬ ‭apparent‬ ‭possible‬ ‭causes‬ ‭of‬ ‭AT‬ ‭elevation‬ ‭and‬ ‭hyperbilirubinemia,‬
‭including,‬‭but‬‭not‬‭limited‬‭to,‬‭viral‬‭hepatitis,‬‭pre-existing‬‭chronic‬‭or‬‭acute‬‭liver‬‭disease,‬‭or‬‭the‬
‭administration of other drug(s) known to be hepatotoxic.‬
‭AEs‬ ‭of‬ ‭Special‬ ‭Interest‬ ‭(Product‬ ‭Specific‬ ‭Usually‬ ‭a‬ ‭regulatory‬ ‭requirement.‬
‭Remove‬ ‭if‬ ‭not‬
‭applicable)‬
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‭Pregnancy‬
‭If,‬ ‭following‬ ‭initiation‬ ‭of‬ ‭the‬ ‭investigational‬ ‭product,‬ ‭it‬ ‭is‬ ‭subsequently‬ ‭discovered‬ ‭that‬ ‭a‬ ‭study‬
‭participant‬‭is‬‭pregnant‬‭or‬‭may‬‭have‬‭been‬‭pregnant‬‭at‬‭the‬‭time‬‭of‬‭investigational‬‭product‬‭exposure,‬
‭including‬‭during‬‭at‬‭least‬‭5‬‭half-lives‬‭after‬‭product‬‭administration,‬‭the‬‭investigational‬‭product‬‭will‬‭be‬
‭permanently discontinued in an appropriate manner (eg, dose tapering if necessary for participant).‬
‭The‬ ‭investigator‬ ‭must‬ ‭immediately‬‭notify‬‭Worldwide.Safety@bms.com‬‭of‬‭this‬‭event‬‭and‬‭complete‬
‭one‬ ‭of‬ ‭the‬ ‭following‬ ‭forms‬ ‭within‬ ‭24‬ ‭hours‬ ‭of‬ ‭awareness‬ ‭of‬ ‭the‬ ‭event‬ ‭via‬ ‭either‬ ‭the‬ ‭CIOMS,‬
‭MedWatch‬ ‭or‬ ‭appropriate‬ ‭Pregnancy‬ ‭Surveillance‬ ‭Form‬ ‭in‬ ‭accordance‬ ‭with‬ ‭SAE‬ ‭reporting‬
‭procedures.‬
‭Protocol-required‬ ‭procedures‬ ‭for‬ ‭study‬ ‭discontinuation‬ ‭and‬ ‭follow-up‬ ‭must‬ ‭be‬ ‭performed‬ ‭on‬ ‭the‬
‭participant.‬
‭Follow-up‬ ‭information‬ ‭regarding‬ ‭the‬ ‭course‬ ‭of‬ ‭the‬ ‭pregnancy,‬ ‭including‬ ‭perinatal‬ ‭and‬ ‭neonatal‬
‭outcome‬‭and,‬‭where‬‭applicable,‬‭offspring‬‭information‬‭must‬‭be‬‭reported‬‭on‬‭the‬‭CIOMS,‬‭MedWatch,‬
‭BMS‬ ‭Pregnancy‬ ‭Surveillance‬‭Form,‬‭or‬‭approved‬‭site‬‭SAE‬‭form.‬ ‭A‬‭BMS‬‭Pregnancy‬‭Surveillance‬
‭Form may be provided upon request.‬
‭Any‬‭pregnancy‬‭that‬‭occurs‬‭in‬‭a‬‭female‬‭partner‬‭of‬‭a‬‭male‬‭study‬‭participant‬‭should‬‭be‬‭reported‬‭to‬‭BMS.‬
‭Information‬ ‭on‬ ‭this‬‭pregnancy‬‭will‬‭be‬‭collected‬‭on‬‭the‬‭Pregnancy‬‭Surveillance‬‭Form.‬‭In‬‭order‬‭for‬
‭Sponsor‬‭or‬‭designee‬‭to‬‭collect‬‭any‬‭pregnancy‬‭surveillance‬‭information‬‭from‬‭the‬‭female‬‭partner,‬‭the‬
‭female partner must sign an informed consent form for disclosure of this information.‬
‭Other Safety Considerations‬
‭Any‬‭significant‬‭worsening‬‭noted‬‭during‬‭interim‬‭or‬‭final‬‭physical‬‭examinations,‬‭electrocardiograms,‬
‭X-rays,‬‭and‬‭any‬‭other‬‭potential‬‭safety‬‭assessments,‬‭whether‬‭or‬‭not‬‭these‬‭procedures‬‭are‬‭required‬‭by‬
‭the‬ ‭protocol,‬‭should‬‭also‬‭be‬‭recorded‬‭as‬‭a‬‭non-serious‬‭or‬‭serious‬‭AE,‬‭as‬‭appropriate,‬‭and‬‭reported‬
‭accordingly.‬
‭MFAR‬
‭Clinical‬
‭Research‬
‭on‬
‭behalf‬
‭of‬
‭GETNE‬
‭will‬
‭request‬
‭from‬
‭BMS‬ ‭GPV&E,‬
‭aepbusinessprocess@bms.com‬‭the‬‭SAE‬‭reconciliation‬‭report‬‭and‬‭include‬‭the‬‭BMS‬‭protocol‬‭number‬
‭every 3 months and prior to database lock or final data summary.‬
‭GPV&E‬‭will‬‭send‬‭the‬‭investigator‬‭the‬‭report‬‭to‬‭verify‬‭and‬‭confirm‬‭all‬‭SAEs‬‭have‬‭been‬‭transmitted‬‭to‬
‭BMS GPV&E.‬
‭The‬ ‭data‬ ‭elements‬ ‭listed‬ ‭on‬ ‭the‬ ‭GPV&E‬ ‭reconciliation‬ ‭report‬ ‭will‬‭be‬‭used‬‭for‬‭case‬‭identification‬
‭purposes.‬‭If‬‭the‬‭Sponsor‬‭determines‬‭a‬‭case‬‭was‬‭not‬‭transmitted‬‭to‬‭BMS‬‭GPV&E,‬‭the‬‭case‬‭should‬‭be‬
‭sent immediately to BMS‬‭(‬‭Worldwide.Safety@bms.com‬‭).‬
‭13.‬
‭Quality assurance‬
‭13.1.‬ ‭Control of data consistency‬
‭The‬ ‭investigator‬ ‭or‬ ‭qualified‬ ‭designee‬ ‭is‬ ‭responsible‬ ‭for‬ ‭recording‬ ‭and‬ ‭verifying‬ ‭the‬ ‭accuracy‬ ‭of‬
‭subject data.‬
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‭●‬ ‭The‬‭study‬‭will‬‭use‬‭eCRFs.‬‭A‬‭designated‬‭CRO‬‭will‬‭review‬‭the‬‭data‬‭entered‬‭by‬‭investigational‬
‭staff‬‭for‬‭completeness‬‭and‬‭accuracy.‬‭Electronic‬‭data‬‭queries‬‭stating‬‭the‬‭nature‬‭of‬‭the‬‭problem‬
‭and‬‭requesting‬‭clarification‬‭will‬‭be‬‭created‬‭for‬‭discrepancies‬‭and‬‭missing‬‭values‬‭and‬‭sent‬‭to‬
‭the‬‭investigational‬‭site‬‭via‬‭the‬‭EDC‬‭system.‬‭Designated‬‭investigator‬‭site‬‭staff‬‭is‬‭required‬‭to‬
‭respond promptly to queries and to make any necessary changes to the data.‬
‭●‬ ‭Concomitant‬‭treatments‬‭and‬‭prior‬‭medications‬‭entered‬‭into‬‭the‬‭database‬‭will‬‭be‬‭coded‬‭using‬
‭the‬ ‭WHO‬ ‭Drug‬ ‭Reference‬ ‭List,‬ ‭which‬ ‭employs‬ ‭the‬ ‭Anatomical‬ ‭Therapeutic‬ ‭Chemical‬
‭classification system.‬
‭●‬ ‭Medical‬ ‭history/current‬ ‭medical‬ ‭conditions‬ ‭and‬ ‭adverse‬ ‭events‬ ‭will‬ ‭be‬ ‭coded‬ ‭using‬ ‭the‬
‭Medical dictionary for regulatory activities (MedDRA) terminology.‬
‭●‬ ‭The‬ ‭site‬ ‭staff‬ ‭designated‬ ‭by‬ ‭the‬ ‭investigator‬ ‭will‬ ‭enter‬ ‭the‬ ‭information‬ ‭required‬ ‭by‬ ‭the‬
‭protocol onto the eCRFs as well as onto the designated CRO’s requisition form.‬
‭13.2.‬ ‭On-site‬‭quality‬‭control‬‭(for‬‭multi-centre‬‭studies‬‭only‬‭when‬‭data‬‭are‬‭sent‬
‭to a Data Centre or similar)‬
‭●‬ ‭Before‬‭study‬‭initiation,‬‭at‬‭a‬‭site‬‭initiation‬‭visit‬‭or‬‭at‬‭an‬‭investigator’s‬‭meeting,‬‭the‬‭protocol‬
‭and CRFs will be reviewed with the investigators and their staff.‬
‭●‬ ‭During‬‭the‬‭study,‬‭the‬‭field‬‭monitor‬‭will‬‭visit‬‭the‬‭site‬‭regularly‬‭to‬‭check‬‭the‬‭completeness‬‭of‬
‭patient‬‭records,‬‭the‬‭accuracy‬‭of‬‭entries‬‭on‬‭the‬‭CRFs,‬‭the‬‭adherence‬‭to‬‭the‬‭protocol‬‭to‬‭Good‬
‭Clinical‬ ‭Practice,‬ ‭the‬ ‭progress‬ ‭of‬ ‭enrollment,‬ ‭and‬ ‭to‬ ‭ensure‬ ‭that‬ ‭study‬ ‭treatment‬ ‭is‬ ‭being‬
‭stored,‬‭dispensed,‬‭and‬‭accounted‬‭for‬‭according‬‭to‬‭specifications.‬‭Key‬‭study‬‭personnel‬‭must‬‭be‬
‭available to assist the field monitor during these visits.‬
‭●‬ ‭The‬‭investigator‬‭must‬‭maintain‬‭source‬‭documents‬‭for‬‭each‬‭patient‬‭in‬‭the‬‭study,‬‭consisting‬‭of‬
‭case‬‭and‬‭visit‬‭notes‬‭(hospital‬‭or‬‭clinic‬‭medical‬‭records)‬‭containing‬‭demographic‬‭and‬‭medical‬
‭information,‬ ‭laboratory‬ ‭data,‬ ‭electrocardiograms,‬ ‭and‬ ‭the‬ ‭results‬ ‭of‬ ‭any‬ ‭other‬ ‭tests‬ ‭or‬
‭assessments.‬‭All‬‭information‬‭recorded‬‭on‬‭CRFs‬‭must‬‭be‬‭traceable‬‭to‬‭source‬‭documents‬‭in‬‭the‬
‭patient's‬‭file.‬‭The‬‭investigator‬‭must‬‭also‬‭keep‬‭the‬‭original‬‭signed‬‭informed‬‭consent‬‭form‬‭(a‬
‭signed copy is given to the patient).‬
‭●‬ ‭The‬‭investigator‬‭must‬‭give‬‭the‬‭monitor‬‭access‬‭to‬‭all‬‭relevant‬‭source‬‭documents‬‭to‬‭confirm‬
‭their consistency with the CRF entries.‬
‭13.3.‬ ‭Audits‬‭(for‬‭multi-centre‬‭studies‬‭only‬‭when‬‭data‬‭are‬‭sent‬‭to‬‭Data‬‭Centre‬‭or‬
‭similar)‬
‭●‬ ‭To‬‭ensure‬‭quality‬‭of‬‭data,‬‭study‬‭integrity,‬‭and‬‭compliance‬‭with‬‭the‬‭protocol‬‭and‬‭the‬‭various‬
‭applicable‬ ‭regulations‬ ‭and‬‭guidelines,‬‭the‬‭“Sponsor”‬‭may‬‭conduct‬‭site‬‭visits‬‭to‬‭institutions‬
‭participating to protocols.‬
‭●‬ ‭The‬‭investigator,‬‭by‬‭accepting‬‭to‬‭participate‬‭to‬‭this‬‭protocol,‬‭agrees‬‭to‬‭cooperate‬‭fully‬‭with‬
‭any‬ ‭quality‬ ‭assurance‬ ‭visit‬ ‭undertaken‬ ‭by‬ ‭third‬ ‭parties,‬‭including‬‭representatives‬‭from‬‭the‬
‭“Sponsor”,‬‭national‬‭and/or‬‭foreign‬‭regulatory‬‭authorities‬‭or‬‭company‬‭supplying‬‭the‬‭product‬
‭under‬ ‭investigation,‬ ‭as‬ ‭well‬ ‭as‬ ‭to‬ ‭allow‬ ‭direct‬ ‭access‬ ‭to‬ ‭documentation‬ ‭pertaining‬ ‭to‬ ‭the‬
‭clinical‬‭trial‬‭(including‬‭CRFs,‬‭source‬‭documents,‬‭hospital‬‭patient‬‭charts‬‭and‬‭other‬‭study‬‭files)‬
‭to these authorized individuals.‬
‭●‬ ‭The‬ ‭investigator‬ ‭must‬ ‭inform‬ ‭the‬ ‭“Sponsor”‬ ‭immediately‬ ‭in‬ ‭case‬ ‭a‬ ‭regulatory‬ ‭authority‬
‭inspection would be scheduled.‬
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‭13.4.‬ ‭Central review of pathology‬
‭No central pathology review is planned.‬
‭13.5 Central review of Images‬
‭All‬‭images‬‭of‬‭patients‬‭will‬‭be‬‭uploaded‬‭to‬‭a‬‭platform‬‭in‬‭DICOM‬‭format‬‭and‬‭will‬‭be‬‭reviewed‬‭centrally‬
‭by‬ ‭a‬ ‭radiologist‬ ‭specialised‬ ‭in‬ ‭pathology‬ ‭to‬ ‭avoid‬ ‭bias.‬ ‭Information‬ ‭for‬ ‭test‬ ‭uploading‬ ‭and‬
‭management is provided in a central reviewing manual located at the ISF.‬
‭14.‬
‭Ethical considerations‬
‭14.1.‬ ‭Patient protection‬
‭This‬ ‭protocol‬ ‭has‬ ‭been‬ ‭written,‬ ‭and‬ ‭the‬ ‭study‬ ‭will‬ ‭be‬ ‭conducted‬ ‭according‬ ‭to‬ ‭the‬ ‭ICH‬
‭Harmonized‬
‭Tripartite‬
‭Guideline‬
‭for‬
‭Good‬
‭Clinical‬
‭Practice‬
‭(ref:‬
‭http://www.ifpma.org/pdfifpma/e6.pdf‬‭)‬ ‭with‬ ‭applicable‬ ‭local‬ ‭regulations‬ ‭(including‬ ‭European‬
‭Directive‬‭2001/20/EC‬‭and‬‭US‬‭Code‬‭of‬‭Federal‬‭Regulations‬‭Title‬‭21),‬‭and‬‭with‬‭the‬‭ethical‬‭principles‬
‭laid down in the Declaration of Helsinki.‬
‭The‬‭protocol‬‭and‬‭the‬‭proposed‬‭informed‬‭consent‬‭form‬‭must‬‭be‬‭reviewed‬‭and‬‭approved‬‭by‬‭a‬
‭properly‬‭constituted‬‭Institutional‬‭Review‬‭Board/Independent‬‭Ethics‬‭Committee/Research‬‭required‬‭to‬
‭sign‬‭a‬‭protocol‬‭signature‬‭page‬‭confirming‬‭his/her‬‭agreement‬‭to‬‭conduct‬‭the‬‭study‬‭in‬‭accordance‬‭with‬
‭these‬‭documents‬‭and‬‭all‬‭of‬‭the‬‭instructions‬‭and‬‭procedures‬‭found‬‭in‬‭this‬‭protocol‬‭and‬‭to‬‭give‬‭access‬‭to‬
‭all‬ ‭relevant‬ ‭data‬ ‭and‬ ‭records‬ ‭to‬ ‭auditors,‬ ‭Quality‬‭Assurance‬‭representatives,‬‭IRBs/IECs/REBs‬‭and‬
‭regulatory authorities as required.‬
‭14.2.‬ ‭Subject identification‬
‭●‬ ‭The‬ ‭investigator‬‭must‬‭ensure‬‭anonymity‬‭of‬‭the‬‭patients;‬‭patients‬‭must‬‭not‬‭be‬‭identified‬‭by‬
‭names in any documents submitted to the Sponsor.‬
‭●‬ ‭Signed‬‭informed‬‭consent‬‭forms‬‭and‬‭patient‬‭enrollment‬‭log‬‭must‬‭be‬‭kept‬‭strictly‬‭confidential‬
‭to enable patient identification at the site.‬
‭●‬ ‭The‬‭investigator‬‭agrees‬‭that‬‭the‬‭IRB/ERC,‬‭or‬‭regulatory‬‭authority‬‭representatives‬‭may‬‭consult‬
‭and/or‬‭copy‬‭trial‬‭documents‬‭in‬‭order‬‭to‬‭verify‬‭worksheet/case‬‭report‬‭form‬‭data.‬‭By‬‭signing‬‭the‬
‭consent‬‭form,‬‭the‬‭subject‬‭agrees‬‭to‬‭this‬‭process.‬‭If‬‭trial‬‭documents‬‭will‬‭be‬‭photocopied‬‭during‬
‭the‬‭process‬‭of‬‭verifying‬‭worksheet/case‬‭report‬‭form‬‭information,‬‭the‬‭subject‬‭will‬‭be‬‭identified‬
‭by unique code only; full names/initials will be masked prior to transmission.‬
‭●‬ ‭By‬‭signing‬‭this‬‭protocol,‬‭the‬‭investigator‬‭agrees‬‭to‬‭treat‬‭all‬‭subject‬‭data‬‭used‬‭and‬‭disclosed‬‭in‬
‭connection‬ ‭with‬ ‭this‬ ‭trial‬ ‭in‬ ‭accordance‬ ‭with‬ ‭all‬ ‭applicable‬ ‭privacy‬ ‭laws,‬ ‭rules‬ ‭and‬
‭regulations.‬
‭14.3.‬ ‭Informed consent‬
‭●‬ ‭Eligible‬‭patients‬‭may‬‭only‬‭be‬‭included‬‭in‬‭the‬‭study‬‭after‬‭providing‬‭written‬‭(witnessed,‬‭where‬
‭required by law or regulation), IRB/IEC/REB-approved informed consent.‬
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‭●‬ ‭Informed‬‭consent‬‭must‬‭be‬‭obtained‬‭before‬‭conducting‬‭any‬‭study-specific‬‭procedures‬‭(i.e.‬‭all‬
‭of‬ ‭the‬ ‭procedures‬ ‭described‬ ‭in‬ ‭the‬ ‭protocol).‬ ‭The‬ ‭process‬ ‭of‬ ‭obtaining‬ ‭informed‬ ‭consent‬
‭should be documented in the patient source documents.‬
‭●‬ ‭The‬‭date‬‭when‬‭a‬‭patient’s‬‭Informed‬‭Consent‬‭was‬‭actually‬‭obtained‬‭will‬‭be‬‭captured‬‭in‬‭their‬
‭CRFs.‬
‭●‬ ‭An‬‭informed‬‭consent‬‭form‬‭(ICF)‬‭that‬‭is‬‭considered‬‭appropriate‬‭for‬‭this‬‭study‬‭and‬‭complies‬
‭with the ICH GCP guideline and regulatory requirements will be provided with this protocol.‬
‭●‬ ‭Women‬‭of‬‭childbearing‬‭potential‬‭should‬‭be‬‭informed‬‭that‬‭taking‬‭the‬‭study‬‭medication‬‭may‬
‭involve‬‭unknown‬‭risks‬‭to‬‭the‬‭fetus‬‭if‬‭pregnancy‬‭were‬‭to‬‭occur‬‭during‬‭the‬‭study‬‭and‬‭agree‬‭that‬
‭in‬‭order‬‭to‬‭participate‬‭in‬‭the‬‭study‬‭they‬‭must‬‭adhere‬‭to‬‭the‬‭contraception‬‭requirement‬‭for‬‭the‬
‭duration‬‭of‬‭the‬‭study.‬‭If‬‭there‬‭is‬‭any‬‭question‬‭that‬‭the‬‭patient‬‭will‬‭not‬‭reliably‬‭comply,‬‭they‬
‭should not be entered in the study.‬
‭Additional consent form‬
‭Sub-studies‬‭and‬‭studies‬‭with‬‭an‬‭optional‬‭biomarker‬‭component‬‭may‬‭have‬‭a‬‭separate‬‭consent‬
‭form‬‭covering‬‭those‬‭studies.‬‭This‬‭form‬‭will‬‭be‬‭adapted‬‭for‬‭each‬‭study.‬‭These‬‭informed‬‭consent‬‭forms‬
‭will‬‭be‬‭submitted‬‭for‬‭ethical‬‭approval‬‭together‬‭with‬‭the‬‭Study‬‭Protocol‬‭and‬‭the‬‭main‬‭informed‬‭consent‬
‭form‬‭of‬‭the‬‭study.‬‭If‬‭a‬‭patient‬‭opts‬‭not‬‭to‬‭participate‬‭in‬‭the‬‭optional‬‭assessments,‬‭this‬‭in‬‭no‬‭way‬‭will‬
‭affect the patient’s ability to participate in the main research study.‬
‭15.‬
‭Publication policy‬
‭This‬‭trial‬‭is‬‭intended‬‭for‬‭publication,‬‭even‬‭if‬‭terminated‬‭prematurely.‬‭Publication‬‭may‬‭include‬‭any‬‭or‬
‭all‬ ‭of‬ ‭the‬ ‭following:‬ ‭posting‬ ‭of‬ ‭a‬ ‭synopsis‬ ‭online,‬ ‭abstract‬ ‭and/or‬ ‭presentation‬ ‭at‬ ‭a‬ ‭scientific‬
‭conference, or publication of a full manuscript.‬
‭The‬‭authors‬‭will‬‭work‬‭to‬‭submit‬‭a‬‭manuscript‬‭describing‬‭trial‬‭results‬‭within‬‭12‬‭months‬‭after‬‭the‬‭last‬
‭data become available.‬
‭A‬ ‭synopsis‬ ‭of‬ ‭trial‬ ‭results‬ ‭for‬ ‭approved‬ ‭products‬ ‭will‬ ‭be‬ ‭posted‬ ‭on‬ ‭www.clinicaltrials.gov‬ ‭by‬‭12‬
‭months‬ ‭after‬ ‭the‬ ‭last‬ ‭subject's‬ ‭last‬ ‭visit‬ ‭for‬ ‭the‬ ‭primary‬‭outcome,‬‭12‬‭months‬‭after‬‭the‬‭decision‬‭to‬
‭discontinue‬ ‭development,‬ ‭or‬ ‭product‬ ‭marketing‬ ‭(dispensed,‬ ‭administered,‬ ‭delivered‬ ‭or‬ ‭promoted),‬
‭whichever is later.‬
‭These‬ ‭timelines‬ ‭may‬ ‭be‬ ‭extended,‬ ‭if‬ ‭additional‬ ‭time‬‭is‬‭needed‬‭for‬‭analysis,‬‭to‬‭protect‬‭intellectual‬
‭property, or to comply with confidentiality agreements with other parties.‬
‭Authors‬ ‭of‬ ‭the‬ ‭primary‬‭results‬‭manuscript‬‭will‬‭be‬‭provided‬‭the‬‭complete‬‭results‬‭from‬‭the‬‭Clinical‬
‭Study Report, subject to the confidentiality agreement.‬
‭When‬‭a‬‭manuscript‬‭is‬‭submitted‬‭to‬‭a‬‭biomedical‬‭journal‬‭the‬‭protocol‬‭and‬‭statistical‬‭analysis‬‭plan‬‭will‬
‭also‬‭be‬‭submitted‬‭to‬‭facilitate‬‭the‬‭peer‬‭and‬‭editorial‬‭review‬‭of‬‭the‬‭manuscript.‬‭If‬‭the‬‭manuscript‬‭is‬
‭subsequently‬ ‭accepted‬ ‭for‬ ‭publication‬ ‭the‬ ‭journal‬ ‭will‬ ‭be‬ ‭allowed,‬ ‭to‬ ‭post‬ ‭on‬‭its‬‭website‬‭the‬‭key‬
‭sections‬‭of‬‭the‬‭protocol‬‭that‬‭are‬‭relevant‬‭to‬‭evaluating‬‭the‬‭trial,‬‭specifically‬‭those‬‭sections‬‭describing‬
‭the‬‭trial‬‭objectives‬‭and‬‭hypotheses,‬‭the‬‭subject‬‭inclusion‬‭and‬‭exclusion‬‭criteria,‬‭the‬‭trial‬‭design‬‭and‬
‭procedures,‬ ‭the‬ ‭efficacy‬ ‭and‬ ‭safety‬ ‭measures,‬ ‭the‬ ‭statistical‬ ‭analysis‬ ‭plan,‬ ‭and‬ ‭any‬ ‭amendments‬
‭relating to those sections.‬
‭The‬‭first‬‭author‬‭is‬‭responsible‬‭for‬‭defending‬‭the‬‭integrity‬‭of‬‭the‬‭data,‬‭method(s)‬‭of‬‭data‬‭analysis‬‭and‬
‭the scientific content of the manuscript.‬
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‭APPENDICES‬
‭Appendix A. Performance Status Criteria‬
‭WHO Performance Status Scale‬
‭Karnofsky Performance Scale‬
‭Grade‬
‭Descriptions‬
‭Percent‬
‭Description‬
‭0‬
‭Normal‬ ‭activity.‬ ‭Fully‬‭active,‬‭able‬‭to‬
‭carry‬ ‭on‬ ‭all‬ ‭pre-disease‬ ‭performance‬
‭without restriction.‬
‭100‬
‭Normal, no complaints, no evidence of disease.‬
‭90‬
‭Able‬ ‭to‬ ‭carry‬ ‭on‬ ‭normal‬ ‭activity;‬ ‭minor‬ ‭signs‬ ‭or‬
‭symptoms of disease.‬
‭1‬
‭Symptoms,‬
‭but‬
‭ambulatory.‬
‭Restricted‬ ‭in‬ ‭physically‬ ‭strenuous‬
‭activity,‬ ‭but‬ ‭ambulatory‬ ‭and‬ ‭able‬ ‭to‬
‭carry‬ ‭out‬‭work‬‭of‬‭a‬‭light‬‭or‬‭sedentary‬
‭nature‬ ‭(e.g.,‬ ‭light‬ ‭housework,‬ ‭office‬
‭work)‬
‭80‬
‭Normal‬ ‭activity‬ ‭with‬ ‭effort;‬ ‭some‬ ‭signs‬ ‭or‬
‭symptoms of disease.‬
‭70‬
‭Cares‬‭for‬‭self,‬‭unable‬‭to‬‭carry‬‭on‬‭normal‬‭activity‬‭or‬
‭to do active work.‬
‭2‬
‭In‬‭bed‬‭<50%‬‭of‬‭the‬‭time.‬ ‭Ambulatory‬
‭and‬‭capable‬‭of‬‭all‬‭self-care,‬‭but‬‭unable‬
‭to‬ ‭carry‬ ‭out‬ ‭any‬ ‭work‬ ‭activities.‬ ‭Up‬
‭and‬ ‭about‬ ‭more‬ ‭than‬ ‭50%‬ ‭of‬ ‭waking‬
‭hours.‬
‭60‬
‭Requires‬ ‭occasional‬ ‭assistance,‬ ‭but‬ ‭is‬ ‭able‬ ‭to‬ ‭care‬
‭for most of his/her needs.‬
‭50‬
‭Requires‬ ‭considerable‬ ‭assistance‬ ‭and‬ ‭frequent‬
‭medical care.‬
‭3‬
‭In‬ ‭bed‬ ‭>50%‬ ‭of‬ ‭the‬ ‭time.‬
‭Capable‬
‭of‬
‭only‬
‭limited‬
‭self-care,‬ ‭confined‬ ‭in‬ ‭bed‬ ‭or‬
‭chair‬ ‭more‬ ‭than‬ ‭50%‬‭of‬‭waking‬
‭hours.‬
‭40‬
‭Disabled, requires special care and assistance.‬
‭30‬
‭Severely‬ ‭disabled,‬‭hospitalization‬‭indicated.‬ ‭Death‬
‭not imminent.‬
‭4‬
‭100%‬ ‭bedridden.‬
‭Completely‬
‭disabled.‬ ‭Cannot‬ ‭carry‬ ‭on‬ ‭any‬
‭self-care.‬
‭Totally‬ ‭confined‬ ‭to‬
‭bed or chair‬
‭20‬
‭Very‬ ‭sick,‬ ‭hospitalization‬ ‭indicated.‬
‭Death‬ ‭not‬
‭imminent.‬
‭10‬
‭Moribund, fatal processes progressing rapidly.‬
‭5‬
‭Deceased.‬
‭0‬
‭Deceased.‬
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‭Appendix B. References‬
‭[i]‬
‭Garcia-Carbonero‬‭R‬‭,‬‭Capdevila‬‭J,‬‭Crespo-Herrero‬‭G‬‭et‬‭al.‬‭Incidence,‬‭patterns‬‭of‬‭care‬
‭and‬ ‭prognostic‬ ‭factors‬ ‭for‬‭outcome‬‭of‬‭gastroenteropancreatic‬‭neuroendocrine‬‭tumors‬‭(GEP-NETs):‬
‭results‬
‭from‬
‭the‬
‭National‬ ‭Cancer‬ ‭Registry‬ ‭of‬ ‭Spain‬ ‭(RGETNE).‬ ‭Ann‬ ‭Oncol.‬ ‭2010‬
‭Sep;21(9):1794-803.‬
‭[ii]‬
‭Yao‬‭JC,‬‭Hassan‬‭M,‬‭Phan‬‭A,‬‭et‬‭al.‬‭One‬‭hundred‬‭years‬‭after‬‭"carcinoid":‬‭epidemiology‬
‭of‬ ‭and‬ ‭prognostic‬ ‭factors‬ ‭for‬ ‭neuroendocrine‬ ‭tumors‬ ‭in‬ ‭35,825‬ ‭cases‬ ‭in‬ ‭the‬‭United‬‭States.‬‭J‬‭Clin‬
‭Oncol. 2008 Jun 20;26(18):3063-72‬
‭[iii]‬
‭Rindi‬ ‭G,‬ ‭Arnold‬ ‭R,‬ ‭Bosman‬ ‭FT,‬ ‭et‬ ‭al.‬ ‭Nomenclature‬ ‭and‬ ‭classification‬ ‭of‬
‭neuroendocrine‬‭neoplasms‬‭of‬‭the‬‭digestive‬‭system.‬‭WHO‬‭classification‬‭of‬‭tumours‬‭of‬‭the‬‭digestive‬
‭system. 4th ed Lyon: International Agency for Research on cancer (IARC); 2010.‬
‭[iv]‬
‭Sorbye‬ ‭H,‬ ‭Strosberg‬ ‭J,‬ ‭Baudin‬ ‭E,‬ ‭et‬ ‭al.‬ ‭Gastroenteropancreatic‬ ‭high-grade‬
‭neuroendocrine carcinoma. Cancer 2014;120: 2814-23.‬
‭[v]‬
‭Sorbye‬‭H,‬‭Welin‬‭S,‬‭Langer‬‭SW‬‭et‬‭al.‬‭Predictive‬‭and‬‭prognostic‬‭factors‬‭for‬‭treatment‬
‭and‬‭survival‬‭in‬‭305‬‭patients‬‭with‬‭advanced‬‭gastrointestinal‬‭neuroendocrine‬‭carcinoma‬‭(WHO‬‭G3):‬‭the‬
‭NORDIC NEC study. Ann Oncol, 2013. 24(1): p. 152-60.‬
‭[vi]‬
‭Moertel‬‭CG,‬‭Kvols‬‭LK,‬‭O'Connell‬‭MJ‬‭et‬‭al.‬‭Treatment‬‭of‬‭neuroendocrine‬‭carcinomas‬
‭with‬ ‭combined‬ ‭etoposide‬ ‭and‬ ‭cisplatin.‬ ‭Evidence‬ ‭of‬ ‭major‬ ‭therapeutic‬ ‭activity‬ ‭in‬ ‭the‬ ‭anaplastic‬
‭variants of these neoplasms. Cancer, 1991. 68(2): p. 227-232.‬
‭[vii]‬
‭Mitry‬ ‭E,‬ ‭Baudin‬ ‭E,‬ ‭Ducreux‬ ‭M‬ ‭et‬ ‭al.‬ ‭Treatment‬ ‭of‬ ‭poorly‬ ‭differentiated‬
‭neuroendocrine tumours with etoposide and cisplatin. Br J Cancer, 1999. 81(8): p. 1351.‬
‭[viii]‬
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‭First-Line...‬
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‭II‬‭trial‬‭of‬‭consolidation‬‭with‬‭nivolumab‬‭and‬‭ipilimumab‬‭in‬‭limited-stage‬‭SCLC‬‭after‬‭standard‬‭of‬‭care‬
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‭with‬ ‭extensive-stage‬ ‭small‬ ‭cell‬ ‭lung‬ ‭cancer‬ ‭(SCLC):‬ ‭Preliminary‬ ‭safety‬ ‭and‬ ‭efficacy‬‭results‬‭from‬
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‭open-label,‬ ‭multiple‬ ‭cohort,‬ ‭phase‬ ‭1/2‬ ‭study‬ ‭to‬ ‭evaluate‬ ‭nivolumab‬ ‭(NIVO)‬ ‭in‬ ‭patients‬ ‭with‬
‭virus-associated‬ ‭tumors‬ ‭(CheckMate‬ ‭358):‬ ‭Efficacy‬ ‭and‬ ‭safety‬ ‭in‬ ‭Merkel‬ ‭cell‬ ‭carcinoma‬ ‭(MCC).‬
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‭patients‬‭with‬‭advanced‬‭neuroendocrine‬‭neoplasms:‬‭a‬‭non-randomized,‬‭open-label,‬‭phase‬‭1b‬‭trial.‬‭Ann‬
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‭Platinum-Based‬ ‭Chemotherapy‬ ‭in‬ ‭Non-Small‬ ‭Cell‬‭Lung‬‭Cancer‬‭(NSCLC):‬‭A‬‭Phase‬‭Ib‬‭Safety‬‭and‬
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‭and‬ ‭prognostic‬ ‭factors‬ ‭for‬‭outcome‬‭of‬‭gastroenteropancreatic‬‭neuroendocrine‬‭tumors‬‭(GEP-NETs):‬
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‭Study Protocol CA209- 73D (GETNE-T1913) v3.1 17 June 2019‬
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‭A phase II study of Platinum-doublet‬
‭chemotherapy in combination with nivolumab as‬
‭first-line treatment, in subjects with unresectable,‬
‭locally advanced or metastatic G3 Neuroendocrine‬
‭Neoplasms (NENs) of the gastroenteropancreatic‬
‭(GEP) tract or of unknown (UK) origin.‬
‭Protocol identification number / code / Registration n°:  CA209-73D‬
‭Sponsor code:‬‭GETNE-T1913‬
‭EudraCT number:‬ ‭2019-001546-18‬
‭Acronym:‬‭NICE-NEC‬
‭Study Coordinator or Chair:‬
‭Rocío García-Carbonero, MD, PhD‬
‭Maria del Carmen Riesco-Martínez, MD, PhD‬
‭Phone: +34-913908003/+34 913908926‬
‭e-mail: rgcarbonero@gmail.com/ m.carmen.riesco@gmail.com‬
‭19/08/2019‬
‭Protocol approval‬
‭(date)‬
‭Amendment 3‬
‭Version: (4.1) / 15 November, 2021‬
‭Study Protocol CA209- 73D (GETNE-T1913) v4.1 15 November 2021‬
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‭Sponsor Signature Page‬
‭Protocol Number:‬‭GETNE-T1913‬
‭Study‬‭Title:‬‭A‬‭phase‬‭II‬‭study‬‭of‬‭Platinum-doublet‬‭chemotherapy‬‭in‬‭combination‬‭with‬‭nivolumab‬‭as‬
‭first-line‬‭treatment,‬‭in‬‭subjects‬‭with‬‭unresectable,‬‭locally‬‭advanced‬‭or‬‭metastatic‬‭G3‬‭Neuroendocrine‬
‭Neoplasms (NENs) of the gastroenteropancreatic (GEP) tract or of unknown (UK) origin‬
‭EudraCT Number:‬ ‭2019-001546-18‬
‭Version number and date:‬ ‭Protocol version 4.1, November‬‭15‬‭th‬‭2021‬
‭I‬‭have‬‭received‬‭and‬‭read‬‭the‬‭Investigator’s‬‭Brochure‬‭for‬‭Nivolumab.‬‭I‬‭have‬‭read‬‭the‬‭GETNE-T1913‬‭-‬
‭NICE-NEC‬ ‭STUDY‬ ‭protocol‬ ‭and‬ ‭agree‬‭to‬‭conduct‬‭the‬‭study‬‭as‬‭outlined.‬‭I‬‭agree‬‭to‬‭maintain‬‭the‬
‭confidentiality‬‭of‬‭all‬‭information‬‭received‬‭or‬‭developed‬‭in‬‭connection‬‭with‬‭this‬‭protocol‬‭and‬‭I‬‭agree‬‭to‬
‭conduct‬ ‭this‬ ‭trial‬ ‭in‬ ‭accordance‬ ‭with‬ ‭all‬ ‭provisions‬ ‭of‬ ‭the‬ ‭protocol,‬‭GCPs‬‭and‬‭the‬‭Declaration‬‭of‬
‭Helsinki.‬
‭Dr. Jaume Capdevila‬
‭__________________________________________‬
‭____________________________‬
‭Sponsor signature‬
‭Signature date (DD-MM-YYYY)‬
‭Dr. Rocío García-Carbonero‬
‭______________________________‬
‭____________________________‬
‭Coordinating Investigator signature‬
‭Signature date‬‭(DD-MM-YYYY)‬
‭Dr. Carmen Riesco Martínez‬
‭_________________________________________‬
‭____________________________‬
‭Coordinating Investigator signature‬
‭Signature date‬‭(DD-MM-YYYY)‬
‭Study Protocol CA209- 73D (GETNE-T1913) v4.1 15 November 2021‬
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‭Investigator’s Agreement‬
‭Protocol Number:‬‭GETNE-T1913‬
‭Study‬‭Title:‬‭A‬‭phase‬‭II‬‭study‬‭of‬‭Platinum-doublet‬‭chemotherapy‬‭in‬‭combination‬‭with‬‭nivolumab‬‭as‬
‭first-line‬‭treatment,‬‭in‬‭subjects‬‭with‬‭unresectable,‬‭locally‬‭advanced‬‭or‬‭metastatic‬‭G3‬‭Neuroendocrine‬
‭Neoplasms (NENs) of the gastroenteropancreatic (GEP) tract or of unknown (UK) origin‬
‭EudraCT Number:‬ ‭2019-001546-18‬
‭Version number and date:‬‭Protocol version 4.1, November‬‭15‬‭th‬‭2021‬
‭I‬‭have‬‭received‬‭and‬‭read‬‭the‬‭Investigator’s‬‭Brochure‬‭for‬‭Nivolumab.‬‭I‬‭have‬‭read‬‭the‬‭GETNE-T1913‬‭-‬
‭NICE-NEC‬ ‭STUDY‬ ‭protocol‬ ‭and‬ ‭agree‬‭to‬‭conduct‬‭the‬‭study‬‭as‬‭outlined.‬‭I‬‭agree‬‭to‬‭maintain‬‭the‬
‭confidentiality‬‭of‬‭all‬‭information‬‭received‬‭or‬‭developed‬‭in‬‭connection‬‭with‬‭this‬‭protocol‬‭and‬‭I‬‭agree‬‭to‬
‭conduct‬ ‭this‬ ‭trial‬ ‭in‬ ‭accordance‬ ‭with‬ ‭all‬ ‭provisions‬ ‭of‬ ‭the‬ ‭protocol,‬‭GCPs‬‭and‬‭the‬‭Declaration‬‭of‬
‭Helsinki.‬
‭Investigator Printed Name‬
‭Investigator Signature‬
‭Date:‬
‭Study Protocol CA209- 73D (GETNE-T1913) v4.1 15 November 2021‬
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‭SYNOPSIS‬
‭Clinical Protocol‬‭CA209- 73D‬
‭Sponsor code:‬‭GETNE-T1913‬
‭EudraCT number:‬ ‭2019-001546-18‬
‭Protocol‬‭Title:‬‭A‬‭phase‬‭II‬‭study‬‭of‬‭platinum-doublet‬‭chemotherapy‬‭in‬‭combination‬‭with‬‭nivolumab‬‭as‬
‭first-line‬‭treatment‬‭in‬‭subjects‬‭with‬‭unresectable,‬‭locally‬‭advanced‬‭or‬‭metastatic‬‭G3‬‭neuroendocrine‬
‭neoplasms (NENs) of the gastroenteropancreatic (GEP) tract or of unknown (UK) origin.‬
‭Sponsor:‬‭Grupo Español de Tumores Neuroendocrinos‬‭y Endocrinos (GETNE)‬
‭Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with‬
‭Investigational Product(s):‬
‭INDUCTION PHASE‬
‭●‬ ‭Nivolumab 360 mg IV will be administered every 3 weeks (±3 days) for 6 cycles‬
‭●‬ ‭Carboplatin‬‭(AUC=5)‬‭IV‬‭will‬‭be‬‭administered‬‭every‬‭3‬‭weeks‬‭(±3‬‭days)‬‭for‬‭6‬‭cycles‬‭following‬
‭the administration of nivolumab.‬
‭●‬ ‭Etoposide‬‭100‬‭mg/m‬‭2‬‭/day‬‭IV‬‭will‬‭be‬‭administered‬‭on‬‭D1-3‬‭every‬‭3‬‭weeks‬‭(±3‬‭days)‬‭for‬‭6‬
‭cycles following the administration of carboplatin.‬
‭MAINTENANCE PHASE‬
‭●‬ ‭Nivolumab 480 mg IV will be administered every 4 weeks (±3 days) for 2 years‬
‭Study Phase:‬‭Non-randomized phase II‬
‭Study Population:‬
‭●‬ ‭Patients with histologically confirmed non-resectable or stage IV G3 (Ki-67>20%)‬
‭neuroendocrine neoplasms of the GEP tract or of UK origin.‬
‭●‬
‭No prior systemic therapy.‬
‭●‬ ‭Available tumor sample for translational research.‬
‭Research Hypothesis:‬
‭●‬ ‭The‬‭addition‬‭of‬‭Nivolumab‬‭to‬‭platinum-based‬‭chemotherapy‬‭doublet‬‭will‬‭induce‬‭deeper‬‭and‬
‭more‬‭durable‬‭tumor‬‭responses‬‭and‬‭prolong‬‭overall‬‭survival‬‭(OS)‬‭of‬‭patients‬‭with‬‭advanced‬
‭G3‬‭NENs‬‭of‬‭gastroenteropancreatic‬‭(GEP)‬‭or‬‭unknown‬‭(UK)‬‭origin,‬‭as‬‭compared‬‭to‬‭historical‬
‭cohorts of patients treated with standard chemotherapy alone.‬
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‭Objectives:‬
‭Objectives‬
‭Endpoints‬
‭Primary‬
‭●‬ ‭To‬ ‭determine‬ ‭the‬‭overall‬‭survival‬‭patients‬
‭with‬ ‭advanced‬ ‭G3‬ ‭NENs‬ ‭treated‬ ‭with‬
‭nivolumab‬
‭+‬
‭platinum-based‬
‭chemotherapy.‬
‭●‬
‭1 year-OS rate‬
‭Secondary‬
‭●‬ ‭To‬ ‭determine‬ ‭other‬‭efficacy‬‭outcomes‬ ‭of‬
‭nivolumab‬‭+‬‭platinum-based‬‭chemotherapy‬
‭in patients with advanced G3 NENs.‬
‭●‬
‭ORR‬
‭●‬
‭Duration of response‬
‭●‬
‭PFS‬
‭●‬
‭OS‬
‭●‬ ‭To‬ ‭evaluate‬ ‭the‬ ‭safety‬ ‭and‬ ‭tolerability‬ ‭of‬
‭nivolumab‬‭+‬‭platinum-based‬‭chemotherapy‬
‭in this patient population.‬
‭●‬ ‭Incidence of AEs, SAEs and selected AEs‬
‭●‬ ‭To‬ ‭evaluate‬ ‭biochemical‬ ‭response‬ ‭as‬
‭predictive‬
‭biomarker‬
‭of‬
‭efficacy‬
‭of‬
‭nivolumab‬ ‭+‬‭chemotherapy‬‭in‬‭this‬‭patient‬
‭population.‬
‭●‬ ‭Chromogranin‬ ‭A‬ ‭and‬ ‭enolase‬ ‭values‬ ‭and‬
‭their association with ORR, PFS and OS.‬
‭●‬ ‭To‬
‭explore‬
‭potential‬
‭predictive‬
‭and‬
‭prognostic biomarkers.‬
‭●‬ ‭Mutational‬
‭burden,‬
‭gene‬
‭expression‬
‭signature,‬
‭soluble‬
‭factors‬
‭and‬
‭other‬
‭molecular‬ ‭markers‬‭in‬‭peripheral‬‭blood‬‭and‬
‭their association with clinical outcomes.‬
‭Study Design:‬
‭Protocol‬‭CA209-‬‭73D‬‭is‬‭a‬‭non-randomized,‬‭open-label,‬‭phase‬‭2‬‭trial‬‭that‬‭will‬‭enroll‬‭38‬‭≥‬‭18‬‭years‬‭old‬
‭with‬‭untreated‬‭metastatic‬‭or‬‭unresectable‬‭G3‬‭NENs‬‭of‬‭gastroenteropancreatic‬‭or‬‭UK‬‭origin,‬‭evaluating‬
‭the‬ ‭efficacy‬ ‭of‬ ‭nivolumab‬ ‭combined‬ ‭with‬ ‭platinum-based‬ ‭doublet‬ ‭chemotherapy‬ ‭as‬ ‭first-line‬
‭treatment,‬‭followed‬‭by‬‭maintenance‬‭treatment‬‭with‬‭nivolumab‬‭in‬‭patients‬‭who‬‭have‬‭not‬‭progressed‬
‭after 6 months of first line platinum-based induction chemotherapy.‬
‭Tumor‬‭progression‬‭and‬‭response‬‭endpoints‬‭will‬‭be‬‭assessed‬‭using‬‭RECIST‬‭1.1‬‭criteria.‬‭If‬‭there‬‭is‬‭no‬
‭evidence‬ ‭of‬ ‭disease‬ ‭progression‬ ‭after‬‭the‬‭induction‬‭phase,‬‭treatment‬‭with‬‭nivolumab‬‭will‬‭continue‬
‭until‬ ‭RECIST‬ ‭1.1‬ ‭defined‬ ‭progression‬ ‭or‬ ‭death,‬ ‭unacceptable‬ ‭toxicity,‬ ‭24‬ ‭months‬‭of‬‭treatment‬‭or‬
‭withdrawal of consent.‬
‭Dose‬ ‭reductions‬ ‭will‬‭not‬‭be‬‭allowed‬‭for‬‭nivolumab.‬‭Treatment‬‭beyond‬‭initial‬‭investigator-assessed‬
‭progression‬ ‭(either‬ ‭clinical‬ ‭or‬ ‭radiological)‬ ‭is‬ ‭permitted‬ ‭for‬ ‭nivolumab‬ ‭if‬ ‭the‬ ‭subject‬ ‭has‬ ‭an‬
‭investigator-assessed clinical benefit and is tolerating well study drug.‬
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‭The‬‭study‬‭period‬‭will‬‭include‬‭18‬‭months‬‭of‬‭accrual‬‭plus‬‭24‬‭months‬‭of‬‭follow-up‬‭after‬‭the‬‭induction‬
‭phase. The study will end once survival follow-up has concluded.‬
‭Study Treatment‬
‭Medication‬
‭Potency‬
‭IP/Non-IP‬
‭Nivolumab‬
‭100 mg/vial‬
‭IP‬
‭Carboplatin‬
‭450 mg/vial‬
‭IP‬
‭Etoposide‬
‭100 mg/vial‬
‭IP‬
‭Figure-1. Study Schema‬
‭Study Population:‬
‭For study entry all the following criteria MUST be met:‬
‭Key Inclusion Criteria (See Protocol Section 4.1 for full list of criteria)‬
‭●‬ ‭Histologically‬ ‭confirmed‬ ‭G3‬ ‭NENs‬ ‭originated‬ ‭in‬ ‭the‬ ‭gastroenteropancreatic‬ ‭tract‬ ‭(WHO‬
‭2015/2019‬‭classification).‬‭Patients‬‭with‬‭a‬‭G3‬‭NEN‬‭of‬‭unknown‬‭primary‬‭will‬‭also‬‭be‬‭eligible‬
‭for this trial.‬
‭●‬
‭Ki-67 >20% or mitotic rate > 20 per 10 HPF.‬
‭●‬ ‭Metastatic‬‭or‬‭locally‬‭advanced‬‭unresectable‬‭disease‬‭not‬‭amenable‬‭to‬‭treatment‬‭with‬‭curative‬
‭intent.‬
‭●‬ ‭No prior systemic treatment for advanced disease nor as adjuvant therapy permitted.‬
‭●‬ ‭Availability‬‭of‬‭fresh‬‭or‬‭archive‬‭formalin-fixed,‬‭paraffin-embedded‬‭tumor‬‭tissue‬‭for‬‭biomarker‬
‭assessment.‬
‭●‬ ‭Patients must have clinically and/or radiographically documented measurable disease.‬
‭●‬ ‭Adequate organ function as defined by the following criteria‬
‭○‬ ‭Absolute neutrophil count (ANC) ≥1500 cells/mm3;‬
‭○‬ ‭Platelets ≥100,000 cells/mm3;‬
‭○‬ ‭Hemoglobin ≥9.0 g/dL;‬
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‭○‬ ‭AST‬‭and‬‭ALT‬‭≤2.5‬‭x‬‭upper‬‭limit‬‭of‬‭normal‬‭(ULN);‬‭in‬‭patients‬‭with‬‭liver‬‭metastases‬
‭AST and ALT ≤5.0 x ULN;‬
‭○‬ ‭Total bilirubin ≤1.5 x ULN;‬
‭○‬ ‭Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min.‬
‭●‬ ‭ECOG performance status of 0-2.‬
‭Key Exclusion Criteria (See Protocol Section 4.2 for full list of criteria)‬
‭●‬ ‭The‬‭following‬‭endocrine‬‭tumor‬‭types‬‭may‬‭not‬‭be‬‭included:‬‭paraganglioma,‬‭adrenal,‬‭thyroid‬
‭parathyroid‬‭or‬‭pituitary‬‭endocrine‬‭tumors.‬‭Large‬‭or‬‭small‬‭cell‬‭lung‬‭neuroendocrine‬‭carcinoma‬
‭of the lung will also be excluded.‬
‭●‬ ‭Prior therapy with any immune checkpoint inhibitor.‬
‭●‬ ‭Prior organ transplantation, including allogeneic stem-cell transplantation.‬
‭●‬ ‭Systemic‬ ‭chronic‬ ‭steroid‬ ‭therapy‬ ‭(‬‭>‬ ‭10‬ ‭mg/day‬ ‭prednisone‬ ‭or‬ ‭equivalent)‬ ‭or‬ ‭other‬
‭immunosuppressive‬‭agents‬‭or‬‭use‬‭of‬‭any‬‭investigational‬‭drug‬‭within‬‭28‬‭days‬‭before‬‭the‬‭start‬
‭of trial treatment.‬
‭●‬ ‭Known‬ ‭history‬ ‭of‬ ‭positive‬ ‭testing‬ ‭for‬ ‭Human‬ ‭Immunodeficiency‬ ‭Virus‬ ‭(HIV)‬ ‭infection,‬
‭known‬‭history‬‭of‬‭positive‬‭tests‬‭for‬‭Hepatitis‬‭B‬‭virus‬‭surface‬‭antigen‬‭(HBVsAg)‬‭or‬‭Hepatitis‬‭C‬
‭ribonucleic‬‭acid‬‭(HCV‬‭RNA)‬‭indicating‬‭acute‬‭or‬‭chronic‬‭infection‬‭or‬‭other‬‭significant‬‭acute‬
‭or chronic infections requiring medication at study entry.‬
‭Study Assessments:‬
‭The‬ ‭primary‬ ‭objective‬ ‭is‬ ‭to‬ ‭determine‬ ‭one-year‬ ‭OS‬ ‭rate‬ ‭of‬ ‭nivolumab‬ ‭in‬ ‭combination‬ ‭with‬
‭platinum-doublet‬‭chemotherapy‬‭in‬‭treatment-naïve‬‭patients‬‭with‬‭unresectable‬‭G3‬‭NENs.‬‭This‬‭will‬‭be‬
‭calculated‬ ‭from‬ ‭the‬ ‭date‬ ‭of‬ ‭treatment‬‭initiation‬‭with‬‭platinum-based‬‭chemotherapy‬‭and‬‭nivolumab‬
‭until‬‭the‬‭date‬‭of‬‭death‬‭from‬‭any‬‭cause.‬‭Subjects‬‭will‬‭be‬‭assessed‬‭for‬‭response‬‭every‬‭8‬‭weeks‬‭(±‬‭7‬‭days)‬
‭after‬ ‭the‬ ‭date‬ ‭of‬ ‭administration‬ ‭of‬ ‭the‬ ‭first‬ ‭dose‬ ‭for‬ ‭12‬ ‭months‬ ‭and‬ ‭every‬ ‭12‬ ‭weeks‬ ‭(±‬ ‭7‬ ‭days)‬
‭thereafter‬‭until‬‭disease‬‭progression.‬‭Patients‬‭that‬‭stop‬‭therapy‬‭due‬‭to‬‭toxicity‬‭in‬‭the‬‭absence‬‭of‬‭disease‬
‭progression‬ ‭shall‬ ‭continue‬ ‭to‬ ‭be‬ ‭assessed‬ ‭with‬ ‭CT‬ ‭scans‬ ‭with‬ ‭the‬ ‭same‬ ‭frequency‬ ‭until‬ ‭disease‬
‭progression‬‭or‬‭initiation‬‭of‬‭a‬‭new‬‭line‬‭of‬‭therapy.‬‭Upon‬‭treatment‬‭discontinuation,‬‭subjects‬‭will‬‭be‬
‭followed‬‭for‬‭survival‬‭every‬‭3‬‭months‬‭(via‬‭telephone‬‭contact‬‭allowed)‬‭until‬‭death.‬‭All‬‭patients‬‭included‬
‭will be followed.‬
‭Statistical Considerations:‬
‭Sample Size‬
‭A‬‭sample‬‭size‬‭of‬‭38‬‭subjects‬‭will‬‭provide‬‭80%‬‭power‬‭to‬‭test‬‭the‬‭null‬‭hypothesis‬‭(H‬‭0‬‭)‬‭that‬‭one-year‬‭OS‬
‭rate‬ ‭for‬ ‭advanced‬ ‭G3‬ ‭NENs‬ ‭treated‬ ‭with‬ ‭nivolumab‬ ‭in‬ ‭combination‬ ‭with‬ ‭platinum-doublet‬
‭chemotherapy‬‭is‬‭0.5‬‭against‬‭a‬‭two-sided‬‭alternative.‬‭This‬‭design‬‭yields‬‭a‬‭two-sided‬‭type‬‭I‬‭error‬‭rate‬‭of‬
‭5% when the true one-year OS rate is 0.72.‬
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‭Study Calendar:‬
‭-‬
‭Study start (real)‬
‭11/10/20199‬
‭-‬
‭First patient First visit (real)‬
‭4/11/2019‬
‭-‬
‭End or recruitment (real)‬
‭26/1/2021‬
‭-‬
‭Last patient Last visit (estimated)‬
‭1Q 2023‬
‭-‬
‭End of study (estimation)‬
‭2Q 2023‬
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‭Table of contents‬
‭1. Background and introduction‬
‭14‬
‭1.1. Background Disease Information‬
‭14‬
‭1.2.         Background Therapeutic Information‬
‭15‬
‭1.2.1.  Nivolumab: mechanism of action‬
‭15‬
‭1.2.2. Preclinical experience with Nivolumab‬
‭15‬
‭1.2.3. Clinical experience with Nivolumab in SCLC‬
‭15‬
‭1.2.4. Immune checkpoint inhibitors in other high grade NENs‬
‭17‬
‭1.2.5. Chemotherapy in combination with immune checkpoint inhibitors‬
‭17‬
‭1.2.6. Potential for drug-drug interactions‬
‭19‬
‭2. Objectives and Endpoints of the trial‬
‭20‬
‭2.1.  Primary objective‬
‭20‬
‭2.2. Secondary Objectives‬
‭20‬
‭3. Study Design‬
‭22‬
‭3.1. Overall Design‬
‭22‬
‭3.1.1. Data Monitoring Committee and Other External Committees‬
‭22‬
‭3.2. Number of participants‬
‭23‬
‭3.3. End of Study Definition‬
‭23‬
‭3.4. Study Calendar‬
‭23‬
‭4. Patient selection criteria‬
‭24‬
‭4.1. Inclusion Criteria‬
‭24‬
‭4.2. Exclusion Criteria‬
‭24‬
‭4.3. Screening Failures‬
‭26‬
‭4.3.1. Retesting during Screening Period‬
‭26‬
‭5. Therapeutic Regimens, Expected Toxicity, Dose Modifications‬
‭27‬
‭5.1. Treatments Administered‬
‭27‬
‭5.1.1. Dosing‬
‭28‬
‭5.1.1.1. Nivolumab‬
‭28‬
‭5.1.1.2 Chemotherapy dosing‬
‭29‬
‭5.1.1.3 Premedication‬
‭29‬
‭5.1.2. Patient Monitoring‬
‭30‬
‭5.1.3. Treatment of Nivolumab Infusion Reactions‬
‭30‬
‭5.2. Dose Adjustments‬
‭32‬
‭5.2.1. Dose modifications for Nivolumab‬
‭33‬
‭5.2.2. Dose modifications for Chemotherapy‬
‭36‬
‭5.2.2.1 Dose Reductions for Hematologic Adverse Events‬
‭37‬
‭5.2.2.2. Dose Reductions for Non-Hematologic Adverse Events‬
‭38‬
‭5.2.3. Dose Delay Criteria‬
‭38‬
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‭5.2.3.1. Dose delay Criteria for Nivolumab‬
‭38‬
‭5.2.3.2. Dose delay Criteria for Chemotherapy‬
‭39‬
‭5.2.4. Criteria to Resume Dosing‬
‭39‬
‭5.2.4.1. Criteria to Resume Nivolumab Dosing‬
‭39‬
‭5.2.4.2. Criteria to Resume Treatment with Chemotherapy‬
‭40‬
‭5.3. Duration of Therapy‬
‭40‬
‭5.3.1. Treatment Beyond Disease Progression‬
‭40‬
‭5.4. Preparation/Handling/Storage/ Accountability‬
‭41‬
‭5.5. Concomitant therapy‬
‭42‬
‭5.5.1. Prohibited and/or Restricted Therapy‬
‭42‬
‭5.5.2. Permitted Therapy‬
‭42‬
‭5.5.3. Palliative Local Therapy‬
‭43‬
‭5.5.4. Imaging Restrictions and Precautions‬
‭43‬
‭6. Discontinuation Criteria‬
‭45‬
‭6.1. Discontinuation from Study Treatment‬
‭45‬
‭6.1.1. Nivolumab Dose Discontinuation‬
‭45‬
‭6.1.2. Chemotherapy Dose Discontinuation‬
‭46‬
‭6.2. Discontinuation from Study‬
‭47‬
‭6.2.1. Post Study Treatment Study Follow-up‬
‭48‬
‭6.3. Lost to Follow-up‬
‭48‬
‭7. Clinical evaluation, laboratory tests, follow-up‬
‭49‬
‭7.1. Before treatment start‬
‭49‬
‭7.1.1. Informed Consent‬
‭49‬
‭7.1.1.1. General Informed Consent‬
‭49‬
‭7.1.1.2. Consent and Collection of Specimens for Future Biomedical Research‬
‭49‬
‭7.1.2. Inclusion/Exclusion Criteria Assessment‬
‭50‬
‭7.1.3. Medical History‬
‭50‬
‭7.1.4. Prior and concomitant medications review‬
‭50‬
‭7.1.4.1. Prior Medications‬
‭50‬
‭7.1.4.2. Concomitant Medications‬
‭50‬
‭7.1.5. Assignment of Screening Number‬
‭50‬
‭7.1.6. Subject Identification Card‬
‭50‬
‭7.1.7. Submitting Tumor Sample‬
‭50‬
‭7.1.8. Tumor Imaging‬
‭51‬
‭7.1.8.1. Computed  (CT) with IV contrast or Magnetic Resonance Imaging (MRI) of‬
‭chest, abdomen and pelvis.‬
‭51‬
‭7.1.8.2. Brain CT with IV contrast or MRI scan‬
‭51‬
‭7.1.8.3. Whole body bone scan‬
‭51‬
‭7.1.9. Laboratory Assessments‬
‭51‬
‭7.1.10. 12-Lead Electrocardiogram (ECG)‬
‭52‬
‭7.2. During treatment‬
‭52‬
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‭7.2.1. Adverse Event (AE) Monitoring‬
‭52‬
‭7.2.2. Physical Exam‬
‭52‬
‭7.2.3. Vital Signs‬
‭52‬
‭7.2.4. 12-Lead Electrocardiogram (ECG)‬
‭52‬
‭7.2.5. Eastern Cooperative Oncology Group (ECOG) Performance Status‬
‭53‬
‭7.2.6. Tumor Imaging and Assessment of Disease‬
‭53‬
‭7.2.7. Laboratory Assessments‬
‭53‬
‭7.2.8. Serum/Urine β-hCG‬
‭54‬
‭7.3. After the end of treatment (Follow-up)‬
‭54‬
‭7.4. Summary table‬
‭54‬
‭8.  Evaluation criteria‬
‭57‬
‭8.1. Definitions‬
‭57‬
‭8.2. Evaluation of efficacy‬
‭57‬
‭8.2.1. Measurability of tumour lesions at baseline‬
‭57‬
‭8.2.1.1. Definitions‬
‭57‬
‭8.2.1.2. Methods of measurements‬
‭58‬
‭8.2.2. Tumor response evaluation‬
‭58‬
‭8.2.2.1. Response evaluation according RECIST 1.1 [xliv]‬
‭58‬
‭8.2.2.2. Response evaluation according irRECIST [xlvi]‬
‭61‬
‭8.2.2.3. Frequency of tumor re-evaluation‬
‭61‬
‭8.2.3. Reporting of tumor response‬
‭62‬
‭8.2.3.1. Response duration‬
‭62‬
‭8.2.3.2. Stable disease duration‬
‭62‬
‭8.2.3.3. Progression Free Survival‬
‭62‬
‭8.2.3.4. Overall Survival‬
‭62‬
‭9. Statistical considerations‬
‭63‬
‭9.1. Statistical design‬
‭63‬
‭9.1.1. Sample Size Determination‬
‭63‬
‭9.2. Populations for Analysis‬
‭63‬
‭9.3. Statistical Analysis‬
‭63‬
‭9.3.1. Efficacy Analysis‬
‭63‬
‭9.3.1.1. Methods for Primary Endpoint‬
‭64‬
‭9.3.1.2. Methods for Secondary Endpoints‬
‭64‬
‭9.3.2. Safety Analysis‬
‭65‬
‭10. Translational research‬
‭66‬
‭11. Patient registration  procedure‬
‭67‬
‭12. Reporting adverse events‬
‭68‬
‭12.1. Definitions for adverse event reporting‬
‭68‬
‭12.2. Reporting procedure‬
‭68‬
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‭13. Quality assurance‬
‭73‬
‭13.1. Control of data consistency‬
‭73‬
‭13.2. On-site quality control (for multi-centre studies only when data are sent to a Data Centre or‬
‭similar)‬
‭73‬
‭13.3. Audits (for multi-centre studies only when data are sent to Data Centre or similar)‬
‭73‬
‭13.4. Central review of pathology‬
‭74‬
‭14. Ethical considerations‬
‭75‬
‭14.1. Patient protection‬
‭75‬
‭14.2. Subject identification‬
‭75‬
‭14.3. Informed consent‬
‭75‬
‭15. Publication policy‬
‭77‬
‭APPENDICES‬
‭78‬
‭Appendix A. Performance Status Criteria‬
‭78‬
‭Appendix B. References‬
‭79‬
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‭Schema:‬
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‭1.‬
‭Background and introduction‬
‭1.1.‬
‭Background Disease Information‬
‭NENs‬‭comprise‬‭a‬‭heterogeneous‬‭family‬‭of‬‭neoplasms‬‭with‬‭a‬‭wide‬‭and‬‭complex‬‭spectrum‬‭of‬‭clinical‬
‭behaviour.‬‭They‬‭are‬‭uncommon‬‭tumours‬‭with‬‭an‬‭estimated‬‭incidence‬‭per‬‭year‬‭that‬‭ranges‬‭from‬‭5‬‭to‬‭7‬
‭cases‬‭per‬‭100,000‬‭in‬‭the‬‭Caucasian‬‭population.‬ ‭The‬‭reported‬‭incidence‬‭has‬‭substantially‬‭increased‬
‭over‬ ‭the‬ ‭last‬ ‭decades,‬ ‭al‬ ‭least‬ ‭partially‬ ‭due‬ ‭to‬ ‭improved‬ ‭diagnostic‬ ‭techniques‬ ‭and‬ ‭clinical‬
‭awareness.‬‭[i],[ii]‬
‭G3‬‭NENs‬‭are‬‭defined‬‭according‬‭to‬‭the‬‭World‬‭Health‬‭Organization‬‭(WHO)‬‭as‬‭those‬‭with‬‭high‬
‭proliferative‬‭index‬‭(Ki-67‬‭index‬‭greater‬‭than‬‭20%‬‭or‬‭a‬‭mitotic‬‭rate‬‭greater‬‭than‬‭20‬‭per‬‭10‬‭high‬‭power‬
‭fields (HPF)), which are generally, but not always, poorly differentiated tumors‬‭[iii]‬‭.‬
‭The‬ ‭gastroenteropancreatic‬ ‭tract‬ ‭is‬ ‭the‬ ‭most‬ ‭common‬ ‭site‬ ‭for‬ ‭extra-pulmonary‬ ‭G3‬ ‭NENs‬
‭accounting‬‭for‬‭35-55%‬‭of‬‭all‬‭NENs‬‭outside‬‭the‬‭lung.‬‭Approximately‬‭50-60%‬‭of‬‭patients‬‭present‬‭with‬
‭metastatic‬‭disease‬‭at‬‭the‬‭time‬‭of‬‭diagnosis‬‭and‬‭have‬‭a‬‭fateful‬‭prognosis.‬‭Median‬‭OS‬‭of‬‭patients‬‭with‬
‭advanced‬‭disease‬‭is‬‭5‬‭months,‬‭ranging‬‭from‬‭less‬‭than‬‭a‬‭month‬‭for‬‭patients‬‭receiving‬‭best‬‭supportive‬
‭care‬ ‭only,‬ ‭up‬ ‭to‬ ‭11‬ ‭months‬ ‭with‬ ‭best‬ ‭available‬ ‭therapy‬‭[iv]‬‭,‬‭[v]‬‭.‬ ‭Historically,‬ ‭treatment‬ ‭strategies‬ ‭for‬
‭extra-pulmonary‬‭G3‬‭NENs‬‭have‬‭been‬‭often‬‭extrapolated‬‭from‬‭the‬‭treatment‬‭paradigm‬‭for‬‭small‬‭cell‬
‭lung‬ ‭cancer‬ ‭(SCLC)‬ ‭given‬ ‭the‬ ‭histologic‬ ‭similarities‬ ‭between‬ ‭both‬ ‭entities.‬ ‭Therefore,‬ ‭standard‬
‭front-line‬ ‭therapy‬ ‭involves‬ ‭the‬ ‭administration‬ ‭of‬ ‭a‬ ‭platinum‬ ‭agent‬ ‭(cisplatin‬ ‭or‬ ‭carboplatin)‬ ‭and‬
‭etoposide,‬‭with‬‭response‬‭rates‬‭in‬‭the‬‭largest‬‭recent‬‭western‬‭series‬‭of‬‭~‬‭30%‬‭and‬‭median‬‭survival‬‭of‬
‭about‬‭one‬‭year‬‭[vi],[vii],[viii],[ix],[x]‬‭.‬‭The‬‭optimal‬‭duration‬‭of‬‭first‬‭line‬‭(1L)‬‭treatment‬‭is‬‭unclear.‬‭However,‬‭in‬
‭the‬‭absence‬‭of‬‭progression,‬‭chemotherapy‬‭is‬‭usually‬‭stopped‬‭after‬‭4‬‭to‬‭6‬‭cycles‬‭due‬‭to‬‭cumulative‬
‭toxicity‬ ‭and‬ ‭the‬ ‭lack‬ ‭of‬ ‭evidence‬ ‭demonstrating‬ ‭greater‬ ‭clinical‬ ‭benefit‬ ‭with‬ ‭extended‬ ‭treatment.‬
‭Progression-free‬‭survival‬‭after‬‭this‬‭induction‬‭period‬‭remains‬‭poor,‬‭lasting‬‭2-‬‭3‬‭months.‬‭Therefore,‬‭new‬
‭therapeutic‬‭strategies‬‭are‬‭needed‬‭in‬‭this‬‭setting‬‭to‬‭improve‬‭response‬‭rates‬‭and‬‭prolong‬‭progression‬‭free‬
‭survival‬‭without‬‭increasing‬‭toxicity‬‭in‬‭these‬‭patients.‬‭The‬‭addition‬‭of‬‭an‬‭immune‬‭checkpoint‬‭inhibitor‬
‭to‬ ‭1L‬ ‭chemotherapy,‬ ‭followed‬ ‭by‬ ‭maintenance‬ ‭immunotherapy‬ ‭could‬ ‭be‬‭a‬‭valuable‬‭option‬‭in‬‭this‬
‭scenario.‬
‭More‬‭recently,‬‭a‬‭better‬‭understanding‬‭of‬‭the‬‭role‬‭of‬‭the‬‭immunological‬‭system‬‭in‬‭tumor‬‭control‬
‭has‬ ‭opened‬ ‭multiple‬ ‭doors‬ ‭to‬ ‭implement‬ ‭different‬ ‭strategies‬ ‭to‬ ‭enhance‬ ‭immune‬‭response‬‭against‬
‭cancer‬‭cells‬‭[xi]‬‭.‬‭It‬‭is‬‭well‬‭known‬‭that‬‭tumor‬‭cells‬‭elude‬‭immune‬‭response‬‭by‬‭several‬‭mechanisms.‬‭The‬
‭programmed‬ ‭death-1‬ ‭receptor‬ ‭(PD-1)‬ ‭and‬ ‭its‬ ‭ligand‬ ‭(PD-L1)‬ ‭are‬ ‭key‬ ‭therapeutic‬ ‭targets‬ ‭in‬ ‭the‬
‭reactivation‬ ‭of‬ ‭the‬ ‭immune‬ ‭response‬ ‭against‬ ‭multiple‬ ‭cancers.‬ ‭PD-1‬ ‭receptor‬ ‭is‬ ‭expressed‬ ‭on‬
‭activated‬‭T‬‭cells‬‭and‬‭interacts‬‭with‬‭its‬‭ligand‬‭(PD-L1),‬‭which‬‭is‬‭expressed‬‭in‬‭tumor‬‭and‬‭immune‬‭cells,‬
‭to‬‭down-regulate‬‭T-cell‬‭activation‬‭and‬‭promote‬‭tumor‬‭immune‬‭escape‬‭,‬‭a‬‭mechanism‬‭by‬‭which‬‭tumor‬
‭cells‬‭avoid‬‭recognition‬‭and‬‭elimination‬‭by‬‭the‬‭immune‬‭system‬‭[xii]‬‭.‬‭The‬‭development‬‭of‬‭monoclonal‬
‭antibodies‬ ‭against‬ ‭the‬ ‭PD-1/‬ ‭PD-L1‬ ‭pathway,‬ ‭that‬ ‭disrupt‬ ‭PD-1–mediated‬ ‭signalling‬ ‭and‬ ‭restore‬
‭thereby‬‭antitumor‬‭immunity,‬‭has‬‭led‬‭to‬‭significant‬‭antitumor‬‭activity‬‭in‬‭a‬‭wide‬‭spectrum‬‭of‬‭neoplastic‬
‭diseases,‬‭inducing‬‭increased‬‭progression-free-survival‬‭(PFS),‬‭overall‬‭survival‬‭(OS)‬‭and‬‭long‬‭lasting‬
‭responses in different tumor types such as melanoma or lung cancer‬‭[xiii],[xiv],[xv],[xvi]‬‭.‬
‭On‬‭the‬‭other‬‭hand,‬‭an‬‭increasing‬‭body‬‭of‬‭evidence‬‭has‬‭demonstrated‬‭that‬‭mutational‬‭burden‬‭is‬
‭strongly‬‭associated‬‭with‬‭increased‬‭response‬‭to‬‭immunotherapy.‬‭In‬‭this‬‭regard,‬‭high‬‭grade‬‭NENs‬‭are‬
‭suitable‬‭candidates‬‭for‬‭these‬‭treatment‬‭strategies‬‭as‬‭they‬‭are‬‭highly‬‭mutated‬‭tumours‬‭with‬‭high‬‭PD-L1‬
‭expression.‬ ‭For‬ ‭example,‬ ‭some‬ ‭authors‬ ‭have‬ ‭shown‬ ‭that‬ ‭virus-negative‬ ‭Merkel‬ ‭Cell‬ ‭Carcinomas‬
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‭(MCCs),‬‭a‬‭type‬‭of‬‭high‬‭grade‬‭NEN,‬‭harbour‬‭more‬‭tumor‬‭neoantigens‬‭than‬‭melanomas‬‭or‬‭non-small‬
‭cell‬ ‭lung‬ ‭cancers‬ ‭(median‬ ‭of‬ ‭173,‬ ‭65,‬ ‭and‬ ‭111‬ ‭neoantigens/sample,‬‭respectively),‬‭two‬‭cancers‬‭for‬
‭which immune checkpoint blockade can produce durable clinical responses‬‭[xvii]‬‭.‬
‭In‬‭summary,‬‭the‬‭addition‬‭of‬‭a‬‭checkpoint‬‭inhibitor‬‭could‬‭be‬‭a‬‭valuable‬‭treatment‬‭option‬‭in‬‭these‬
‭patients.‬‭The‬‭objective‬‭of‬‭this‬‭trial‬‭is‬‭to‬‭determine‬‭the‬‭one-year‬‭overall‬‭survival‬‭rate‬‭of‬‭nivolumab‬‭in‬
‭addition to platinum-doublet chemotherapy in advanced G3 NENs without prior therapy.‬
‭1.2.         Background Therapeutic Information‬
‭1.2.1.‬ ‭Nivolumab: mechanism of action‬
‭Nivolumab‬‭(BMS-936558)‬‭is‬‭a‬‭fully‬‭human,‬‭IgG4‬‭mAb‬‭that‬‭binds‬‭PD-1‬‭on‬‭activated‬‭immune‬‭cells‬
‭and‬ ‭disrupts‬ ‭engagement‬ ‭of‬ ‭the‬‭receptor‬‭with‬‭its‬‭ligands‬‭PD-L1‬‭and‬‭PD-L2,‬‭abrogating‬‭inhibitory‬
‭signals‬‭and‬‭augmenting‬‭the‬‭host‬‭antitumor‬‭response.‬‭The‬‭PD-1‬‭receptor-ligand‬‭interaction‬‭is‬‭a‬‭major‬
‭pathway‬‭hijacked‬‭by‬‭tumors‬‭to‬‭suppress‬‭immune‬‭control.‬‭The‬‭normal‬‭function‬‭of‬‭PD-1,‬‭expressed‬‭on‬
‭the‬‭cell‬‭surface‬‭of‬‭activated‬‭T‬‭cells‬‭under‬‭physiological‬‭conditions,‬‭is‬‭to‬‭down-modulate‬‭unwanted‬‭or‬
‭excessive‬‭immune‬‭responses,‬‭including‬‭autoimmune‬‭reactions.‬‭PD-1‬‭has‬‭been‬‭shown‬‭to‬‭negatively‬
‭regulate‬‭antigen‬‭receptor‬‭signaling‬‭upon‬‭engagement‬‭of‬‭its‬‭ligands‬‭(PD-L1‬‭and/or‬‭PD‬‭L2)‬‭[xviii]‬‭.‬‭These‬
‭ligands‬ ‭are‬‭constitutively‬‭expressed‬‭or‬‭can‬‭be‬‭induced‬‭in‬‭a‬‭variety‬‭of‬‭cell‬‭types,‬‭including‬‭various‬
‭tumors‬‭[xix],[xx],[xxi]‬‭.‬‭Binding‬‭of‬‭PD-1‬‭to‬‭its‬‭ligands‬‭inhibits‬‭T‬‭cell‬‭activation‬‭triggered‬‭through‬‭the‬‭T-cell‬
‭receptor.‬ ‭PD-L2‬‭is‬‭thought‬‭to‬‭control‬‭immune‬‭T-cell‬‭activation‬‭in‬‭lymphoid‬‭organs,‬‭whereas‬‭PD-L1‬
‭serves‬‭to‬‭dampen‬‭unwarranted‬‭T-cell‬‭function‬‭in‬‭peripheral‬‭tissues.‬‭A‬‭variety‬‭of‬‭cancers‬‭have‬‭been‬
‭shown‬‭to‬‭express‬‭abundant‬‭levels‬‭of‬‭this‬‭PD-L1.‬‭This‬‭suggests‬‭that‬‭the‬‭PD-1/PD-L1‬‭pathway‬‭plays‬‭a‬
‭critical role in tumor immune evasion and can be an attractive target for therapeutic intervention.‬
‭1.2.2.‬ ‭Preclinical experience with Nivolumab‬
‭In‬ ‭vitro,‬ ‭nivolumab‬ ‭(BMS-936558)‬ ‭binds‬ ‭to‬ ‭PD-1‬ ‭with‬‭high‬‭affinity‬‭(EC50‬‭0.39‬‭-‬‭2.62‬‭nM),‬‭and‬
‭inhibits‬ ‭the‬ ‭binding‬ ‭of‬ ‭PD-1‬ ‭to‬ ‭its‬ ‭ligands‬ ‭PD-L1‬ ‭and‬ ‭PD-L2‬ ‭(IC50:‬ ‭1‬ ‭nM).‬ ‭Nivolumab‬ ‭binds‬
‭specifically‬‭to‬‭PD-1‬‭and‬‭not‬‭to‬‭related‬‭members‬‭of‬‭the‬‭CD28‬‭family‬‭such‬‭as‬‭CD28,‬‭ICOS,‬‭CTLA-4,‬
‭and‬‭BTLA.‬‭Blockade‬‭of‬‭the‬‭PD-1‬‭pathway‬‭by‬‭nivolumab‬‭results‬‭in‬‭a‬‭reproducible‬‭enhancement‬‭of‬
‭both‬ ‭proliferation‬ ‭and‬ ‭IFN-γ‬ ‭release‬ ‭in‬ ‭the‬ ‭mixed‬ ‭lymphocyte‬ ‭reaction‬ ‭(MLR).‬ ‭Using‬ ‭a‬ ‭CMV‬
‭re-stimulation‬‭assay‬‭with‬‭human‬‭PBMC,‬‭the‬‭effect‬‭of‬‭nivolumab‬‭on‬‭antigen‬‭specific‬‭recall‬‭response‬
‭indicates‬ ‭that‬ ‭nivolumab‬ ‭augmented‬ ‭IFN-γ‬ ‭secretion‬ ‭from‬ ‭CMV‬ ‭specific‬ ‭memory‬ ‭T‬ ‭cells‬ ‭in‬ ‭a‬
‭dose-dependent‬‭manner‬‭versus‬‭isotype-matched‬‭control.‬‭In‬‭vivo‬‭blockade‬‭of‬‭PD-1‬‭by‬‭a‬‭murine‬‭analog‬
‭of‬ ‭nivolumab‬ ‭enhances‬ ‭the‬ ‭anti-tumor‬ ‭immune‬ ‭response‬ ‭and‬ ‭result‬ ‭in‬ ‭tumor‬ ‭rejection‬ ‭in‬ ‭several‬
‭immunocompetent mouse tumor models (MC38, SA1/N, and PAN02)‬‭[xxii]‬‭.‬
‭1.2.3.‬ ‭Clinical experience with Nivolumab in SCLC‬
‭In‬ ‭early‬ ‭clinical‬ ‭trials,‬ ‭nivolumab‬ ‭has‬ ‭demonstrated‬ ‭activity‬ ‭in‬ ‭several‬ ‭tumor‬ ‭types,‬ ‭including‬
‭melanoma, renal cell cancer (RCC), and NSCLC‬‭[xxiii]‬‭.‬
‭Nivolumab‬‭is‬‭now‬‭approved‬‭in‬‭the‬‭U.S.‬‭and‬‭Europe‬‭to‬‭treat‬‭different‬‭tumor‬‭types‬‭including:‬
‭melanoma‬‭(both‬‭adjuvant‬‭and‬‭metastatic‬‭setting),‬‭metastatic‬‭NSCLC‬‭in‬‭patients‬‭with‬‭progression‬‭on‬
‭or‬ ‭after‬ ‭platinum-based‬ ‭chemotherapy,‬ ‭advanced‬ ‭SCLC‬ ‭with‬ ‭progression‬ ‭after‬ ‭platinum-based‬
‭chemotherapy,‬‭advanced‬‭renal‬‭cell‬‭carcinoma,‬‭metastatic‬‭urothelial‬‭cancer‬‭and‬‭advanced‬‭squamous‬
‭cell carcinoma of head and neck‬‭[xxiv]‬‭.‬
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‭The‬ ‭approval‬ ‭in‬ ‭SCLC‬ ‭was‬ ‭based‬ ‭on‬ ‭the‬ ‭results‬ ‭of‬ ‭Checkmate-032‬ ‭[xxv]‬‭,‬ ‭This‬ ‭was‬ ‭a‬ ‭phase‬ ‭I/II‬
‭multicentre,‬‭multi-arm,‬‭open-label‬‭trial‬‭that‬‭included‬‭a‬‭cohort‬‭of‬‭216‬‭patients‬‭with‬‭SCLC.‬ ‭Patients‬
‭progressing‬ ‭after‬ ‭at‬ ‭least‬ ‭one‬ ‭platinum-containing‬ ‭therapy‬ ‭were‬‭allocated‬‭to‬‭three‬‭treatment‬‭arms:‬
‭nivolumab‬‭plus‬‭ipilimumab‬‭[1‬‭mg/kg‬‭+‬‭1‬‭mg/kg‬‭iv‬‭(n‬‭=‬‭3),‬‭1‬‭mg/kg‬‭+‬‭3‬‭mg/kg‬‭iv‬‭(n‬‭=‬‭61),‬‭and‬‭3‬
‭mg/kg‬‭+‬‭1‬‭mg/kg‬‭iv‬‭(n‬‭=‬‭54)]‬‭versus‬‭nivolumab‬‭monotherapy‬‭(3‬‭mg/kg‬‭iv)‬‭(n‬‭=‬‭98).‬‭Nivolumab‬‭plus‬
‭ipilimumab‬‭was‬‭administered‬‭every‬‭3‬‭weeks‬‭for‬‭four‬‭cycles‬‭followed‬‭by‬‭nivolumab‬‭3‬‭mg/kg‬‭iv‬‭every‬
‭other‬‭week.‬‭The‬‭primary‬‭endpoint‬‭was‬‭objective‬‭response‬‭per‬‭RECIST‬‭v1.1.‬‭Objective‬‭response‬‭was‬
‭achieved‬ ‭in‬ ‭14/61‬ ‭(23%)‬ ‭receiving‬ ‭nivolumab‬ ‭1‬ ‭mg/kg‬ ‭plus‬ ‭ipilimumab‬ ‭3‬ ‭mg/kg;‬ ‭10/54‬ ‭(19%)‬
‭receiving‬‭nivolumab‬‭3‬‭mg/kg‬‭plus‬‭ipilimumab‬‭1‬‭mg/kg,‬‭1/3‬‭(33%)‬‭receiving‬‭nivolumab‬‭1‬‭mg/kg‬‭plus‬
‭ipilimumab‬ ‭1‬ ‭mg/kg,‬ ‭and‬ ‭10/98‬ ‭(10%)‬ ‭patients‬ ‭in‬ ‭the‬ ‭nivolumab‬ ‭monotherapy‬ ‭arm.‬ ‭The‬ ‭median‬
‭duration‬‭of‬‭response‬‭was‬‭17.9‬‭months‬‭for‬‭nivolumab‬‭monotherapy,‬‭and‬‭14.2‬‭months‬‭with‬‭nivolumab‬‭1‬
‭mg/kg‬‭plus‬‭ipilimumab‬‭3‬‭mg/kg.‬‭Patients‬‭with‬‭ongoing‬‭responses‬‭at‬‭2‬‭years‬‭were‬‭45%‬‭for‬‭nivolumab‬
‭monotherapy‬ ‭and‬ ‭36%‬ ‭in‬ ‭the‬ ‭combination.‬ ‭Responses‬ ‭were‬ ‭observed‬ ‭regardless‬ ‭of‬ ‭platinum‬
‭sensitivity,‬‭line‬‭of‬‭therapy,‬‭or‬‭PD-L1‬‭status.‬‭Two-year‬‭OS‬‭rates‬‭were‬‭14%‬‭for‬‭nivolumab‬‭monotherapy‬
‭and‬ ‭26%‬ ‭in‬ ‭the‬ ‭combination‬ ‭arm,‬ ‭with‬ ‭a‬ ‭median‬ ‭OS‬ ‭of‬ ‭4.1‬ ‭(95%‬ ‭CI‬ ‭3.0–6.8)‬ ‭and‬ ‭7.8‬‭(95%‬‭CI‬
‭3.6–14.2),‬ ‭respectively.‬ ‭In‬ ‭a‬ ‭randomized,‬‭phase‬‭II‬‭cohort‬‭from‬‭CheckMate‬‭032‬‭to‬‭further‬‭evaluate‬
‭nivolumab‬ ‭±‬ ‭ipilimumab,‬ ‭the‬ ‭initial‬ ‭efficacy‬ ‭of‬ ‭242‬ ‭patients‬ ‭was‬ ‭consistent‬ ‭with‬ ‭that‬ ‭in‬ ‭the‬
‭non-randomized‬‭cohort‬‭[xxvi]‬‭.‬‭Grade‬‭≥‬‭3‬‭toxicities‬‭occurred‬‭in‬‭18/61‬‭(30%)‬‭in‬‭the‬‭nivolumab‬‭1‬‭mg/kg‬
‭plus‬‭ipilimumab‬‭3‬‭mg/kg‬‭group,‬‭10/54‬‭(19%)‬‭in‬‭the‬‭nivolumab‬‭3‬‭mg/kg‬‭plus‬‭ipilimumab‬‭1‬‭mg/kg,‬‭and‬
‭13/98‬‭(13%)‬‭in‬‭the‬‭nivolumab‬‭monotherapy.‬‭Six‬‭(6%)‬‭patients‬‭in‬‭the‬‭nivolumab‬‭3‬‭mg/kg‬‭group,‬‭seven‬
‭(11%)‬‭in‬‭the‬‭nivolumab‬‭1‬‭mg/kg‬‭plus‬‭ipilimumab‬‭3‬‭mg/kg‬‭group,‬‭and‬‭four‬‭(7%)‬‭in‬‭the‬‭nivolumab‬‭3‬
‭mg/kg‬ ‭plus‬ ‭ipilimumab‬ ‭1‬ ‭mg/kg‬ ‭group‬ ‭discontinued‬ ‭treatment‬ ‭due‬ ‭to‬ ‭treatments‬ ‭related‬ ‭adverse‬
‭events‬ ‭(TRAEs).‬ ‭Four‬ ‭patients‬ ‭who‬ ‭received‬ ‭nivolumab‬ ‭plus‬ ‭ipilimumab‬ ‭died‬ ‭from‬ ‭TRAEs‬
‭(myasthenia‬‭gravis,‬‭pneumonitis,‬‭encephalitis‬‭and‬‭hepatitis),‬‭and‬‭one‬‭patient‬‭who‬‭received‬‭nivolumab‬
‭monotherapy died from treatment-related pneumonitis.‬
‭Several‬ ‭trials‬ ‭are‬ ‭currently‬ ‭evaluating‬ ‭nivolumab‬ ‭±‬ ‭ipilimumab.‬ ‭Initial‬ ‭results‬ ‭from‬ ‭the‬
‭randomized‬ ‭phase‬‭III‬‭clinical‬‭trial‬‭Checkmate‬‭331(NCT02481830)‬‭evaluating‬‭the‬‭role‬‭of‬‭nivolumab‬
‭versus‬ ‭chemotherapy‬ ‭(topotecan‬ ‭or‬‭amrubicin)‬‭in‬‭patients‬‭with‬‭relapsed‬‭SCLC‬‭have‬‭been‬‭recently‬
‭presented‬‭showing‬‭no‬‭statistically‬‭significant‬‭improvement‬‭in‬‭OS‬‭with‬‭nivolumab‬‭vs‬‭chemotherapy‬
‭(HR,‬‭0.86‬‭[95%‬‭CI,‬‭0.72–1.04]);‬‭however‬‭OS‬‭curves‬‭showed‬‭delayed‬‭separation‬‭after‬‭month‬‭12.‬‭HR‬
‭for‬‭OS‬‭with‬‭nivolumab‬‭vs‬‭chemotherapy‬‭in‬‭patients‬‭with‬‭platinum-resistant‬‭SCLC‬‭was‬‭0.71‬‭(95%‬‭CI,‬
‭0.54–0.94)‬‭[xxvii]‬‭.‬
‭Checkmate‬ ‭451‬ ‭evaluated‬ ‭the‬ ‭role‬ ‭of‬ ‭nivolumab‬ ‭alone,‬ ‭nivolumab‬ ‭1‬ ‭mg/kg‬ ‭in‬ ‭combination‬ ‭with‬
‭ipilimumab‬ ‭3‬ ‭mg/kg,‬ ‭or‬ ‭placebo‬ ‭as‬ ‭consolidation/maintenance‬ ‭therapy‬ ‭after‬ ‭completion‬ ‭of‬
‭platinum-based‬ ‭first-line‬ ‭chemotherapy‬ ‭in‬ ‭patients‬ ‭with‬ ‭extended‬ ‭disease‬ ‭SCLC.‬ ‭The‬ ‭primary‬
‭endpoint‬‭of‬‭OS‬‭has‬‭not‬‭been‬‭met‬‭[xxviii]‬‭.‬ ‭Results‬‭from‬‭a‬‭phase‬‭II‬‭trial‬‭of‬‭consolidation‬‭with‬‭nivolumab‬
‭and‬
‭ipilimumab‬
‭in‬ ‭localized‬ ‭SCLC‬ ‭after‬ ‭chemo-radiotherapy‬ ‭are‬ ‭pending‬ ‭(STIMULI,‬
‭NCT02046733)‬‭[xxix]‬‭.‬
‭In‬ ‭general,‬ ‭nivolumab‬ ‭has‬ ‭been‬ ‭well‬ ‭tolerated‬ ‭to‬ ‭date,‬ ‭with‬ ‭a‬ ‭favorable‬ ‭safety‬ ‭profile‬ ‭relative‬‭to‬
‭anticipated toxicities based on an immunostimulatory mechanism of action.‬
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‭1.2.4.‬ ‭Immune checkpoint inhibitors in other high grade NENs‬
‭Further‬‭research‬‭of‬‭these‬‭therapeutic‬‭strategies‬‭in‬‭other‬‭types‬‭of‬‭high‬‭grade‬‭NENs,‬‭such‬‭as‬
‭Merkel‬ ‭cell‬ ‭carcinomas‬ ‭(MCC),‬ ‭has‬ ‭also‬ ‭proven‬ ‭to‬ ‭be‬ ‭highly‬ ‭effective‬ ‭both‬ ‭in‬ ‭chemonaive‬ ‭and‬
‭pretreated‬‭patients.‬‭In‬‭a‬‭multicenter‬‭phase‬‭2‬‭trial,‬‭patients‬‭with‬‭advanced‬‭MCC‬‭who‬‭had‬‭received‬‭no‬
‭previous‬‭systemic‬‭therapy‬‭were‬‭assigned‬‭to‬‭receive‬‭pembrolizumab‬‭at‬‭a‬‭dose‬‭of‬‭2‬‭mg‬‭per‬‭kilogram‬
‭every‬ ‭3‬ ‭weeks.‬ ‭The‬ ‭primary‬‭endpoint‬‭was‬‭the‬‭objective‬‭response‬‭rate‬‭(ORR).‬‭Twenty-six‬‭patients‬
‭were‬‭treated‬‭with‬‭pembrolizumab,‬‭with‬‭an‬‭ORR‬‭of‬‭56%‬‭(95%‬‭confidence‬‭interval‬‭[CI],‬‭35‬‭–‬‭76%)‬‭and‬
‭a‬‭rate‬‭of‬‭progression‬‭free‬‭survival‬‭at‬‭6‬‭months‬‭of‬‭67%‬ ‭[xxx]‬‭.‬‭Avelumab,‬‭an‬‭anti-PD-L1‬‭monoclonal‬
‭antibody,‬‭also‬‭showed‬‭efficacy‬‭in‬‭MCC‬‭refractory‬‭to‬‭chemotherapy‬‭in‬‭a‬‭phase‬‭II‬‭trial‬‭that‬‭enrolled‬‭88‬
‭patients‬ ‭with‬ ‭advanced‬ ‭disease.‬‭Responses‬‭were‬‭achieved‬‭in‬‭32%‬‭of‬‭patients,‬‭82%‬‭of‬‭which‬‭were‬
‭maintained‬‭at‬‭10‬‭months‬‭of‬‭follow-up‬‭time.‬‭Grade‬‭3‬‭treatment-related‬‭events‬‭occurred‬‭in‬‭only‬‭5%‬‭of‬
‭patients‬‭with‬‭no‬‭grade‬‭4‬‭events‬‭described‬ ‭[xxxi]‬‭.‬‭These‬‭promising‬‭results‬‭represent‬‭a‬‭new‬‭therapeutic‬
‭option‬‭for‬‭advanced‬‭MCC‬‭and‬‭open‬‭a‬‭new‬‭path‬‭for‬‭future‬‭clinical‬‭trials‬‭in‬‭G3‬‭NENs.‬‭In‬‭SCLC,‬‭which‬
‭shares‬ ‭many‬ ‭histopathological‬ ‭and‬ ‭biological‬ ‭features‬ ‭with‬ ‭extrapulmonary‬ ‭high‬ ‭grade‬ ‭NEN,‬
‭Nivolumab‬ ‭has‬ ‭recently‬ ‭shown‬ ‭clinical‬ ‭activity‬ ‭in‬‭a‬‭phase‬‭I/II‬‭study‬‭of‬‭SCLC‬‭patients‬‭previously‬
‭treated‬‭with‬‭platinum-based‬‭chemotherapy‬‭[xxxii]‬‭.‬‭An‬‭objective‬‭response‬‭rate‬‭of‬‭18%‬‭was‬‭documented‬
‭in‬ ‭40‬ ‭patients‬ ‭treated‬ ‭with‬ ‭nivolumab‬ ‭monotherapy.‬ ‭Pembrolizumab‬ ‭has‬ ‭also‬ ‭recently‬ ‭showed‬
‭promising‬ ‭activity‬ ‭in‬ ‭a‬ ‭phase‬ ‭IB‬ ‭study‬ ‭of‬ ‭20‬ ‭patients‬ ‭who‬ ‭had‬ ‭received‬ ‭prior‬ ‭platinum-based‬
‭combination‬ ‭chemotherapy‬ ‭[xxxiii]‬‭.‬ ‭Preliminary‬ ‭results‬ ‭reported‬ ‭objective‬ ‭responses‬ ‭in‬ ‭35%‬ ‭of‬ ‭the‬
‭treated‬‭patients.‬‭Nivolumab‬‭has‬‭also‬‭been‬‭tested‬‭in‬‭a‬‭cohort‬‭of‬‭25‬‭patients‬‭with‬‭advanced‬‭MCC‬‭within‬
‭the‬‭CheckMate‬‭358‬‭trial‬‭(NCT02488759)‬‭[xxxiv]‬‭.‬‭Preliminary‬‭results‬‭have‬‭reported‬‭an‬‭overall‬‭response‬
‭rate‬ ‭of‬ ‭68%‬ ‭in‬ ‭22‬ ‭evaluable‬ ‭patients.‬ ‭Responses‬ ‭occurred‬ ‭in‬ ‭both‬ ‭treatment-naïve‬ ‭(71%)‬ ‭and‬
‭-experienced‬‭(63%)‬‭patients,‬‭regardless‬‭of‬‭tumor‬‭MCPyV‬‭or‬‭PD-L1‬‭expression.‬‭Expansion‬‭cohorts‬
‭will evaluate combinations of nivolumab with ipilimumab or anti-LAG-3.‬
‭More‬‭recently,‬‭initial‬‭results‬‭from‬‭an‬‭open-label,‬‭phase‬‭1b‬‭trial‬‭evaluating‬‭the‬‭efficacy‬‭and‬
‭safety‬ ‭of‬ ‭JS001‬ ‭on‬ ‭advanced‬ ‭NENs‬ ‭with‬ ‭high‬ ‭proliferative‬ ‭index‬ ‭(Ki67>10%)‬ ‭who‬‭had‬‭failed‬‭to‬
‭standard‬‭therapy,‬‭have‬‭been‬‭presented.‬‭JS001‬‭is‬‭a‬‭monoclonal‬‭humanized‬‭IgG4‬‭PD-1‬‭antibody‬‭with‬‭a‬
‭hinge‬‭S228P‬‭mutation‬‭that‬‭completely‬‭blocks‬‭PD-1‬‭interactions‬‭with‬‭PD-L1‬‭and‬‭PD-L2.‬‭A‬‭total‬‭of‬‭35‬
‭patients‬‭were‬‭enrolled,‬‭with‬‭a‬‭majority‬‭of‬‭NECs‬‭(n=28).‬‭An‬‭encouraging‬‭18%‬‭overall‬‭response‬‭rate‬
‭and‬ ‭25%‬ ‭disease‬ ‭control‬ ‭rate‬ ‭was‬ ‭achieved‬ ‭in‬ ‭NECs,‬ ‭with‬ ‭a‬ ‭50%‬ ‭response‬ ‭rate‬ ‭in‬ ‭patients‬ ‭with‬
‭PD1-positive‬‭tumors,‬ ‭and‬‭the‬‭median‬‭OS‬‭had‬‭not‬‭been‬‭reached.‬‭JS001‬‭was‬‭tolerable‬‭in‬‭patients‬‭with‬
‭NENs‬ ‭with‬ ‭<3%‬ ‭of‬ ‭severe‬ ‭adverse‬ ‭events‬ ‭[xxxv]‬‭.‬ ‭Other‬ ‭checkpoint‬ ‭inhibitors‬ ‭have‬ ‭not‬ ‭shown‬
‭significant‬ ‭activity‬ ‭as‬ ‭monotherapy‬ ‭in‬ ‭G3‬‭heavily‬‭pretreated‬‭NEN‬‭(i.e.‬‭pembrolizumab,‬‭PDR001).‬
‭Currently,‬‭ongoing‬‭trials‬‭are‬‭evaluating‬‭the‬‭role‬‭of‬‭these‬‭immunomodulating‬‭agents‬‭as‬‭maintenance‬
‭treatment‬ ‭at‬ ‭earlier‬ ‭stages‬ ‭of‬ ‭disease,‬ ‭and‬ ‭in‬ ‭combination‬ ‭with‬ ‭different‬ ‭therapeutic‬ ‭strategies‬
‭including chemotherapy.‬
‭1.2.5.‬ ‭Chemotherapy in combination with immune checkpoint inhibitors‬
‭There‬ ‭is‬ ‭increasing‬ ‭evidence‬ ‭suggesting‬ ‭that‬ ‭chemotherapy‬‭not‬‭only‬‭has‬‭antitumor‬‭activity‬‭due‬‭to‬
‭cytotoxic‬‭effects,‬‭but‬‭also‬‭through‬‭immunological‬‭effects,‬‭including‬‭reducing‬‭T-regulatory‬‭cell‬‭activity‬
‭and‬‭enhancing‬‭cross-presentation‬‭of‬‭tumour‬‭antigens‬‭[xxxvi],[xxxvii]‬‭.‬‭Chemotherapy‬‭has‬‭also‬‭been‬‭shown‬
‭to‬ ‭induce‬ ‭PD-L1‬ ‭expression‬ ‭on‬ ‭tumour‬ ‭cells.‬ ‭Therefore,‬ ‭combining‬ ‭immunotherapy‬ ‭and‬
‭chemotherapy‬ ‭could‬ ‭synergistically‬ ‭improve‬ ‭the‬ ‭anticancer‬ ‭activity‬ ‭of‬ ‭anti-PD-1‬ ‭and‬ ‭anti-PD-L1‬
‭monotherapy.‬
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‭Results‬‭from‬‭PD-1‬‭inhibitors‬‭in‬‭combination‬‭with‬‭platinum-based‬‭chemotherapy‬‭in‬‭first‬‭line‬
‭phase‬‭Ib/II‬‭trials‬‭have‬‭shown‬‭promising‬‭results‬‭in‬‭NSCLC.‬‭A‬‭phase‬‭I‬‭multicohort‬‭study‬‭was‬‭conducted‬
‭to‬ ‭explore‬ ‭the‬ ‭efficacy‬ ‭and‬ ‭safety‬ ‭of‬ ‭nivolumab‬ ‭in‬ ‭combination‬ ‭with‬ ‭standard‬ ‭chemotherapy‬ ‭in‬
‭first-line‬‭NSCLC‬ ‭[xxxviii]‬‭.‬‭56‬‭patients‬‭were‬‭assigned‬‭by‬‭histology‬‭to‬‭receive‬‭nivolumab‬‭10‬‭mg/kg‬‭iv‬
‭every‬ ‭3‬ ‭weeks‬ ‭plus‬ ‭gemcitabine‬ ‭and‬ ‭cisplatin‬ ‭(squamous)‬ ‭or‬ ‭pemetrexed‬ ‭plus‬ ‭cisplatin‬
‭(non-squamous)‬ ‭or‬ ‭nivolumab‬ ‭5‬ ‭or‬ ‭10‬ ‭mg/kg‬ ‭plus‬‭carboplatin-paclitaxel‬‭(all‬‭histologies).‬‭Patients‬
‭received‬‭the‬‭combination‬‭treatment‬‭for‬‭four‬‭cycles‬‭followed‬‭by‬‭nivolumab‬‭alone‬‭until‬‭progression‬‭or‬
‭unacceptable‬ ‭toxicity.‬ ‭No‬ ‭dose-limiting‬ ‭toxicities‬ ‭(DLTs)‬ ‭occurred‬ ‭during‬ ‭the‬ ‭first‬ ‭6‬ ‭weeks‬ ‭of‬
‭treatment.‬‭Consistent‬‭with‬‭previous‬‭reports‬‭for‬‭immune‬‭checkpoint‬‭inhibitors‬‭monotherapy,‬‭grade‬‭3-4‬
‭treatment-related‬‭adverse‬‭events‬‭were‬‭reported‬‭in‬‭45%‬‭of‬‭patients.‬‭ORR‬‭were‬‭33%,‬‭47%,‬‭47%‬‭and‬
‭43%‬
‭for‬
‭nivolumab‬ ‭10‬ ‭mg/kg‬ ‭plus‬ ‭gemcitabine-cisplatin,‬ ‭nivolumab‬ ‭10‬ ‭mg/kg‬ ‭plus‬
‭pemetrexed-cisplatin,‬‭nivolumab‬‭10‬‭mg/kg‬‭plus‬‭paclitaxel-carboplatin,‬‭and‬‭nivolumab‬‭5‬‭mg/kg‬‭plus‬
‭paclitaxel-carboplatin‬‭respectively.‬‭Responses‬‭were‬‭achieved‬‭regardless‬‭of‬‭tumor‬‭programmed‬‭death‬
‭ligand-1‬‭expression.‬‭The‬‭safety‬‭profile‬‭of‬‭nivolumab‬‭was‬‭consistent‬‭with‬‭that‬‭expected‬‭for‬‭individual‬
‭agents with no particular concerns.‬
‭Recently,‬‭the‬‭international,‬‭multicohort,‬‭phase‬‭1/2‬‭KEYNOTE-021‬‭study‬‭assessed‬‭the‬‭safety‬
‭and‬ ‭anti-tumour‬ ‭activity‬ ‭of‬ ‭pembrolizumab‬ ‭added‬ ‭to‬ ‭three‬‭different‬‭platinum-based‬‭chemotherapy‬
‭doublets‬‭in‬‭patients‬‭with‬‭advanced‬‭NSCLC‬ ‭[xxxix]‬‭.‬‭Chemotherapy-naïve‬‭NSCLC‬‭pts‬‭were‬‭randomly‬
‭assigned‬‭to‬‭pembrolizumab‬‭2‬‭or‬‭10‬‭mg/kg‬‭every‬‭3‬‭weeks‬‭plus‬‭carboplatin‬‭(AUC‬‭6)‬‭+‬‭paclitaxel‬‭200‬
‭mg/m2‬ ‭(any‬ ‭histology)‬‭or‬‭carboplatin‬‭(AUC‬‭6)‬‭+‬‭paclitaxel‬‭200‬‭mg/m2‬‭+‬‭bevacizumab‬‭15‬‭mg/kg‬
‭(non-squamous)‬ ‭or‬ ‭carboplatin‬ ‭(AUC‬ ‭5)‬‭plus‬‭pemetrexed‬‭500‬‭mg/m2‬‭(nonsquamous)‬‭for‬‭4‬‭cycles‬
‭followed‬ ‭by‬ ‭maintenance‬ ‭treatment‬ ‭with‬ ‭pembrolizumab,‬ ‭pembrolizumab‬ ‭+‬ ‭bevacizumab‬ ‭or‬
‭pembrolizumab‬ ‭plus‬ ‭pemetrexed‬ ‭respectively.‬ ‭Seventy-four‬ ‭pts‬ ‭were‬ ‭included‬ ‭in‬ ‭the‬ ‭study.‬ ‭All‬
‭combinations‬‭showed‬‭promising‬‭anti-tumour‬‭activity‬‭irrespective‬‭of‬‭tumour‬‭PD-L1‬‭expression,‬‭with‬
‭manageable‬‭safety‬‭profiles.‬‭One‬‭DLT‬‭occurred‬‭in‬‭cycle‬‭1‬‭(grade‬‭3‬‭rash).‬‭Grade‬‭3-4‬‭treatment-related‬
‭AEs‬‭occurred‬‭in‬‭36%,‬‭46%‬‭and‬‭42%‬‭of‬‭pts‬‭in‬‭each‬‭cohort‬‭respectively.‬‭Most‬‭common‬‭AEs‬‭were‬‭AST‬
‭elevation‬ ‭(n=3),‬ ‭anemia‬ ‭(n=2),‬ ‭neutropenia‬ ‭(n=2)‬ ‭and‬ ‭febrile‬ ‭neutropenia‬ ‭(n=2).‬ ‭Based‬ ‭on‬ ‭these‬
‭results,‬ ‭123‬ ‭patients‬ ‭with‬ ‭advanced‬ ‭chemotherapy-naïve‬ ‭NSCLC‬ ‭were‬ ‭randomized‬ ‭(1:1)‬ ‭in‬ ‭an‬
‭open-label‬‭phase‬‭II‬‭trial‬‭to‬‭four‬‭cycles‬‭of‬‭carboplatin‬‭(AUC‬‭5)‬‭plus‬‭pemetrexed‬‭500‬‭mg/m2‬‭iv‬‭every‬
‭three‬‭weeks‬‭alone‬‭or‬‭in‬‭combination‬‭with‬‭pembrolizumab‬‭200‬‭mg‬‭iv,‬‭flat‬‭dose,‬‭every‬‭three‬‭weeks,‬
‭followed‬ ‭by‬ ‭maintenance‬ ‭with‬ ‭pembrolizumab‬ ‭for‬ ‭24‬ ‭months‬ ‭and‬ ‭pemetrexed‬ ‭until‬ ‭progressive‬
‭disease‬‭or‬‭unacceptable‬‭toxicity.‬‭Patients‬‭were‬‭stratified‬‭according‬‭to‬‭PD-L1‬‭expression‬‭(<1%‬‭vs‬‭≥‬
‭1%).‬ ‭55%‬‭of‬‭patients‬‭in‬‭the‬‭pembrolizumab‬‭plus‬‭chemotherapy‬‭group‬‭achieved‬‭an‬‭objective‬‭response‬
‭compared‬‭with‬‭29%‬‭in‬‭the‬‭chemotherapy‬‭alone‬‭group‬‭(p=0.0016).‬‭The‬‭incidence‬‭of‬‭grade‬‭3‬‭or‬‭worse‬
‭treatment-related‬ ‭adverse‬ ‭events‬ ‭was‬ ‭similar‬ ‭between‬ ‭both‬ ‭arms‬‭occurring‬‭in‬‭23‬‭pts‬‭(39%)‬‭in‬‭the‬
‭pembrolizumab‬‭plus‬‭chemotherapy‬‭arm‬‭and‬‭16‬‭(26%)‬‭in‬‭the‬‭chemotherapy‬‭alone‬‭arm.‬ ‭Most‬‭common‬
‭grade‬ ‭3‬ ‭or‬ ‭worse‬‭treatment-related‬‭adverse‬‭events‬‭were‬‭anaemia‬‭(12%‬‭in‬‭the‬‭pembrolizumab‬‭plus‬
‭chemotherapy‬‭group‬‭vs‬‭15%‬‭in‬‭the‬‭chemotherapy‬‭alone‬‭group),‬‭decreased‬‭neutrophil‬‭count‬‭(5%‬‭vs‬
‭3%),‬‭thrombocytopenia‬‭(3%‬‭in‬‭both‬‭arms)‬‭and‬‭decreased‬‭lymphocyte‬‭count,‬‭neutropenia,‬‭and‬‭sepsis‬
‭(3%‬‭vs‬‭2%‬‭each).‬‭The‬‭incidence‬‭of‬‭adverse‬‭events‬‭based‬‭on‬‭a‬‭presumed‬‭immunological‬‭mechanism‬‭of‬
‭action,‬‭was‬‭22%‬‭in‬‭the‬‭pembrolizumab‬‭plus‬‭chemotherapy‬‭group‬‭and‬‭11%‬‭in‬‭the‬‭chemotherapy‬‭group.‬
‭The‬ ‭only‬ ‭events‬ ‭of‬ ‭grade‬ ‭3‬ ‭or‬ ‭worse‬ ‭were‬ ‭one‬ ‭infusion‬‭reaction‬‭(2%‬‭in‬‭the‬‭pembrolizumab‬‭plus‬
‭chemotherapy‬‭group‬‭vs‬‭none‬‭in‬‭the‬‭chemotherapy‬‭alone‬‭group),‬‭grade‬‭3‬‭skin‬‭reaction‬‭(one‬‭[2%]‬‭in‬‭the‬
‭pembrolizumab‬ ‭plus‬ ‭chemotherapy‬ ‭group‬ ‭vs‬ ‭one‬ ‭[2%]‬ ‭in‬ ‭the‬ ‭chemotherapy‬ ‭group,‬ ‭and‬ ‭grade‬ ‭3‬
‭pneumonitis‬‭(one‬‭[2%]‬‭in‬‭the‬‭pembrolizumab‬‭plus‬‭chemotherapy‬‭group).‬‭Deaths‬‭attributed‬‭to‬‭study‬
‭treatment‬‭occurred‬‭in‬‭one‬‭patient‬‭(1%)‬‭in‬‭the‬‭pembrolizumab‬‭plus‬‭chemotherapy‬‭group‬‭due‬‭to‬‭sepsis‬
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‭and‬‭two‬‭patients‬‭(3%)‬‭in‬‭the‬‭chemotherapy‬‭alone‬‭group‬‭(pancytopenia‬‭and‬‭sepsis).‬‭This‬‭study‬‭showed‬
‭that‬ ‭the‬ ‭combination‬ ‭of‬ ‭pembrolizumab‬ ‭and‬ ‭platinum‬ ‭chemotherapy‬ ‭could‬ ‭be‬ ‭an‬ ‭effective‬ ‭and‬
‭tolerable first-line treatment option for patients with NSCLC‬‭[xl]‬‭.‬
‭Furthermore,‬‭a‬‭recently‬‭published‬‭clinical‬‭trial‬‭assessing‬‭atezolizumab‬‭in‬‭combination‬‭with‬
‭different‬‭platinum-doublets‬‭in‬‭patients‬‭with‬‭newly‬‭diagnosed‬‭metastatic‬‭NSCLC‬‭showed‬‭encouraging‬
‭efficacy.‬‭Seventy-six‬‭NSCLC‬‭patients‬‭were‬‭enrolled‬‭and‬‭assigned‬‭to‬‭three‬‭different‬‭treatment‬‭arms:‬
‭atezolizumab‬‭plus‬‭carboplatin‬‭and‬‭paclitaxel‬‭(Arm‬‭C),‬‭atezolizumab‬‭plus‬‭carboplatin‬‭and‬‭pemetrexed‬
‭(Arm‬ ‭D)‬ ‭or‬ ‭atezolizumab‬‭plus‬‭carboplatin‬‭and‬‭nab-paclitaxel‬‭(Arm‬‭E).‬‭Common‬‭treatment-related‬
‭grade‬ ‭3-4‬‭adverse‬‭events‬‭were‬‭neutropenia‬‭(36%‬‭Arm‬‭C,‬‭36%‬‭Arm‬‭D,‬‭42%‬‭Arm‬‭E)‬‭and‬‭anaemia‬
‭(16%‬‭Arm‬‭C,‬‭16%‬‭Arm‬‭D,‬‭31%‬‭Arm‬‭E).‬‭Confirmed‬‭ORRs‬‭were‬‭36%‬‭Arm‬‭C,‬‭68%‬‭Arm‬‭D‬‭(one‬‭CR)‬
‭and‬‭46%‬‭Arm‬‭E‬‭(four‬‭CRs).‬‭Median‬‭PFS‬‭was‬‭7.1‬‭months,‬‭(95%‬‭CI:‬‭4.2-8.3),‬‭8.4‬‭months‬‭(95%‬‭CI:‬
‭4.7-11)‬ ‭and‬ ‭5.7‬ ‭months‬ ‭(95%‬ ‭CI:‬ ‭4.4-14.8),‬ ‭respectively.‬ ‭Median‬ ‭OS‬ ‭was‬‭12.9‬‭months‬‭(95%‬‭CI:‬
‭8.8-21.3),‬ ‭18.9‬ ‭months‬ ‭(95%‬ ‭CI:‬ ‭9.9-27.4)‬ ‭and‬ ‭17.0‬ ‭months‬ ‭(95%‬ ‭CI:‬ ‭12.7-not‬ ‭evaluable),‬
‭respectively.‬ ‭Atezolizumab‬ ‭was‬ ‭well‬ ‭tolerated‬ ‭in‬ ‭combination‬ ‭with‬ ‭all‬ ‭chemotherapy‬ ‭regimens‬
‭tested‬‭[xli],[xlii]‬‭.‬
‭Currently‬ ‭several‬ ‭phase‬ ‭Ib/II‬ ‭trials‬ ‭evaluating‬ ‭the‬ ‭combination‬ ‭of‬ ‭immune‬ ‭checkpoint‬
‭inhibitors plus chemotherapy are ongoing.‬
‭1.2.6.‬ ‭Potential for drug-drug interactions‬
‭Given‬‭nivolumab‬‭is‬‭a‬‭therapeutic‬‭monoclonal‬‭antibody,‬‭it‬‭is‬‭not‬‭anticipated‬‭to‬‭be‬‭directly‬‭eliminated‬
‭through‬‭hepatic/renal‬‭metabolism‬‭to‬‭compete‬‭with‬‭the‬‭elimination‬‭of‬‭platinum-doublet‬‭chemotherapy‬
‭agents, which are mainly eliminated through metabolism and renal excretion.‬
‭As‬‭nivolumab‬‭is‬‭not‬‭considered‬‭a‬‭cytokine‬‭modulator,‬‭it‬‭is‬‭unlikely‬‭to‬‭have‬‭an‬‭effect‬‭on‬‭drug‬
‭metabolizing‬‭enzymes‬‭or‬‭transporters‬‭in‬‭terms‬‭of‬‭inhibition‬‭or‬‭induction‬‭such‬‭as‬‭cytochrome‬‭P450‬
‭(CYP)‬ ‭enzymes.‬ ‭Therefore‬ ‭the‬ ‭risk‬ ‭of‬ ‭drug-drug‬ ‭interactions‬ ‭between‬ ‭nivolumab‬ ‭and‬
‭platinum-doublet chemotherapy agents is anticipated to be low.‬
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‭2.‬
‭Objectives and Endpoints of the trial‬
‭The objectives and endpoints of the trial are summarized in Table 2-1.‬
‭2.1.‬
‭Primary objective‬
‭●‬ ‭To‬ ‭determine‬ ‭the‬ ‭efficacy‬ ‭of‬ ‭nivolumab‬ ‭in‬ ‭combination‬ ‭with‬ ‭platinum-chemotherapy‬ ‭in‬
‭patients‬ ‭with‬ ‭high‬‭grade‬‭neuroendocrine‬‭neoplasms,‬‭evaluated‬‭as‬‭one-year‬‭overall‬‭survival‬
‭(OS)‬ ‭rate‬ ‭calculated‬ ‭from‬ ‭the‬‭date‬‭of‬‭treatment‬‭initiation‬‭until‬‭the‬‭date‬‭of‬‭death‬‭from‬‭any‬
‭cause.‬
‭2.2.‬
‭Secondary Objectives‬
‭●‬ ‭To‬ ‭determine‬ ‭overall‬ ‭response‬ ‭rate‬ ‭(ORR)‬ ‭as‬ ‭per‬ ‭Response‬ ‭Evaluation‬ ‭Criteria‬ ‭in‬ ‭Solid‬
‭Tumors version 1.1 (RECIST v1.1) and the immune-related RECIST (irRECIST).‬
‭●‬ ‭To‬‭determine‬‭progression‬‭free‬‭survival‬‭(PFS)‬‭calculated‬‭from‬‭the‬‭date‬‭of‬‭treatment‬‭initiation‬
‭with‬ ‭first-line‬ ‭chemotherapy‬ ‭and‬ ‭nivolumab‬ ‭until‬ ‭the‬ ‭date‬ ‭of‬ ‭first‬ ‭documentation‬ ‭of‬
‭progressive disease as per RECIST v1.1 or death.‬
‭●‬ ‭To‬ ‭determine‬ ‭the‬ ‭OS‬ ‭calculated‬ ‭from‬ ‭the‬ ‭date‬ ‭of‬‭treatment‬‭initiation‬‭with‬‭nivolumab‬‭and‬
‭platinum-based chemotherapy until the date of death from any cause.‬
‭●‬ ‭To‬‭assess‬‭biochemical‬‭response‬‭in‬‭patients‬‭with‬‭baseline‬‭elevation‬‭of‬‭chromogranin‬‭A‬‭and/or‬
‭enolase, and correlate it with clinical outcome.‬
‭●‬ ‭To‬‭assess‬‭the‬‭safety‬‭and‬‭toxicity‬‭profile‬‭of‬‭nivolumab‬‭in‬‭combination‬‭with‬‭platinum-doublets‬
‭in‬‭this‬‭patient‬‭population‬‭according‬‭to‬‭the‬‭Common‬‭Terminology‬‭Criteria‬‭for‬‭Adverse‬‭Events‬
‭v.5.0 (CTCAE).‬
‭●‬ ‭To explore potential predictive or prognostic blood or tissue biomarkers.‬
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‭Objectives‬
‭Endpoints‬
‭Primary‬
‭●‬ ‭To‬ ‭determine‬ ‭the‬ ‭overall‬ ‭survival‬
‭patients‬ ‭with‬ ‭advanced‬ ‭G3‬ ‭NENs‬
‭treated‬
‭with‬
‭nivolumab‬
‭+‬
‭platinum-based chemotherapy.‬
‭●‬ ‭1 year-OS rate‬
‭Secondary‬
‭●‬ ‭To‬
‭determine‬
‭other‬
‭efficacy‬
‭outcomes‬
‭of‬
‭nivolumab‬
‭+‬
‭platinum-based‬ ‭chemotherapy‬ ‭in‬
‭patients with advanced G3 NENs.‬
‭●‬ ‭ORR‬
‭●‬ ‭Duration of response‬
‭●‬ ‭PFS‬
‭●‬ ‭OS‬
‭●‬ ‭To‬
‭evaluate‬
‭the‬
‭safety‬
‭and‬
‭tolerability‬
‭of‬
‭nivolumab‬
‭+‬
‭platinum-based‬ ‭chemotherapy‬ ‭in‬
‭this patient population.‬
‭●‬ ‭Incidence‬ ‭of‬ ‭AEs,‬ ‭SAEs‬ ‭and‬ ‭selected‬
‭AEs‬
‭●‬ ‭To‬‭evaluate‬‭biochemical‬‭response‬‭as‬
‭predictive‬ ‭biomarker‬ ‭of‬‭efficacy‬‭of‬
‭nivolumab‬ ‭+‬ ‭chemotherapy‬ ‭in‬ ‭this‬
‭patient population..‬
‭●‬ ‭Chromogranin‬ ‭A‬ ‭and‬ ‭enolase‬ ‭values‬
‭and‬ ‭their‬ ‭association‬ ‭with‬ ‭ORR,‬ ‭PFS‬
‭and OS.‬
‭●‬ ‭To‬ ‭explore‬ ‭potential‬‭predictive‬‭and‬
‭prognostic biomarkers.‬
‭●‬ ‭Mutational‬ ‭burden,‬ ‭gene‬ ‭expression‬
‭signature,‬ ‭soluble‬ ‭factors‬ ‭and‬ ‭other‬
‭molecular‬ ‭markers‬‭in‬‭peripheral‬‭blood‬
‭and‬ ‭their‬ ‭association‬ ‭with‬ ‭clinical‬
‭outcomes.‬
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‭3.‬
‭Study Design‬
‭3.1.‬
‭Overall Design‬
‭This‬ ‭is‬ ‭a‬ ‭multi-center‬ ‭phase‬ ‭II‬ ‭non-randomized,‬ ‭open-label‬ ‭trial‬ ‭investigating‬ ‭platinum-doublet‬
‭chemotherapy‬‭in‬‭combination‬‭with‬‭nivolumab‬‭in‬‭patients‬‭with‬‭advanced‬‭G3‬‭NENs‬‭of‬‭GEP‬‭or‬‭UK‬
‭origin‬ ‭followed‬ ‭by‬ ‭maintenance‬ ‭treatment‬ ‭with‬‭nivolumab‬‭for‬‭up‬‭to‬‭2‬‭years‬‭in‬‭patients‬‭who‬‭have‬
‭achieved‬‭complete‬‭response‬‭(CR),‬‭partial‬‭response‬‭(PR)‬‭or‬‭stable‬‭disease‬‭(SD)‬‭after‬‭6‬‭months‬‭of‬‭first‬
‭line platinum-based induction chemotherapy with nivolumab.‬
‭All participants will be treated as described below:‬
‭●‬ ‭6‬‭cycles‬‭of‬‭chemotherapy‬‭(carboplatin‬‭(AUC=‬‭5)‬‭iv‬‭on‬‭day‬‭1‬‭and‬‭etoposide‬‭100‬‭mg/m2/day‬‭iv‬
‭on‬‭days‬‭1-3,‬‭administered‬‭every‬‭3‬‭weeks)‬‭in‬‭combination‬‭with‬‭nivolumab‬‭360‬‭mg‬‭iv‬‭q3w‬‭(flat‬
‭dose).‬
‭●‬ ‭In‬ ‭the‬‭absence‬‭of‬‭disease‬‭progression,‬‭nivolumab‬‭treatment‬‭will‬‭be‬‭continued‬‭until‬‭disease‬
‭progression,‬ ‭unacceptable‬ ‭toxicity,‬ ‭death,‬ ‭withdrawal‬ ‭of‬‭consent,‬‭or‬‭a‬‭maximum‬‭treatment‬
‭duration‬ ‭of‬ ‭2‬ ‭years,‬ ‭whichever‬ ‭occurs‬ ‭first.‬ ‭Participants‬ ‭will‬ ‭be‬ ‭permitted‬ ‭to‬ ‭continue‬‭on‬
‭nivolumab‬‭beyond‬‭initial‬‭RECIST‬‭1.1‬‭defined‬‭progression,‬‭as‬‭long‬‭as‬‭they‬‭meet‬‭the‬‭criteria‬
‭described in‬‭section 5.3.1‬
‭The study design schematic is presented in Figure‬‭3.1-1‬
‭Figure 3.1-1‬
‭3.1.1.‬ ‭Data Monitoring Committee and Other External Committees‬
‭A Data Monitoring Committee (DMC) will not be required for this study, considering the following:‬
‭1.‬ ‭This study is an open-label study.‬
‭2.‬ ‭Data‬‭from‬‭the‬‭Checkmate-012‬‭study‬‭has‬‭demonstrated‬‭a‬‭favourable‬‭and‬‭manageable‬‭safety‬
‭profile that is consistent with prior experience with these agents.‬
‭3.‬ ‭Safety‬‭data‬‭will‬‭be‬‭closely‬‭monitored‬‭by‬‭BMS‬‭and‬‭the‬‭pharmacovigilance‬‭team‬‭of‬‭MFAR,‬
‭with‬‭real‬‭time‬‭review‬‭and‬‭assessment‬‭of‬‭SAEs‬‭as‬‭they‬‭are‬‭received,‬‭and‬‭periodic‬‭review‬‭of‬‭all‬
‭adverse events data for potential new safety signals.‬
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‭3.2.‬
‭Number of participants‬
‭The‬‭planned‬‭sample‬‭size‬‭is‬‭38‬‭patients‬‭with‬‭G3‬‭NENs‬‭of‬‭gastroenteropancreatic‬‭or‬‭unknown‬‭primary‬
‭origin.‬
‭Participating‬‭centres‬‭will‬‭include‬‭10‬‭academic‬‭hospitals‬‭selected‬‭from‬‭the‬‭GETNE‬‭Spanish‬‭network‬
‭(Please see‬‭Section 9,‬‭statistical considerations,‬‭for specific details).‬
‭3.3.‬
‭End of Study Definition‬
‭The‬‭duration‬‭of‬‭the‬‭study‬‭from‬‭start‬‭of‬‭enrollment‬‭to‬‭the‬‭last‬‭participant‬‭inclusion‬‭is‬‭expected‬‭to‬‭be‬‭18‬
‭months.‬‭The‬‭study‬‭will‬‭end‬‭once‬‭additional‬‭survival‬‭follow-up‬‭of‬‭24‬‭months‬‭after‬‭the‬‭induction‬‭phase‬
‭has concluded.‬
‭3.4.‬
‭Study Calendar‬
‭-‬
‭Study start (real)‬
‭11/10/2019‬
‭-‬
‭First patient First visit (real)‬
‭4/11/2019‬
‭-‬
‭End or recruitment (real)‬
‭26/1/2021‬
‭-‬
‭Last patient Last visit (estimated)‬
‭1Q 2023‬
‭-‬
‭End of study (estimation)‬
‭2Q 2023‬
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‭4.‬
‭Patient selection criteria‬
‭The‬ ‭following‬ ‭eligibility‬ ‭criteria‬ ‭are‬ ‭designed‬ ‭to‬ ‭select‬ ‭subjects‬ ‭for‬ ‭whom‬ ‭protocol‬ ‭treatment‬ ‭is‬
‭considered‬ ‭appropriate.‬ ‭All‬ ‭relevant‬ ‭medical‬ ‭and‬ ‭non-medical‬ ‭conditions‬ ‭should‬ ‭be‬ ‭taken‬ ‭into‬
‭consideration when deciding whether this protocol is suitable for a particular subject.‬
‭4.1.‬
‭Inclusion Criteria‬
‭Patients should meet all of the following inclusion criteria:‬
‭1.‬ ‭Histologically‬‭confirmed‬‭G3‬‭NENs‬‭originated‬‭in‬‭the‬‭gastroenteropancreatic‬‭tract‬‭(WHO‬‭2010‬
‭classification). Patients with a G3 NEN of unknown primary will also be eligible for this trial.‬
‭2.‬ ‭Ki-67 >20% or mitotic rate > 20 per 10 HPF.‬
‭3.‬ ‭Metastatic‬‭or‬‭locally‬‭advanced‬‭unresectable‬‭disease‬‭not‬‭amenable‬‭to‬‭treatment‬‭with‬‭curative‬
‭intent.‬
‭4.‬ ‭No prior systemic treatment for advanced disease‬‭nor as adjuvant therapy.‬
‭5.‬ ‭Availability‬‭of‬‭fresh‬‭or‬‭archive‬‭formalin-fixed,‬‭paraffin-embedded‬‭tumor‬‭tissue‬‭for‬‭biomarker‬
‭assessment.‬
‭6.‬ ‭Patients‬‭must‬‭have‬‭clinically‬‭and/or‬‭radiographically‬‭documented‬‭measurable‬‭disease.‬‭At‬‭least‬
‭one site of disease must be unidimensionally measurable as per RECIST 1.1.‬
‭7.‬ ‭Adequate‬ ‭organ‬ ‭function‬ ‭as‬ ‭defined‬ ‭by‬ ‭the‬ ‭following‬ ‭criteria‬ ‭(within‬ ‭7‬ ‭days‬ ‭prior‬ ‭to‬
‭enrollment):‬
‭a.‬ ‭absolute neutrophil count (ANC) ≥1500 cells/mm3‬
‭b.‬ ‭platelets ≥100,000 cells/mm3‬
‭c.‬ ‭hemoglobin ≥9.0 g/dL‬
‭d.‬ ‭AST‬‭and‬‭ALT‬‭≤2.5‬‭x‬‭upper‬‭limit‬‭of‬‭normal‬‭(ULN);‬‭in‬‭patients‬‭with‬‭liver‬‭metastases‬
‭AST and ALT ≤5.0 x ULN‬
‭e.‬ ‭total bilirubin ≤1.5 x ULN‬
‭f.‬
‭serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min.‬
‭8.‬ ‭Male or female, age ≥18 years.‬
‭9.‬ ‭ECOG performance status of 0-2.‬
‭10.‬‭Life expectancy of ≥12 weeks.‬
‭11.‬ ‭Women‬‭of‬‭childbearing‬‭potential‬‭must‬‭have‬‭a‬‭negative‬‭serum‬‭or‬‭urine‬‭pregnancy‬‭test‬‭within‬‭7‬
‭days prior to treatment initiation.‬
‭12.‬‭Highly‬‭effective‬‭contraception‬‭(i.e.‬‭methods‬‭with‬‭a‬‭failure‬‭rate‬‭of‬‭less‬‭than‬‭1‬‭%‬‭per‬‭year)‬‭for‬
‭both‬‭fertile,‬‭sexually‬‭active‬‭male‬‭and‬‭female‬‭subjects.‬‭Highly‬‭effective‬‭contraception‬‭must‬‭be‬
‭used‬‭28‬‭days‬‭prior‬‭to‬‭first‬‭trial‬‭treatment‬‭administration,‬‭for‬‭the‬‭duration‬‭of‬‭trial‬‭treatment,‬
‭and‬‭at‬‭least‬‭for‬‭5‬‭months‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭nivolumab‬‭and‬‭6‬‭months‬‭after‬‭the‬‭last‬‭dose‬‭of‬
‭carboplatin/etoposide.‬
‭13.‬‭Signed‬ ‭and‬ ‭dated‬ ‭informed‬ ‭consent‬ ‭document‬ ‭must‬ ‭be‬ ‭given‬ ‭according‬ ‭to‬‭ICH/GCP,‬‭and‬
‭national/local‬‭regulations‬‭indicating‬‭that‬‭the‬‭patient‬‭(or‬‭legally‬‭acceptable‬‭representative)‬‭has‬
‭been informed of all pertinent aspects of the trial prior to enrolment.‬
‭4.2.‬
‭Exclusion Criteria‬
‭Subjects shall not meet any of the following exclusion criteria:‬
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‭1.‬ ‭The‬‭following‬‭endocrine‬‭tumor‬‭types‬‭may‬‭not‬‭be‬‭included:‬‭paraganglioma,‬‭adrenal,‬‭thyroid‬
‭parathyroid‬‭or‬‭pituitary‬‭endocrine‬‭tumors.‬‭Large‬‭or‬‭small‬‭cell‬‭lung‬‭neuroendocrine‬‭carcinoma‬
‭of the lung will also be excluded.‬
‭2.‬ ‭Prior therapy with any immune checkpoint inhibitor.‬
‭3.‬ ‭Major‬‭surgery,‬‭except‬‭diagnostic‬‭biopsy,‬‭in‬‭<4‬‭weeks‬‭or‬‭radiation‬‭therapy‬‭<2‬‭weeks‬‭prior‬‭to‬
‭starting‬ ‭study‬ ‭treatment.‬ ‭Prior‬ ‭palliative‬ ‭radiotherapy‬ ‭to‬ ‭metastatic‬ ‭lesion(s)‬ ‭is‬ ‭permitted,‬
‭provided there is at least one measurable lesion that has not been irradiated.‬
‭4.‬ ‭Prior organ transplantation, including allogeneic stem-cell transplantation.‬
‭5.‬ ‭Prior history of non-infectious pneumonitis requiring steroids or current pneumonitis.‬
‭6.‬ ‭Systemic‬ ‭chronic‬ ‭steroid‬ ‭therapy‬ ‭(>‬ ‭10‬ ‭mg/day‬ ‭prednisone‬ ‭or‬ ‭equivalent)‬ ‭or‬ ‭other‬
‭immunosuppressive‬‭agents‬‭or‬‭use‬‭of‬‭any‬‭investigational‬‭drug‬‭within‬‭28‬‭days‬‭before‬‭the‬‭start‬
‭of‬‭trial‬‭treatment.‬‭Short-term‬‭administration‬‭of‬‭steroids‬‭for‬‭allergic‬‭reactions‬‭or‬‭management‬
‭of‬‭immune-related‬‭adverse‬‭events‬‭is‬‭allowed.‬‭Topical,‬‭inhaled,‬‭nasal‬‭and‬‭ophthalmic‬‭steroids‬
‭are also allowed.‬
‭7.‬ ‭Use‬ ‭of‬ ‭any‬ ‭live‬ ‭vaccines‬ ‭against‬ ‭infectious‬ ‭diseases‬‭within‬‭4‬‭weeks‬‭of‬‭initiation‬‭of‬‭study‬
‭treatment.‬
‭8.‬ ‭Known‬ ‭history‬ ‭of‬ ‭positive‬ ‭testing‬ ‭for‬ ‭Human‬ ‭Immunodeficiency‬ ‭Virus‬ ‭(HIV)‬ ‭infection,‬
‭known‬‭history‬‭of‬‭or‬‭positive‬‭tests‬‭for‬‭Hepatitis‬‭B‬‭virus‬‭surface‬‭antigen‬‭(HBVsAg)‬‭or‬‭Hepatitis‬
‭C‬‭ribonucleic‬‭acid‬‭(HCV‬‭RNA)‬‭indicating‬‭acute‬‭or‬‭chronic‬‭infection‬‭or‬‭other‬‭significant‬‭acute‬
‭or chronic infections requiring medication at study entry.‬
‭9.‬ ‭Active,‬ ‭known‬ ‭or‬ ‭suspected‬ ‭autoimmune‬ ‭disease‬ ‭or‬ ‭a‬‭documented‬‭history‬‭of‬‭autoimmune‬
‭disease,‬ ‭including‬ ‭ulcerative‬ ‭colitis‬ ‭and‬ ‭Crohn’s‬ ‭disease.‬ ‭(Patients‬ ‭with‬ ‭vitiligo,‬ ‭type‬ ‭I‬
‭diabetes‬ ‭mellitus,‬ ‭residual‬ ‭hypothyroidism‬ ‭due‬ ‭to‬ ‭autoimmune‬ ‭condition‬ ‭only‬ ‭requiring‬
‭hormone‬‭replacement,‬‭psoriasis‬‭not‬‭requiring‬‭systemic‬‭treatment,‬‭or‬‭conditions‬‭not‬‭expected‬
‭to recur in the absence of an external trigger are permitted to enroll).‬
‭10.‬‭Active‬ ‭seizure‬ ‭disorder‬ ‭or‬ ‭evidence‬ ‭of‬ ‭brain‬ ‭metastases,‬ ‭spinal‬ ‭cord‬ ‭compression,‬ ‭or‬
‭carcinomatous meningitis.‬
‭11.‬ ‭A‬‭serious‬‭uncontrolled‬‭medical‬‭disorder‬‭or‬‭active‬‭infection‬‭that‬‭would‬‭impair‬‭their‬‭ability‬‭to‬
‭receive‬‭study‬‭treatment‬‭will‬‭not‬‭be‬‭allowed‬‭to‬‭enter‬‭the‬‭study.‬‭Any‬‭of‬‭the‬‭following‬‭within‬‭the‬
‭12‬ ‭months‬ ‭prior‬ ‭to‬ ‭study‬ ‭drug‬ ‭administration:‬ ‭myocardial‬ ‭infarction,‬‭uncontrolled‬‭angina,‬
‭coronary/peripheral‬ ‭artery‬ ‭bypass‬ ‭graft,‬ ‭NYHA‬ ‭class‬ ‭>‬ ‭III‬ ‭congestive‬ ‭heart‬ ‭failure,‬
‭cerebrovascular‬‭accident‬‭or‬‭transient‬‭ischemic‬‭attack‬‭and‬‭6‬‭months‬‭for‬‭deep‬‭vein‬‭thrombosis‬
‭or pulmonary embolism.‬
‭12.‬‭Known‬ ‭hypersensitivity‬ ‭reactions‬ ‭to‬ ‭monoclonal‬ ‭antibodies‬ ‭(≥‬ ‭grade‬ ‭3‬ ‭according‬ ‭to‬ ‭NCI‬
‭Common‬‭Terminology‬‭Criteria‬‭for‬‭Adverse‬‭Events‬‭(CTCAE)‬‭v‬‭5.0‬‭[xliii]‬ ‭or‬‭any‬‭past‬‭medical‬
‭history‬‭of‬‭anaphylaxis‬‭or‬‭uncontrolled‬‭asthma‬‭(i.e.,‬‭3‬‭or‬‭more‬‭asthma‬‭characteristics‬‭partially‬
‭controlled).‬
‭13.‬‭Any‬‭other‬‭prior‬‭malignancy‬‭within‬‭5‬‭years‬‭of‬‭study‬‭entry,‬‭with‬‭the‬‭exception‬‭of‬‭adequately‬
‭treated in-situ carcinoma of the cervix, breast or uteri, or non-melanomatous skin cancer.‬
‭14.‬‭Any‬ ‭psychological,‬ ‭familial,‬ ‭sociological‬ ‭or‬ ‭geographical‬ ‭condition‬ ‭potentially‬ ‭hampering‬
‭compliance‬ ‭with‬ ‭the‬ ‭study‬ ‭protocol‬ ‭and‬ ‭follow-up‬ ‭schedule;‬ ‭those‬ ‭conditions‬ ‭should‬ ‭be‬
‭discussed with the patient before registration in the trial.‬
‭15.‬‭Dementia‬ ‭or‬ ‭significantly‬ ‭altered‬ ‭mental‬ ‭status‬ ‭that‬ ‭would‬ ‭prohibit‬ ‭the‬ ‭understanding‬ ‭or‬
‭rendering of informed consent and compliance with the requirements of this protocol.‬
‭16.‬‭Female‬‭patients‬‭who‬‭are‬‭pregnant‬‭or‬‭lactating,‬‭or‬‭men‬‭and‬‭women‬‭of‬‭reproductive‬‭potential‬
‭not‬‭willing‬‭or‬‭not‬‭able‬‭to‬‭employ‬‭an‬‭effective‬‭method‬‭of‬‭birth‬‭control/contraception‬‭to‬‭prevent‬
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‭pregnancy‬ ‭during‬ ‭treatment‬ ‭and‬ ‭for‬ ‭6‬ ‭months‬ ‭after‬ ‭discontinuing‬ ‭study‬ ‭treatment‬ ‭The‬
‭definition‬‭of‬‭effective‬‭contraception‬‭should‬‭be‬‭in‬‭agreement‬‭with‬‭local‬‭regulation‬‭and‬‭based‬
‭on the judgment of the principal investigator or a designated associate.‬
‭17.‬‭Other‬‭severe‬‭acute‬‭or‬‭chronic‬‭medical‬‭or‬‭psychiatric‬‭condition,‬‭or‬‭laboratory‬‭abnormality‬‭that‬
‭may‬‭increase‬‭the‬‭risk‬‭associated‬‭with‬‭study‬‭participation‬‭or‬‭study‬‭drug‬‭administration,‬‭or‬‭may‬
‭interfere‬‭with‬‭the‬‭interpretation‬‭of‬‭study‬‭results,‬‭and‬‭in‬‭the‬‭judgment‬‭of‬‭the‬‭investigator‬‭would‬
‭make the patient inappropriate for study entry.‬
‭4.3.‬
‭Screening Failures‬
‭Screening‬‭failures‬‭are‬‭defined‬‭as‬‭participants‬‭who‬‭consent‬‭to‬‭participate‬‭in‬‭the‬‭clinical‬‭study‬‭but‬‭are‬
‭not‬ ‭subsequently‬ ‭randomized.‬ ‭A‬ ‭minimal‬ ‭set‬ ‭of‬ ‭screen‬ ‭failure‬ ‭information‬ ‭is‬ ‭required‬ ‭to‬ ‭ensure‬
‭transparent‬‭reporting‬‭of‬‭screen‬‭failure‬‭participants,‬‭to‬‭meet‬‭the‬‭Consolidated‬‭Standards‬‭of‬‭Reporting‬
‭Trials‬‭(CONSORT)‬‭publishing‬‭requirements,‬‭and‬‭to‬‭respond‬‭to‬‭queries‬‭from‬‭regulatory‬‭authorities.‬
‭Minimal‬‭information‬‭includes‬‭date‬‭of‬‭consent,‬‭demography,‬‭screen‬‭failure‬‭details,‬‭eligibility‬‭criteria,‬
‭and any serious AEs.‬
‭4.3.1.‬ ‭Retesting during Screening Period‬
‭This‬‭study‬‭permits‬‭the‬‭re-enrollment‬‭of‬‭a‬‭participant‬‭that‬‭has‬‭discontinued‬‭the‬‭study‬‭as‬‭a‬‭pre-treatment‬
‭failure‬ ‭(ie,‬ ‭participant‬ ‭has‬ ‭not‬ ‭been‬ ‭treated).‬ ‭If‬ ‭re-enrolled,‬ ‭the‬ ‭participant‬ ‭must‬ ‭be‬ ‭re-consented.‬
‭Retesting‬ ‭of‬ ‭laboratory‬ ‭parameters‬ ‭and/or‬ ‭other‬ ‭assessments‬ ‭within‬ ‭any‬ ‭single‬ ‭screening‬ ‭will‬ ‭be‬
‭permitted (in addition to any parameters that require a confirmatory value).‬
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‭5.‬
‭Therapeutic Regimens, Expected Toxicity, Dose Modifications‬
‭Study‬ ‭treatment‬ ‭is‬ ‭defined‬ ‭as‬ ‭any‬ ‭investigational‬ ‭treatment(s),‬ ‭marketed‬ ‭product(s),‬ ‭placebo‬ ‭or‬
‭medical‬‭device‬‭intended‬‭to‬‭be‬‭administered‬‭to‬‭a‬‭study‬‭participant‬‭according‬‭to‬‭the‬‭study‬‭treatment‬
‭allocation.‬
‭Study‬‭treatment‬‭includes‬‭both‬‭Investigational‬‭[Medicinal]‬‭Product‬‭(IP/IMP)‬‭and‬‭Non-investigational‬
‭[Medicinal] Product (Non-IP/Non-IMP) and consist of the following:‬
‭●‬ ‭Nivolumab‬
‭●‬ ‭Carboplatin‬
‭●‬ ‭Etoposide‬
‭Other‬‭medications‬‭used‬‭as‬‭support‬‭or‬‭escape‬‭medication‬‭for‬‭preventative,‬‭diagnostic,‬‭or‬‭therapeutic‬
‭reasons,‬ ‭as‬ ‭components‬ ‭of‬ ‭the‬ ‭standard‬ ‭of‬ ‭care‬ ‭for‬ ‭a‬ ‭given‬ ‭diagnosis,‬ ‭may‬ ‭be‬ ‭considered‬ ‭as‬
‭non-investigational products.‬
‭Study Treatments for Study CA209- 73D‬
‭Product‬
‭description and‬
‭dosage Form‬
‭Potency‬
‭IP/Non-‬
‭IP‬
‭Blinded or‬
‭Open‬
‭Label‬
‭Primary‬
‭Packaging‬
‭(Volume)/Label‬
‭Type and‬
‭Secondary‬
‭Packaging‬
‭(Qty)/Label Type‬
‭Appearance‬
‭Storage‬
‭Conditions‬
‭(per label)‬
‭BMS-936558-01‬
‭Nivolumab‬
‭Solution for‬
‭Injection‬‭a‬
‭100‬
‭mg/vial‬
‭(10‬
‭mg/mL)‬
‭IP‬
‭Open Label‬
‭10 mL per vial and‬
‭5 or 10 vials per‬
‭carton‬
‭Clear to‬
‭opalescent‬
‭colorless to pale‬
‭yellow liquid.‬
‭May contain‬
‭particles‬
‭2 to 8 C.‬
‭Protect from‬
‭light and‬
‭freezing‬
‭Carboplatin‬
‭Solution for‬
‭injection‬‭b‬
‭450‬
‭mg/vial‬
‭(10‬
‭mg/mL)‬
‭IP‬
‭Open Label‬
‭Various packaging‬
‭configuration‬
‭Clear, colorless‬
‭or slightly‬
‭yellow solution.‬
‭Product should‬
‭be stored as‬
‭per market‬
‭product‬
‭conditions.‬
‭Etoposide‬
‭100 mg/‬
‭vial‬
‭(20mg/‬
‭mL)‬
‭IP‬
‭Open Label‬
‭Various packaging‬
‭configuration‬
‭Powder, white‬
‭to white with a‬
‭yellow cast.‬
‭Product should‬
‭be stored as‬
‭per market‬
‭product‬
‭conditions.‬
‭NOTES:‬‭a‬‭May be labeled as either “BMS-936558-01”‬‭or “Nivolumab”‬
‭5.1.‬
‭Treatments Administered‬
‭The‬‭treatments‬‭that‬‭will‬‭be‬‭used‬‭in‬‭this‬‭trial‬‭are‬‭outlined‬‭below‬‭(Table-5.1).‬‭They‬‭will‬‭be‬‭administered‬
‭in the order presented.‬
‭All trial treatments may be administered on an outpatient basis.‬
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‭Table-5.1. Trial treatments‬
‭Drug‬
‭Drug‬
‭Frequency‬
‭Administration‬
‭Treatment‬
‭period‬
‭Use‬
‭Nivolumab‬
‭360 mg‬
‭Q3W‬
‭IV infusion‬
‭Day 1 of each‬
‭cycle‬
‭Experimental‬
‭Carboplatin‬
‭AUC5‬
‭Q3W‬
‭IV infusion‬
‭Day 1 of each‬
‭cycle‬
‭Standard‬
‭Etoposide‬
‭100‬
‭mg/m‬‭2‬‭/day‬
‭Q3W‬
‭IV infusion‬
‭Days 1-3 of‬
‭each cycle‬
‭Standard‬
‭Nivolumab‬‭will‬‭be‬‭administered‬‭first‬‭as‬‭a‬‭30‬‭minute‬‭IV‬‭infusion,‬‭followed‬‭by‬‭the‬‭carboplatin‬‭infusion‬
‭and‬‭then‬‭the‬‭etoposide‬‭infusion.‬‭Platinum-doublet‬‭will‬‭start‬‭at‬‭least‬‭30‬‭minutes‬‭after‬‭completion‬‭of‬‭the‬
‭nivolumab‬‭infusion.‬‭At‬‭the‬‭investigator’s‬‭discretion,‬‭nivolumab‬‭may‬‭be‬‭administered‬‭over‬‭a‬‭longer‬
‭infusion time (60 minutes) if the participant developed a prior infusion reaction.‬
‭Nivolumab‬ ‭treatment‬ ‭will‬ ‭continue‬ ‭until‬ ‭disease‬ ‭progression,‬ ‭discontinuation‬ ‭due‬ ‭to‬‭unacceptable‬
‭toxicity,‬ ‭or‬ ‭withdrawal‬ ‭of‬ ‭consent.‬ ‭Participants‬ ‭will‬ ‭be‬‭treated‬‭up‬‭to‬‭24‬‭months‬‭in‬‭the‬‭absence‬‭of‬
‭disease progression or unacceptable toxicity.‬
‭All‬‭participants‬‭will‬‭be‬‭monitored‬‭continuously‬‭for‬‭adverse‬‭events‬‭(AEs)‬‭while‬‭on‬‭study‬‭treatment.‬
‭Treatment‬‭modifications‬‭(eg,‬‭dose‬‭delay,‬‭reduction,‬‭retreatment,‬‭or‬‭discontinuation)‬‭will‬‭be‬‭based‬‭on‬
‭specific laboratory and adverse event criteria, as described in‬‭sections 5.2-5.3.‬
‭5.1.1.‬ ‭Dosing‬
‭5.1.1.1.‬‭Nivolumab‬
‭Participants‬‭will‬‭receive‬‭nivolumab,‬‭followed‬‭by‬‭chemotherapy‬‭on‬‭day‬‭1‬‭of‬‭every‬‭3‬‭weeks‬
‭cycle‬ ‭for‬ ‭6‬ ‭cycles‬ ‭(‬‭induction‬ ‭phase‬‭).‬ ‭At‬‭the‬‭time‬‭of‬‭completion‬‭of‬‭6‬‭cycles‬‭of‬‭chemotherapy‬‭and‬
‭nivolumab,‬ ‭participants‬ ‭who‬ ‭have‬ ‭not‬ ‭experienced‬ ‭disease‬ ‭progression‬ ‭will‬ ‭continue‬ ‭to‬ ‭receive‬
‭nivolumab‬‭at‬‭a‬‭dose‬‭of‬‭480‬‭mg‬‭as‬‭30‬‭minute‬‭infusion‬‭every‬‭4‬‭weeks‬‭for‬‭up‬‭to‬‭2‬‭years‬‭(‬‭maintenance‬
‭phase‬‭).‬
‭Drug‬
‭Dose‬
‭Frequency‬
‭Administration‬
‭Treatment period‬
‭Use‬
‭Induction phase‬
‭Nivolumab‬
‭360 mg‬
‭Q3W‬
‭IV infusion‬
‭Day 1 of each cycle‬
‭Experimental‬
‭Maintenance phase‬
‭Nivolumab‬
‭480 mg‬
‭Q4W‬
‭IV infusion‬
‭Day 1 of each cycle‬
‭Experimental‬
‭Treatment‬ ‭will‬ ‭continue‬ ‭until‬ ‭progression,‬ ‭unacceptable‬ ‭toxicity,‬ ‭withdrawal‬ ‭of‬ ‭consent,‬
‭whichever‬‭occurs‬‭first.‬‭Treatment‬‭with‬‭nivolumab‬‭will‬‭be‬‭given‬‭for‬‭up‬‭to‬‭24‬‭months‬‭including‬‭the‬
‭induction phase (a total of 34 cycles) in the absence of disease progression or unacceptable toxicity.‬
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‭The‬ ‭assessment‬ ‭for‬ ‭discontinuation‬ ‭of‬ ‭nivolumab‬ ‭should‬ ‭be‬ ‭made‬ ‭separately‬ ‭from‬
‭chemotherapy.‬ ‭If‬ ‭criteria‬ ‭for‬ ‭discontinuation‬ ‭for‬ ‭nivolumab‬ ‭are‬ ‭met,‬ ‭platinum-based‬ ‭doublet‬
‭chemotherapy‬ ‭may‬‭continue‬‭until‬‭6‬‭cycles‬‭have‬‭been‬‭completed.‬‭If‬‭a‬‭participant‬‭meets‬‭criteria‬‭for‬
‭discontinuation‬‭and‬‭investigator‬‭is‬‭unable‬‭to‬‭determine‬‭whether‬‭the‬‭event‬‭is‬‭related‬‭to‬‭all‬‭or‬‭one‬‭study‬
‭drug, the participant should discontinue all study drugs and be taken off the study.‬
‭5.1.1.2 Chemotherapy dosing‬
‭6‬ ‭cycles‬ ‭of‬‭carboplatin‬‭in‬‭combination‬‭with‬‭etoposide‬‭will‬‭be‬‭administered‬‭every‬‭3‬‭weeks‬
‭(Q3W).‬
‭All‬‭chemotherapy‬‭agents’‬‭preparation,‬‭premedication,‬‭administration,‬‭monitoring,‬‭and‬‭management‬‭of‬
‭complications‬‭are‬‭to‬‭follow‬‭local‬‭prescription‬‭guidelines‬‭and‬‭regulations.‬‭The‬‭dose‬‭of‬‭chemotherapy‬
‭may be capped per local standards.‬
‭❏‬ ‭Carboplatin:‬
‭Carboplatin‬‭(AUC=5)‬‭will‬‭be‬‭administered‬‭as‬‭a‬‭15-60‬‭minute‬‭IV‬‭infusion‬‭per‬‭site’s‬‭standard‬‭practice‬
‭Q3W‬‭on‬‭day‬‭1‬‭of‬‭each‬‭treatment‬‭cycle.‬‭Carboplatin‬‭will‬‭be‬‭administered‬‭to‬‭participants‬‭at‬‭least‬‭30‬
‭minutes following the end of the nivolumab infusion.‬
‭The dose of carboplatin will be calculated using the‬‭Calvert formula‬‭as follows:‬
‭Carboplatin dose (mg)= AUC target x ([CrCl (ml/min) + 25]‬
‭Creatinine‬‭clearance‬‭(CrCl)‬‭calculation‬‭is‬‭based‬‭on‬‭the‬‭Cockcroft-Gault‬‭formula‬‭and‬‭should‬‭include‬
‭the most recent serum creatinine and the most recent weight.‬
‭NOTE‬‭:‬‭If‬‭calculation‬‭of‬‭the‬‭CrCl‬‭by‬‭the‬‭Cockcroft-Gault‬‭formula‬‭yields‬‭a‬‭result‬‭of‬‭>‬‭125‬‭mL/min,‬
‭then‬‭a‬‭CrCl‬‭should‬‭be‬‭calculated‬‭by‬‭an‬‭alternative‬‭formula‬‭per‬‭institutional‬‭standards‬‭or‬‭capped‬‭at‬‭125‬
‭mL/min.‬
‭The dose of carboplatin may be capped per local standards.‬
‭❏‬ ‭Etoposide:‬
‭Etoposide‬ ‭100‬ ‭mg/m‬‭2‬‭/day‬‭will‬ ‭be‬ ‭administered‬ ‭as‬ ‭a‬ ‭30-60‬ ‭minute‬ ‭IV‬ ‭infusion‬‭per‬‭site’s‬‭standard‬
‭practice‬‭Q3W‬‭on‬‭days‬‭1,‬‭2‬‭and‬‭3‬‭of‬‭each‬‭treatment‬‭cycle.‬‭Etoposide‬‭will‬‭be‬‭administered‬‭following‬
‭the end of carboplatin infusion.‬
‭5.1.1.3 Premedication‬
‭❏‬ ‭Nivolumab‬
‭Patients‬ ‭should‬ ‭not‬ ‭receive‬‭pre-medication‬‭to‬‭prevent‬‭infusion‬‭reaction‬‭before‬‭the‬‭first‬‭infusion‬‭of‬
‭nivolumab.‬‭If‬‭a‬‭patient‬‭experiences‬‭an‬‭infusion‬‭reaction,‬‭he/she‬‭may‬‭receive‬‭premedication‬‭prior‬‭to‬
‭subsequent dosing days  (‬‭Table 5.1.3).‬
‭❏‬ ‭Carboplatin and Etoposide:‬
‭Antiemetic‬ ‭premedication‬ ‭will‬ ‭be‬ ‭administered‬ ‭according‬ ‭to‬ ‭local‬ ‭standards.‬ ‭Recommended‬
‭antiemetic treatments are:‬
‭❏‬ ‭Dexamethasone‬‭(dosing‬‭according‬‭to‬‭local‬‭standards;‬‭an‬‭equivalent‬‭dose‬‭of‬‭another‬
‭corticosteroid may be administered).‬
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‭❏‬ ‭A‬ ‭5-HT3‬ ‭receptor‬ ‭antagonist‬ ‭(type‬ ‭per‬ ‭investigator‬ ‭discretion‬ ‭and‬ ‭local‬
‭standards-of-care).‬
‭Additional‬‭use‬‭of‬‭antiemetic‬‭premedications‬‭may‬‭be‬‭employed‬‭at‬‭the‬‭discretion‬‭of‬‭the‬‭Investigator.‬
‭Please‬‭refer‬‭to‬‭the‬‭product‬‭label‬‭or‬‭local‬‭standards‬‭of‬‭care‬‭for‬‭carboplatin‬‭and‬‭etoposide‬‭supportive‬
‭measures.‬
‭5.1.2.‬ ‭Patient Monitoring‬
‭Vital‬ ‭signs‬ ‭including‬ ‭temperature,‬ ‭pulse,‬ ‭respiratory‬ ‭rate,‬ ‭weight‬ ‭and‬ ‭blood‬ ‭pressure‬ ‭prior‬ ‭to‬ ‭the‬
‭administration of each dose of trial treatment will be measured as specified in‬‭section 7.4.‬
‭5.1.3.‬ ‭Treatment of Nivolumab Infusion Reactions‬
‭Since‬‭nivolumab‬‭contains‬‭only‬‭human‬‭immunoglobulin‬‭protein‬‭sequences,‬‭it‬‭is‬‭unlikely‬‭to‬‭be‬
‭immunogenic‬‭and‬‭induce‬‭infusion‬‭or‬‭hypersensitivity‬‭reactions.‬‭However,‬‭if‬‭such‬‭a‬‭reaction‬‭were‬‭to‬
‭occur,‬ ‭it‬ ‭might‬ ‭manifest‬ ‭with‬ ‭fever,‬ ‭chills,‬ ‭rigors,‬ ‭headache,‬ ‭rash,‬ ‭pruritus,‬ ‭arthralgias,‬ ‭hypo-‬ ‭or‬
‭hypertension,‬ ‭bronchospasm,‬ ‭or‬ ‭other‬ ‭symptoms.‬ ‭All‬ ‭Grade‬ ‭3‬ ‭or‬ ‭4‬ ‭infusion‬ ‭reactions‬ ‭should‬ ‭be‬
‭reported‬ ‭within‬ ‭24‬ ‭hours‬ ‭to‬ ‭the‬‭BMS‬‭Medical‬‭Monitor‬‭and‬‭reported‬‭as‬‭a‬‭SAE‬‭if‬‭criteria‬‭are‬‭met.‬
‭Infusion reactions should be graded according to NCI CTCAE (Version 5.0) guidelines.‬
‭Treatment‬ ‭recommendations‬ ‭are‬ ‭provided‬ ‭below‬ ‭and‬ ‭may‬ ‭be‬ ‭modified‬ ‭based‬ ‭on‬ ‭local‬ ‭treatment‬
‭standards and guidelines, as appropriate:‬
‭For‬ ‭Grade‬ ‭1‬ ‭symptoms:‬‭(mild‬‭reaction;‬‭infusion‬‭interruption‬‭not‬‭indicated;‬‭intervention‬‭not‬
‭indicated)‬
‭●‬ ‭Remain‬ ‭at‬ ‭bedside‬ ‭and‬ ‭monitor‬ ‭the‬ ‭patient‬ ‭until‬ ‭recovery‬ ‭from‬‭symptoms.‬‭The‬‭following‬
‭prophylactic‬‭premedications‬‭are‬‭recommended‬‭for‬‭future‬‭infusions:‬‭diphenhydramine‬‭50‬‭mg‬
‭(or‬‭equivalent)‬‭and/or‬‭acetaminophen/paracetamol‬‭325‬‭to‬‭1000‬‭mg‬‭at‬‭least‬‭30‬‭minutes‬‭before‬
‭additional nivolumab administration.‬
‭For‬ ‭Grade‬ ‭2‬ ‭symptoms:‬ ‭(moderate‬ ‭reaction‬ ‭requires‬ ‭therapy‬ ‭or‬ ‭infusion‬ ‭interruption‬ ‭but‬
‭responds‬
‭promptly‬
‭to‬
‭symptomatic‬
‭treatment‬
‭[eg,‬
‭antihistamines,‬
‭non-steroidal‬
‭anti-inflammatory‬ ‭drugs,‬ ‭narcotics,‬ ‭corticosteroids,‬ ‭bronchodilators,‬ ‭IV‬ ‭fluids];‬ ‭prophylactic‬
‭medications indicated for < 24 hours)‬
‭●‬ ‭Stop‬‭the‬‭nivolumab‬‭infusion,‬‭begin‬‭an‬‭IV‬‭infusion‬‭of‬‭normal‬‭saline,‬‭and‬‭treat‬‭the‬‭participant‬
‭with‬ ‭diphenhydramine‬‭50‬‭mg‬‭IV‬‭(or‬‭equivalent)‬‭and/or‬‭acetaminophen/paracetamol‬‭325‬‭to‬
‭1000‬ ‭mg;‬ ‭remain‬ ‭at‬ ‭bedside‬ ‭and‬ ‭monitor‬ ‭participant‬ ‭until‬ ‭resolution‬ ‭of‬ ‭symptoms.‬
‭Corticosteroid‬‭and/or‬‭bronchodilator‬‭therapy‬‭may‬‭also‬‭be‬‭administered‬‭as‬‭appropriate.‬‭If‬‭the‬
‭infusion‬ ‭is‬ ‭interrupted,‬ ‭then‬ ‭restart‬ ‭the‬‭infusion‬‭at‬‭50%‬‭of‬‭the‬‭original‬‭infusion‬‭rate‬‭when‬
‭symptoms‬ ‭resolve;‬ ‭if‬ ‭no‬ ‭further‬ ‭complications‬ ‭ensue‬ ‭after‬ ‭30‬ ‭minutes,‬ ‭the‬ ‭rate‬ ‭may‬ ‭be‬
‭increased‬ ‭to‬ ‭100%‬ ‭of‬ ‭the‬ ‭original‬ ‭infusion‬ ‭rate.‬ ‭Monitor‬ ‭participant‬ ‭closely.‬‭If‬‭symptoms‬
‭recur,‬ ‭then‬ ‭no‬ ‭further‬ ‭nivolumab‬ ‭will‬ ‭be‬ ‭administered‬ ‭at‬ ‭that‬ ‭visit.‬ ‭Administer‬
‭diphenhydramine‬‭50‬‭mg‬‭IV,‬‭and‬‭remain‬‭at‬‭bedside‬‭and‬‭monitor‬‭the‬‭participant‬‭until‬‭resolution‬
‭of‬ ‭symptoms.‬ ‭The‬ ‭amount‬ ‭of‬ ‭study‬ ‭drug‬ ‭infused‬ ‭must‬‭be‬‭recorded‬‭on‬‭the‬‭electronic‬‭case‬
‭report form (eCRF).‬
‭●‬ ‭For‬ ‭future‬ ‭infusions,‬ ‭the‬ ‭following‬ ‭prophylactic‬ ‭premedications‬ ‭are‬ ‭recommended:‬
‭diphenhydramine‬‭50‬‭mg‬‭(or‬‭equivalent)‬‭and/or‬‭acetaminophen/paracetamol‬‭325‬‭to‬‭1000‬‭mg‬
‭should‬ ‭be‬ ‭administered‬ ‭at‬ ‭least‬ ‭30‬ ‭minutes‬ ‭before‬ ‭nivolumab‬ ‭infusion.‬ ‭If‬ ‭necessary,‬
‭corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.‬
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‭For‬‭Grade‬‭3‬‭or‬‭4‬‭symptoms:‬‭(severe‬‭reaction,‬‭Grade‬‭3:‬‭prolonged‬‭[ie,‬‭not‬‭rapidly‬‭responsive‬‭to‬
‭symptomatic‬ ‭medication‬ ‭and/or‬ ‭brief‬ ‭interruption‬ ‭of‬ ‭infusion];‬ ‭recurrence‬ ‭of‬ ‭symptoms‬
‭following‬ ‭initial‬ ‭improvement;‬ ‭hospitalization‬ ‭indicated‬ ‭for‬ ‭other‬ ‭clinical‬‭sequelae‬‭[eg,‬‭renal‬
‭impairment,‬ ‭pulmonary‬ ‭infiltrates].‬ ‭Grade‬ ‭4:‬‭Life‬‭threatening;‬‭pressor‬‭or‬‭ventilator‬‭support‬
‭indicated)‬
‭●‬ ‭Immediately‬‭discontinue‬‭infusion‬‭of‬‭nivolumab.‬‭Begin‬‭an‬‭IV‬‭infusion‬‭of‬‭normal‬‭saline‬‭and‬
‭treat‬ ‭the‬ ‭participant‬ ‭as‬ ‭follows:‬ ‭Recommend‬‭bronchodilators,‬‭epinephrine‬‭0.2‬‭to‬‭1mg‬‭of‬‭a‬
‭1:1000‬ ‭solution‬ ‭for‬ ‭subcutaneous‬ ‭administration‬ ‭or‬ ‭0.1‬ ‭to‬‭0.25‬‭mg‬‭of‬‭a‬‭1:10.000‬‭solution‬
‭injected‬ ‭slowly‬ ‭for‬ ‭IV‬ ‭administration,‬ ‭and/or‬ ‭diphenhydramine‬ ‭50‬ ‭mg‬ ‭IV‬ ‭with‬
‭methylprednisolone‬‭100‬‭mg‬‭IV‬‭(or‬‭equivalent),‬‭as‬‭needed.‬‭Participant‬‭should‬‭be‬‭monitored‬
‭until‬ ‭the‬ ‭investigator‬ ‭is‬ ‭comfortable‬ ‭that‬ ‭the‬ ‭symptoms‬ ‭will‬‭not‬‭recur.‬‭Nivolumab‬‭will‬‭be‬
‭permanently‬ ‭discontinued.‬ ‭Investigators‬ ‭should‬ ‭follow‬ ‭their‬‭institutional‬‭guidelines‬‭for‬‭the‬
‭treatment‬ ‭of‬ ‭anaphylaxis.‬ ‭Remain‬ ‭at‬ ‭bedside‬‭and‬‭monitor‬‭participant‬‭until‬‭recovery‬‭of‬‭the‬
‭symptoms.‬
‭In‬ ‭case‬ ‭of‬ ‭late-occurring‬ ‭hypersensitivity‬ ‭symptoms‬ ‭(eg,‬ ‭appearance‬ ‭of‬‭a‬‭localized‬‭or‬‭generalized‬
‭pruritus‬‭within‬‭1‬‭week‬‭after‬‭treatment),‬‭symptomatic‬‭treatment‬‭may‬‭be‬‭given‬‭(eg,‬‭oral‬‭antihistamine‬
‭or corticosteroids).‬
‭Table 5.1.3 Infusion reaction guidelines‬
‭Grade‬
‭Treatment‬
‭Premedication at subsequent dosing‬
‭Grade 1‬
‭Increase monitoring of vital signs‬
‭until the subject is deemed medically‬
‭stable in the opinion of the investigator.‬
‭Subject‬ ‭may‬ ‭be‬ ‭premedicated‬ ‭at‬ ‭least‬ ‭30‬
‭minutes prior to nivolumab infusion with:‬
‭●‬
‭Diphenhydramine‬
‭50‬
‭mg‬ ‭po‬ ‭(or‬
‭equivalent dose of antihistamine).‬
‭●‬
‭Acetaminophen 325-1000 mg po.‬
‭Grade 2‬
‭Stop Infusion and monitor symptoms.‬
‭Treat the participant with:‬
‭●‬
‭IV infusion of normal saline‬
‭●‬
‭Diphenhydramine 50 mg IV‬
‭●‬
‭Acetaminophen/‬
‭paracetamol‬
‭325-1000mg.‬
‭●‬
‭Increase‬ ‭monitoring‬ ‭of‬ ‭vital‬ ‭signs‬ ‭as‬
‭medically‬‭indicated‬‭until‬‭the‬‭subject‬‭is‬
‭deemed‬
‭medically‬
‭stable‬
‭in‬ ‭the‬
‭opinion of the investigator.‬
‭●‬
‭If‬ ‭symptoms‬ ‭resolve‬ ‭within‬ ‭one‬‭hour‬
‭of‬‭stopping‬‭drug‬‭infusion,‬‭the‬‭infusion‬
‭may‬‭be‬‭restarted‬‭at‬‭50%‬‭of‬‭the‬‭original‬
‭infusion‬‭rate‬‭(e.g.,‬‭from‬‭100‬‭mL/hr‬‭to‬
‭50‬ ‭mL/hr).‬ ‭Otherwise‬ ‭dosing‬ ‭will‬ ‭be‬
‭held‬ ‭until‬ ‭symptoms‬ ‭resolve‬ ‭and‬ ‭the‬
‭subject‬‭should‬‭be‬‭premedicated‬‭for‬‭the‬
‭next scheduled dose.‬
‭Subject should be premedicated at least 30‬
‭minutes prior to nivolumab infusion with:‬
‭●‬
‭Diphenhydramine‬
‭50‬
‭mg‬ ‭po‬ ‭(or‬
‭equivalent dose of antihistamine).‬
‭●‬
‭Acetaminophen 325-1000 mg po.‬
‭●‬
‭If‬ ‭necessary‬ ‭corticosteroids‬ ‭may‬ ‭be‬
‭used‬‭(up‬‭to‬‭25‬‭mg‬‭of‬‭hydrocortisone‬‭or‬
‭equivalent).‬
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‭Grade 3-4‬
‭Stop Infusion.‬
‭Treat the participant with:‬
‭●‬
‭IV infusion of normal saline.‬
‭●‬
‭Bronchodilators if required.‬
‭●‬
‭Epinephrine‬ ‭0.2‬ ‭to‬ ‭1‬ ‭mg‬ ‭of‬‭a‬‭1:1000‬
‭solution sc.‬
‭●‬
‭Diphenhydramine 50 mg IV.‬
‭●‬
‭Methylprednisolone‬ ‭100‬ ‭mg‬ ‭IV‬ ‭(or‬
‭equivalent).‬
‭●‬
‭Remain‬
‭at‬ ‭bedside‬ ‭and‬ ‭monitor‬
‭participant‬ ‭until‬ ‭recovery‬ ‭of‬ ‭the‬
‭symptoms‬‭and‬‭stable‬‭in‬‭the‬‭opinion‬‭of‬
‭the investigator.‬
‭●‬
‭Hospitalization may be indicated.‬
‭Nivolumab permanently discontinued‬
‭No subsequent dosing‬
‭Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug‬
‭administration.‬
‭5.2.‬
‭Dose Adjustments‬
‭●‬ ‭The‬ ‭Investigator‬ ‭may‬ ‭attribute‬ ‭each‬ ‭toxicity‬ ‭event‬ ‭to‬ ‭carboplatin,‬ ‭etoposide‬‭or‬‭nivolumab‬
‭alone‬ ‭and‬ ‭use‬ ‭a‬ ‭dose‬ ‭reduction‬ ‭according‬ ‭to‬ ‭Tables‬ ‭5.2,‬ ‭5.1.3.‬ ‭For‬ ‭individual‬ ‭subjects‬
‭requiring‬‭a‬‭dose‬‭modification,‬‭treatment‬‭for‬‭each‬‭new‬‭cycle‬‭may‬‭be‬‭delayed‬‭if‬‭the‬‭scheduled‬
‭off-drug‬‭periods‬‭are‬‭not‬‭adequate‬‭to‬‭allow‬‭for‬‭recovery‬‭to‬‭Grade‬‭≤1‬‭or‬‭the‬‭baseline‬‭status‬‭of‬
‭the subject.‬
‭●‬ ‭Nivolumab‬ ‭dose‬ ‭reductions‬ ‭are‬ ‭not‬‭permitted.‬‭Nivolumab‬‭treatment‬‭may‬‭be‬‭interrupted‬‭or‬
‭discontinued‬‭due‬‭to‬‭toxicity‬‭for‬‭up‬‭to‬‭6‬‭weeks‬‭(longer‬‭interruptions‬‭shall‬‭be‬‭discussed‬‭and‬
‭approved‬‭by‬‭the‬‭medical‬‭monitor‬‭on‬‭an‬‭individual‬‭basis).‬‭If‬‭toxicity‬‭has‬‭not‬‭recovered‬‭to‬‭at‬
‭least‬ ‭a‬ ‭grade‬ ‭1‬‭the‬‭patient‬‭shall‬‭be‬‭permanently‬‭discontinued‬‭from‬‭the‬‭study.‬‭Longer‬‭dose‬
‭interruptions.‬
‭●‬ ‭If‬ ‭a‬ ‭dose‬ ‭reduction‬ ‭for‬ ‭toxicity‬ ‭occurs‬ ‭with‬ ‭any‬ ‭agent,‬ ‭the‬ ‭dose‬‭may‬‭not‬‭be‬‭re-escalated.‬
‭Subjects‬‭can‬‭have‬‭a‬‭maximum‬‭of‬‭2‬‭dose‬‭modifications‬‭to‬‭each‬‭of‬‭the‬‭components‬‭of‬‭study‬
‭therapy‬ ‭throughout‬ ‭the‬ ‭course‬ ‭of‬ ‭the‬ ‭study‬ ‭for‬ ‭toxicities.‬ ‭If‬ ‭a‬‭subject‬‭experiences‬‭several‬
‭toxicities‬‭and‬‭there‬‭are‬‭conflicting‬‭recommendations,‬‭dose‬‭reduction‬‭will‬‭be‬‭done‬‭according‬
‭to‬‭the‬‭most‬‭severe‬‭toxicity.‬‭Subjects‬‭who‬‭require‬‭a‬‭3rd‬‭dose‬‭modification‬‭to‬‭any‬‭particular‬
‭component will have that agent discontinued.‬
‭●‬ ‭Reduction‬‭of‬‭one‬‭chemotherapy‬‭agent‬‭and‬‭not‬‭the‬‭other‬‭agent‬‭is‬‭appropriate‬‭if,‬‭in‬‭the‬‭opinion‬
‭of‬‭the‬‭investigator,‬‭the‬‭toxicity‬‭is‬‭clearly‬‭related‬‭to‬‭one‬‭of‬‭the‬‭treatments.‬‭If,‬‭in‬‭the‬‭opinion‬‭of‬
‭the‬‭investigator,‬‭the‬‭toxicity‬‭is‬‭related‬‭to‬‭the‬‭combination‬‭of‬‭both‬‭chemotherapy‬‭agents,‬‭both‬
‭drugs‬ ‭should‬ ‭be‬ ‭reduced‬ ‭according‬ ‭to‬ ‭recommended‬ ‭dose‬ ‭modifications.‬‭If‬‭the‬‭toxicity‬‭is‬
‭related‬‭to‬‭the‬‭combination‬‭of‬‭three‬‭agents,‬‭chemotherapy‬‭should‬‭be‬‭reduced,‬‭interrupted‬‭or‬
‭discontinued‬ ‭and‬ ‭nivolumab‬ ‭should‬ ‭be‬ ‭interrupted‬ ‭or‬ ‭discontinued‬ ‭according‬ ‭to‬ ‭the‬
‭recommended dose modifications.‬
‭Table 5.2. Dose modifications for trial medications‬
‭Drug‬
‭Dose level 0‬
‭Dose level -1‬
‭Dose level -2‬
‭Dose level -3‬
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‭Carboplatin‬
‭AUC 5‬
‭AUC 4‬
‭AUC 3‬
‭Discontinue‬
‭Etoposide‬
‭100 mg/m2‬
‭80 mg/m2‬
‭60 mg/m2‬
‭Discontinue‬
‭Nivolumab‬
‭360 mg/m2‬
‭Dose reductions not permitted‬
‭5.2.1.‬ ‭Dose modifications for Nivolumab‬
‭There‬‭will‬‭be‬‭no‬‭dose‬‭reductions‬‭for‬‭nivolumab.‬‭Adverse‬‭events‬‭(AEs),‬‭both‬‭non-serious‬‭and‬‭serious,‬
‭associated‬‭with‬‭nivolumab‬‭exposure‬‭may‬‭represent‬‭an‬‭immunologic‬‭etiology.‬‭These‬‭adverse‬‭events‬
‭may‬‭occur‬‭shortly‬‭after‬‭the‬‭first‬‭dose‬‭or‬‭several‬‭months‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭treatment.‬‭AEs‬‭can‬‭differ‬
‭in‬ ‭severity‬ ‭and‬ ‭duration‬ ‭from‬ ‭AEs‬ ‭caused‬ ‭by‬ ‭other‬ ‭therapeutic‬ ‭classes.‬ ‭Early‬ ‭recognition‬ ‭and‬
‭management‬ ‭of‬ ‭AEs‬ ‭associated‬ ‭with‬ ‭immune-oncology‬ ‭agents‬ ‭may‬ ‭mitigate‬ ‭severe‬ ‭toxicity.‬
‭Nivolumab‬ ‭must‬ ‭be‬ ‭withheld‬ ‭for‬ ‭drug-related‬ ‭toxicities‬ ‭and‬ ‭severe‬‭or‬‭life-threatening‬‭AEs‬‭as‬‭per‬
‭Table 5.2.1‬‭below.‬
‭Table 5.2.1 Nivolumab guidelines for drug-related adverse events.‬
‭Toxicity‬
‭Grade‬
‭of event‬
‭Management‬
‭Follow-up‬
‭Diarrhea/Colitis‬
‭1‬
‭Continue immunotherapy per‬
‭protocol.‬
‭Symptomatic treatment‬
‭-Close monitoring for worsening‬
‭symptoms.‬
‭-Educate patient to report worsening‬
‭immediately.‬
‭If worsens:‬
‭-Treat as Grade 2 or 3/4.‬
‭2‬
‭Hold treatment until toxicity resolves‬
‭to grade 0-1.‬
‭Symptomatic treatment.‬
‭If improves to grade 1‬‭:‬
‭-resume therapy per protocol‬
‭If persists> 5-7 days or recur‬‭:‬
‭-0.5-1.0 mg/kg/day methylprednisolone‬
‭or equivalent.‬
‭-When symptoms improve to grade 1,‬
‭taper steroids over at least 1 month,‬
‭consider prophylactic antibiotic for‬
‭opportunistic infections, and resume‬
‭immunotherapy per protocol.‬
‭If worsens or persists>3-5 days with oral‬
‭steroids:‬
‭-Treat as grade 3-4.‬
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‭3-4‬
‭-Discontinue treatment.‬
‭-1.0 to 2.0 mg/kg/day‬
‭methylprednisolone IV or equivalent.‬
‭- Add prophylactic antibiotics for‬
‭opportunistic infections.‬
‭-Consider lower endoscopy‬
‭If improves:‬
‭-Continue steroids until grade 1, then‬
‭taper over at least 1 month.‬
‭If persists >3-5 days or recurs after‬
‭improvement:‬
‭-Add infliximab 5mg/kg (if no‬
‭contraindication).‬
‭Note: infliximab should not be used in‬
‭cases of perforation or sepsis.‬
‭AST, ALT,‬
‭Bilirubin‬
‭1‬
‭Continue treatment per protocol‬
‭Continue LFT monitoring per protocol.‬
‭If worsens:‬
‭-Treat as Grade 2 or 3-4.‬
‭2‬
‭-Hold treatment until toxicity resolves‬
‭to grade 0-1‬
‭-Increase frequency of monitoring to‬
‭every 3 days.‬
‭If returns to baseline:‬
‭-Resume routine monitoring, resume‬
‭therapy per protocol.‬
‭If elevations persist >5-7 days or worsen:‬
‭-0.5-1 mg/kg/day methylprednisolone or‬
‭oral equivalent and when LFT returns to‬
‭grade 1 or baseline, taper steroids over at‬
‭least 1 month, consider prophylactic‬
‭antibiotics for opportunistic infections‬
‭and resumen therapy per protocol.‬
‭AST, ALT,‬
‭Bilirubin‬
‭3-4‬
‭-Discontinue nivolumab‬‭1‬
‭-Increase frequency of monitoring to‬
‭every 1-2 days.‬
‭-1.0 to 2.0 mg/kg/day‬
‭methylprednisolone IV or IV‬
‭equivalent‬‭2‬
‭If returns to grade 2‬‭:‬
‭-Taper steroids over at least 1 month.‬
‭If does not improve in >3-5 days, worsens‬
‭or rebounds:‬
‭-Add mycophenolate mofetil 1 g BID.‬
‭-If no response within an additional 3-5‬
‭days, consider other immunosuppressants‬
‭per local guidelines.‬
‭Skin Rash‬
‭1-2‬
‭-Symptomatic therapy (eg.‬
‭antihistamines, topical steroids).‬
‭-Continue nivolumab per protocol.‬
‭If persists >1-2 weeks or recurs:‬
‭-Consider skin biopsy.‬
‭-Delay nivolumab per protocol.‬
‭-Consider 0.5-1.0 mg/kg/day‬
‭methylprednisolone IV or oral equivalent.‬
‭Once improving, taper steroids over at‬
‭least 1 month, consider prophylactic‬
‭antibiotics for opportunistic infections,‬
‭and resume nivolumab per protocol.‬
‭If worsens:‬
‭-Treat as Grade 3-4.‬
‭3-4‬
‭-Hold or discontinue nivolumab per‬
‭protocol.‬
‭-Consider skin biopsy.‬
‭-Dermatology consult.‬
‭-1.0 to 2.0 mg/kg/day‬
‭methylprednisolone IV or IV‬
‭equivalent.‬
‭If it improves to Grade 1:‬
‭-Taper steroids over at least 1 month and‬
‭add prophylactic antibiotics for‬
‭opportunistic infections.‬
‭- Resume nivolumab per protocol.‬
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‭Pneumonitis‬
‭1‬
‭-Consider delay of nivolumab.‬
‭-Monitor for symptoms every 2-3‬
‭days.‬
‭-Consider Pulmonary and ID consults.‬
‭-Re-image at least every 3 weeks.‬
‭If worsens:‬
‭-Treat as Grade 2 or 3-4‬
‭2‬
‭-Delay of nivolumab per protocol.‬
‭-Monitor for symptoms daily,consider‬
‭hospitalization.‬
‭- Pulmonary and ID consults.‬
‭-1.0 mg/kg/day methylprednisolone‬
‭IV or oral equivalent.‬
‭- Consider bronchoscopy, lung biopsy.‬
‭-Re-image every 1-3 days.‬
‭If improves:‬
‭-When symptoms return to near baseline,‬
‭taper steroids over at least 1 month and‬
‭then resume nivolumab per protocol and‬
‭consider prophylactic antibiotics.‬
‭If not improving after 2 weeks or‬
‭worsening:‬
‭-Treat as Grade 3-4.‬
‭Pneumonitis‬
‭3-4‬
‭-Discontinue nivolumab per protocol.‬
‭-Hospitalize.‬
‭-Pulmonary and ID consults.‬
‭-2-4 mg/kg/day methylprednisolone‬
‭IV or equivalent.‬
‭-Add prophylactic antibiotics for‬
‭opportunistic infections.‬
‭- Consider bronchoscopy, lung biopsy.‬
‭If improves to baseline:‬
‭-Taper steroids over at least 6 weeks.‬
‭If not improving after 48 hours or‬
‭worsening‬‭:‬
‭-Add additional immunosuppression.‬
‭Renal failure or‬
‭nephritis‬
‭1‬
‭-Continue nivolumab per protocol.‬
‭-Monitor creatinine weekly‬
‭If returns to baseline:‬
‭-Resume routine creatinine monitoring‬
‭per protocol.‬
‭If worsens:‬
‭-Treat as Grade 2 or 3-4.‬
‭2-3‬
‭-Hold nivolumab per protocol.‬
‭-Monitor creatinine every 2-3 days.‬
‭0.5-1 mg/kg/day methylprednisolone‬
‭IV or equivalent.‬
‭-Consider renal biopsy with‬
‭nephrology consult.‬
‭If returns to Grade 1‬‭:‬
‭-Taper steroids over at least 1 month,‬
‭consider prophylactic antibiotics for‬
‭opportunistic infections, and resume‬
‭nivolumab and routine creatinine‬
‭monitoring per protocol.‬
‭If elevations persist >7 days or worsen:‬
‭-Treat as Grade 4.‬
‭4‬
‭-Discontinue nivolumab per protocol.‬
‭-Monitor creatinine daily.‬
‭-1.0-2.0mg/kg/day‬
‭methylprednisolone IV or IV‬
‭equivalent.‬
‭-Consider renal biopsy.‬
‭- Consult nephrologist.‬
‭If returns to Grade 1‬‭:‬
‭-Taper steroids over at least 1 month,‬
‭consider prophylactic antibiotics for‬
‭opportunistic infections.‬
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‭Management‬
‭Follow-up‬
‭Asymptomatic‬
‭TSH elevation‬
‭-Continue nivolumab per protocol.‬
‭-If TSH<0.5 X LLN, or TSH>2 x ULN, or consistently out of range in 2 subsequent‬
‭measurements :include fT4 at subsequent cycles as clinically indicated; consider endocrinology‬
‭consult.‬
‭Symptomatic‬
‭endocrinopathy‬
‭-Evaluate endocrine function.‬
‭-Consider pituitary scan.‬
‭Symptomatic with abnormal lab/pituitary scan:‬
‭-Delay nivolumab per protocol.‬
‭-1-2 mg/kg/day methylprednisolone or PO‬
‭equivalent.‬
‭-Initiate appropriate hormone therapy.‬
‭No abnormal lab/pituitary MRI scan but‬
‭symptoms persist:‬
‭-Repeat labs in 1-3 weeks/MRI in 1 month.‬
‭If improves (with or without hormone‬
‭replacement):‬
‭-Taper steroids over at least 1 month,‬
‭consider prophylactic antibiotics for‬
‭opportunistic infections.‬
‭-Resume nivolumab per protocol.‬
‭- Patients with adrenal insufficiency may‬
‭need to continue steroids with‬
‭mineralocorticoid component.‬
‭Suspicion of‬
‭adrenal crisis (e.g.‬
‭severe‬
‭dehydration,‬
‭hypotension, shock‬
‭out of proportion‬
‭to current illness)‬
‭-Delay or Discontinue nivolumab therapy per protocol.‬
‭-Rule out sepsis.‬
‭-Stress dose of IV steroids with mineralocorticoid activity.‬
‭-IV fluids.‬
‭-Consult endocrinologist.‬
‭-If adrenal crisis ruled out, then trat as above for symptomatic endocrinopathy.‬
‭1‬‭Nivolumab may be delayed rather than discontinued‬‭if AST/ALT ≤ 8 X ULN or Total Bilirubin ≤ 5 x ULN.‬
‭2‬‭The recommended starting dose for grade 4 hepatitis‬‭is 2 mg/kg/day methylprednisolone IV.‬
‭3‬‭Patients with intolerable or persistent Grade 2‬‭drug-related AE may hold study medication at physician discretion.‬
‭Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has‬
‭been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.‬
‭5.2.2.‬ ‭Dose modifications for Chemotherapy‬
‭Dose‬‭reductions‬‭of‬‭chemotherapy‬‭may‬‭be‬‭required,‬‭and‬‭will‬‭be‬‭performed‬‭according‬‭to‬‭Table‬‭5.2.2.‬
‭Chemotherapy‬‭dose‬‭reductions‬‭are‬‭permanent;‬‭once‬‭the‬‭dose‬‭of‬‭any‬‭chemotherapy‬‭agent‬‭is‬‭reduced,‬‭it‬
‭may‬ ‭not‬ ‭be‬ ‭re-escalated‬ ‭in‬ ‭subsequent‬ ‭cycles.‬ ‭The‬ ‭dose‬ ‭reductions‬ ‭for‬ ‭each‬ ‭agent‬ ‭in‬ ‭the‬
‭platinum-based‬‭doublet‬‭chemotherapy‬‭regimen‬‭are‬‭not‬‭linked‬‭and‬‭may‬‭be‬‭adjusted‬‭independently‬‭as‬
‭summarized below.‬
‭Table 5.2.2 Dose modifications for Chemotherapeutic Agents‬
‭Drug‬
‭Dose level 0‬
‭Dose level -1‬
‭Dose level -2‬
‭Dose level -3‬
‭Carboplatin‬
‭AUC 5‬
‭AUC 4‬
‭AUC 3‬
‭Discontinue‬
‭Etoposide‬
‭100 mg/m2‬
‭80 mg/m2‬
‭60 mg/m2‬
‭Discontinue‬
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‭Any‬‭participants‬‭with‬‭two‬‭prior‬‭dose‬‭reductions‬‭for‬‭one‬‭agent‬‭who‬‭experiences‬‭a‬‭toxicity‬‭that‬‭would‬
‭cause a third dose reduction must be discontinued from that agent.‬
‭5.2.2.1 Dose Reductions for Hematologic Adverse Events‬
‭Dose‬‭modifications‬‭for‬‭hematologic‬‭toxicities‬‭(according‬‭to‬‭CTCAE‬‭version‬‭5.0)‬‭are‬‭summarized‬‭in‬
‭Table-5.2.2.1‬‭.‬
‭Dose‬ ‭adjustments‬ ‭are‬ ‭based‬ ‭on‬ ‭nadir‬ ‭blood‬ ‭counts‬ ‭(assessed‬ ‭as‬ ‭per‬ ‭local‬ ‭standards)‬ ‭since‬ ‭the‬
‭preceding‬‭drug‬‭administration.‬‭Dose‬‭level‬‭adjustments‬‭for‬‭platinum-based‬‭doublet‬‭chemotherapy‬‭are‬
‭relative‬ ‭to‬ ‭that‬ ‭of‬ ‭the‬ ‭preceding‬ ‭administration.‬ ‭Generally,‬ ‭both‬ ‭chemotherapy‬ ‭agents‬ ‭in‬ ‭the‬
‭platinum-based‬ ‭doublet‬ ‭chemotherapy‬ ‭regimen‬ ‭should‬ ‭be‬ ‭dose‬ ‭reduced‬ ‭together‬ ‭for‬ ‭hematologic‬
‭toxicity.‬‭After‬‭the‬‭first‬‭cycle,‬‭growth‬‭factors‬‭may‬‭be‬‭used‬‭to‬‭assist‬‭hematologic‬‭recovery.‬‭Use‬‭local‬
‭standards‬‭of‬‭care‬‭in‬‭the‬‭use‬‭of‬‭these‬‭supportive‬‭measures.‬‭Additionally,‬‭prophylactic‬‭antibiotics‬‭may‬
‭be‬‭used‬‭according‬‭to‬‭local‬‭standards‬‭of‬‭care.‬‭Please‬‭report‬‭any‬‭antibiotic‬‭or‬‭growth‬‭factor‬‭use‬‭on‬‭the‬
‭eCRF.‬
‭Table 5.2.2.1 Dose modifications for carboplatin/etoposide hematologic adverse events‬
‭Toxicity‬
‭Grade‬
‭Action‬
‭Treatment Restart‬
‭Treatment discontinuation‬
‭Neutropenia‬
‭3‬
‭Hold treatment until‬
‭Neutrophil count resolves‬
‭to >1,500/mm3‬
‭No dose reduction‬
‭required if‬
‭neutropenia does not‬
‭induce treatment‬
‭delay. If neutropenia‬
‭induces treatment‬
‭delay consider G-CSF‬
‭support. If already con‬
‭G-CSF support reduce‬
‭by 1 DL (at the‬
‭discretion of the‬
‭investigator)‬
‭Toxicity does not resolve‬
‭within 6 weeks of last‬
‭infusion‬
‭or if > 2 Dose Level‬
‭reductions are‬
‭exceeded‬
‭4‬
‭Hold treatment until‬
‭neutrophil count resolves‬
‭to >1,500/mm‬‭3‬
‭Reduce by 1 DL‬
‭*consider G-CSF‬
‭Febrile Neutropenia‬
‭3-4‬
‭Hold treatment until‬
‭toxicity resolves to‬
‭Grade 0-1‬
‭Reduce by 1 DL‬
‭Toxicity does not resolve‬
‭within 6 weeks of last‬
‭infusion‬
‭or if > 2 Dose Level‬
‭reductions are‬
‭exceeded‬
‭Thrombocytopenia‬
‭3-4‬
‭Platelet count resolves‬
‭to >100,000/mm3‬
‭Reduce by 1 DL‬
‭Toxicity does not resolve‬
‭within 6 weeks of last‬
‭infusion or if > 2 Dose Level‬
‭reductions‬
‭exceeded‬
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‭5.2.2.2.‬‭Dose Reductions for Non-Hematologic Adverse Events‬
‭Dose‬‭adjustments‬‭for‬‭chemotherapy‬‭for‬‭non-hematologic‬‭toxicities‬‭during‬‭treatment‬‭are‬‭described‬‭in‬
‭Section‬‭5.2.2.‬‭All‬‭dose‬‭reductions‬‭should‬‭be‬‭made‬‭based‬‭on‬‭the‬‭worst‬‭grade‬‭toxicity‬‭during‬‭the‬‭prior‬
‭cycle.‬ ‭Participants‬ ‭experiencing‬ ‭any‬ ‭toxicity‬ ‭during‬ ‭the‬ ‭previous‬ ‭cycle‬ ‭should‬ ‭have‬ ‭their‬
‭chemotherapy‬ ‭delayed‬ ‭up‬ ‭to‬ ‭3‬ ‭weeks‬ ‭(6‬ ‭weeks‬ ‭since‬‭the‬‭administration‬‭of‬‭the‬‭last‬‭chemotherapy‬
‭infusion)‬‭until‬‭retreatment‬‭criteria‬‭are‬‭met‬‭and‬‭then‬‭reduced‬‭for‬‭all‬‭subsequent‬‭cycles‬‭by‬‭1‬‭dose‬‭level‬
‭or‬‭discontinued‬‭as‬‭appropriate.‬‭Dose‬‭levels‬‭for‬‭the‬‭two‬‭drugs‬‭in‬‭the‬‭platinum-doublet‬‭chemotherapy‬
‭regimen are not linked and may be reduced independently, as summarized in‬‭Table-5.2.2.2.‬
‭Table 5.2.2.2. Dose modifications for non-hematologic adverse events‬
‭Toxicity‬
‭Grade‬
‭Action‬
‭Treatment Restart‬
‭Creatinine increased‬
‭2‬
‭Hold treatment until toxicity resolves to‬
‭Grade 0-1‬
‭Reduce cisplatin by 1‬
‭DL‬
‭3-4‬‭1‬
‭Discontinue carboplatin if creatinine‬
‭clearance <20 ml/min‬
‭Discontinue treatment‬
‭Ototoxicity or sensory‬
‭neuropathy‬
‭2‬
‭Hold treatment  until toxicity resolves to‬
‭Grade 0-1‬
‭Reduce cisplatin by 1‬
‭DL‬
‭≥ 3‬
‭Discontinue chemotherapy‬
‭Discontinue‬
‭chemotherapy‬
‭Allergic reaction‬‭a‬
‭≥ 3‬
‭Discontinue chemotherapy‬
‭Discontinue‬
‭chemotherapy‬
‭All other non-hematological‬
‭toxicities‬
‭3-4‬
‭Hold treatment until toxicity resolves to‬
‭Grade 0-1.‬
‭Reduce by 1 DL‬
‭a‬ ‭Only‬ ‭the‬ ‭drug(s)‬ ‭causing‬ ‭the‬ ‭hypersensitivity‬ ‭reaction‬ ‭or‬ ‭acute‬ ‭infusion‬ ‭reaction‬ ‭(≥‬ ‭Grade‬ ‭3)‬ ‭require‬
‭discontinuation. All other drugs may be continued.‬
‭5.2.3.‬ ‭Dose Delay Criteria‬
‭5.2.3.1.‬‭Dose delay Criteria for Nivolumab‬
‭Tumor assessments for all participants should continue as per protocol even if dosing is delayed.‬
‭Nivolumab administration should be delayed for the following:‬
‭●‬ ‭Any‬ ‭Grade‬ ‭≥‬ ‭2‬ ‭non-skin,‬ ‭drug-related‬ ‭adverse‬ ‭event,‬ ‭except‬ ‭for‬ ‭fatigue‬ ‭and‬ ‭laboratory‬
‭abnormalities.‬
‭●‬ ‭Any Grade ≥ 3 skin drug-related AE.‬
‭●‬ ‭Any‬ ‭Grade‬ ‭≥‬ ‭3‬ ‭drug-related‬ ‭laboratory‬ ‭abnormality‬ ‭with‬ ‭the‬ ‭following‬ ‭exceptions‬ ‭for‬
‭lymphopenia, AST, ALT, or total bilirubin or asymptomatic amylase or lipase:‬
‭○‬ ‭Grade 3 lymphopenia does not require a dose delay‬
‭If‬‭a‬‭participant‬‭has‬‭a‬‭baseline‬‭AST,‬‭ALT,‬‭or‬‭total‬‭bilirubin‬‭that‬‭is‬‭within‬‭normal‬‭limits,‬‭delay‬‭dosing‬
‭for drug-related Grade 2 toxicity.‬
‭If‬‭a‬‭participant‬‭has‬‭baseline‬‭AST,‬‭ALT,‬‭or‬‭total‬‭bilirubin‬‭within‬‭the‬‭Grade‬‭1‬‭toxicity‬‭range,‬‭delay‬
‭dosing for drug-related Grade ≥ 3 toxicity.‬
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‭●‬ ‭Any‬ ‭Grade‬ ‭≥‬ ‭3‬ ‭drug-related‬ ‭amylase‬ ‭or‬ ‭lipase‬ ‭abnormality‬ ‭that‬ ‭is‬ ‭not‬ ‭associated‬ ‭with‬
‭symptoms or clinical manifestations of pancreatitis does not require dose delay.‬
‭●‬ ‭Any‬ ‭AE,‬ ‭laboratory‬ ‭abnormality‬ ‭or‬ ‭intercurrent‬ ‭illness,‬ ‭which,‬ ‭in‬ ‭the‬ ‭judgment‬ ‭of‬ ‭the‬
‭investigator, warrants delaying the dose of study medication.‬
‭Participants‬ ‭who‬ ‭require‬ ‭delay‬ ‭should‬ ‭be‬ ‭re-evaluated‬ ‭weekly‬ ‭or‬ ‭more‬ ‭frequently‬ ‭if‬ ‭clinically‬
‭indicated. Participants should resume dosing when re-treatment criteria are met.‬
‭5.2.3.2.‬‭Dose delay Criteria for Chemotherapy‬
‭Chemotherapy drugs should be delayed for any of the following on the Day 1 of each cycle:‬
‭●‬ ‭Absolute neutrophil count (ANC) < 1500/L‬
‭●‬ ‭Platelets < 100,000/mm3‬
‭●‬ ‭Any‬ ‭Grade‬ ‭≥‬ ‭2‬‭non-skin,‬‭non-hematologic,‬‭drug-related‬‭adverse‬‭event‬‭(excluding‬‭Grade‬‭2‬
‭alopecia, Grade 2 fatigue, and Grade 2 laboratory abnormalities)‬
‭●‬ ‭Any Grade ≥ 3 skin, drug-related adverse event‬
‭●‬ ‭Any‬ ‭Grade‬ ‭≥‬ ‭3‬ ‭drug-related‬ ‭laboratory‬ ‭abnormality,‬ ‭with‬ ‭the‬ ‭following‬ ‭exceptions‬ ‭for‬
‭lymphopenia, AST, ALT, or total bilirubin:‬
‭○‬ ‭Grade 3 lymphopenia does not require dose delay.‬
‭○‬ ‭If‬‭a‬‭participant‬‭has‬‭a‬‭baseline‬‭AST,‬‭ALT‬‭or‬‭total‬‭bilirubin‬‭that‬‭is‬‭within‬‭normal‬‭limits,‬
‭delay dosing for drug-related Grade ≥ 2 toxicity.‬
‭o‬ ‭If‬‭a‬‭participant‬‭has‬‭baseline‬‭AST,‬‭ALT,‬‭or‬‭total‬‭bilirubin‬‭within‬‭the‬‭Grade‬‭1‬‭toxicity‬‭range,‬
‭delay dosing for drug-related Grade ≥ 3 toxicity.‬
‭●‬ ‭Any‬‭adverse‬‭event,‬‭laboratory‬‭abnormality,‬‭or‬‭intercurrent‬‭illness,‬‭which,‬‭in‬‭the‬‭judgment‬‭of‬
‭the investigator, warrants delaying the dose of study medication.‬
‭Investigators‬ ‭should‬ ‭consult‬ ‭local‬ ‭labeling‬ ‭for‬ ‭the‬ ‭chemotherapy‬ ‭drugs‬ ‭being‬‭administered‬‭to‬‭any‬
‭given participant for additional guidance on dose delays.‬
‭If‬‭any‬‭non-hematologic‬‭adverse‬‭event‬‭meeting‬‭the‬‭dose‬‭delay‬‭criteria‬‭above‬‭is‬‭felt‬‭to‬‭be‬‭related‬‭to‬‭only‬
‭one‬‭particular‬‭agent‬‭in‬‭the‬‭platinum-based‬‭doublet‬‭chemotherapy‬‭regimen,‬‭then‬‭that‬‭agent‬‭alone‬‭may‬
‭be‬‭omitted‬‭for‬‭that‬‭cycle‬‭while‬‭the‬‭other‬‭agent‬‭is‬‭given.‬‭In‬‭order‬‭to‬‭maintain‬‭synchronized‬‭dosing‬‭of‬
‭the‬ ‭regimen,‬‭the‬‭omitted‬‭agent‬‭should‬‭be‬‭resumed‬‭with‬‭the‬‭next‬‭scheduled‬‭cycle‬‭once‬‭the‬‭AE‬‭has‬
‭improved‬‭and‬‭retreatment‬‭criteria‬‭are‬‭met.‬‭Please‬‭refer‬‭to‬‭Section‬‭5.2.2‬‭to‬‭determine‬‭if‬‭dose‬‭reduction‬
‭of the resumed agent is required.‬
‭If‬‭both‬‭drugs‬‭in‬‭the‬‭platinum-based‬‭doublet‬‭chemotherapy‬‭regimen‬‭are‬‭delayed,‬‭then‬‭the‬‭participant‬
‭should‬‭be‬‭re-evaluated‬‭weekly‬‭or‬‭more‬‭frequently‬‭if‬‭clinically‬‭indicated‬‭until‬‭retreatment‬‭criteria‬‭are‬
‭met (as per‬‭Section 5.2.4‬‭).‬
‭5.2.4.‬ ‭Criteria to Resume Dosing‬
‭5.2.4.1.‬‭Criteria to Resume Nivolumab Dosing‬
‭Participants‬‭may‬‭resume‬‭treatment‬‭with‬‭nivolumab‬‭when‬‭the‬‭drug-related‬‭AE(s)‬‭resolve(s)‬‭to‬‭Grade‬‭≤‬
‭1 or baseline, with the following exceptions:‬
‭●‬ ‭Participants may resume treatment in the presence of Grade 2 fatigue.‬
‭●‬ ‭Participants‬‭who‬‭have‬‭not‬‭experienced‬‭a‬‭Grade‬‭3‬‭drug-related‬‭skin‬‭AE‬‭may‬‭resume‬‭treatment‬
‭in the presence of Grade 2 skin toxicity.‬
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‭●‬ ‭Participants‬‭with‬‭baseline‬‭Grade‬‭1‬‭AST/ALT‬‭or‬‭total‬‭bilirubin‬‭who‬‭require‬‭dose‬‭delays‬‭for‬
‭reasons‬‭other‬‭than‬‭a‬‭2-grade‬‭shift‬‭in‬‭AST/ALT‬‭or‬‭total‬‭bilirubin‬‭may‬‭resume‬‭treatment‬‭in‬‭the‬
‭presence of Grade 2 AST/ALT OR total bilirubin.‬
‭●‬ ‭Participants‬ ‭with‬ ‭combined‬ ‭Grade‬ ‭2‬ ‭AST/ALT‬ ‭and‬ ‭total‬ ‭bilirubin‬ ‭values‬ ‭meeting‬
‭discontinuation parameters (‬‭Section 6.1.1‬‭) should‬‭have treatment permanently discontinued.‬
‭●‬ ‭Drug-related‬ ‭pulmonary‬ ‭toxicity,‬ ‭diarrhea,‬‭or‬‭colitis‬‭must‬‭have‬‭resolved‬‭to‬‭baseline‬‭before‬
‭treatment‬‭is‬‭resumed.‬‭Participants‬‭with‬‭persistent‬‭Grade‬‭1‬‭pneumonitis‬‭after‬‭completion‬‭of‬‭a‬
‭steroid‬ ‭taper‬ ‭over‬ ‭at‬ ‭least‬ ‭1‬ ‭month‬ ‭may‬ ‭be‬ ‭eligible‬ ‭for‬ ‭retreatment‬ ‭if‬‭discussed‬‭with‬‭and‬
‭approved by the BMS Medical Monitor.‬
‭●‬ ‭Participants‬ ‭who‬ ‭received‬ ‭systemic‬ ‭corticosteroids‬ ‭for‬ ‭management‬ ‭of‬ ‭any‬ ‭drug-related‬
‭toxicity‬‭must‬‭be‬‭off‬‭corticosteroids‬‭or‬‭have‬‭tapered‬‭down‬‭to‬‭an‬‭equivalent‬‭dose‬‭of‬‭prednisone‬
‭≤ 10 mg/day.‬
‭●‬ ‭Drug-related‬ ‭endocrinopathies‬ ‭adequately‬ ‭controlled‬ ‭with‬ ‭only‬ ‭physiologic‬ ‭hormone‬
‭replacement may resume treatment.‬
‭●‬ ‭Dose‬ ‭delay‬ ‭of‬ ‭nivolumab‬ ‭which‬ ‭results‬ ‭in‬ ‭treatment‬ ‭interruption‬ ‭of‬ ‭>‬ ‭6‬ ‭weeks‬ ‭requires‬
‭treatment discontinuation, with exceptions as noted in‬‭Section 6.1.1‬
‭5.2.4.2.‬‭Criteria to Resume Treatment with Chemotherapy‬
‭●‬ ‭Participants‬‭may‬‭resume‬‭treatment‬‭with‬‭chemotherapy‬‭when‬‭the‬‭ANC‬‭returns‬‭to‬‭1500/μl,‬‭the‬
‭platelet‬‭count‬‭returns‬‭to‬‭100,000/mm3,‬‭and‬‭all‬‭other‬‭drug-related‬‭toxicities‬‭have‬‭returned‬‭to‬
‭baseline or Grade 1 (or Grade 2 for alopecia and fatigue).‬
‭●‬ ‭If‬‭a‬‭participant‬‭fails‬‭to‬‭meet‬‭criteria‬‭for‬‭re-treatment,‬‭then‬‭re-treatment‬‭should‬‭be‬‭delayed,‬‭and‬
‭the‬‭participant‬‭should‬‭be‬‭re-evaluated‬‭weekly‬‭or‬‭more‬‭frequently‬‭as‬‭clinically‬‭indicated.‬‭Any‬
‭participant‬ ‭who‬ ‭fails‬ ‭to‬ ‭recover‬ ‭from‬ ‭toxicity‬ ‭attributable‬ ‭to‬ ‭chemotherapy‬ ‭to‬ ‭baseline‬‭or‬
‭Grade‬‭1‬‭(except‬‭Grade‬‭2‬‭alopecia‬‭and‬‭fatigue)‬‭within‬‭6‬‭weeks‬‭from‬‭the‬‭last‬‭dose‬‭given‬‭should‬
‭discontinue the drug(s) that caused the delay.‬
‭●‬ ‭When‬‭resuming‬‭chemotherapy‬‭treatment,‬‭please‬‭follow‬‭the‬‭dose‬‭reduction‬‭recommendations‬
‭in‬‭Section 5.2.2.‬
‭5.3.‬
‭Duration of Therapy‬
‭●‬ ‭During‬‭the‬‭“induction‬‭phase”‬‭six‬‭cycles‬‭of‬‭chemotherapy‬‭in‬‭combination‬‭with‬‭nivolumab‬‭will‬
‭be‬ ‭given‬ ‭unless‬ ‭disease‬‭progression‬‭(see‬‭definition‬‭Section‬‭7)‬‭or‬‭unacceptable‬‭toxicity‬‭are‬
‭encountered.‬
‭●‬ ‭If‬‭no‬‭progression‬‭or‬‭unacceptable‬‭toxicity‬‭are‬‭observed‬‭after‬‭the‬‭induction‬‭phase,‬‭the‬‭patient‬
‭will‬‭continue‬‭to‬‭receive‬‭nivolumab‬‭480‬‭mg‬‭every‬‭4‬‭weeks.‬‭The‬‭maximum‬‭treatment‬‭duration‬
‭is 24 months or 34 cycles including the induction phase.‬
‭●‬ ‭End of treatment‬
‭Patients‬ ‭will‬ ‭continue‬ ‭study‬ ‭treatment‬ ‭until‬ ‭disease‬ ‭progression‬ ‭per‬ ‭RECIST‬ ‭1.1‬ ‭or,‬
‭unacceptable‬‭toxicity,‬‭withdrawal‬‭of‬‭consent,‬‭physician’s‬‭decision,‬‭subject/guardian‬‭decision,‬
‭lost‬‭to‬‭follow-up,‬‭death,‬‭study‬‭treatment‬‭completion‬‭(24‬‭months)‬‭or‬‭the‬‭study‬‭is‬‭terminated‬‭by‬
‭the Sponsor.‬
‭5.3.1.‬ ‭Treatment Beyond Disease Progression‬
‭Accumulating‬‭evidence‬‭indicates‬‭a‬‭minority‬‭of‬‭participants‬‭treated‬‭with‬‭immunotherapy‬‭may‬‭derive‬
‭clinical benefit despite initial evidence of PD.‬
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‭Participants‬ ‭will‬ ‭be‬ ‭permitted‬ ‭to‬ ‭continue‬ ‭on‬ ‭nivolumab‬ ‭for‬‭treatment‬‭beyond‬‭initial‬‭RECIST‬‭1.1‬
‭defined PD as long as they meet the following criteria:‬
‭●‬ ‭Investigator-assessed clinical benefit and no rapid disease progression.‬
‭●‬ ‭Participant is tolerating study treatment.‬
‭●‬ ‭Stable performance status.‬
‭●‬ ‭Treatment‬ ‭beyond‬ ‭progression‬ ‭will‬ ‭not‬ ‭delay‬ ‭an‬ ‭imminent‬ ‭intervention‬ ‭to‬‭prevent‬‭serious‬
‭complications of disease progression (eg, CNS metastases).‬
‭●‬ ‭Participant‬ ‭provides‬ ‭written‬ ‭informed‬ ‭consent‬ ‭prior‬ ‭to‬ ‭receiving‬ ‭additional‬ ‭nivolumab‬
‭treatment,‬‭using‬‭an‬‭ICF‬‭describing‬‭any‬‭reasonably‬‭foreseeable‬‭risks‬‭or‬‭discomforts,‬‭or‬‭other‬
‭alternative treatment options.‬
‭The‬‭decision‬‭to‬‭continue‬‭treatment‬‭beyond‬‭initial‬‭investigator-assessed‬‭progression‬‭should‬‭be‬
‭discussed‬‭with‬‭the‬‭BMS‬‭Medical‬‭Monitor‬‭and‬‭documented‬‭in‬‭the‬‭study‬‭records.‬‭A‬‭follow-up‬‭scan‬
‭should‬‭be‬‭performed‬‭within‬‭six‬‭weeks‬‭+/-‬‭7‬‭days‬‭of‬‭original‬‭PD‬‭to‬‭determine‬‭whether‬‭there‬‭has‬‭been‬‭a‬
‭decrease‬ ‭in‬ ‭the‬ ‭tumor‬ ‭size,‬ ‭or‬ ‭continued‬ ‭progression‬ ‭of‬ ‭disease.‬ ‭Subsequent‬ ‭scans‬ ‭should‬ ‭be‬
‭performed per protocol defined schedule +/- 7 days until further progression is determined.‬
‭If‬ ‭the‬ ‭investigator‬ ‭feels‬ ‭that‬ ‭the‬ ‭participant‬ ‭continues‬ ‭to‬ ‭achieve‬ ‭clinical‬ ‭benefit‬ ‭by‬ ‭continuing‬
‭treatment,‬‭the‬‭participant‬‭should‬‭remain‬‭on‬‭the‬‭trial‬‭and‬‭continue‬‭to‬‭receive‬‭monitoring‬‭according‬‭to‬
‭the Time and Events Schedule in Section‬‭7.2.‬
‭For‬‭the‬‭participants‬‭who‬‭continue‬‭study‬‭therapy‬‭beyond‬‭progression,‬‭further‬‭progression‬‭is‬
‭defined‬ ‭as‬ ‭an‬ ‭additional‬ ‭10%‬ ‭increase‬ ‭in‬ ‭tumor‬ ‭burden‬‭from‬‭time‬‭of‬‭initial‬‭PD.‬‭This‬‭includes‬‭an‬
‭increase‬‭in‬‭the‬‭sum‬‭of‬‭diameters‬‭of‬‭all‬‭target‬‭lesions‬‭and/or‬‭the‬‭diameters‬‭of‬‭new‬‭measurable‬‭lesions‬
‭compared‬‭to‬‭the‬‭time‬‭of‬‭initial‬‭PD.‬‭Nivolumab‬‭treatment‬‭should‬‭be‬‭discontinued‬‭permanently‬‭upon‬
‭documentation of further progression.‬
‭New‬ ‭lesions‬ ‭are‬ ‭considered‬ ‭measurable‬ ‭at‬ ‭the‬ ‭time‬ ‭of‬ ‭initial‬ ‭progression‬ ‭if‬ ‭the‬ ‭longest‬
‭diameter‬‭is‬‭at‬‭least‬‭10‬‭mm‬‭(except‬‭for‬‭pathological‬‭lymph‬‭nodes‬‭which‬‭must‬‭have‬‭a‬‭short‬‭axis‬‭of‬‭at‬
‭least 15 mm).‬
‭Any‬‭new‬‭lesion‬‭considered‬‭non-measurable‬‭at‬‭the‬‭time‬‭of‬‭initial‬‭progression‬‭may‬‭become‬‭measurable‬
‭and‬‭therefore‬‭included‬‭in‬‭the‬‭tumor‬‭burden‬‭if‬‭the‬‭longest‬‭diameter‬‭increases‬‭to‬‭at‬‭least‬‭10‬‭mm‬‭(except‬
‭for‬‭pathological‬‭lymph‬‭nodes‬‭which‬‭must‬‭have‬‭a‬‭short‬‭axis‬‭of‬‭at‬‭least‬‭15‬‭mm).‬‭In‬‭situations‬‭where‬‭the‬
‭relative‬‭increase‬‭in‬‭total‬‭tumor‬‭burden‬‭by‬‭10%‬‭is‬‭solely‬‭due‬‭to‬‭inclusion‬‭of‬‭new‬‭lesions‬‭which‬‭become‬
‭measurable, these new lesions must demonstrate an absolute increase of at least 5 mm.‬
‭5.4.‬
‭Preparation/Handling/Storage/ Accountability‬
‭The‬‭investigational‬‭product‬‭should‬‭be‬‭stored‬‭in‬‭a‬‭secure‬‭area‬‭according‬‭to‬‭local‬‭regulations.‬‭It‬
‭is‬‭the‬‭responsibility‬‭of‬‭the‬‭investigator‬‭to‬‭ensure‬‭that‬‭investigational‬‭product‬‭is‬‭only‬‭dispensed‬‭to‬‭study‬
‭participants.‬ ‭The‬ ‭investigational‬ ‭product‬ ‭must‬ ‭be‬ ‭dispensed‬ ‭only‬ ‭from‬ ‭official‬ ‭study‬ ‭sites‬ ‭by‬
‭authorized personnel according to local regulations.‬
‭The‬‭product‬‭storage‬‭manager‬‭should‬‭ensure‬‭that‬‭the‬‭study‬‭treatment‬‭is‬‭stored‬‭in‬‭accordance‬
‭with‬ ‭the‬ ‭environmental‬ ‭conditions‬ ‭(temperature,‬ ‭light,‬ ‭and‬ ‭humidity)‬ ‭as‬ ‭determined‬ ‭by‬ ‭BMS.‬ ‭If‬
‭concerns‬‭regarding‬‭the‬‭quality‬‭or‬‭appearance‬‭of‬‭the‬‭study‬‭treatment‬‭arise,‬‭the‬‭study‬‭treatment‬‭should‬
‭not be dispensed and contact BMS immediately.‬
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‭Study treatment not supplied by BMS will be stored in accordance with the package insert.‬
‭Investigational‬‭product‬‭documentation‬‭(whether‬‭supplied‬‭by‬‭BMS‬‭or‬‭not)‬‭must‬‭be‬‭maintained‬
‭that‬ ‭includes‬ ‭all‬ ‭processes‬ ‭required‬ ‭to‬ ‭ensure‬ ‭drug‬ ‭is‬ ‭accurately‬ ‭administered.‬ ‭This‬ ‭includes‬
‭documentation‬‭of‬‭drug‬‭storage,‬‭administration‬‭and,‬‭as‬‭applicable,‬‭storage‬‭temperatures,‬‭reconstitution,‬
‭and use of required processes (eg, required diluents, administration sets).‬
‭5.5.‬
‭Concomitant therapy‬
‭5.5.1.‬
‭Prohibited and/or Restricted Therapy‬
‭Subjects‬ ‭are‬ ‭prohibited‬ ‭from‬ ‭receiving‬ ‭the‬ ‭following‬ ‭therapies‬ ‭during‬ ‭screening‬ ‭to‬ ‭the‬ ‭end‬ ‭of‬
‭treatment of this trial:‬
‭●‬ ‭Antineoplastic systemic chemotherapy or biological therapy not specified in the protocol‬
‭●‬ ‭Immunotherapy not specified in this protocol.‬
‭●‬ ‭Investigational agents other than nivolumab.‬
‭●‬ ‭Radiation‬‭therapy;‬‭palliative‬‭radiation‬‭therapy‬‭to‬‭a‬‭symptomatic‬‭lesion‬‭(e.g.‬‭bony‬‭metastasis),‬
‭or to the brain may be permitted.‬
‭●‬ ‭Live‬‭vaccines‬‭within‬‭30‬‭days‬‭prior‬‭to‬‭the‬‭first‬‭dose‬‭of‬‭trial‬‭treatment‬‭and‬‭while‬‭participating‬‭in‬
‭the‬‭trial.‬‭Live‬‭vaccines‬‭include,‬‭but‬‭are‬‭not‬‭limited‬‭to,‬‭the‬‭following:‬‭measles,‬‭mumps,‬‭rubella,‬
‭chicken‬‭pox,‬‭yellow‬‭fever,‬‭rabies,‬‭BCG,‬‭and‬‭typhoid‬‭(oral)‬‭vaccine.‬‭The‬‭killed‬‭virus‬‭vaccines‬
‭used‬ ‭for‬ ‭seasonal‬ ‭influenza‬ ‭vaccines‬ ‭for‬ ‭injection‬ ‭are‬ ‭allowed;‬ ‭however‬ ‭live‬ ‭attenuated‬
‭intranasal influenza vaccines (e.g. Flu - Mist®) are not allowed.‬
‭●‬ ‭The‬‭use‬‭of‬‭systemic‬‭steroid‬‭therapy‬‭and‬‭other‬‭immunosuppressive‬‭drugs‬‭is‬‭not‬‭allowed‬‭except‬
‭for‬‭the‬‭treatment‬‭of‬‭infusion‬‭reaction,‬‭irAEs,‬‭and‬‭for‬‭prophylaxis‬‭against‬‭imaging‬‭contrast‬‭dye‬
‭allergy‬‭or‬‭replacement-dose‬‭steroids‬‭in‬‭the‬‭setting‬‭of‬‭adrenal‬‭insufficiency‬‭(providing‬‭this‬‭is‬
‭<10‬‭mg/day‬‭prednisone‬‭or‬‭equivalent),‬‭or‬‭transient‬‭exacerbations‬‭of‬‭other‬‭underlying‬‭diseases‬
‭such‬‭as‬‭COPD‬‭requiring‬‭treatment‬‭for‬‭≤‬‭3‬‭weeks.‬‭If‬‭systemic‬‭corticosteroids‬‭are‬‭required‬‭for‬
‭the‬ ‭control‬ ‭of‬ ‭infusion‬ ‭reactions‬ ‭or‬ ‭irAEs,‬ ‭it‬ ‭must‬ ‭be‬ ‭tapered‬ ‭and‬ ‭be‬ ‭at‬ ‭non‬
‭immunosuppressive‬ ‭doses‬ ‭(<‬ ‭10‬ ‭mg/day‬ ‭of‬ ‭prednisone‬ ‭or‬ ‭equivalent)‬ ‭before‬ ‭the‬ ‭next‬
‭administration‬‭of‬‭study‬‭treatment.‬‭If‬‭the‬‭dose‬‭of‬‭prednisone‬‭or‬‭equivalent‬‭cannot‬‭be‬‭reduced‬
‭to‬ ‭less‬ ‭than‬ ‭10‬ ‭mg/day‬ ‭before‬ ‭the‬ ‭administration‬ ‭of‬ ‭next‬ ‭dose‬ ‭of‬ ‭study‬ ‭treatment‬ ‭then‬
‭nivolumab must be discontinued.‬
‭Caution‬‭should‬‭be‬‭used‬‭regarding‬‭the‬‭use‬‭of‬‭herbal‬‭medications‬‭as‬‭there‬‭may‬‭be‬‭yet‬‭unknown‬
‭interactions‬ ‭with‬ ‭nivolumab.‬ ‭Discontinuation‬ ‭of‬ ‭the‬ ‭use‬ ‭of‬ ‭herbal‬ ‭medications‬ ‭prior‬ ‭to‬ ‭study‬
‭enrollment‬‭is‬‭encouraged.‬‭Except‬‭for‬‭the‬‭permitted‬‭procedures‬‭specified‬‭as‬‭palliative‬‭local‬‭therapies‬
‭(Section‬‭5.5.3),‬‭all‬‭other‬‭radiation‬‭therapy‬‭or‬‭surgery‬‭to‬‭any‬‭tumor‬‭lesion‬‭is‬‭not‬‭permitted‬‭during‬‭study‬
‭treatment.‬
‭There are no prohibited therapies during the post-treatment follow-up phase.‬
‭5.5.2.‬ ‭Permitted Therapy‬
‭All‬‭treatments‬‭that‬‭the‬‭investigator‬‭considers‬‭necessary‬‭for‬‭a‬‭subject’s‬‭welfare‬‭may‬‭be‬‭administered‬
‭at the discretion of the investigator in keeping with the standards of medical care.‬
‭Participants‬ ‭are‬ ‭permitted‬ ‭the‬ ‭use‬ ‭of‬ ‭topical,‬ ‭ocular,‬ ‭intra-articular,‬ ‭intranasal,‬‭and‬‭inhalational‬
‭corticosteroids‬‭(with‬‭minimal‬‭systemic‬‭absorption).‬‭Adrenal‬‭replacement‬‭steroid‬‭doses‬‭>10‬‭mg‬‭daily‬
‭prednisone‬‭are‬‭permitted.‬‭A‬‭brief‬‭(less‬‭than‬‭3‬‭weeks)‬‭course‬‭of‬‭corticosteroids‬‭for‬‭prophylaxis‬‭(eg,‬
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‭contrast‬ ‭dye‬ ‭allergy)‬ ‭or‬ ‭for‬ ‭treatment‬ ‭of‬ ‭non-autoimmune‬ ‭conditions‬ ‭(eg,‬ ‭delayed-type‬
‭hypersensitivity reaction caused by a contact allergen) is permitted.‬
‭All‬ ‭concomitant‬ ‭medication‬ ‭will‬ ‭be‬ ‭recorded‬ ‭on‬ ‭the‬ ‭case‬ ‭report‬ ‭form‬ ‭(CRF)‬ ‭including‬ ‭all‬
‭prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids.‬
‭If‬‭changes‬‭occur‬‭during‬‭the‬‭trial‬‭period,‬‭documentation‬‭of‬‭drug‬‭dosage,‬‭frequency,‬‭route,‬‭and‬‭date‬
‭may also be included on the CRF.‬
‭All‬‭concomitant‬‭medications‬‭received‬‭during‬‭the‬‭trial‬‭through‬‭30‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭trial‬
‭treatment should be recorded.‬
‭5.5.3.‬ ‭Palliative Local Therapy‬
‭Palliative‬‭local‬‭therapy,‬‭including‬‭palliative‬‭radiation‬‭therapy‬‭and‬‭palliative‬‭surgical‬‭resection,‬
‭to‬ ‭symptomatic‬ ‭non-target‬ ‭bone‬ ‭lesions,‬ ‭skin‬ ‭lesions,‬ ‭or‬ ‭CNS‬ ‭lesions‬ ‭is‬ ‭permitted‬ ‭prior‬ ‭to‬
‭discontinuation‬‭of‬‭study‬‭treatment‬‭for‬‭participants‬‭who‬‭do‬‭not‬‭have‬‭evidence‬‭of‬‭overall‬‭clinical‬‭or‬
‭radiographic progression per RECIST 1.1.‬
‭Palliative‬ ‭local‬ ‭therapy‬ ‭to‬ ‭lesions‬ ‭causing‬ ‭gastrointestinal‬ ‭bleeding‬‭may‬‭also‬‭be‬‭permitted‬
‭prior‬‭to‬‭discontinuation‬‭of‬‭study‬‭treatment‬‭in‬‭participants‬‭who‬‭do‬‭not‬‭have‬‭evidence‬‭of‬‭overall‬‭clinical‬
‭or‬ ‭radiographic‬ ‭progression‬ ‭per‬ ‭RECIST‬ ‭1.1,‬‭provided‬‭that‬‭the‬‭lesions‬‭undergoing‬‭palliative‬‭local‬
‭therapy‬‭are‬‭not‬‭the‬‭only‬‭sites‬‭of‬‭measurable‬‭disease‬‭and‬‭the‬‭case‬‭is‬‭discussed‬‭with‬‭and‬‭approved‬‭by‬
‭the BMS Medical Monitor.‬
‭Participants‬‭requiring‬‭palliative‬‭local‬‭therapy‬‭should‬‭be‬‭evaluated‬‭for‬‭objective‬‭evidence‬‭of‬
‭disease‬ ‭progression‬ ‭prior‬ ‭to‬ ‭the‬ ‭initiation‬ ‭of‬ ‭such‬ ‭therapy,‬ ‭particularly‬ ‭if‬ ‭the‬ ‭most‬ ‭recent‬ ‭tumor‬
‭assessment‬‭was‬‭more‬‭than‬‭4‬‭weeks‬‭prior‬‭to‬‭the‬‭start‬‭of‬‭local‬‭therapy.‬‭If‬‭progression‬‭per‬‭RECIST‬‭1.1‬‭is‬
‭identified‬‭on‬‭any‬‭tumor‬‭assessments‬‭prior‬‭to‬‭the‬‭initiation‬‭of‬‭palliative‬‭local‬‭therapy,‬‭then‬‭participants‬
‭must‬‭either‬‭discontinue‬‭study‬‭drug‬‭treatment‬‭or‬‭they‬‭must‬‭meet‬‭criteria‬‭to‬‭continue‬‭treatment‬‭beyond‬
‭progression (‬‭Section 5.3.1‬‭) in order to resume immunotherapy‬‭after palliative local therapy.‬
‭The‬ ‭potential‬ ‭for‬ ‭overlapping‬ ‭toxicities‬ ‭with‬ ‭radiotherapy‬ ‭and‬ ‭nivolumab‬ ‭currently‬ ‭is‬ ‭not‬
‭known;‬ ‭however,‬ ‭anecdotal‬ ‭data‬ ‭suggests‬ ‭that‬ ‭it‬ ‭is‬ ‭tolerable.‬ ‭As‬ ‭concurrent‬ ‭radiotherapy‬ ‭and‬
‭nivolumab‬‭have‬‭not‬‭been‬‭formally‬‭evaluated,‬‭in‬‭cases‬‭where‬‭palliative‬‭radiotherapy‬‭is‬‭required‬‭for‬‭a‬
‭tumor‬‭lesion,‬‭then‬‭nivolumab‬‭should‬‭be‬‭withheld‬‭for‬‭at‬‭least‬‭1‬‭week‬‭before,‬‭during,‬‭and‬‭1‬‭week‬‭after‬
‭radiation.‬ ‭Participants‬ ‭should‬ ‭be‬ ‭closely‬ ‭monitored‬ ‭for‬ ‭any‬ ‭potential‬ ‭toxicity‬ ‭during‬ ‭and‬ ‭after‬
‭receiving radiotherapy, and AEs should resolve to Grade ≤ 1 prior to resuming nivolumab.‬
‭5.5.4.‬ ‭Imaging Restrictions and Precautions‬
‭It‬‭is‬‭the‬‭local‬‭imaging‬‭facility’s‬‭responsibility‬‭to‬‭determine,‬‭based‬‭on‬‭participant‬‭attributes‬‭(eg,‬
‭allergy‬ ‭history,‬ ‭diabetic‬ ‭history‬ ‭and‬ ‭renal‬ ‭status),‬ ‭the‬ ‭appropriate‬ ‭imaging‬ ‭modality‬ ‭and‬ ‭contrast‬
‭regimen‬‭for‬‭each‬‭participant.‬‭Imaging‬‭contraindications‬‭and‬‭contrast‬‭risks‬‭should‬‭be‬‭considered‬‭in‬‭this‬
‭assessment.‬‭Participants‬‭with‬‭renal‬‭insufficiency‬‭should‬‭be‬‭assessed‬‭as‬‭to‬‭whether‬‭or‬‭not‬‭they‬‭should‬
‭receive‬‭contrast‬‭and‬‭if‬‭so,‬‭what‬‭type‬‭and‬‭dose‬‭of‬‭contrast‬‭is‬‭appropriate.‬‭Should‬‭a‬‭participant‬‭have‬‭a‬
‭contraindication‬‭for‬‭CT‬‭IV‬‭contrast,‬‭a‬‭non-contrast‬‭CT‬‭of‬‭the‬‭chest‬‭and‬‭a‬‭contrast‬‭enhanced‬‭MRI‬‭of‬
‭the abdomen and pelvis may be obtained.‬
‭Specific‬ ‭to‬ ‭MRI,‬ ‭participants‬ ‭with‬ ‭severe‬ ‭renal‬ ‭insufficiency‬ ‭(ie,‬ ‭estimated‬ ‭glomerular‬
‭filtration‬‭rate‬‭(eGFR)‬‭<‬‭30‬‭mL/min/1.73‬‭m2)‬‭are‬‭at‬‭increased‬‭risk‬‭of‬‭nephrogenic‬‭systemic‬‭fibrosis.‬
‭MRI‬‭contrast‬‭should‬‭not‬‭be‬‭given‬‭to‬‭this‬‭participant‬‭population.‬‭In‬‭addition,‬‭participants‬‭are‬‭excluded‬
‭from‬‭MRI‬‭if‬‭they‬‭have‬‭tattoos,‬‭metallic‬‭implants,‬‭pacemakers,‬‭etc.‬‭The‬‭ultimate‬‭decision‬‭to‬‭perform‬
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‭MRI‬‭in‬‭an‬‭individual‬‭participant‬‭in‬‭this‬‭study‬‭rests‬‭with‬‭the‬‭site‬‭radiologist,‬‭the‬‭investigator‬‭and‬‭the‬
‭standard set by the local Ethics Committee.‬
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‭6.‬
‭Discontinuation Criteria‬
‭6.1.‬
‭Discontinuation from Study Treatment‬
‭For‬‭all‬‭participants,‬‭global‬‭deterioration‬‭of‬‭health‬‭status‬‭requiring‬‭discontinuation‬‭of‬‭treatment‬
‭without‬ ‭objective‬‭evidence‬‭of‬‭disease‬‭progression‬‭at‬‭that‬‭time‬‭should‬‭be‬‭reported‬‭as‬‭‘symptomatic‬
‭deterioration’ in the source data and in the case report form.‬
‭Tumor‬ ‭assessments‬ ‭for‬ ‭participants,‬ ‭who‬ ‭discontinue‬ ‭study‬ ‭treatment‬ ‭without‬ ‭radiographic‬
‭progression, should continue as per protocol until radiographic progression is determined.‬
‭Chemotherapy‬‭dose‬‭reduction‬‭is‬‭allowed‬‭on‬‭study.‬‭Any‬‭participant‬‭with‬‭two‬‭prior‬‭dose‬‭reductions‬
‭to‬‭one‬‭agent‬‭who‬‭experiences‬‭a‬‭toxicity‬‭that‬‭would‬‭cause‬‭a‬‭third‬‭dose‬‭reduction‬‭must‬‭be‬‭discontinued‬
‭from‬‭that‬‭agent.‬‭A‬‭participant‬‭who‬‭is‬‭discontinued‬‭from‬‭the‬‭chemotherapy‬‭treatment‬‭will‬‭remain‬‭on‬
‭the study and receive nivolumab.‬
‭6.1.1.‬ ‭Nivolumab Dose Discontinuation‬
‭Treatment with nivolumab should be permanently discontinued for any of the following:‬
‭●‬ ‭Any‬ ‭Grade‬ ‭≥‬‭2‬‭drug-related‬‭uveitis‬‭or‬‭eye‬‭pain‬‭or‬‭blurred‬‭vision‬‭that‬‭does‬‭not‬‭respond‬‭to‬
‭topical‬‭therapy‬‭and‬‭does‬‭not‬‭improve‬‭to‬‭Grade‬‭1‬‭severity‬‭within‬‭the‬‭re-treatment‬‭period‬‭OR‬
‭requires systemic treatment.‬
‭●‬ ‭Any‬‭Grade‬‭≥‬‭2‬‭drug-related‬‭pneumonitis‬‭or‬‭interstitial‬‭lung‬‭disease‬‭that‬‭does‬‭not‬‭resolve‬‭after‬
‭a dose delay and systemic steroids (also see‬‭Table‬‭5.2.1).‬
‭●‬ ‭Any‬ ‭Grade‬ ‭3‬ ‭drug-related‬ ‭bronchospasm,‬ ‭hypersensitivity‬ ‭reaction,‬ ‭or‬ ‭infusion‬ ‭reaction,‬
‭regardless of duration;‬
‭●‬ ‭Any‬ ‭Grade‬ ‭3‬ ‭non-skin,‬ ‭drug-related‬ ‭adverse‬ ‭event‬ ‭lasting‬ ‭>‬ ‭7‬ ‭days,‬ ‭with‬ ‭the‬ ‭following‬
‭exceptions‬ ‭for‬ ‭uveitis,‬ ‭pneumonitis,‬ ‭bronchospasm,‬ ‭diarrhea,‬ ‭colitis,‬ ‭neurologic‬ ‭toxicity,‬
‭hypersensitivity reactions, infusion reactions, endocrinopathies, and laboratory abnormalities:‬
‭○‬ ‭Grade‬‭3‬‭drug-related‬‭uveitis,‬‭pneumonitis,‬‭bronchospasm,‬‭diarrhea,‬‭colitis,‬‭neurologic‬
‭toxicity,‬ ‭hypersensitivity‬ ‭reaction,‬ ‭or‬ ‭infusion‬ ‭reaction‬ ‭of‬ ‭any‬ ‭duration‬ ‭requires‬
‭discontinuation.‬
‭○‬ ‭Grade‬ ‭3‬ ‭drug-related‬‭endocrinopathies‬‭adequately‬‭controlled‬‭with‬‭only‬‭physiologic‬
‭hormone replacement do not require discontinuation.‬
‭○‬ ‭Grade‬
‭3‬
‭drug-related‬
‭laboratory‬ ‭abnormalities‬ ‭do‬ ‭not‬ ‭require‬ ‭treatment‬
‭discontinuation except:‬
‭■‬ ‭Grade‬‭3‬‭drug-related‬‭thrombocytopenia‬‭>‬‭7‬‭days‬‭or‬‭associated‬‭with‬‭bleeding‬
‭requires discontinuation.‬
‭■‬ ‭Any‬ ‭drug-related‬ ‭liver‬ ‭function‬ ‭test‬ ‭(LFT)‬ ‭abnormality‬ ‭that‬ ‭meets‬ ‭the‬
‭following‬‭criteria‬‭require‬‭discontinuation:‬‭Grade‬‭≥‬‭3‬‭drug-related‬‭AST,‬‭ALT‬
‭or Total Bilirubin requires discontinuation.*‬
‭*‬ ‭In‬ ‭most‬ ‭cases‬ ‭of‬ ‭Grade‬ ‭3‬ ‭AST‬ ‭or‬ ‭ALT‬ ‭elevation,‬ ‭study‬ ‭drugs(s)‬ ‭will‬ ‭be‬ ‭permanently‬
‭discontinued.‬ ‭If‬ ‭the‬ ‭investigator‬ ‭determines‬ ‭a‬ ‭possible‬ ‭favorable‬ ‭benefit/risk‬ ‭ratio‬ ‭that‬
‭warrants‬‭continuation‬‭of‬‭study‬‭drugs(s),‬‭a‬‭discussion‬‭between‬‭the‬‭investigator‬‭and‬‭the‬‭BMS‬
‭medical monitor or designee must occur.‬
‭Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN‬
‭●‬ ‭Any‬‭Grade‬‭4‬‭drug-related‬‭adverse‬‭event‬‭or‬‭laboratory‬‭abnormality,‬‭except‬‭for‬‭the‬‭following‬
‭events, which do not require discontinuation:‬
‭○‬ ‭Grade 4 neutropenia ≤ 7 days.‬
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‭○‬ ‭Grade 4 lymphopenia or leukopenia.‬
‭○‬ ‭Isolated‬ ‭Grade‬ ‭4‬ ‭amylase‬ ‭or‬ ‭lipase‬ ‭abnormalities‬ ‭that‬ ‭are‬ ‭not‬ ‭associated‬ ‭with‬
‭symptoms‬ ‭or‬‭clinical‬‭manifestations‬‭of‬‭pancreatitis‬‭and‬‭decrease‬‭to‬‭<‬‭Grade‬‭4‬‭within‬
‭1 week of onset.‬
‭○‬ ‭Isolated‬ ‭Grade‬ ‭4‬ ‭electrolyte‬ ‭imbalances/abnormalities‬ ‭that‬ ‭are‬ ‭not‬ ‭associated‬‭with‬
‭clinical‬ ‭sequelae‬ ‭and‬ ‭are‬ ‭corrected‬ ‭with‬ ‭supplementation/appropriate‬ ‭management‬
‭within 72 hours of their onset.‬
‭●‬ ‭Grade‬ ‭4‬ ‭drug-related‬ ‭endocrinopathy‬ ‭adverse‬ ‭events‬ ‭such‬ ‭as‬‭adrenal‬‭insufficiency,‬‭ACTH‬
‭deficiency,‬‭hyper-‬‭or‬‭hypothyroidism,‬‭or‬‭glucose‬‭intolerance,‬‭which‬‭resolve‬‭or‬‭are‬‭adequately‬
‭controlled‬ ‭with‬ ‭physiologic‬ ‭hormone‬ ‭replacement‬ ‭(corticosteroids,‬ ‭thyroid‬ ‭hormones)‬ ‭or‬
‭glucose‬‭controlling‬‭agents,‬‭respectively,‬‭may‬‭not‬‭require‬‭discontinuation‬‭after‬‭discussion‬‭with‬
‭and approval from the BMS Medical Monitor.‬
‭●‬ ‭Dosing‬ ‭delays‬ ‭lasting‬ ‭>‬ ‭6‬ ‭weeks‬ ‭from‬ ‭the‬ ‭previous‬ ‭dose‬ ‭that‬ ‭occur‬ ‭for‬ ‭non-drug-related‬
‭reasons‬ ‭may‬ ‭be‬ ‭allowed‬ ‭if‬ ‭approved‬ ‭by‬ ‭the‬ ‭BMS‬ ‭medical‬ ‭monitor.‬ ‭Prior‬ ‭to‬ ‭re-initiating‬
‭treatment‬‭in‬‭a‬‭participant‬‭with‬‭a‬‭dosing‬‭delay‬‭lasting‬‭>‬‭6‬‭weeks,‬‭the‬‭BMS‬‭medical‬‭monitor‬
‭must‬ ‭be‬ ‭consulted.‬ ‭Tumor‬ ‭assessments‬ ‭should‬ ‭continue‬ ‭as‬ ‭per‬ ‭protocol‬ ‭even‬ ‭if‬ ‭dosing‬‭is‬
‭delayed.‬ ‭Periodic‬ ‭study‬ ‭visits‬ ‭to‬ ‭assess‬ ‭safety‬ ‭and‬‭laboratory‬‭studies‬‭should‬‭also‬‭continue‬
‭every 6 weeks or more frequently if clinically indicated during such dosing delays.‬
‭●‬ ‭Any‬‭adverse‬‭event,‬‭laboratory‬‭abnormality,‬‭or‬‭intercurrent‬‭illness‬‭which,‬‭in‬‭the‬‭judgment‬‭of‬
‭the‬ ‭Investigator,‬ ‭presents‬ ‭a‬ ‭substantial‬ ‭clinical‬ ‭risk‬ ‭to‬ ‭the‬ ‭participant‬ ‭with‬ ‭continued‬
‭nivolumab dosing.‬
‭The‬ ‭assessment‬ ‭for‬ ‭discontinuation‬ ‭of‬ ‭nivolumab‬ ‭should‬ ‭be‬ ‭made‬ ‭separately‬ ‭from‬ ‭the‬
‭assessment made for discontinuation of chemotherapy.‬
‭If‬ ‭a‬ ‭participant‬ ‭meets‬ ‭criteria‬ ‭for‬ ‭discontinuation‬ ‭and‬ ‭investigator‬ ‭is‬ ‭unable‬ ‭to‬ ‭determine‬
‭whether‬ ‭the‬ ‭event‬ ‭is‬ ‭related‬ ‭to‬ ‭nivolumab‬ ‭or‬‭chemotherapy,‬‭the‬‭participant‬‭should‬‭discontinue‬‭all‬
‭treatment.‬
‭The‬ ‭assessment‬ ‭for‬ ‭discontinuation‬ ‭of‬ ‭nivolumab‬ ‭should‬ ‭be‬ ‭made‬ ‭separately‬ ‭from‬ ‭the‬
‭assessment‬ ‭made‬ ‭for‬ ‭discontinuation‬ ‭of‬ ‭chemotherapy‬ ‭doublet.‬ ‭If‬ ‭criteria‬ ‭for‬ ‭discontinuation‬ ‭for‬
‭nivolumab‬‭are‬‭met‬‭before‬‭the‬‭nivolumab‬‭plus‬‭platinum-based‬‭doublet‬‭chemotherapy‬‭cycles‬‭have‬‭been‬
‭completed, platinum-based doublet chemotherapy may continue until 6 cycles have been completed.‬
‭6.1.2.‬ ‭Chemotherapy Dose Discontinuation‬
‭Except‬ ‭where‬ ‭specified‬ ‭below,‬ ‭chemotherapy‬ ‭drugs‬ ‭in‬ ‭the‬ ‭platinum-based‬ ‭doublet‬ ‭chemotherapy‬
‭regimen should be discontinued for any of the following:‬
‭●‬ ‭Any Grade  ≥ 3 peripheral neuropathy‬
‭●‬ ‭Any‬ ‭drug-related‬ ‭liver‬ ‭function‬ ‭test‬ ‭(LFT)‬ ‭abnormality‬ ‭that‬ ‭meets‬ ‭the‬ ‭following‬ ‭criteria‬
‭requires discontinuation:‬
‭○‬ ‭AST or ALT > 5-10 x ULN for > 2 weeks‬
‭○‬ ‭AST or ALT > 10 x ULN‬
‭○‬ ‭Total bilirubin > 5 x ULN‬
‭○‬ ‭Concurrent AST or ALT > 3x ULN and total bilirubin > 2 x ULN‬
‭●‬ ‭Any‬ ‭drug-related‬ ‭adverse‬ ‭event‬ ‭which‬‭recurs‬‭after‬‭two‬‭prior‬‭dose‬‭reductions‬‭for‬‭the‬‭same‬
‭drug-related‬‭adverse‬‭event‬‭requires‬‭discontinuation‬‭of‬‭the‬‭drug(s)‬‭which‬‭was/were‬‭previously‬
‭dose reduced.‬
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‭●‬ ‭Any‬ ‭Grade‬ ‭≥‬ ‭3‬ ‭drug-related‬ ‭hypersensitivity‬ ‭reaction‬ ‭or‬ ‭infusion‬ ‭reaction‬ ‭requires‬
‭discontinuation‬‭of‬‭the‬‭drug(s)‬‭felt‬‭to‬‭be‬‭causing‬‭the‬‭reaction.‬‭The‬‭drug‬‭not‬‭felt‬‭to‬‭be‬‭related‬‭to‬
‭the hypersensitivity reaction or infusion reaction may be continued.‬
‭●‬ ‭Any‬‭Grade‬‭4‬‭drug-related‬‭adverse‬‭event‬‭which‬‭the‬‭investigator‬‭deems‬‭is‬‭inappropriate‬‭to‬‭be‬
‭managed‬‭by‬‭dose‬‭reduction(s)‬‭requires‬‭discontinuation‬‭of‬‭the‬‭drug(s)‬‭felt‬‭to‬‭be‬‭causing‬‭the‬
‭event. The drug not felt to be related to the event may be continued.‬
‭●‬ ‭Any‬‭event‬‭that‬‭leads‬‭to‬‭delay‬‭in‬‭dosing‬‭of‬‭any‬‭study‬‭drug(s)‬‭for‬‭>‬‭6‬‭weeks‬‭from‬‭the‬‭previous‬
‭dose requires discontinuation of that drug(s) with the following exception:‬
‭○‬ ‭Dosing‬ ‭delays‬ ‭lasting‬ ‭>‬ ‭6‬ ‭weeks‬ ‭from‬ ‭the‬ ‭previous‬ ‭dose‬ ‭that‬ ‭occur‬ ‭for‬
‭non-drug-related‬‭reasons‬‭may‬‭be‬‭allowed‬‭if‬‭approved‬‭by‬‭the‬‭BMS‬‭medical‬‭monitor.‬
‭Prior‬‭to‬‭re-initiating‬‭treatment‬‭in‬‭a‬‭participant‬‭with‬‭a‬‭dosing‬‭delay‬‭lasting‬‭>‬‭6‬‭weeks,‬
‭the‬‭BMS‬‭medical‬‭monitor‬‭must‬‭be‬‭consulted.‬‭Periodic‬‭study‬‭visits‬‭to‬‭assess‬‭safety‬
‭and‬ ‭laboratory‬ ‭studies‬ ‭should‬ ‭also‬ ‭continue‬ ‭every‬ ‭6‬ ‭weeks‬ ‭or‬ ‭more‬ ‭frequently‬ ‭if‬
‭clinically indicated during such dosing delays.‬
‭●‬ ‭Any‬‭adverse‬‭event,‬‭laboratory‬‭abnormality,‬‭or‬‭intercurrent‬‭illness‬‭which,‬‭in‬‭the‬‭judgment‬‭of‬
‭the‬ ‭Investigator,‬ ‭presents‬ ‭a‬ ‭substantial‬ ‭clinical‬ ‭risk‬ ‭to‬ ‭the‬ ‭participant‬ ‭with‬ ‭continued‬
‭platinum-based‬‭doublet‬‭chemotherapy‬‭dosing.‬‭Investigators‬‭should‬‭consult‬‭local‬‭labeling‬‭for‬
‭the‬‭chemotherapy‬‭drugs‬‭being‬‭administered‬‭to‬‭any‬‭given‬‭participant‬‭for‬‭additional‬‭guidance‬
‭on dose discontinuation.‬
‭6.2.‬
‭Discontinuation from Study‬
‭Participants‬ ‭who‬ ‭request‬ ‭to‬‭discontinue‬‭study‬‭treatment‬‭will‬‭remain‬‭in‬‭the‬‭study‬‭and‬‭must‬
‭continue‬ ‭to‬‭be‬‭followed‬‭for‬‭protocol‬‭specified‬‭follow-up‬‭procedures.‬‭The‬‭only‬‭exception‬‭to‬‭this‬‭is‬
‭when‬ ‭a‬ ‭participant‬ ‭specifically‬ ‭withdraws‬‭consent‬‭for‬‭any‬‭further‬‭contact‬‭with‬‭him/her‬‭or‬‭persons‬
‭previously authorized by participant to provide this information.‬
‭●‬ ‭Participants‬ ‭should‬‭notify‬‭the‬‭investigator‬‭of‬‭the‬‭decision‬‭to‬‭withdraw‬‭consent‬‭from‬‭future‬
‭follow-up in writing, whenever possible.‬
‭●‬ ‭The‬ ‭withdrawal‬ ‭of‬ ‭consent‬ ‭should‬ ‭be‬ ‭explained‬ ‭in‬ ‭detail‬ ‭in‬ ‭the‬ ‭medical‬ ‭records‬ ‭by‬ ‭the‬
‭investigator,‬‭as‬‭to‬‭whether‬‭the‬‭withdrawal‬‭is‬‭from‬‭further‬‭treatment‬‭with‬‭study‬‭treatment‬‭only‬
‭or‬ ‭also‬ ‭from‬ ‭study‬ ‭procedures‬ ‭and/or‬ ‭post‬ ‭treatment‬ ‭study‬ ‭follow-up,‬ ‭and‬ ‭entered‬ ‭on‬‭the‬
‭appropriate CRF page.‬
‭●‬ ‭In‬ ‭the‬ ‭event‬ ‭that‬ ‭vital‬ ‭status‬ ‭(whether‬ ‭the‬‭participant‬‭is‬‭alive‬‭or‬‭dead)‬‭is‬‭being‬‭measured,‬
‭publicly‬‭available‬‭information‬‭should‬‭be‬‭used‬‭to‬‭determine‬‭vital‬‭status‬‭only‬‭as‬‭appropriately‬
‭directed in accordance with local law.‬
‭●‬ ‭If‬ ‭the‬ ‭participant‬ ‭withdraws‬ ‭consent‬‭for‬‭disclosure‬‭of‬‭future‬‭information,‬‭the‬‭sponsor‬‭may‬
‭retain and continue to use any data collected before such a withdrawal of consent.‬
‭In‬ ‭the‬ ‭case‬ ‭of‬ ‭pregnancy,‬ ‭the‬ ‭investigator‬ ‭must‬ ‭immediately‬ ‭notify‬ ‭the‬ ‭BMS‬ ‭Medical‬
‭Monitor/designee‬‭of‬‭this‬‭event.‬‭In‬‭the‬‭event‬‭a‬‭normal‬‭healthy‬‭female‬‭participant‬‭becomes‬‭pregnant‬
‭during‬‭a‬‭clinical‬‭trial,‬‭the‬‭study‬‭treatment‬‭must‬‭be‬‭discontinued‬‭immediately.‬‭In‬‭most‬‭cases,‬‭the‬‭study‬
‭treatment‬‭will‬‭be‬‭permanently‬‭discontinued‬‭in‬‭an‬‭appropriate‬‭manner‬‭(eg,‬‭dose‬‭tapering‬‭if‬‭necessary‬
‭for‬ ‭participant‬ ‭safety).‬‭Please‬‭call‬‭the‬‭BMS‬‭Medical‬‭Monitor‬‭within‬‭24‬‭hours‬‭of‬‭awareness‬‭of‬‭the‬
‭pregnancy.‬ ‭If‬ ‭the‬ ‭investigator‬ ‭determines‬ ‭a‬ ‭possible‬ ‭favorable‬ ‭benefit/risk‬ ‭ratio‬ ‭that‬ ‭warrants‬
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‭continuation‬ ‭of‬ ‭study‬ ‭treatment,‬ ‭a‬ ‭discussion‬ ‭between‬ ‭the‬ ‭investigator‬ ‭and‬ ‭the‬ ‭BMS‬ ‭Medical‬
‭Monitor/designee must occur.‬
‭All‬ ‭participants‬ ‭who‬ ‭discontinue‬ ‭study‬ ‭treatment‬ ‭should‬ ‭comply‬ ‭with‬ ‭protocol‬ ‭specified‬
‭follow-up‬ ‭procedures‬ ‭as‬ ‭outlined‬ ‭in‬ ‭Section‬ ‭7‬‭.‬ ‭The‬ ‭only‬ ‭exception‬ ‭to‬ ‭this‬‭requirement‬‭is‬‭when‬‭a‬
‭participant‬ ‭withdraws‬‭consent‬‭for‬‭all‬‭study‬‭procedures‬‭including‬‭post-treatment‬‭study‬‭follow-up‬‭or‬
‭loses‬‭the‬‭ability‬‭to‬‭consent‬‭freely‬‭(ie,‬‭is‬‭imprisoned‬‭or‬‭involuntarily‬‭incarcerated‬‭for‬‭the‬‭treatment‬‭of‬
‭either a psychiatric or physical illness).‬
‭If‬‭study‬‭treatment‬‭is‬‭discontinued‬‭prior‬‭to‬‭the‬‭participant’s‬‭completion‬‭of‬‭the‬‭study,‬‭the‬‭reason‬
‭for‬‭the‬‭discontinuation‬‭must‬‭be‬‭documented‬‭in‬‭the‬‭participant’s‬‭medical‬‭records‬‭and‬‭entered‬‭on‬‭the‬
‭appropriate case report form (CRF) page.‬
‭6.2.1.‬ ‭Post Study Treatment Study Follow-up‬
‭In‬‭this‬‭study,‬‭OS‬‭is‬‭a‬‭key‬‭endpoint‬‭of‬‭the‬‭study.‬‭Post‬‭study‬‭follow-up‬‭is‬‭of‬‭critical‬‭importance‬
‭and‬ ‭is‬ ‭essential‬ ‭to‬ ‭preserving‬ ‭participant‬ ‭safety‬ ‭and‬ ‭the‬ ‭integrity‬ ‭of‬ ‭the‬ ‭study.‬ ‭Participants‬ ‭who‬
‭discontinue‬‭study‬‭treatment‬‭must‬‭continue‬‭to‬‭be‬‭followed‬‭for‬‭collection‬‭of‬‭outcome‬‭and/or‬‭survival‬
‭follow-up data as required and in line with‬‭Section‬‭7‬‭until death or the conclusion of the study.‬
‭6.3.‬
‭Lost to Follow-up‬
‭All‬ ‭reasonable‬ ‭efforts‬ ‭must‬ ‭be‬ ‭made‬ ‭to‬ ‭locate‬ ‭participants‬ ‭to‬ ‭determine‬ ‭and‬ ‭report‬ ‭their‬
‭ongoing status. This includes follow-up with persons authorized by the participant.‬
‭Lost‬‭to‬‭follow-up‬‭is‬‭defined‬‭by‬‭the‬‭inability‬‭to‬‭reach‬‭the‬‭participant‬‭after‬‭a‬‭minimum‬‭of‬‭three‬
‭documented‬‭phone‬‭calls,‬‭faxes,‬‭or‬‭emails‬‭as‬‭well‬‭as‬‭lack‬‭of‬‭response‬‭by‬‭participant‬‭to‬‭one‬‭registered‬
‭mail letter. All attempts should be documented in the participant’s medical records.‬
‭If‬‭it‬‭is‬‭determined‬‭that‬‭the‬‭participant‬‭has‬‭died,‬‭the‬‭site‬‭will‬‭use‬‭permissible‬‭local‬‭methods‬‭to‬
‭obtain date and cause of death.‬
‭If‬‭investigator’s‬‭use‬‭of‬‭third‬‭party‬‭representative‬‭to‬‭assist‬‭in‬‭the‬‭follow-up‬‭portion‬‭of‬‭the‬‭study‬
‭has‬ ‭been‬ ‭included‬ ‭in‬ ‭the‬ ‭participant’s‬ ‭informed‬ ‭consent,‬ ‭then‬ ‭the‬‭investigator‬‭may‬‭use‬‭a‬‭Sponsor‬
‭retained‬‭third‬‭party‬‭representative‬‭to‬‭assist‬‭site‬‭staff‬‭with‬‭obtaining‬‭participant’s‬‭contact‬‭information‬‭or‬
‭other public vital status data necessary to complete the follow-up portion of the study.‬
‭The‬‭site‬‭staff‬‭and‬‭representative‬‭will‬‭consult‬‭publicly‬‭available‬‭sources,‬‭such‬‭as‬‭public‬‭health‬
‭registries and databases, in order to obtain updated contact information.‬
‭If‬‭after‬‭all‬‭attempts,‬‭the‬‭participant‬‭remains‬‭lost‬‭to‬‭follow-up,‬‭then‬‭the‬‭last‬‭known‬‭alive‬‭date‬‭as‬
‭determined‬ ‭by‬ ‭the‬ ‭investigator‬ ‭should‬ ‭be‬ ‭reported‬ ‭and‬ ‭documented‬ ‭in‬ ‭the‬ ‭participant’s‬ ‭medical‬
‭records.‬
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‭7.‬
‭Clinical evaluation, laboratory tests, follow-up‬
‭Study procedures and timing are summarized in the Schedule of Activities.‬
‭●‬ ‭All‬ ‭immediate‬ ‭safety‬ ‭concerns‬ ‭must‬ ‭be‬ ‭discussed‬ ‭with‬ ‭the‬ ‭Sponsor‬ ‭immediately‬ ‭upon‬
‭occurrence‬ ‭or‬ ‭awareness‬ ‭to‬ ‭determine‬ ‭if‬ ‭the‬ ‭participant‬ ‭should‬ ‭continue‬ ‭or‬ ‭discontinue‬
‭treatment.‬
‭●‬ ‭Adherence‬ ‭to‬ ‭the‬ ‭study‬ ‭design‬ ‭requirements,‬ ‭including‬ ‭those‬ ‭specified‬‭in‬‭the‬‭Schedule‬‭of‬
‭Activities, is essential and required for study conduct.‬
‭●‬ ‭All‬ ‭screening‬ ‭evaluations‬ ‭must‬ ‭be‬ ‭completed‬ ‭and‬ ‭reviewed‬ ‭to‬ ‭confirm‬ ‭that‬ ‭potential‬
‭participants‬‭meet‬‭all‬‭eligibility‬‭criteria‬‭before‬‭randomization.‬‭The‬‭investigator‬‭will‬‭maintain‬‭a‬
‭screening‬‭log‬‭to‬‭record‬‭details‬‭of‬‭all‬‭participants‬‭screened‬‭and‬‭to‬‭confirm‬‭eligibility‬‭or‬‭record‬
‭reasons for screening failure, as applicable.‬
‭7.1.‬
‭Before treatment start‬
‭7.1.1.‬
‭Informed Consent‬
‭The‬‭investigator‬‭or‬‭qualified‬‭designee‬‭must‬‭obtain‬‭documented‬‭consent‬‭from‬‭each‬‭potential‬‭subject‬‭or‬
‭each‬ ‭subject’s‬ ‭legally‬ ‭acceptable‬ ‭representative‬ ‭prior‬ ‭to‬ ‭participating‬ ‭in‬ ‭a‬ ‭clinical‬ ‭trial‬ ‭or‬ ‭Future‬
‭Biomedical Research.‬
‭7.1.1.1.‬‭General Informed Consent‬
‭●‬ ‭Consent‬ ‭must‬ ‭be‬ ‭documented‬ ‭by‬ ‭the‬ ‭subject’s‬ ‭dated‬ ‭signature‬ ‭or‬ ‭by‬ ‭the‬ ‭subject’s‬‭legally‬
‭acceptable‬‭representative‬‭dated‬‭signature‬‭on‬‭a‬‭consent‬‭form‬‭along‬‭with‬‭the‬‭dated‬‭signature‬‭of‬
‭the person conducting the consent discussion.‬
‭●‬ ‭A‬ ‭copy‬ ‭of‬ ‭the‬ ‭signed‬ ‭and‬ ‭dated‬ ‭consent‬ ‭form‬ ‭should‬ ‭be‬ ‭given‬ ‭to‬ ‭the‬ ‭subject‬ ‭before‬
‭participation‬‭in‬‭the‬‭trial.‬‭The‬‭initial‬‭informed‬‭consent‬‭form,‬‭any‬‭subsequent‬‭revised‬‭written‬
‭informed‬‭consent‬‭form‬‭and‬‭any‬‭written‬‭information‬‭provided‬‭to‬‭the‬‭subject‬‭must‬‭receive‬‭the‬
‭IRB/ERC’s approval/favorable opinion in advance of use.‬
‭●‬ ‭The‬ ‭subject‬ ‭or‬ ‭his/her‬ ‭legally‬ ‭acceptable‬ ‭representative‬ ‭should‬ ‭be‬ ‭informed‬ ‭in‬ ‭a‬ ‭timely‬
‭manner‬ ‭if‬ ‭new‬ ‭information‬ ‭becomes‬ ‭available‬ ‭that‬ ‭may‬ ‭be‬ ‭relevant‬ ‭to‬ ‭the‬ ‭subject’s‬
‭willingness‬‭to‬‭continue‬‭participation‬‭in‬‭the‬‭trial.‬‭The‬‭communication‬‭of‬‭this‬‭information‬‭will‬
‭be‬‭provided‬‭and‬‭documented‬‭via‬‭a‬‭revised‬‭consent‬‭form‬‭or‬‭addendum‬‭to‬‭the‬‭original‬‭consent‬
‭form‬ ‭that‬ ‭captures‬ ‭the‬ ‭subject’s‬ ‭dated‬ ‭signature‬ ‭or‬ ‭by‬ ‭the‬ ‭subject’s‬ ‭legally‬ ‭acceptable‬
‭representative dated signature.‬
‭●‬ ‭The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations.‬
‭7.1.1.2. Consent and Collection of Specimens for Future Biomedical Research‬
‭●‬ ‭The‬‭investigator‬‭or‬‭qualified‬‭designee‬‭will‬‭explain‬‭the‬‭Future‬‭Biomedical‬‭Research‬‭consent‬‭to‬
‭the‬ ‭subject,‬ ‭answer‬ ‭all‬ ‭of‬ ‭his/her‬ ‭questions,‬ ‭and‬ ‭obtain‬ ‭written‬ ‭informed‬ ‭consent‬ ‭before‬
‭performing any procedure related to the Future Biomedical Research sub-trial.‬
‭●‬ ‭A copy of the informed consent will be given to the subject.‬
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‭7.1.2.‬ ‭Inclusion/Exclusion Criteria Assessment‬
‭All‬ ‭inclusion‬ ‭and‬ ‭exclusion‬ ‭criteria‬ ‭will‬ ‭be‬ ‭reviewed‬ ‭by‬ ‭the‬ ‭investigator‬ ‭or‬ ‭qualified‬‭designee‬‭to‬
‭ensure‬‭that‬‭the‬‭subject‬‭qualifies‬‭for‬‭the‬‭trial.‬‭More‬‭details‬‭on‬‭criteria‬‭for‬‭patients‬‭eligibility‬‭section‬‭4.1‬
‭and 4.2.‬
‭7.1.3.‬ ‭Medical History‬
‭●‬ ‭A‬‭medical‬‭history‬‭will‬‭be‬‭obtained‬‭by‬‭the‬‭investigator‬‭or‬‭qualified‬‭designee.‬‭Medical‬‭history‬
‭will‬‭include‬‭all‬‭active‬‭conditions,‬‭and‬‭any‬‭condition‬‭diagnosed‬‭within‬‭the‬‭prior‬‭10‬‭years‬‭that‬
‭are considered to be clinically significant by the Investigator.‬
‭●‬ ‭Any autoimmune disorders, regardless of onset date, should be recorded.‬
‭7.1.4.‬ ‭Prior and concomitant medications review‬
‭7.1.4.1.‬‭Prior Medications‬
‭The‬ ‭investigator‬ ‭or‬ ‭qualified‬ ‭designee‬ ‭will‬ ‭review‬ ‭prior‬ ‭medication‬ ‭use,‬ ‭including‬ ‭any‬
‭protocol-specified‬‭washout‬‭requirement,‬‭and‬‭record‬‭prior‬‭medication‬‭taken‬‭by‬‭the‬‭subject‬‭within‬‭30‬
‭days of first dose.‬
‭7.1.4.2.‬‭Concomitant Medications‬
‭●‬ ‭The‬ ‭investigator‬ ‭or‬ ‭qualified‬ ‭designee‬‭will‬‭record‬‭medication,‬‭if‬‭any,‬‭taken‬‭by‬‭the‬‭subject‬
‭during‬‭the‬‭trial‬‭from‬‭the‬‭time‬‭of‬‭signing‬‭the‬‭informed‬‭consent‬‭form‬‭until‬‭the‬‭Safety‬‭Follow-up‬
‭Visit.‬
‭●‬ ‭All medications related to reportable SAEs should be recorded.‬
‭7.1.5.‬ ‭Assignment of Screening Number‬
‭●‬ ‭All‬‭consented‬‭subjects‬‭will‬‭be‬‭given‬‭a‬‭unique‬‭screening‬‭number‬‭that‬‭will‬‭be‬‭used‬‭to‬‭identify‬
‭the subject for all procedures that occur.‬
‭●‬ ‭Each‬ ‭subject‬‭will‬‭be‬‭assigned‬‭only‬‭one‬‭screening‬‭number.‬‭Screening‬‭numbers‬‭must‬‭not‬‭be‬
‭re-used‬ ‭for‬ ‭different‬ ‭subjects.‬ ‭Any‬ ‭subject‬ ‭who‬ ‭is‬ ‭screened‬ ‭multiple‬ ‭times‬ ‭will‬‭retain‬‭the‬
‭original screening number assigned at the initial screening visit.‬
‭7.1.6.‬ ‭Subject Identification Card‬
‭●‬ ‭All‬‭subjects‬‭will‬‭be‬‭given‬‭a‬‭Subject‬‭Identification‬‭Card‬‭identifying‬‭them‬‭as‬‭participants‬‭in‬‭a‬
‭research‬‭trial.‬‭The‬‭card‬‭will‬‭contain‬‭trial‬‭site‬‭contact‬‭information‬‭(including‬‭direct‬‭telephone‬
‭numbers) to be utilized in the event of an emergency.‬
‭●‬ ‭The‬‭investigator‬‭or‬‭qualified‬‭designee‬‭will‬‭provide‬‭the‬‭subject‬‭with‬‭a‬‭Subject‬‭Identification‬
‭Card immediately after the subject provides written informed consent.‬
‭7.1.7.‬ ‭Submitting Tumor Sample‬
‭●‬ ‭Tumor tissue sample is mandatory to participate in this trial.‬
‭●‬ ‭Either‬ ‭pre-existing‬ ‭archived‬‭or‬‭newly-obtained‬‭(fresh‬‭tissue)‬‭biopsy‬‭specimens‬‭from‬‭either‬
‭primary or metastatic tumor, whichever is most recent.‬
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‭○‬ ‭Newly-obtained‬‭(fresh‬‭tissue)‬‭is‬‭defined‬‭as‬‭a‬‭specimen‬‭obtained‬‭up‬‭to‬‭42‬‭days‬‭prior‬‭to‬
‭administration‬‭of‬‭study‬‭treatment‬‭on‬‭Day‬‭1‬‭of‬‭Cycle‬‭1,‬‭and‬‭no‬‭additional‬‭anti-cancer‬
‭treatment has been given after the specimen was obtained.‬
‭○‬ ‭Pre-existing,‬‭archived‬‭tissue‬‭must‬‭be‬‭obtained‬‭prior‬‭to‬‭time‬‭point‬‭that‬‭any‬‭anti-cancer‬
‭treatment was given.‬
‭●‬ ‭A‬‭fine‬‭needle‬‭aspirate‬‭(FNA)‬‭or‬‭cytologic‬‭specimen‬‭will‬‭not‬‭be‬‭acceptable.‬‭In‬‭the‬‭event‬‭the‬
‭most‬ ‭recent‬ ‭available‬ ‭tumor‬‭tissue‬‭specimen‬‭is‬‭an‬‭FNA‬‭or‬‭cytologic‬‭specimen,‬‭a‬‭previous‬
‭specimen‬‭obtained‬‭prior‬‭to‬‭any‬‭anti-cancer‬‭therapy‬‭was‬‭given‬‭may‬‭be‬‭submitted‬‭(provided‬‭it‬
‭is not an FNA or cytologic specimen).‬
‭●‬ ‭Where‬ ‭available,‬ ‭both‬ ‭newly-obtained‬ ‭(fresh‬ ‭tissue)‬ ‭and‬ ‭pre-existing‬ ‭archived‬ ‭tissues‬ ‭are‬
‭requested.‬
‭●‬ ‭Tumor tissue specimen submitted in either formalin solution or FFPE block is acceptable.‬
‭7.1.8.‬ ‭Tumor Imaging‬
‭●‬ ‭To‬‭meet‬‭screening‬‭criteria,‬‭initial‬‭tumor‬‭imaging‬‭must‬‭be‬‭performed‬‭within‬‭28‬‭days‬‭prior‬‭to‬
‭the‬‭beginning‬‭of‬‭the‬‭treatment.‬‭This‬‭scan‬‭will‬‭be‬‭considered‬‭the‬‭baseline‬‭assessment‬‭for‬‭the‬
‭study.‬‭Scans‬‭performed‬‭as‬‭part‬‭of‬‭routine‬‭clinical‬‭management‬‭are‬‭acceptable‬‭for‬‭use‬‭as‬‭the‬
‭baseline‬‭scan‬‭if‬‭they‬‭are‬‭of‬‭diagnostic‬‭quality,‬‭include‬‭all‬‭required‬‭anatomy,‬‭and‬‭performed‬
‭within 28 days prior to the beginning of the treatment.‬
‭●‬ ‭The‬‭site‬‭study‬‭team‬‭must‬‭review‬‭pre-trial‬‭images‬‭to‬‭confirm‬‭the‬‭subject‬‭has‬‭at‬‭least‬‭one‬‭target‬
‭lesion (i.e. meets measurability requirements) per RECIST 1.1.‬
‭●‬ ‭The following assessments are required at screening:‬
‭7.1.8.1.‬‭Computed‬ ‭(CT)‬‭with‬‭IV‬‭contrast‬‭or‬‭Magnetic‬‭Resonance‬‭Imaging‬‭(MRI)‬‭of‬‭chest,‬‭abdomen‬
‭and pelvis.‬
‭●‬ ‭The‬‭preferred‬‭radiologic‬‭technique‬‭is‬‭CT‬‭with‬‭intravenous‬‭(IV)‬‭contrast.‬‭If‬‭a‬‭patient‬‭is‬‭known‬
‭to‬ ‭have‬‭a‬‭contraindication‬‭to‬‭CT‬‭contrast‬‭or‬‭develops‬‭a‬‭contraindication‬‭during‬‭the‬‭trial,‬‭a‬
‭non-contrast‬‭CT‬‭of‬‭the‬‭chest‬‭(MRI‬‭is‬‭not‬‭recommended‬‭due‬‭to‬‭respiratory‬‭artifacts)‬‭plus‬‭a‬
‭contrast-enhanced MRI (if possible) of the abdomen and pelvis should be performed.‬
‭7.1.8.2.‬‭Brain CT with IV contrast or MRI scan‬
‭Patients‬‭with‬‭known‬‭baseline‬‭brain‬‭lesions‬‭are‬‭not‬‭eligible‬‭for‬‭this‬‭study,‬‭but‬‭brain‬‭CT‬‭scan‬‭or‬‭MRI‬‭is‬
‭not required neither at baseline nor in the follow-up in the absence of neurological signs or symptoms.‬
‭7.1.8.3.‬‭Whole body bone scan‬
‭This is not required at any time point unless clinically indicated.‬
‭7.1.9.‬ ‭Laboratory Assessments‬
‭●‬ ‭Laboratory‬‭tests‬‭for‬‭screening‬‭should‬‭be‬‭performed‬‭within‬‭7‬‭days‬‭prior‬‭to‬‭study‬‭enrollment.‬‭If‬
‭performed‬‭<‬‭7‬‭days‬‭prior‬‭to‬‭the‬‭first‬‭dose‬‭of‬‭trial‬‭therapy‬‭the‬‭screening‬‭laboratory‬‭tests‬‭will‬
‭serve‬‭as‬‭cycle‬‭1‬‭day‬‭1‬‭laboratory‬‭tests.‬‭If‬‭not,‬‭laboratory‬‭tests‬‭will‬‭need‬‭to‬‭be‬‭performed‬‭again‬
‭on day 1 of cycle 1.‬
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‭○‬ ‭Serum‬‭and‬‭plasma‬‭samples‬‭for‬‭optional‬‭biomarker‬‭studies‬‭will‬‭be‬‭collected‬‭prior‬‭to‬
‭the beginning of treatment.‬
‭A summary of the procedures required is summarized in Table 1 and flow chart- Section 7.4.‬
‭7.1.10.‬ ‭12-Lead Electrocardiogram (ECG)‬
‭A‬ ‭standard‬ ‭12-lead‬ ‭ECG‬ ‭will‬ ‭be‬ ‭performed‬ ‭using‬ ‭local‬ ‭standard‬ ‭procedures‬ ‭once‬ ‭at‬ ‭screening.‬
‭Clinically‬ ‭significant‬ ‭abnormal‬ ‭findings‬ ‭should‬ ‭be‬ ‭recorded‬ ‭as‬ ‭medical‬ ‭history‬ ‭and‬ ‭monitored‬ ‭if‬
‭needed. No new ECGs will be performed unless clinically indicated.‬
‭7.2.‬
‭During treatment‬
‭7.2.1.‬ ‭Adverse Event (AE) Monitoring‬
‭●‬ ‭The‬‭investigator‬‭or‬‭qualified‬‭designee‬‭will‬‭assess‬‭each‬‭subject‬‭to‬‭evaluate‬‭for‬‭potential‬‭new‬‭or‬
‭worsening‬ ‭AEs‬ ‭as‬ ‭specified‬ ‭in‬ ‭the‬ ‭Trial‬ ‭Flow‬ ‭Chart‬ ‭and‬ ‭more‬ ‭frequently‬ ‭if‬ ‭clinically‬
‭indicated.‬
‭●‬ ‭Adverse‬ ‭events‬ ‭will‬ ‭be‬‭graded‬‭and‬‭recorded‬‭throughout‬‭the‬‭trial‬‭and‬‭during‬‭the‬‭follow-up‬
‭period‬ ‭according‬ ‭to‬ ‭NCI‬ ‭CTCAE‬ ‭Version‬ ‭5.0.‬ ‭Toxicities‬ ‭will‬ ‭be‬ ‭characterized‬ ‭in‬ ‭terms‬
‭regarding‬ ‭seriousness,‬ ‭causality,‬ ‭toxicity‬ ‭grading,‬ ‭and‬ ‭action‬ ‭taken‬ ‭with‬ ‭regard‬ ‭to‬ ‭trial‬
‭treatment.‬
‭●‬ ‭All‬ ‭AEs‬ ‭of‬ ‭unknown‬ ‭etiology‬‭associated‬‭with‬‭nivolumab‬‭exposure‬‭should‬‭be‬‭evaluated‬‭to‬
‭determine‬ ‭if‬ ‭it‬ ‭is‬ ‭possibly‬ ‭an‬ ‭ECI‬ ‭of‬ ‭a‬ ‭potentially‬ ‭immunologic‬ ‭etiology‬ ‭(termed‬
‭immune-related adverse events, or irAEs).‬
‭7.2.2.‬ ‭Physical Exam‬
‭The‬ ‭investigator‬ ‭or‬ ‭clinical‬ ‭designee‬ ‭will‬ ‭perform‬‭a‬‭complete‬‭physical‬‭exam‬‭during‬‭the‬‭screening‬
‭period. Clinically significant abnormal findings should be recorded as medical history.‬
‭Additional‬‭full‬‭physical‬‭exams‬‭should‬‭be‬‭performed‬‭as‬‭specified‬‭in‬‭the‬‭Trial‬‭Flow‬‭Chart-Section‬‭7.4.‬
‭After‬‭the‬‭first‬‭dose‬‭of‬‭trial‬‭treatment‬‭new‬‭clinically‬‭significant‬‭abnormal‬‭findings‬‭should‬‭be‬‭recorded‬
‭as AEs.‬
‭7.2.3.‬ ‭Vital Signs‬
‭●‬ ‭The‬ ‭investigator‬ ‭or‬ ‭qualified‬ ‭designee‬ ‭will‬ ‭take‬ ‭vital‬ ‭signs‬ ‭at‬ ‭screening,‬ ‭prior‬ ‭to‬ ‭the‬
‭administration‬‭of‬‭each‬‭dose‬‭of‬‭trial‬‭treatment‬‭and‬‭at‬‭treatment‬‭discontinuation‬‭as‬‭specified‬‭in‬
‭the Trial Flow Chart-Section 7.4.‬
‭●‬ ‭Vital‬ ‭signs‬ ‭should‬ ‭include‬ ‭temperature,‬ ‭pulse,‬ ‭respiratory‬‭rate,‬‭weight‬‭and‬‭blood‬‭pressure.‬
‭Height will be measured at screening only.‬
‭7.2.4.‬ ‭12-Lead Electrocardiogram (ECG)‬
‭No ECGs will be performed unless clinically indicated.‬
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‭7.2.5.‬ ‭Eastern Cooperative Oncology Group (ECOG) Performance Status‬
‭The‬‭investigator‬‭or‬‭qualified‬‭designee‬‭will‬‭assess‬‭ECOG‬‭status‬‭(see‬‭appendix)‬‭at‬‭screening,‬‭prior‬‭to‬
‭dosing‬‭on‬‭day‬‭1‬‭of‬‭each‬‭treatment‬‭cycle‬‭and‬‭at‬‭discontinuation‬‭of‬‭trial‬‭treatment‬‭as‬‭specified‬‭in‬‭the‬
‭Trial Flow Chart.‬
‭7.2.6.‬ ‭Tumor Imaging and Assessment of Disease‬
‭●‬ ‭Tumor‬‭imaging‬‭will‬‭be‬‭performed‬‭by‬‭whole‬‭body‬‭contrast-enhanced‬‭computed‬‭tomography‬
‭(CT; preferred).‬
‭●‬ ‭The‬‭first‬‭on-study‬‭imaging‬‭assessment‬‭should‬‭be‬‭performed‬‭at‬‭8‬‭weeks‬‭(±‬‭7‬‭days)‬‭after‬‭the‬
‭first‬ ‭dose‬ ‭of‬‭trial‬‭treatment.‬‭Subsequent‬‭imaging‬‭should‬‭be‬‭performed‬‭every‬‭8‬‭weeks‬‭(±‬‭7‬
‭days)‬ ‭during‬‭the‬‭first‬‭12‬‭months‬‭and‬‭every‬‭12‬‭weeks‬‭thereafter‬‭until‬‭PD.‬‭Imaging‬‭may‬‭be‬
‭more frequently performed if clinically indicated.‬
‭7.2.7.‬ ‭Laboratory Assessments‬
‭●‬ ‭After‬ ‭Cycle‬ ‭1,‬ ‭pre-dose‬ ‭laboratory‬ ‭procedures‬ ‭can‬ ‭be‬ ‭conducted‬ ‭within‬ ‭72‬‭hours‬‭prior‬‭to‬
‭dosing.‬‭Results‬‭must‬‭be‬‭reviewed‬‭by‬‭the‬‭investigator‬‭or‬‭qualified‬‭designee‬‭and‬‭found‬‭to‬‭be‬
‭acceptable prior to each dose of trial treatment.‬
‭●‬ ‭The main laboratory determinations are summarized in Table 7‬
‭Table 7. Laboratory determinations required during the study‬
‭Test category‬
‭Determinations‬
‭Hematology‬
‭Hematocrit,‬ ‭Hemoglobin,‬ ‭Platelets,‬ ‭Red‬ ‭blood‬ ‭cells,‬ ‭White‬ ‭blood‬ ‭cells,‬ ‭Differential‬
‭(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, Other).‬
‭Chemistry‬
‭Albumin,‬ ‭Alkaline‬ ‭phosphatase,‬ ‭ALT,‬ ‭AST,‬ ‭Gamma-glutamyl-transferase‬ ‭(GGT),‬
‭Lactate‬‭Dehydrogenase‬‭(LDH),‬‭Calcium,‬‭Magnesium,‬‭Phosphorus,,‬‭Sodium,‬‭Potassium,‬
‭Creatinine,‬ ‭Creatine‬‭kinase,‬‭Direct‬‭Bilirubin,‬‭Indirect‬‭Bilirubin,‬‭Total‬‭Bilirubin,,,‬‭Total‬
‭Protein, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose.‬
‭Coagulation‬
‭At‬‭Screening:‬‭Prothrombin‬‭time‬‭(PT),‬‭International‬‭normalized‬‭ratio‬‭(INR]),‬‭Activated‬
‭partial thromboplastin time (APTT).‬
‭Thyroid‬
‭At screening‬‭: TSH (Thyroid Stimulating Hormone), Free‬‭T3 and Free T4.‬
‭At the subsequent visits as indicated in the flow chart: TSH only.‬
‭If TSH is abnormal, Free T3 and T4 shall be tested.‬
‭Hepatitis markers‬
‭At screening‬‭: HBV-DNA, HBsAg, HBsAb, HBcAb, HCV RNA-PCR.‬
‭Cytokines‬
‭IFN-γ, IL-6, IL-1,TNF-α.‬
‭Tumor markers‬
‭At screening‬‭: NSE, CGA.‬
‭On treatment:‬‭every 2 cycles if elevated at baseline.‬
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‭Urinalysis‬
‭At‬ ‭Screening‬‭:‬ ‭Macroscopic‬ ‭Panel‬ ‭(Dipstick)‬ ‭(Color,‬ ‭Bilirubin,‬ ‭Blood,‬ ‭Glucose,‬
‭Ketones, Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)‬
‭If‬ ‭dipstick‬ ‭is‬ ‭abnormal‬ ‭then‬ ‭perform‬ ‭local‬ ‭laboratory‬ ‭Microscopic‬ ‭Panel‬ ‭(Red‬ ‭Blood‬
‭Cells, White Blood Cells, Casts, Crystals, Bacteria, Epithelial cells).‬
‭Pregnancy test‬
‭A‬‭serum‬‭pregnancy‬‭test‬‭must‬‭be‬‭performed‬‭at‬‭screening‬‭(at‬‭the‬‭local‬‭laboratory)‬‭within‬
‭≤72 hours before first dose of study treatment.‬
‭7.2.8.‬ ‭Serum/Urine β-hCG‬
‭●‬ ‭All‬‭women‬‭who‬‭are‬‭being‬‭considered‬‭for‬‭participation‬‭in‬‭the‬‭trial,‬‭and‬‭who‬‭are‬‭not‬‭surgically‬
‭sterilized‬‭or‬‭postmenopausal‬‭(defined‬‭as:‬‭a‬‭woman‬‭who‬‭is‬‭≥45‬‭years‬‭of‬‭age‬‭and‬‭has‬‭not‬‭had‬
‭menses‬‭for‬‭more‬‭than‬‭1‬‭year),‬‭will‬‭be‬‭tested‬‭for‬‭pregnancy‬‭within‬‭72‬‭hours‬‭prior‬‭to‬‭each‬‭cycle‬
‭of trial treatment and 30 days post treatment.‬
‭●‬ ‭Subjects‬‭must‬‭be‬‭excluded/discontinued‬‭in‬‭the‬‭event‬‭of‬‭a‬‭positive‬‭or‬‭borderline-positive‬‭test‬
‭result.‬‭If‬‭a‬‭urine‬‭test‬‭is‬‭positive‬‭or‬‭borderline‬‭a‬‭serum‬‭β-HCG‬‭test‬‭will‬‭be‬‭required.‬‭The‬‭results‬
‭of the pregnancy testing will not be recorded.‬
‭7.3.‬
‭After the end of treatment (Follow-up)‬
‭●‬ ‭After‬ ‭the‬ ‭end‬ ‭of‬ ‭the‬ ‭treatment‬ ‭clinical‬ ‭procedures‬ ‭and‬ ‭assessment‬ ‭will‬ ‭be‬ ‭performed‬ ‭as‬
‭previously explained and is reflected in the summary table (section 7.4).‬
‭●‬ ‭Serum and plasma samples for optional biomarker studies will also be collected at this point.‬
‭7.4.‬
‭Summary table‬
‭Table 7.4. Trial  flow chart‬
‭Screening‬
‭phase‬
‭Treatment cycles‬‭a‬
‭(chemotherapy +‬
‭nivolumab)‬
‭Maintenance‬
‭phase Cycles‬ ‭End of treatment‬
‭Post-treatment‬
‭Pre-Study‬
‭1‬
‭2‬
‭3‬
‭4‬
‭5‬
‭6‬
‭1‬
‭2 and‬
‭beyond‬
‭Time of treatment‬
‭discontinuation‬
‭Safety‬
‭follow up‬
‭Follow up‬
‭visits‬
‭Survival‬
‭follow up‬‭o‬
‭30 days‬
‭after last‬
‭dose‬
‭Every 12 w‬
‭after last‬
‭dose‬
‭Every 12w‬
‭Scheduling window (days)‬
‭-28 to -1‬
‭±3‬
‭±3‬
‭±3‬ ‭±3‬ ‭±3‬ ‭±3‬
‭±3‬
‭±3‬
‭±7‬
‭±7‬
‭±7‬
‭Study Drug Admin‬‭a‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Cycle of Chemotherapy‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Informed consent‬‭b‬
‭X‬
‭Informed consent for future‬
‭biomedical research‬‭b‬
‭X‬
‭History/Demographics‬‭c‬
‭X‬
‭Physical exam‬‭d‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Concomitant meds‬‭e‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭ECOG - Performance status‬‭f‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
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‭Vital signs, Weight‬‭g‬
‭X‬
‭X (when clinically indicated)‬
‭x‬
‭x‬
‭Adverse event evaluation‬‭h‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Tumor sample collection‬‭i‬
‭X‬
‭Hematology‬‭j‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Serum chemistry‬‭j‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭TSH, T3, FT4‬‭j‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Hepatitis testing‬‭j‬
‭X‬
‭If clinically indicated, perform test as needed.‬
‭Screening‬
‭phase‬
‭Treatment cycles‬‭a‬
‭(chemotherapy +‬
‭nivolumab)‬
‭Maintenance‬
‭phase Cycles‬ ‭End of treatment‬
‭Post-treatment‬
‭Pre-Study‬
‭1‬
‭2‬
‭3‬
‭4‬
‭5‬
‭6‬
‭1‬
‭2 and‬
‭beyond‬
‭Time of treatment‬
‭discontinuation‬
‭Safety‬
‭follow up‬
‭Follow up‬
‭visits‬
‭Survival‬
‭follow up‬‭o‬
‭30 days‬
‭after last‬
‭dose‬
‭Every 12 w‬
‭after last‬
‭dose‬
‭Every 12w‬
‭Cytokines‬‭j‬
‭X‬
‭Anytime when a suspected cytokine release syndrome occurs, immediately after the AE, and one week‬
‭after occurrence of the AE‬
‭Optional serum and plasma‬
‭samples for biomedical‬
‭research‬‭K‬
‭X‬
‭X‬
‭Urinalysis‬‭j‬
‭X‬
‭Serum or urine pregnancy test‬‭l‬
‭X‬
‭EKG‬‭m‬
‭X‬
‭Radiologic evaluation‬‭n‬
‭X‬
‭Treatment‬ ‭Period:‬ ‭Every‬ ‭8‬ ‭weeks‬ ‭counting‬ ‭from‬ ‭Cycle‬ ‭1‬ ‭Day‬ ‭1‬ ‭for‬ ‭12‬ ‭months,‬ ‭and‬ ‭every‬ ‭12‬ ‭weeks‬
‭thereafter.‬
‭EOT: If a scan was not conducted within 30 days prior to end of study treatment‬
‭Efficacy‬ ‭follow-up:‬ ‭Continue‬ ‭same‬ ‭schedule‬ ‭as‬ ‭during‬ ‭treatment‬ ‭period‬‭until‬‭central‬‭review‬‭confirmed‬
‭irRECIST progression.‬
‭a) Unless otherwise specified, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle.‬
‭b)‬‭Informed‬‭consent‬‭must‬‭be‬‭obtained‬‭before‬‭conducting‬‭any‬‭study-specific‬‭procedures‬‭(i.e.‬‭all‬‭of‬‭the‬‭procedures‬‭described‬‭in‬‭the‬‭protocol).‬‭The‬‭process‬
‭of‬‭obtaining‬‭informed‬‭consent‬‭should‬‭be‬‭documented‬‭in‬‭the‬‭patient‬‭source‬‭documents.‬‭If‬‭a‬‭patient‬‭decides‬‭not‬‭to‬‭participate‬‭in‬‭the‬‭optional‬‭biomarker‬
‭study, this in no way will affect the patient’s ability to participate in the main research study.‬
‭c)‬‭All‬‭active‬‭conditions,‬‭and‬‭any‬‭condition‬‭diagnosed‬‭within‬‭the‬‭prior‬‭10‬‭years‬‭that‬‭are‬‭considered‬‭to‬‭be‬‭clinically‬‭significant‬‭by‬‭the‬‭Investigator.‬‭Any‬
‭autoimmune disorders, regardless of onset date, should be recorded‬
‭d)‬‭Complete‬‭physical‬‭exam‬‭during‬‭the‬‭screening‬‭period.‬‭Clinically‬‭significant‬‭abnormal‬‭findings‬‭should‬‭be‬‭recorded‬‭as‬‭medical‬‭history.‬‭After‬‭the‬‭first‬
‭dose of trial treatment new clinically significant abnormal findings should be recorded as AEs.‬
‭e)‬‭Site‬‭staff‬‭will‬‭review‬‭and‬‭record‬‭prior‬‭medication‬‭taken‬‭by‬‭the‬‭subject‬‭within‬‭30‬‭days‬‭of‬‭first‬‭dose.All‬‭concomitant‬‭medications‬‭received‬‭during‬‭the‬
‭trial through 30 days after the last dose of trial treatment should be recorded.‬
‭f)‬ ‭ECOG‬‭status‬‭should‬‭be‬‭measured‬‭and‬‭registered‬‭at‬‭patient‬‭records‬‭and‬‭eCRF‬‭at‬‭screening,‬‭prior‬‭to‬‭dosing‬‭on‬‭day‬‭1‬‭of‬‭each‬‭treatment‬‭cycle‬‭and‬‭at‬
‭discontinuation of trial treatment.‬
‭g) Vital signs should include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at screening only.‬
‭h)‬‭Adverse‬‭events‬‭will‬‭be‬‭graded‬‭and‬‭recorded‬‭throughout‬‭the‬‭trial‬‭and‬‭during‬‭the‬‭follow-up‬‭period‬‭according‬‭to‬‭NCI‬‭CTCAE‬‭Version‬‭5.0.‬ ‭Toxicities‬
‭will be characterized in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial treatment.‬
‭i)‬ ‭Tumor‬ ‭tissue‬ ‭sample‬ ‭is‬ ‭mandatory‬ ‭to‬ ‭participate‬ ‭in‬ ‭this‬ ‭trial.‬ ‭It‬ ‭is‬ ‭accepted‬ ‭either‬ ‭pre-existing‬ ‭archived‬ ‭or‬ ‭newly-obtained‬ ‭(fresh‬ ‭tissue)‬ ‭biopsy‬
‭specimens from either primary or metastatic tumor, whichever is most recent.‬
‭j)‬‭Laboratory‬‭tests‬‭for‬‭screening‬‭should‬‭be‬‭performed‬‭within‬‭7‬‭days‬‭prior‬‭to‬‭study‬‭enrollment.‬‭If‬‭performed‬‭<‬‭7‬‭days‬‭prior‬‭to‬‭the‬‭first‬‭dose‬‭of‬‭trial‬‭therapy‬
‭the‬‭screening‬‭laboratory‬‭tests‬‭will‬‭serve‬‭as‬‭cycle‬‭1‬‭day‬‭1‬‭laboratory‬‭tests.‬‭If‬‭not,‬‭laboratory‬‭tests‬‭will‬‭need‬‭to‬‭be‬‭performed‬‭again‬‭on‬‭day‬‭1‬‭of‬‭cycle‬‭1.‬
‭Biochemistry‬ ‭includes:‬ ‭Albumin,‬ ‭Alkaline‬ ‭phosphatase,‬ ‭ALT,‬ ‭AST,‬ ‭Gamma-glutamyl-transferase‬ ‭(GGT),‬ ‭Lactate‬ ‭Dehydrogenase‬ ‭(LDH),‬ ‭Calcium,‬
‭Magnesium,‬‭Phosphorus,‬‭Sodium,‬‭Potassium,‬‭Creatinine,‬‭Creatine‬‭kinase,‬‭Direct‬‭Bilirubin,‬‭Indirect‬‭Bilirubin,‬‭Total‬‭Bilirubin,‬‭Total‬‭Protein,‬‭Blood‬‭Urea‬
‭Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose. The main laboratory determinations are summarized in Table 7 of the protocol.‬
‭k) Serum and plasma samples for optional biomarker studies will be collected prior to the beginning of treatment and at end of treatment.‬
‭l) Serum/Urine β-hCG A serum pregnancy test must be performed at screening (at the local laboratory) and when clinically indicated.‬
‭m) A standard 12-Lead Electrocardiogram (ECG) using local procedures at screening, additional ECGs will be performed‬‭only‬‭if clinically indicated.‬
‭n)‬‭The‬‭preferred‬‭radiologic‬‭technique‬‭is‬‭CT‬‭with‬‭intravenous‬‭(IV)‬‭contrast.‬‭If‬‭a‬‭patient‬‭is‬‭known‬‭to‬‭have‬‭a‬‭contraindication‬‭to‬‭CT‬‭contrast‬‭or‬‭develops‬‭a‬
‭contraindication‬‭during‬‭the‬‭trial,‬‭a‬‭non-contrast‬‭CT‬‭of‬‭the‬‭chest‬‭(MRI‬‭is‬‭not‬‭recommended‬‭due‬‭to‬‭respiratory‬‭artifacts)‬‭plus‬‭a‬‭contrast-enhanced‬‭MRI‬‭(if‬
‭possible)‬‭of‬‭the‬‭abdomen‬‭and‬‭pelvis‬‭should‬‭be‬‭performed.‬‭Brain‬‭CT‬‭scan‬‭or‬‭MRI‬‭or‬‭Whole‬‭Body‬‭Bone‬‭Scan‬‭are‬‭not‬‭required‬‭neither‬‭at‬‭baseline‬‭nor‬‭in‬
‭the‬‭follow-up‬‭in‬‭the‬‭absence‬‭of‬‭neurological/bone‬‭signs‬‭or‬‭symptoms.‬‭Participants‬‭who‬‭discontinue‬‭study‬‭treatment‬‭in‬‭absence‬‭of‬‭disease‬‭progression,‬
‭must continue their follow-up every 12 weeks (+/-7 days) by imaging until disease progression.‬
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‭o)‬ ‭In‬‭this‬‭study,‬‭OS‬‭is‬‭a‬‭key‬‭endpoint‬‭of‬‭the‬‭study.‬‭Post-study‬‭follow-up‬‭is‬‭of‬‭critical‬‭importance‬‭and‬‭is‬‭essential.‬‭Participants‬‭who‬‭discontinue‬‭study‬
‭treatment must continue their follow-up every 12 weeks (+/- 7 days), until death or the conclusion of the study (phone contacts are allowed).‬
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‭8.‬
‭Evaluation criteria‬
‭8.1.‬
‭Definitions‬
‭●‬ ‭Evaluable‬‭for‬‭toxicity‬‭:‬‭All‬‭patients‬‭will‬‭be‬‭evaluable‬‭for‬‭toxicity‬‭from‬‭the‬‭time‬‭of‬‭their‬‭first‬
‭treatment with nivolumab in combination with platinum-doublet chemotherapy.‬
‭●‬ ‭Evaluable‬‭for‬‭response‬‭:‬ ‭All‬‭eligible‬‭patients‬‭will‬‭be‬‭included‬‭in‬‭the‬‭response‬‭rate‬‭calculation.‬
‭The‬‭subset‬‭that‬‭will‬‭be‬‭assigned‬‭a‬‭response‬‭category‬‭(Complete‬‭Response,‬‭Partial‬‭Response,‬
‭Stable‬ ‭Disease‬ ‭or‬ ‭Progressive‬ ‭Disease;‬ ‭see‬ ‭definitions‬ ‭below)‬ ‭are‬ ‭all‬ ‭patients‬ ‭who‬ ‭have‬
‭received‬‭at‬‭least‬‭one‬‭treatment‬‭and‬‭have‬‭their‬‭disease‬‭re-evaluated.‬‭Patients‬‭will‬‭have‬‭their‬
‭response classified according to the definitions set out below‬‭(Eisenhauer E, 2009)‬‭.‬
‭8.2.‬
‭Evaluation of efficacy‬
‭●‬ ‭Study‬‭evaluations‬‭will‬‭take‬‭place‬‭in‬‭accordance‬‭with‬‭the‬‭Schedule‬‭of‬‭Activities‬‭described‬‭in‬
‭Section 7.4.‬
‭●‬ ‭Objective‬ ‭tumor‬ ‭response‬‭and‬‭time‬‭of‬‭progression‬‭will‬‭be‬‭measured‬‭according‬‭to‬‭RECIST‬
‭criteria v.1.1.‬
‭●‬ ‭Response‬‭criteria‬‭are‬‭essentially‬‭based‬‭on‬‭a‬‭set‬‭of‬‭measurable‬‭lesions‬‭identified‬‭at‬‭baseline‬‭as‬
‭target‬ ‭lesions,‬ ‭and‬ ‭–‬ ‭together‬ ‭with‬ ‭other‬ ‭lesions‬ ‭that‬ ‭are‬ ‭denoted‬ ‭as‬ ‭non-target‬ ‭lesions‬ ‭–‬
‭followed until disease progression.‬
‭8.2.1.‬ ‭Measurability of tumour lesions at baseline‬
‭●‬ ‭Chest-‬ ‭abdominal‬ ‭and‬ ‭pelvic‬ ‭CT‬ ‭scan‬ ‭will‬ ‭be‬ ‭used‬ ‭to‬ ‭measure‬ ‭the‬ ‭lesions‬ ‭according‬ ‭to‬
‭RECIST criteria.‬
‭●‬ ‭To‬‭meet‬‭screening‬‭criteria,‬‭initial‬‭tumor‬‭imaging‬‭must‬‭be‬‭performed‬‭within‬‭28‬‭days‬‭prior‬‭to‬
‭the‬‭beginning‬‭of‬‭treatment.‬‭This‬‭scan‬‭will‬‭be‬‭considered‬‭the‬‭baseline‬‭assessment‬‭for‬‭the‬‭study.‬
‭The‬‭site‬‭study‬‭team‬‭must‬‭review‬‭pre-trial‬‭images‬‭to‬‭confirm‬‭the‬‭subject‬‭has‬‭at‬‭least‬‭one‬‭target‬
‭lesion (i.e. meets measurability requirements) per RECIST 1.1.‬
‭●‬ ‭irRECIST criteria will be used to measure ORR as secondary endpoint.‬
‭8.2.1.1.‬‭Definitions‬
‭●‬ ‭Measurable‬‭disease‬‭:‬‭the‬‭presence‬‭of‬‭at‬‭least‬‭one‬‭measurable‬‭lesion.‬‭If‬‭the‬‭measurable‬‭disease‬
‭is‬ ‭restricted‬ ‭to‬ ‭a‬ ‭solitary‬ ‭lesion,‬ ‭its‬ ‭neoplastic‬ ‭nature‬ ‭should‬ ‭be‬ ‭confirmed‬ ‭by‬
‭cytology/histology.‬
‭●‬ ‭Measurable‬‭lesions‬‭:‬‭tumour‬‭lesions‬‭that‬‭can‬‭be‬‭accurately‬‭measured‬‭in‬‭at‬‭least‬‭one‬‭dimension‬
‭(longest‬‭diameter‬‭to‬‭be‬‭recorded)‬‭as‬‭≥‬‭20‬‭mm‬‭with‬‭chest‬‭x-ray,‬‭and‬‭as‬‭≥‬‭10‬‭mm‬‭with‬‭CT‬‭scan‬
‭or‬ ‭clinical‬ ‭examination‬ ‭[using‬ ‭calipers].‬ ‭Bone‬ ‭lesions‬ ‭are‬ ‭considered‬ ‭measurable‬ ‭only‬ ‭if‬
‭assessed‬ ‭by‬ ‭CT‬ ‭scan‬ ‭and‬ ‭have‬ ‭an‬ ‭identifiable‬ ‭soft‬ ‭tissue‬ ‭component‬ ‭that‬ ‭meets‬ ‭these‬
‭requirements‬‭(soft‬‭tissue‬‭component‬‭>‬‭10‬‭mm‬‭by‬‭CT‬‭scan).‬ ‭Malignant‬‭lymph‬‭nodes‬‭must‬‭be‬
‭≥‬‭15‬‭mm‬‭in‬‭the‬‭short‬‭axis‬‭to‬‭be‬‭considered‬‭measurable;‬‭only‬‭the‬‭short‬‭axis‬‭will‬‭be‬‭measured‬
‭and‬‭followed.‬‭All‬‭tumour‬‭measurements‬‭must‬‭be‬‭recorded‬‭in‬‭millimeters‬‭(or‬‭decimal‬‭fractions‬
‭of‬‭centimeters)‬‭by‬‭use‬‭of‬‭a‬‭ruler‬‭or‬‭calipers.‬‭Tumour‬‭lesions‬‭situated‬‭in‬‭a‬‭previously‬‭irradiated‬
‭area,‬ ‭or‬ ‭in‬ ‭an‬ ‭area‬ ‭subjected‬ ‭to‬ ‭other‬ ‭locoregional‬ ‭therapy,‬ ‭are‬ ‭usually‬ ‭not‬ ‭considered‬
‭measurable‬‭unless‬‭there‬‭has‬‭been‬‭demonstrated‬‭progression‬‭in‬‭the‬‭lesion.‬‭Provide‬‭detail‬‭on‬‭the‬
‭conditions under which such lesions would be considered measurable.‬
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‭●‬ ‭Non-measurable‬ ‭lesions‬‭:‬ ‭all‬ ‭other‬ ‭lesions‬ ‭(or‬ ‭sites‬‭of‬‭disease),‬‭including‬‭small‬‭lesions‬‭are‬
‭considered‬‭non-measurable‬‭disease.‬‭Bone‬‭lesions‬‭without‬‭a‬‭measurable‬‭soft‬‭tissue‬‭component,‬
‭leptomeningeal‬ ‭disease,‬ ‭ascites,‬ ‭pleural/pericardial‬ ‭effusions,‬ ‭lymphangitis‬ ‭cutis/pulmonis,‬
‭inflammatory‬‭breast‬‭disease,‬‭lymphangitic‬‭involvement‬‭of‬‭lung‬‭or‬‭skin‬‭and‬‭abdominal‬‭masses‬
‭followed‬‭by‬‭clinical‬‭examination‬‭are‬‭all‬‭non-measurable.‬‭Nodes‬‭that‬‭have‬‭a‬‭short‬‭axis‬‭<10‬
‭mm at baseline are considered non-pathological and should not be recorded or followed.‬
‭●‬ ‭Target‬‭Lesions:‬‭when‬‭more‬‭than‬‭one‬‭measurable‬‭tumour‬‭lesion‬‭or‬‭malignant‬‭lymph‬‭node‬‭is‬
‭present‬‭at‬‭baseline‬‭all‬‭lesions‬‭up‬‭to‬‭a‬‭maximum‬‭of‬‭5‬‭lesions‬‭total‬‭(and‬‭a‬‭maximum‬‭of‬‭2‬‭lesions‬
‭per‬‭organ‬‭)‬‭representative‬‭of‬‭all‬‭involved‬‭organs‬‭should‬‭be‬‭identified‬‭as‬‭target‬‭lesions‬‭and‬‭will‬
‭be‬‭recorded‬‭and‬‭measured‬‭at‬‭baseline.‬‭Target‬‭lesions‬‭should‬‭be‬‭selected‬‭on‬‭the‬‭basis‬‭of‬‭their‬
‭size‬ ‭(lesions‬ ‭with‬ ‭the‬ ‭longest‬ ‭diameter),‬ ‭be‬ ‭representative‬ ‭of‬ ‭all‬ ‭involved‬ ‭organs,‬ ‭but‬ ‭in‬
‭addition‬‭should‬‭be‬‭those‬‭that‬‭lend‬‭themselves‬‭to‬‭reproducible‬‭repeated‬‭measurements‬‭.‬‭Note‬
‭that‬‭pathological‬‭nodes‬‭must‬‭meet‬‭the‬‭criterion‬‭of‬‭a‬‭short‬‭axis‬‭of‬‭≥‬‭15‬‭mm‬‭by‬‭CT‬‭scan‬‭and‬
‭only‬‭the‬‭short‬‭axis‬‭of‬‭these‬‭nodes‬‭will‬‭contribute‬‭to‬‭the‬‭baseline‬‭sum.‬‭At‬‭baseline,‬‭the‬‭sum‬‭of‬
‭the‬‭target‬‭lesions‬‭(longest‬‭diameter‬‭of‬‭tumour‬‭lesions‬‭plus‬‭short‬‭axis‬‭of‬‭lymph‬‭nodes:‬‭overall‬
‭maximum of 5 ) is to be calculated and recorded.‬
‭●‬ ‭Non-target‬ ‭Lesions:‬ ‭all‬ ‭non-measurable‬ ‭lesions‬‭(or‬‭sites‬‭of‬‭disease)‬‭including‬‭pathological‬
‭nodes‬‭(those‬‭with‬‭short‬‭axis‬‭≥‬‭10‬‭mm‬‭but‬‭<‬‭15‬‭mm),‬‭plus‬‭any‬‭measurable‬‭lesions‬‭over‬‭and‬
‭above‬‭those‬‭listed‬‭as‬‭target‬‭lesions‬‭are‬‭considered‬‭non-target‬‭lesions‬‭.‬‭Measurements‬‭are‬‭not‬
‭required‬‭but‬‭these‬‭lesions‬‭should‬‭be‬‭noted‬‭at‬‭baseline‬‭and‬‭should‬‭be‬‭followed‬‭as‬‭“present”‬‭or‬
‭“absent”.‬
‭8.2.1.2.‬‭Methods of measurements‬
‭●‬ ‭Patient‬‭must‬‭have‬‭measurable‬‭lesions‬‭on‬‭CT‬‭according‬‭to‬‭RECIST‬‭1.1‬‭in‬‭order‬‭to‬‭enter‬‭the‬
‭study.‬
‭●‬ ‭The‬‭preferred‬‭radiologic‬‭technique‬‭is‬‭CT‬‭with‬‭IV‬‭contrast.‬‭If‬‭a‬‭patient‬‭is‬‭known‬‭to‬‭have‬‭a‬
‭contraindication‬‭to‬‭CT‬‭contrast‬‭or‬‭develops‬‭a‬‭contraindication‬‭during‬‭the‬‭trial,‬‭a‬‭non-contrast‬
‭CT‬ ‭of‬ ‭the‬ ‭chest‬ ‭(MRI‬ ‭is‬ ‭not‬ ‭recommended‬ ‭due‬ ‭to‬ ‭respiratory‬ ‭artifacts)‬ ‭plus‬ ‭a‬
‭contrast-enhanced MRI (if possible) of the abdomen and pelvis should be performed.‬
‭8.2.2.‬ ‭Tumor response evaluation‬
‭8.2.2.1.‬‭Response evaluation according RECIST 1.1‬‭[xliv]‬
‭●‬ ‭All‬‭patients‬‭will‬‭have‬‭their‬‭best‬‭response‬‭according‬‭to‬‭RECIST‬‭criteria‬‭1.1‬‭from‬‭the‬‭start‬‭of‬
‭study treatment until the end of treatment classified as outlined below:‬
‭○‬ ‭Complete‬‭or‬‭partial‬‭responses‬‭may‬‭be‬‭claimed‬‭only‬‭if‬‭the‬‭criteria‬‭for‬‭each‬‭are‬‭met‬‭at‬‭a‬
‭subsequent‬ ‭time‬ ‭point‬ ‭at‬ ‭least‬ ‭4‬ ‭weeks‬ ‭later.‬ ‭Refer‬ ‭to‬ ‭the‬ ‭table‬ ‭below‬ ‭(Table‬
‭8.2.2.1-a).‬
‭○‬ ‭Complete‬ ‭Response‬ ‭(CR):‬ ‭disappearance‬ ‭of‬ ‭all‬ ‭target‬ ‭and‬ ‭non-target‬ ‭lesions‬ ‭and‬
‭normalization‬ ‭of‬ ‭tumour‬ ‭markers.‬ ‭Pathological‬ ‭lymph‬ ‭nodes‬ ‭must‬ ‭have‬‭short‬‭axis‬
‭measures‬‭<‬‭10‬‭mm‬‭(‬‭Note‬‭:‬‭continue‬‭to‬‭record‬‭the‬‭measurement‬‭even‬‭if‬‭<‬‭10‬‭mm‬‭and‬
‭considered‬‭CR).‬‭Tumour‬‭markers‬‭must‬‭have‬‭normalized.‬‭Residual‬‭lesions‬‭(other‬‭than‬
‭nodes‬ ‭<‬ ‭10‬ ‭mm)‬ ‭thought‬ ‭to‬ ‭be‬ ‭non-malignant‬ ‭should‬ ‭be‬ ‭further‬ ‭investigated‬ ‭(by‬
‭cytology or PET scans) before CR can be accepted.‬
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‭○‬ ‭Partial‬ ‭Response‬ ‭(PR):‬ ‭at‬ ‭least‬ ‭a‬ ‭30%‬ ‭decrease‬ ‭in‬ ‭the‬ ‭sum‬ ‭of‬ ‭measures‬ ‭(longest‬
‭diameter‬‭for‬‭tumour‬‭lesions‬‭and‬‭short‬‭axis‬‭measure‬‭for‬‭nodes)‬‭of‬‭target‬‭lesions,‬‭taking‬
‭as reference the baseline sum of diameters. Non target lesions must be non-PD.‬
‭○‬ ‭Stable‬ ‭Disease‬ ‭(SD):‬ ‭Neither‬ ‭sufficient‬ ‭shrinkage‬ ‭to‬ ‭qualify‬ ‭for‬ ‭PR‬ ‭nor‬‭sufficient‬
‭increase to qualify for PD taking as reference the smallest sum of diameters on study.‬
‭○‬ ‭Progressive‬ ‭Disease‬ ‭(PD):‬ ‭at‬ ‭least‬ ‭a‬ ‭20%‬ ‭increase‬ ‭in‬ ‭the‬ ‭sum‬ ‭of‬ ‭diameters‬ ‭of‬
‭measured‬ ‭lesions‬ ‭taking‬ ‭as‬ ‭references‬ ‭the‬ ‭smallest‬ ‭sum‬ ‭of‬ ‭diameters‬ ‭recorded‬ ‭on‬
‭study‬‭(including‬‭baseline)‬‭AND‬‭an‬‭absolute‬‭increase‬‭of‬‭≥‬‭5‬‭mm.‬‭Appearance‬‭of‬‭new‬
‭lesions‬‭will‬‭also‬‭constitute‬‭PD‬‭(including‬‭lesions‬‭in‬‭previously‬‭unassessed‬‭areas).‬‭In‬
‭exceptional‬ ‭circumstances,‬ ‭unequivocal‬ ‭progression‬ ‭of‬ ‭non-target‬ ‭disease‬ ‭may‬ ‭be‬
‭accepted‬ ‭as‬ ‭evidence‬ ‭of‬ ‭disease‬‭progression,‬‭where‬‭the‬‭overall‬‭tumour‬‭burden‬‭has‬
‭increased‬ ‭sufficiently‬ ‭to‬‭merit‬‭discontinuation‬‭of‬‭treatment,‬‭for‬‭example‬‭where‬‭the‬
‭tumour‬ ‭burden‬‭appears‬‭to‬‭have‬‭increased‬‭by‬‭at‬‭least‬‭73%‬‭in‬‭volume‬‭(which‬‭is‬‭the‬
‭increase‬‭in‬‭volume‬‭when‬‭all‬‭dimensions‬‭of‬‭a‬‭single‬‭lesion‬‭increase‬‭by‬‭20%).‬‭Modest‬
‭increases‬ ‭in‬ ‭the‬ ‭size‬ ‭of‬ ‭one‬ ‭or‬ ‭more‬ ‭non-target‬ ‭lesions‬ ‭are‬ ‭NOT‬ ‭considered‬
‭unequivocal‬‭progression.‬ ‭If‬‭the‬‭evidence‬‭of‬‭PD‬‭is‬‭equivocal‬‭(target‬‭or‬‭non-target),‬
‭treatment‬‭may‬‭continue‬‭until‬‭the‬‭next‬‭assessment,‬‭but‬‭on‬‭further‬‭documentation,‬‭the‬
‭earlier date must be used‬‭[xlv]‬‭.‬
‭Table 8.2.2.1-a: Integration of target, non-target and new lesions into response assessment:‬
‭Target Lesions‬
‭Non-Target Lesions‬
‭New Lesions‬ ‭Overall Response‬ ‭Best Response for this category‬
‭also requires‬
‭Patients with Target lesions ± non target lesions‬
‭CR‬
‭CR‬
‭No‬
‭CR‬
‭Normalization of tumour‬
‭markers, tumour nodes < 10 mm‬
‭CR‬
‭Non-CR/Non-PD‬
‭No‬
‭PR‬
‭CR‬
‭Not all evaluated‬
‭No‬
‭PR‬
‭PR‬
‭Non-PD/ not all evaluated‬
‭No‬
‭PR‬
‭SD‬
‭Non-PD/ not all evaluated‬
‭No‬
‭SD‬
‭Documented at least once ≥‬‭4‬
‭weeks from baseline [note,‬
‭protocol may define;  6-8 weeks‬
‭is recommended]‬
‭Not all evaluated‬
‭Non-PD‬
‭No‬
‭NE‬
‭PD‬
‭Any‬
‭Any‬
‭PD‬
‭Any‬
‭PD‬
‭Any‬
‭PD‬
‭Any‬
‭Any‬
‭Yes‬
‭PD‬
‭Patients with Non target lesions ONLY‬
‭No Target‬
‭CR‬
‭No‬
‭CR‬
‭Normalization of tumour‬
‭markers, all tumour nodes‬
‭<10 mm‬
‭Non-CR/Non-PD‬
‭No‬
‭Non-CR/Non-PD‬
‭Not all evaluated‬
‭No‬
‭NE‬
‭Unequivocal PD‬
‭Any‬
‭PD‬
‭Any‬
‭Yes‬
‭PD‬
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‭Note‬‭: Patients with a global deterioration of health‬‭status requiring discontinuation of treatment without objective evidence‬
‭of disease progression [or evidence of unequivocal disease progression] at that time should be reported as “‬‭symptomatic‬
‭deterioration”‬‭. This is a reason for stopping therapy,‬‭but is NOT objective PD.  Every effort should be made to document‬
‭the objective progression even after discontinuation of treatment.‬
‭The best overall response can be interpreted as below‬‭(Table 8.2.2.1-b)‬‭:‬
‭Table 8.2.2.1-b. Response on confirmation‬
‭Response:‬
‭First time point‬
‭Subsequent time point‬
‭BEST overall response‬
‭Also requires‬
‭CR‬
‭CR‬
‭CR‬
‭Normalization of tumour‬
‭markers, tumour nodes < 10‬
‭mm‬
‭CR‬
‭PR‬
‭SD, PD or PR (see‬
‭comment*)‬
‭-‬
‭CR‬
‭SD‬
‭SD provided minimum‬
‭criteria for SD duration met,‬
‭otherwise, PD‬
‭-‬
‭CR‬
‭PD‬
‭SD provided minimum‬
‭criteria for SD duration met,‬
‭otherwise, PD‬
‭-‬
‭CR‬
‭NE‬
‭SD provided minimum‬
‭criteria for SD duration met,‬
‭otherwise NE‬
‭-‬
‭PR‬
‭CR‬
‭PR‬
‭-‬
‭PR‬
‭PR‬
‭PR‬
‭-‬
‭PR‬
‭SD‬
‭SD‬
‭-‬
‭PR‬
‭PD‬
‭SD provided minimum‬
‭criteria for SD duration met,‬
‭otherwise, PD‬
‭-‬
‭PR‬
‭NE‬
‭SD provide minimum‬
‭criteria for SD duration met,‬
‭otherwise, NE‬
‭-‬
‭NE‬
‭NE‬
‭NE‬
‭-‬
*‬‭May‬‭consider‬‭PR‬‭providing‬‭initial‬‭“CR”‬‭likely‬‭PR‬‭on‬‭subsequent‬‭review‬‭–‬‭then‬‭original‬‭CR‬‭should‬‭be‬‭corrected.‬ ‭Recurrence‬‭of‬‭lesion‬
after true CR is PD.‬
‭8.2.2.2.‬‭Response evaluation according irRECIST‬‭[xlvi]‬
‭●‬ ‭Following‬‭radiological‬‭assessment‬‭of‬‭PD‬‭by‬‭RECIST‬‭1.1,‬‭sites‬‭will‬‭assess‬‭tumor‬‭response‬‭and‬
‭progression per immune-related RECIST (irRECIST) for all subjects included in the trial.‬
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‭●‬ ‭If‬‭imaging‬‭shows‬‭PD‬‭per‬‭RECIST‬‭1.1,‬‭tumor‬‭assessment‬‭may‬‭be‬‭repeated‬‭at‬‭the‬‭site‬‭at‬‭least‬‭4‬
‭weeks‬‭later‬‭to‬‭confirm‬‭PD‬‭(per‬‭irRECIST)‬‭with‬‭the‬‭option‬‭of‬‭continuing‬‭treatment‬‭until‬‭this‬
‭scan‬‭is‬‭obtained‬‭for‬‭clinically‬‭stable‬‭subjects‬‭(see‬‭Table‬‭11).‬‭Subjects‬‭who‬‭have‬‭unconfirmed‬
‭disease‬ ‭progression‬ ‭(per‬ ‭irRECIST)‬ ‭may‬ ‭continue‬ ‭on‬ ‭treatment‬ ‭and‬ ‭follow‬ ‭the‬ ‭regular‬
‭imaging‬‭schedule‬‭intervals‬‭until‬‭documented‬‭disease‬‭progression,‬‭the‬‭start‬‭of‬‭new‬‭anti-cancer‬
‭treatment, withdrawal of consent, death, or the end of the trial, whichever occurs first.‬
‭●‬ ‭In‬ ‭determining‬ ‭whether‬ ‭or‬ ‭not‬ ‭the‬ ‭tumor‬ ‭burden‬‭has‬‭increased‬‭or‬‭decreased,‬‭investigators‬
‭should consider all target lesions as well as non-target lesions.‬
‭●‬ ‭Subjects‬ ‭that‬ ‭are‬ ‭deemed‬ ‭clinically‬ ‭unstable‬ ‭are‬ ‭not‬ ‭required‬ ‭to‬ ‭have‬ ‭repeat‬ ‭imaging‬ ‭for‬
‭confirmation.‬‭If‬‭radiologic‬‭progression‬‭is‬‭confirmed‬‭by‬‭subsequent‬‭scan,‬‭it‬‭is‬‭recommended‬
‭that‬‭the‬‭subject‬‭be‬‭discontinued‬‭from‬‭trial‬‭treatment‬‭unless,‬‭in‬‭the‬‭investigator’s‬‭opinion,‬‭the‬
‭subject‬‭is‬‭deriving‬‭benefit‬‭from‬‭treatment.‬‭Clinically‬‭stable‬‭subjects‬‭may‬‭continue‬‭to‬‭receive‬
‭trial therapy. Clinically stable is defined as follows:‬
‭○‬ ‭Absence of signs and symptoms indicating disease progression.‬
‭○‬ ‭No decline in ECOG performance status.‬
‭○‬ ‭Absence of rapid progression of disease.‬
‭○‬ ‭Absence‬‭of‬‭progressive‬‭tumor‬‭at‬‭critical‬‭anatomical‬‭sites‬‭requiring‬‭urgent‬‭alternative‬
‭medical intervention.‬
‭Table 8.2.2.2. Management after 1‬‭st‬‭radiological progression‬
‭Clinically stable‬
‭Clinically unstable‬
‭Imaging‬
‭Treatment‬
‭Imaging‬
‭Treatment‬
‭1‬‭st‬‭Radiological‬
‭evidence of PD per‬
‭RECIST 1.1‬
‭Repeat imaging at ≥‬
‭4 weeks to confirm‬
‭PD.‬
‭May continue‬
‭treatment at‬
‭investigator’s‬
‭discretion while‬
‭waiting for‬
‭confirmatory scan.‬
‭Repeat imaging at ≥‬
‭4 weeks to confirm‬
‭PD if possible.‬
‭Discontinue‬
‭treatment.‬
‭Repeat scan confirms‬
‭PD‬
‭No additional‬
‭imaging required‬
‭Discontinue‬
‭treatment.‬
‭No additional‬
‭imaging required‬
‭Repeat scan shows‬
‭SD, PR or CR.‬
‭Continue regularly‬
‭schedule imaging‬
‭every 8 weeks.‬
‭Continue study‬
‭treatment at‬
‭investigator’s‬
‭discretion.‬
‭Continue regularly‬
‭schedule imaging‬
‭every 8 weeks.‬
‭May restart study‬
‭treatment as per‬
‭investigator´s‬
‭discretion.‬
‭8.2.2.3.‬‭Frequency of tumor re-evaluation‬
‭●‬ ‭The‬‭first‬‭on-study‬‭imaging‬‭assessment‬‭should‬‭be‬‭performed‬‭at‬‭12‬‭weeks‬‭(±‬‭7‬‭days)‬‭after‬‭the‬
‭first‬‭dose‬‭of‬‭trial‬‭treatment.‬‭Subsequent‬‭imaging‬‭should‬‭be‬‭performed‬‭every‬‭12‬‭weeks‬‭(±‬‭7‬
‭days) until PD.‬
‭●‬ ‭Imaging‬‭should‬‭be‬‭repeated‬‭at‬‭least‬‭4‬‭weeks‬‭after‬‭the‬‭first‬‭observation‬‭of‬‭a‬‭complete‬‭or‬‭partial‬
‭response.‬
‭●‬ ‭Imaging‬ ‭may‬ ‭be‬ ‭more‬ ‭frequent‬ ‭if‬ ‭clinically‬ ‭indicated.‬ ‭Imaging‬ ‭should‬‭not‬‭be‬‭delayed‬‭for‬
‭delays in cycle starts.‬
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‭●‬ ‭After‬ ‭discontinuation‬ ‭of‬ ‭protocol‬ ‭treatment,‬ ‭patients‬‭who‬‭have‬‭not‬‭progressed‬‭will‬‭still‬‭be‬
‭re-evaluated every 12 weeks.‬
‭8.2.3.‬ ‭Reporting of tumor response‬
‭All‬‭patients‬‭included‬‭in‬‭the‬‭study‬‭must‬‭be‬‭assessed‬‭for‬‭response‬‭to‬‭treatment,‬‭even‬‭if‬‭there‬‭is‬‭a‬
‭major‬‭protocol‬‭treatment‬‭deviation‬‭or‬‭if‬‭they‬‭are‬‭ineligible,‬‭or‬‭not‬‭followed/re-evaluated.‬‭Each‬‭patient‬
‭will‬‭be‬‭assigned‬‭one‬‭of‬‭the‬‭following‬‭categories:‬‭complete‬‭response,‬‭partial‬‭response,‬‭stable‬‭disease,‬
‭progressive‬‭disease,‬‭early‬‭death‬‭from‬‭malignant‬‭disease,‬‭early‬‭death‬‭from‬‭toxicity,‬‭early‬‭death‬‭from‬
‭other cause or unknown (not assessable, insufficient data).‬
‭Early‬ ‭death‬ ‭is‬ ‭defined‬ ‭as‬ ‭any‬ ‭death‬ ‭occurring‬ ‭before‬ ‭the‬ ‭first‬ ‭per‬ ‭protocol‬ ‭time‬ ‭point‬ ‭of‬ ‭tumor‬
‭re-evaluation.‬ ‭The‬ ‭responsible‬ ‭investigator‬ ‭will‬ ‭decide‬ ‭if‬ ‭the‬ ‭cause‬ ‭of‬‭death‬‭is‬‭malignant‬‭disease,‬
‭toxicity or other cause.‬
‭Patients‬‭for‬‭whom‬‭response‬‭is‬‭not‬‭confirmed‬‭will‬‭be‬‭classified‬‭as‬‭"unknown",‬‭unless‬‭they‬‭meet‬‭the‬
‭criteria‬ ‭for‬ ‭stable‬ ‭disease‬ ‭(or‬ ‭the‬ ‭criteria‬ ‭for‬ ‭partial‬‭response‬‭in‬‭case‬‭of‬‭an‬‭unconfirmed‬‭complete‬
‭response).‬‭Patients’‬‭response‬‭will‬‭also‬‭be‬‭classified‬‭as‬‭"unknown"‬‭if‬‭insufficient‬‭data‬‭were‬‭collected‬‭to‬
‭allow evaluation per these criteria. Please refer to table‬‭8.2.2.1-b.‬
‭8.2.3.1.‬‭Response duration‬
‭Response‬‭duration‬‭will‬‭be‬‭measured‬‭from‬‭the‬‭time‬‭measurement‬‭criteria‬‭for‬‭CR/PR‬‭(whichever‬‭is‬‭first‬
‭recorded)‬ ‭are‬ ‭first‬ ‭met‬ ‭until‬ ‭the‬ ‭first‬ ‭date‬ ‭that‬ ‭recurrent‬ ‭or‬ ‭progressive‬ ‭disease‬ ‭is‬ ‭objectively‬
‭documented.‬
‭8.2.3.2.‬‭Stable disease duration‬
‭Stable‬‭disease‬‭duration‬‭will‬‭be‬‭measured‬‭from‬‭the‬‭time‬‭of‬‭start‬‭of‬‭treatment‬‭(or‬‭randomization‬‭for‬
‭randomized studies) until the criteria for progression are met.‬
‭8.2.3.3.‬‭Progression Free Survival‬
‭Progression‬‭free‬‭survival‬‭will‬‭be‬‭calculated‬‭from‬‭the‬‭date‬‭treatment‬‭with‬‭first-line‬‭chemotherapy‬‭and‬
‭nivolumab begins until the date of first progressive disease as per RECIST 1.1 or death.‬
‭8.2.3.4.‬‭Overall Survival‬
‭Overall‬ ‭survival‬ ‭will‬ ‭be‬ ‭calculated‬ ‭from‬ ‭the‬ ‭date‬ ‭treatment‬ ‭with‬ ‭first-line‬ ‭chemotherapy‬ ‭and‬
‭nivolumab begins until the date of death from any cause.‬
‭9.‬
‭Statistical considerations‬
‭9.1.‬
‭Statistical design‬
‭9.1.1.‬ ‭Sample Size Determination‬
‭This‬‭is‬‭a‬‭phase‬‭II‬‭open-label,‬‭single‬‭arm‬‭study.‬‭The‬‭primary‬‭endpoint‬‭is‬‭the‬‭one-year‬‭overall‬
‭survival rate.‬
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‭The‬ ‭sample‬‭size‬‭of‬‭this‬‭study‬‭is‬‭driven‬‭by‬‭its‬‭primary‬‭objective‬‭which‬‭is‬‭to‬‭determine‬‭the‬
‭one-year‬ ‭OS‬ ‭rate‬ ‭calculated‬ ‭from‬ ‭the‬ ‭date‬ ‭treatment‬ ‭with‬ ‭nivolumab‬ ‭and‬ ‭platinum-based‬
‭chemotherapy‬‭begins,‬‭until‬‭the‬‭date‬‭of‬‭death‬‭from‬‭any‬‭cause‬‭in‬‭patients‬‭with‬‭advanced‬‭G3‬‭NENs‬‭of‬
‭GEP‬ ‭tract‬ ‭or‬ ‭unknown‬ ‭primary‬ ‭site,‬ ‭who‬ ‭have‬ ‭not‬ ‭received‬ ‭any‬ ‭prior‬ ‭antineoplastic‬ ‭systemic‬
‭treatment.‬
‭Based‬‭on‬‭data‬‭derived‬‭from‬‭tumor‬‭registries‬‭[xlvii],[xlviii]‬‭,‬‭median‬‭OS‬‭for‬‭these‬‭patients‬‭is‬‭approximately‬
‭11-12‬ ‭months,‬ ‭with‬ ‭1-year‬ ‭overall‬ ‭survival‬ ‭rate‬ ‭of‬ ‭50%.‬ ‭The‬ ‭primary‬ ‭hypothesis‬ ‭(H1)‬ ‭is‬ ‭that‬
‭chemotherapy‬‭in‬‭combination‬‭with‬‭nivolumab‬‭is‬‭superior‬‭to‬‭chemotherapy‬‭in‬‭terms‬‭of‬‭OS,‬‭achieving‬
‭a‬ ‭median‬ ‭OS‬ ‭of‬ ‭14‬ ‭months,‬ ‭with‬ ‭72%‬ ‭patients‬ ‭alive‬‭at‬‭12‬‭months.‬‭The‬‭study‬‭will‬‭be‬‭considered‬
‭successful‬‭if‬‭the‬‭primary‬‭hypothesis‬‭is‬‭statistically‬‭significant.‬‭Considering‬‭the‬‭following‬‭assumptions:‬
‭a‬‭power‬‭of‬‭80%,‬‭alpha‬‭error‬‭of‬‭0.05,‬‭18‬‭months‬‭accrual‬‭time‬‭and‬‭12-month‬‭follow-up‬‭period,‬‭a‬‭total‬
‭number of 38 patients should be included in the study, considering a drop out rate of 10%.‬
‭9.2.‬
‭Populations for Analysis‬
‭For purpose of analysis, the following populations are defined:‬
‭Population‬
‭Description‬
‭Enrolled‬
‭All participants who signed informed consent and were registered.‬
‭Treated‬
‭All‬‭participants‬‭who‬‭received‬‭at‬‭least‬‭one‬‭dose‬‭of‬‭any‬‭study‬‭medication.‬‭This‬‭is‬‭the‬‭primary‬
‭dataset for dosing and safety analysis.‬
‭Response-Evaluable‬
‭All treated subjects who have a baseline and at least one‬
‭on-treatment‬‭imaging‬‭evaluation‬‭or‬‭had‬‭progression‬‭or‬‭death‬‭prior‬‭to‬‭the‬‭first‬‭on-treatment‬
‭scan.‬
‭9.3.‬
‭Statistical Analysis‬
‭9.3.1.‬ ‭Efficacy Analysis‬
‭Endpoint‬
‭Statistical Analysis Methods‬
‭Primary‬
‭Primary‬‭endpoint‬‭is‬‭one‬‭year‬‭OS‬‭rate‬‭with‬‭nivolumab‬‭plus‬‭chemotherapy.‬‭This‬‭is‬‭defined‬
‭as‬ ‭the‬ ‭proportion‬ ‭of‬ ‭patients‬ ‭that‬ ‭remain‬ ‭alive‬ ‭at‬ ‭12‬ ‭months‬ ‭since‬ ‭the‬ ‭beginning‬ ‭of‬
‭treatment. OS will be censored on the last date a participant was known to be alive.‬
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‭Secondary‬
‭PFS and OS with nivolumab plus chemotherapy assessed by Central Review.‬
‭ORR with nivolumab plus chemotherapy assessed by Central Review.‬
‭Chromogranin A and enolase levels and their association with ORR, PFS,‬
‭and OS.‬
‭ORR‬ ‭is‬‭defined‬‭as‬‭the‬‭number‬‭of‬‭participants‬‭with‬‭a‬‭best‬‭overall‬‭response‬‭of‬‭confirmed‬
‭CR‬ ‭or‬ ‭PR‬ ‭divided‬ ‭by‬ ‭the‬ ‭number‬ ‭of‬ ‭enrolled‬ ‭participants.‬ ‭BOR‬ ‭is‬ ‭defined‬ ‭as‬ ‭the‬ ‭best‬
‭response‬ ‭designation,‬ ‭as‬‭determined‬‭by‬‭the‬‭central‬‭review,‬‭recorded‬‭between‬‭the‬‭date‬‭of‬
‭treatment‬‭start‬‭and‬‭the‬‭date‬‭of‬‭objectively‬‭documented‬‭progression‬‭per‬‭RECIST‬‭1.1‬‭or,‬‭the‬
‭date‬ ‭of‬ ‭initiation‬ ‭of‬ ‭subsequent‬ ‭anti-cancer‬ ‭therapy,‬ ‭whichever‬ ‭occurs‬ ‭first.‬ ‭For‬
‭participants without documented‬
‭progression‬ ‭or‬ ‭subsequent‬ ‭anti-cancer‬ ‭therapy,‬ ‭all‬ ‭available‬ ‭response‬ ‭designations‬ ‭will‬
‭contribute‬ ‭to‬ ‭the‬ ‭BOR‬ ‭determination.‬ ‭For‬ ‭participants‬ ‭who‬ ‭continue‬ ‭treatment‬ ‭beyond‬
‭progression,‬ ‭the‬‭BOR‬‭will‬‭be‬‭determined‬‭based‬‭on‬‭response‬‭designations‬‭recorded‬‭up‬‭to‬
‭the‬‭time‬‭of‬‭the‬‭initial‬‭RECIST‬‭1.1-defined‬‭progression.‬‭Complete‬‭or‬‭partial‬‭responses‬‭may‬
‭be‬ ‭claimed‬ ‭only‬‭if‬‭the‬‭criteria‬‭for‬‭each‬‭are‬‭met‬‭at‬‭a‬‭subsequent‬‭time‬‭point‬‭of‬‭≥‬‭4‬‭weeks‬
‭later.‬
‭9.3.1.1.‬‭Methods for Primary Endpoint‬
‭The efficacy analysis will be performed for the treatment population.‬
‭For‬ ‭the‬ ‭primary‬ ‭endpoint,‬ ‭the‬ ‭OS‬ ‭rate‬ ‭at‬ ‭12‬ ‭months‬ ‭with‬ ‭95%‬ ‭CIs‬ ‭will‬ ‭be‬ ‭estimated‬ ‭using‬
‭Kaplan-Meier‬‭methodology‬‭if‬‭follow-up‬‭requirement‬‭is‬‭met.‬‭OS‬‭curves,‬‭medians‬‭with‬‭95%‬‭CIs‬‭and‬
‭OS‬‭rates‬‭at‬‭6,‬‭18‬‭and‬‭24‬‭months‬‭with‬‭95%‬‭CIs‬‭will‬‭be‬‭estimated‬‭if‬‭follow-up‬‭requirement‬‭is‬‭met.‬‭The‬
‭proportion‬ ‭will‬ ‭be‬ ‭calculated‬ ‭by‬ ‭the‬ ‭product‬ ‭limit‬ ‭method‬‭(Kaplan-Meier‬‭[K-M]‬‭estimate),‬‭which‬
‭takes into account censored data.‬
‭9.3.1.2.‬‭Methods for Secondary Endpoints‬
‭The efficacy analysis for secondary endpoints will be performed for all treated patients.‬
‭PFS‬‭is‬‭defined‬‭as‬‭the‬‭time‬‭from‬‭the‬‭randomization‬‭date‬‭to‬‭the‬‭date‬‭of‬‭the‬‭first‬‭documented‬
‭tumor progression per RECIST 1.1, or death due to any cause.‬
‭Participants‬‭who‬‭did‬‭not‬‭progress‬‭or‬‭die‬‭will‬‭be‬‭censored‬‭on‬‭the‬‭date‬‭of‬‭their‬‭last‬‭evaluable‬‭tumor‬
‭assessment.‬‭Participants‬‭who‬‭did‬‭not‬‭have‬‭any‬‭on‬‭study‬‭tumor‬‭assessments‬‭will‬‭be‬‭censored‬‭on‬‭the‬
‭beginning‬‭of‬‭treatment‬‭date.‬‭PFS‬‭curves,‬‭PFS‬‭medians‬‭with‬‭95%‬‭CIs,‬‭and‬‭PFS‬‭rates‬‭at‬‭6,‬‭12,‬‭18,‬‭24,‬
‭36,‬‭and‬‭48‬‭months‬‭with‬‭95%‬‭CIs‬‭will‬‭be‬‭estimated‬‭using‬‭Kaplan-Meier‬‭methodology‬‭if‬‭follow-up‬
‭requirements are met.‬
‭ORR‬ ‭is‬ ‭defined‬ ‭as‬ ‭the‬ ‭number‬ ‭of‬ ‭participants‬ ‭with‬ ‭a‬ ‭best‬ ‭overall‬ ‭response‬ ‭(BOR)‬ ‭of‬
‭confirmed‬ ‭CR‬ ‭or‬ ‭PR‬ ‭divided‬ ‭by‬ ‭the‬ ‭number‬ ‭of‬ ‭enrolled‬ ‭participants.‬‭BOR‬‭is‬‭defined‬‭as‬‭the‬‭best‬
‭response‬‭designation,‬‭as‬‭determined‬‭by‬‭central‬‭review,‬‭recorded‬‭between‬‭the‬‭date‬‭of‬‭treatment‬‭start‬
‭and‬ ‭the‬ ‭date‬ ‭of‬ ‭objectively‬ ‭documented‬ ‭progression‬ ‭per‬ ‭RECIST‬ ‭1.1‬ ‭or,‬ ‭the‬ ‭date‬ ‭of‬‭initiation‬‭of‬
‭subsequent‬ ‭anti-cancer‬ ‭therapy,‬ ‭whichever‬ ‭occurs‬ ‭first.‬ ‭For‬ ‭participants‬ ‭without‬ ‭documented‬
‭progression‬‭or‬‭subsequent‬‭anti-cancer‬‭therapy,‬‭all‬‭available‬‭response‬‭designations‬‭will‬‭contribute‬‭to‬
‭the‬‭BOR‬‭determination.‬‭For‬‭participants‬‭who‬‭continue‬‭treatment‬‭beyond‬‭progression,‬‭the‬‭BOR‬‭will‬‭be‬
‭determined‬‭based‬‭on‬‭response‬‭designations‬‭recorded‬‭up‬‭to‬‭the‬‭time‬‭of‬‭the‬‭initial‬‭RECIST‬‭1.1-defined‬
‭progression.‬‭Complete‬‭or‬‭partial‬‭responses‬‭may‬‭be‬‭claimed‬‭only‬‭if‬‭the‬‭criteria‬‭for‬‭each‬‭are‬‭met‬‭at‬‭a‬
‭subsequent time point of ≥ 4 weeks later.‬
‭An estimate of the response rate and an associated exact two-sided 95% CI will be presented.‬
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‭9.3.2.‬ ‭Safety Analysis‬
‭Safety analysis will be performed in all treated participants.‬
‭Descriptive‬ ‭statistics‬ ‭of‬ ‭safety‬ ‭will‬ ‭be‬ ‭presented‬ ‭using‬ ‭National‬ ‭Cancer‬ ‭Institute‬ ‭(NCI)‬ ‭Common‬
‭Terminology‬‭Criteria‬‭for‬‭Adverse‬‭Events‬‭(CTCAE)‬‭version‬‭5.0.‬‭All‬‭on-study‬‭AEs,‬‭drug‬‭related‬‭AEs,‬
‭SAEs‬ ‭and‬ ‭drug-related‬ ‭SAEs,‬ ‭AEs‬ ‭and‬ ‭drug-related‬ ‭AEs‬ ‭leading‬ ‭to‬ ‭drug‬ ‭discontinuation‬ ‭will‬ ‭be‬
‭tabulated‬‭using‬‭worst‬‭grade‬‭per‬‭NCI‬‭CTCAE‬‭v‬‭5.0‬‭criteria‬‭by‬‭system‬‭organ‬‭class‬‭and‬‭preferred‬‭term,‬
‭based‬ ‭on‬ ‭MedDRA‬ ‭terminology.‬ ‭On-study‬ ‭lab‬ ‭parameters‬ ‭including‬ ‭hematology,‬ ‭coagulation,‬
‭chemistry,‬‭liver‬‭function‬‭and‬‭renal‬‭function‬‭will‬‭be‬‭summarized‬‭using‬‭worst‬‭grade‬‭per‬‭NCI‬‭CTCAE‬‭v‬
‭5.0 criteria.‬
‭A‬‭tabular‬‭summary‬‭of‬‭the‬‭incidence‬‭of‬‭overall‬‭immune-mediated‬‭adverse‬‭events‬‭(imAEs)‬‭and‬‭serious‬
‭imAEs‬‭will‬‭be‬‭performed.‬‭Frequency,‬‭management‬‭and‬‭resolution‬‭of‬‭imAEs‬‭will‬‭be‬‭analyzed‬‭and‬‭a‬
‭descriptive‬ ‭analysis‬ ‭including‬ ‭time-to-onset,‬ ‭severity,‬ ‭duration,‬ ‭action‬ ‭taken‬ ‭with‬ ‭the‬ ‭study‬ ‭drug,‬
‭dosing‬‭delays‬‭of‬‭the‬‭study‬‭drug,‬‭corticosteroid‬‭details,‬‭re-challenge‬‭information‬‭and‬‭outcome‬‭of‬‭the‬
‭AE will be individually characterized by imAE category.‬
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‭10.‬
‭Translational research‬
‭Baseline‬‭tumor‬‭samples‬‭will‬‭be‬‭mandatory‬‭prior‬‭to‬‭the‬‭beginning‬‭of‬‭the‬‭study.‬‭Serial‬‭blood‬‭samples‬
‭(including‬ ‭serum‬ ‭and‬ ‭plasma‬ ‭at‬‭baseline‬‭and‬‭at‬‭disease‬‭progression‬‭or‬‭EOT)‬‭will‬‭be‬‭collected‬‭for‬
‭additional‬ ‭biomarker‬ ‭research‬ ‭to‬ ‭identify‬ ‭prognostic‬ ‭and/or‬ ‭predictive‬ ‭factors‬ ‭of‬ ‭response‬ ‭to‬
‭nivolumab and carboplatin-etoposide chemotherapy.‬
‭Biological‬ ‭samples‬ ‭may‬‭undergo‬‭genomic,‬‭metabolomic,‬‭transcriptomic‬‭and‬‭proteomic‬‭analyses‬‭or‬
‭other‬ ‭molecular‬ ‭assessments‬ ‭related‬ ‭to‬ ‭the‬ ‭disease,‬ ‭the‬ ‭immunological‬ ‭landscape‬ ‭of‬ ‭tumors‬ ‭and‬
‭patients,‬‭or‬‭the‬‭mechanism‬‭of‬‭action‬‭of‬‭drugs‬‭tested‬‭with‬‭this‬‭purpose.‬‭Additional‬‭information‬‭on‬‭this‬
‭subject is available for all participants in the informed consent form.‬
‭The‬ ‭samples‬ ‭will‬ ‭be‬ ‭sent‬ ‭to‬ ‭and‬ ‭stored‬ ‭at‬ ‭the‬ ‭Gastrointestinal‬ ‭Tumors‬ ‭Research‬ ‭Unit‬ ‭from‬ ‭the‬
‭Research Institute at the Hospital Universitario 12 de Octubre, Madrid.‬
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‭11.‬
‭Patient registration  procedure‬
‭●‬ ‭Each‬ ‭patient‬‭is‬‭identified‬‭in‬‭the‬‭study‬‭by‬‭a‬‭Subject‬‭Number‬‭(Subject‬‭No.)‬‭that‬‭is‬‭assigned‬
‭when‬‭the‬‭patient‬‭is‬‭first‬‭enrolled‬‭for‬‭screening‬‭and‬‭is‬‭retained‬‭as‬‭the‬‭primary‬‭identifier‬‭for‬‭the‬
‭patient‬ ‭throughout‬ ‭his/her‬ ‭entire‬ ‭participation‬ ‭in‬ ‭the‬ ‭trial.‬‭The‬‭Subject‬‭No.‬‭consists‬‭of‬‭the‬
‭Center‬ ‭Number‬ ‭(Center‬ ‭No.)‬ ‭with‬ ‭a‬ ‭sequential‬ ‭patient‬‭number‬‭suffixed‬‭to‬‭it,‬‭so‬‭that‬‭each‬
‭patient is numbered uniquely across the entire database.‬
‭●‬ ‭Upon‬‭signing‬‭the‬‭informed‬‭consent‬‭form,‬‭the‬‭patient‬‭is‬‭assigned‬‭to‬‭the‬‭next‬‭sequential‬‭Subject‬
‭No. available to the investigator.‬
‭●‬ ‭The‬‭investigator‬‭or‬‭designated‬‭staff‬‭will‬‭contact‬‭the‬‭IRT‬‭and‬‭provide‬‭the‬‭requested‬‭identifying‬
‭information‬‭for‬‭the‬‭patient‬‭to‬‭register‬‭them‬‭into‬‭the‬‭IRT.‬‭Once‬‭assigned,‬‭the‬‭Subject‬‭No.‬‭must‬
‭not‬ ‭be‬ ‭reused‬ ‭for‬ ‭any‬ ‭other‬ ‭patient‬ ‭and‬ ‭the‬ ‭Subject‬ ‭No.‬ ‭for‬ ‭that‬ ‭individual‬ ‭must‬ ‭not‬ ‭be‬
‭changed,‬‭even‬‭if‬‭the‬‭patient‬‭is‬‭re-screened.‬‭If‬‭the‬‭patient‬‭fails‬‭to‬‭start‬‭treatment‬‭for‬‭any‬‭reason,‬
‭the reason will be entered into the Screening Disposition page.‬
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‭12.‬
‭Reporting adverse events‬
‭12.1.‬ ‭Definitions for adverse event reporting‬
‭●‬ ‭An‬‭Adverse‬‭Event‬‭(AE)‬‭is‬‭defined‬‭as‬‭any‬‭untoward‬‭medical‬‭occurrence‬‭or‬‭experience‬‭in‬‭a‬
‭patient‬‭or‬‭clinical‬‭investigation‬‭subject‬‭which‬‭occurs‬‭following‬‭the‬‭administration‬‭of‬‭the‬‭trial‬
‭medication‬‭regardless‬‭of‬‭the‬‭dose‬‭or‬‭causal‬‭relationship.‬‭This‬‭can‬‭include‬‭any‬‭unfavorable‬‭and‬
‭unintended‬‭signs‬‭(such‬‭as‬‭rash‬‭or‬‭enlarged‬‭liver),‬‭or‬‭symptoms‬‭(such‬‭as‬‭nausea‬‭or‬‭chest‬‭pain),‬
‭an‬ ‭abnormal‬ ‭laboratory‬ ‭finding‬ ‭(including‬ ‭blood‬ ‭tests,‬ ‭x-rays‬ ‭or‬ ‭scans)‬ ‭or‬ ‭a‬ ‭disease‬
‭temporarily associated with the use of the protocol treatment.‬‭(ICH-GCP).‬
‭●‬ ‭An‬‭Adverse‬‭Drug‬‭Reaction‬‭(ADR)‬‭is‬‭defined‬‭as‬‭any‬‭response‬‭to‬‭a‬‭medical‬‭product,‬‭that‬‭is‬
‭noxious‬‭and/or‬‭unexpected,‬‭related‬‭to‬‭any‬‭dose.‬‭(ICH-GCP).‬‭Response‬‭to‬‭a‬‭medicinal‬‭product‬
‭(used‬‭in‬‭the‬‭above‬‭definition)‬‭means‬‭that‬‭a‬‭causal‬‭relationship‬‭between‬‭the‬‭medicinal‬‭product‬
‭and‬‭the‬‭adverse‬‭event‬‭is‬‭at‬‭least‬‭a‬‭reasonable‬‭possibility,‬‭i.e.‬‭the‬‭relationship‬‭cannot‬‭be‬‭ruled‬
‭out.‬
‭●‬ ‭An‬ ‭Unexpected‬ ‭Adverse‬ ‭Drug‬ ‭Reaction‬ ‭is‬ ‭any‬ ‭adverse‬‭reaction‬‭for‬‭which‬‭the‬‭nature‬‭or‬
‭severity‬ ‭is‬ ‭not‬ ‭consistent‬ ‭with‬ ‭the‬ ‭applicable‬ ‭product‬ ‭information‬ ‭(e.g.,‬ ‭Investigator’s‬
‭Brochure).‬‭(ICH-GCP).‬
‭●‬ ‭A‬ ‭Serious‬ ‭Adverse‬ ‭Event‬ ‭(SAE)‬‭is‬‭defined‬‭as‬‭any‬‭undesirable‬‭experience‬‭occurring‬‭to‬‭a‬
‭patient,‬‭whether‬‭or‬‭not‬‭considered‬‭related‬‭to‬‭the‬‭protocol‬‭treatment.‬‭A‬‭Serious‬‭Adverse‬‭Event‬
‭(SAE)‬‭which‬‭is‬‭considered‬‭related‬‭to‬‭the‬‭protocol‬‭treatment‬‭is‬‭defined‬‭as‬‭a‬‭Serious‬‭Adverse‬
‭Drug Reaction (SADR)‬‭.‬
‭●‬ ‭Adverse‬‭events‬‭and‬‭adverse‬‭drug‬‭reactions‬‭which‬‭are‬‭considered‬‭as‬‭serious‬‭are‬‭those‬‭which‬
‭result in:‬
‭○‬ ‭Death‬
‭○‬ ‭A‬‭life‬‭threatening‬‭event‬‭(i.e.‬‭the‬‭patient‬‭was‬‭at‬‭immediate‬‭risk‬‭of‬‭death‬‭at‬‭the‬‭time‬‭the‬
‭reaction was observed)‬
‭○‬ ‭hospitalization or prolongation of hospitalization‬
‭○‬ ‭persistent or significant disability/incapacity‬
‭○‬ ‭a congenital anomaly/birth defect‬
‭○‬ ‭any‬‭other‬‭medically‬‭important‬‭condition‬‭(i.e.‬‭important‬‭adverse‬‭reactions‬‭that‬‭are‬‭not‬
‭immediately‬ ‭life‬ ‭threatening‬ ‭or‬ ‭do‬ ‭not‬ ‭result‬ ‭in‬ ‭death‬ ‭or‬ ‭hospitalization‬ ‭but‬ ‭may‬
‭jeopardize‬ ‭the‬ ‭patient‬ ‭or‬ ‭may‬ ‭require‬ ‭intervention‬ ‭to‬ ‭prevent‬ ‭one‬ ‭of‬ ‭the‬ ‭other‬
‭outcomes listed above)‬
‭12.2.‬ ‭Reporting procedure‬
‭To‬‭ensure‬‭patient‬‭safety,‬‭every‬‭SAE,‬‭regardless‬‭of‬‭suspected‬‭causality,‬‭occurring‬‭after‬‭the‬‭patient‬‭has‬
‭provided informed consent must be reported within 24 hours of knowing of its occurrence and until:‬
‭●‬ ‭Suspected SAEs up to Day 150 safety follow-up.‬
‭●‬ ‭Non-suspected‬ ‭SAEs‬ ‭up‬ ‭to‬ ‭Day‬ ‭150‬ ‭safety‬ ‭follow-up‬ ‭or‬ ‭start‬ ‭of‬ ‭new‬ ‭post‬ ‭treatment‬
‭antineoplastic‬ ‭medication‬ ‭if‬ ‭administered‬ ‭during‬ ‭the‬ ‭period‬ ‭between‬ ‭the‬ ‭30-Day‬ ‭safety‬
‭follow-up and 150-Day safety follow-up, whichever is sooner.‬
‭●‬ ‭If‬‭a‬‭patient‬‭starts‬‭a‬‭post‬‭treatment‬‭antineoplastic‬‭therapy‬‭after‬‭the‬‭30-day‬‭safety‬‭follow-up,‬
‭then‬‭only‬‭SAEs‬‭suspected‬‭to‬‭be‬‭related‬‭to‬‭study‬‭treatment‬‭should‬‭be‬‭collected‬‭out‬‭to‬‭150‬‭days‬
‭after‬‭discontinuation‬‭of‬‭treatment.‬‭SAEs‬‭suspected‬‭to‬‭be‬‭related‬‭to‬‭nivolumab‬‭will‬‭continue‬‭to‬
‭be collected beyond the 150-Day safety visit.‬
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‭●‬ ‭Any‬ ‭additional‬‭information‬‭for‬‭the‬‭SAE‬‭including‬‭complications,‬‭progression‬‭of‬‭the‬‭initial‬
‭SAE,‬‭and‬‭recurrent‬‭episodes‬‭must‬‭be‬‭reported‬‭as‬‭follow-up‬‭to‬‭the‬‭original‬‭episode‬‭within‬‭24‬
‭hours‬‭of‬‭the‬‭investigator‬‭receiving‬‭the‬‭follow-up‬‭information.‬‭A‬‭SAE‬‭occurring‬‭at‬‭a‬‭different‬
‭time‬ ‭interval‬ ‭or‬ ‭otherwise‬ ‭considered‬ ‭completely‬ ‭unrelated‬ ‭to‬ ‭a‬ ‭previously‬ ‭reported‬ ‭one‬
‭should be reported separately as a new event.‬
‭●‬ ‭Any‬‭SAEs‬‭experienced‬‭after‬‭the‬‭reporting‬‭period‬‭described‬‭above‬‭should‬‭only‬‭be‬‭reported‬‭if‬
‭the investigator suspects a causal relationship to the study treatment.‬
‭●‬ ‭Information‬‭about‬‭all‬‭SAEs‬‭is‬‭collected‬‭and‬‭recorded‬‭on‬‭the‬‭Serious‬‭Adverse‬‭Event‬‭Report‬
‭Form;‬‭all‬‭applicable‬‭sections‬‭of‬‭the‬‭form‬‭must‬‭be‬‭completed‬‭in‬‭order‬‭to‬‭provide‬‭a‬‭clinically‬
‭thorough‬‭report.‬‭The‬‭investigator‬‭must‬‭assess‬‭and‬‭record‬‭the‬‭relationship‬‭of‬‭each‬‭SAE‬‭to‬‭each‬
‭specific study treatment (if there is more than one study treatment).‬
‭●‬ ‭Each‬‭reoccurrence,‬‭complication,‬‭or‬‭progression‬‭of‬‭the‬‭original‬‭event‬‭should‬‭be‬‭reported‬‭as‬‭a‬
‭follow-up‬ ‭to‬ ‭that‬ ‭event‬ ‭regardless‬ ‭of‬ ‭when‬ ‭it‬ ‭occurs.‬ ‭The‬ ‭follow-up‬ ‭information‬ ‭should‬
‭describe‬‭whether‬‭the‬‭event‬‭has‬‭resolved‬‭or‬‭continues,‬‭if‬‭and‬‭how‬‭it‬‭was‬‭treated,‬‭and‬‭whether‬
‭the patient continued or withdrew from study participation.‬
‭●‬ ‭Suspected‬‭Unexpected‬‭Serious‬‭Adverse‬‭Reactions‬‭(SUSARs)‬‭will‬‭be‬‭collected‬‭and‬‭reported‬
‭to‬ ‭the‬ ‭competent‬ ‭authorities‬ ‭and‬ ‭relevant‬ ‭ethics‬ ‭committees‬ ‭in‬ ‭accordance‬ ‭with‬ ‭Directive‬
‭2001/20/EC or as per national regulatory requirements in participating countries.‬
‭●‬ ‭SAEs,‬‭whether‬‭related‬‭or‬‭not‬‭related‬‭to‬‭study‬‭drug,‬‭and‬‭pregnancies‬‭must‬‭be‬‭reported‬‭to‬‭BMS‬
‭within‬‭24‬‭hours‬‭\‬‭1‬‭Business‬‭Day‬‭of‬‭becoming‬‭aware‬‭of‬‭the‬‭event.‬‭SAEs‬‭must‬‭be‬‭recorded‬‭on‬
‭either CIOMS, MedWatch, or approved site SAE form.‬
‭●‬ ‭Pregnancies‬ ‭must‬ ‭be‬ ‭reported‬ ‭and‬ ‭submitted‬ ‭to‬ ‭MFAR‬ ‭Clinical‬ ‭Research‬ ‭that‬‭will‬‭act‬‭on‬
‭behalf‬ ‭of‬ ‭GETNE‬ ‭transferring‬ ‭the‬ ‭information‬ ‭to‬ ‭BMS.‬ ‭BMS‬ ‭will‬ ‭perform‬ ‭due‬‭diligence‬
‭follow-up using the BMS Pregnancy Form which the investigator must complete.‬
‭○‬ ‭SAE Email Address:‬‭investigacion@mfar.net‬
‭○‬ ‭SAE Facsimile Number:  + 34 93 253 11 68‬
‭●‬ ‭If‬ ‭only‬ ‭limited‬ ‭information‬ ‭is‬ ‭initially‬ ‭available,‬ ‭follow-up‬ ‭reports‬ ‭are‬ ‭required.‬ ‭(Note:‬
‭Follow-up SAE reports should include the same investigator term(s) initially reported.).‬
‭●‬ ‭If‬‭an‬‭ongoing‬‭SAE‬‭changes‬‭in‬‭its‬‭intensity‬‭or‬‭relationship‬‭to‬‭study‬‭drug‬‭or‬‭if‬‭new‬‭information‬
‭becomes‬‭available,‬‭a‬‭follow-up‬‭SAE‬‭report‬‭should‬‭be‬‭sent‬‭within‬‭24‬‭hours‬‭\‬‭1‬‭Business‬‭Day‬
‭to BMS using the same procedure used for transmitting the initial SAE report.‬
‭●‬
‭All SAEs should be followed to resolution or stabilization.‬
‭SAEs,‬ ‭whether‬ ‭related‬ ‭or‬ ‭not‬ ‭related‬ ‭to‬ ‭study‬ ‭drug,‬ ‭and‬ ‭pregnancies‬ ‭must‬ ‭be‬ ‭reported‬‭to‬‭MFAR‬
‭Clinical‬ ‭Research‬ ‭that‬ ‭will‬ ‭manage,‬ ‭on‬ ‭behalf‬ ‭GETNE,‬‭the‬‭communications‬‭with‬‭BMS‬‭within‬‭24‬
‭hours‬‭\‬‭1‬‭Business‬‭Day‬‭of‬‭becoming‬‭aware‬‭of‬‭the‬‭event.‬‭SAEs‬‭must‬‭be‬‭recorded‬‭on‬‭either‬‭CIOMS,‬
‭MedWatch, or approved site SAE form.‬
‭The causal relationship to study drug is determined by a physician and should be used to assess all‬
‭adverse events (AE). The casual relationship can be one of the following:‬
‭●‬ ‭Related:‬‭There is a reasonable causal relationship‬‭between study drug administration and the‬
‭AE.‬
‭●‬ ‭Not related:‬‭There is not a reasonable causal relationship between study drug administration‬
‭and the AE.‬
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‭The‬‭causal‬‭relationship‬‭to‬‭study‬‭drug‬‭is‬‭determined‬‭by‬‭a‬‭physician‬‭and‬‭should‬‭be‬‭used‬‭to‬‭assess‬‭all‬
‭adverse events (AE). The casual relationship can be one of the following:‬
‭●‬
‭Related:‬‭There‬‭is‬‭a‬‭reasonable‬‭causal‬‭relationship‬‭between‬‭study‬‭drug‬‭administration‬‭and‬‭the‬
‭AE.‬
‭●‬ ‭Not‬‭related:‬‭There‬‭is‬‭not‬‭a‬‭reasonable‬‭causal‬‭relationship‬‭between‬‭study‬‭drug‬‭administration‬
‭and the AE.‬
‭●‬ ‭The‬ ‭term‬ ‭"reasonable‬ ‭causal‬ ‭relationship"‬ ‭means‬ ‭there‬ ‭is‬ ‭evidence‬ ‭to‬ ‭suggest‬ ‭a‬ ‭causal‬
‭relationship.‬
‭●‬ ‭Adverse‬ ‭events‬ ‭can‬ ‭be‬ ‭spontaneously‬ ‭reported‬ ‭or‬ ‭elicited‬ ‭during‬ ‭open-ended‬‭questioning,‬
‭examination,‬‭or‬‭evaluation‬‭of‬‭a‬‭subject.‬‭(In‬‭order‬‭to‬‭prevent‬‭reporting‬‭bias,‬‭subjects‬‭should‬
‭not be questioned regarding the specific occurrence of one or more AEs.)‬
‭NON SERIOUS ADVERSE EVENT‬
‭Non-serious‬‭Adverse‬‭Events‬‭(AE)‬‭are‬‭to‬‭be‬‭provided‬‭to‬‭BMS‬‭in‬‭aggregate‬‭via‬‭interim‬‭or‬‭final‬‭study‬
‭reports‬‭as‬‭specified‬‭in‬‭the‬‭agreement‬‭or,‬‭if‬‭a‬‭regulatory‬‭requirement‬‭[eg,‬‭IND‬‭US‬‭trial]‬‭as‬‭part‬‭of‬‭an‬
‭annual reporting requirement.‬
‭The‬ ‭Sponsor‬ ‭will‬ ‭reconcile‬ ‭the‬ ‭clinical‬ ‭database‬ ‭AE‬ ‭cases‬ ‭(case‬ ‭level‬ ‭only)‬ ‭transmitted‬ ‭to‬ ‭BMS‬
‭Global Pharmacovigilance‬‭(‬‭Worldwide.Safety@bms.com‬‭).‬
‭Non-serious Adverse Event Collection and Reporting‬
‭The‬‭collection‬‭of‬‭non-serious‬‭AE‬‭information‬‭should‬‭begin‬‭following‬‭the‬‭subject’s‬‭written‬‭consent‬‭to‬
‭participate‬‭in‬‭the‬‭study.‬‭All‬‭non‬‭serious‬‭adverse‬‭events‬‭(not‬‭only‬‭those‬‭deemed‬‭to‬‭be‬‭treatment-related)‬
‭should‬‭be‬‭collected‬‭continuously‬‭during‬‭the‬‭treatment‬‭period‬‭and‬‭for‬‭a‬‭minimum‬‭of‬‭(provide‬‭#‬‭of‬‭days‬
‭depending on the asset and study type)  days following the last dose of study treatment.‬
‭Non-serious‬‭AEs‬‭should‬‭be‬‭followed‬‭to‬‭resolution‬‭or‬‭stabilization,‬‭or‬‭reported‬‭as‬‭SAEs‬‭if‬‭they‬‭become‬
‭serious.‬‭Follow-up‬‭is‬‭also‬‭required‬‭for‬‭non-serious‬‭AEs‬‭that‬‭cause‬‭interruption‬‭or‬‭discontinuation‬‭of‬
‭study drug and for those present at the end of study treatment as appropriate.‬
‭Laboratory Test Abnormalities‬
‭All‬ ‭laboratory‬ ‭test‬ ‭results‬ ‭captured‬ ‭as‬ ‭part‬‭of‬‭the‬‭study‬‭should‬‭be‬‭recorded‬‭following‬‭institutional‬
‭procedures. Test results that constitute SAEs should be documented and reported to BMS as such.‬
‭The following laboratory abnormalities should be documented and reported appropriately:‬
‭●‬ ‭any laboratory test result that is clinically significant or meets the definition of an SAE.‬
‭●‬ ‭any‬‭laboratory‬‭abnormality‬‭that‬‭required‬‭the‬‭participant‬‭to‬‭have‬‭study‬‭drug‬‭discontinued‬‭or‬
‭interrupted.‬
‭●‬ ‭any laboratory abnormality that required the subject to receive specific corrective therapy.‬
‭It‬‭is‬‭expected‬‭that‬‭wherever‬‭possible,‬‭the‬‭clinical‬‭rather‬‭than‬‭laboratory‬‭term‬‭would‬‭be‬‭used‬‭by‬‭the‬
‭reporting investigator (eg, anemia versus low hemoglobin value).‬
‭Potential Drug Induced Liver Injury (DILI) Language required as noted below:‬
‭Definition‬ ‭of‬ ‭DILI‬ ‭criteria‬‭is‬‭mandatory‬‭for‬‭all‬‭pre-marketed‬‭asset‬‭protocols‬‭enrolling‬‭participants‬
‭without‬‭known‬‭abnormalities‬‭in‬‭liver‬‭function‬‭at‬‭baseline‬‭AND‬‭for‬‭protocols‬‭involving‬‭participants‬
‭with‬ ‭known‬ ‭liver‬ ‭abnormalities‬‭at‬‭baseline‬‭or‬‭with‬‭other‬‭clinical‬‭confounders‬‭where‬‭asset‬‭specific‬
‭criteria for potential drug induced liver injury have been defined. Use for marketed assets is optional.‬
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‭For‬‭protocols‬‭without‬‭known‬‭abnormalities‬‭in‬‭liver‬‭function‬‭at‬‭baseline,‬‭use‬‭the‬‭mandatory‬‭standard‬
‭DILI‬‭definition‬‭listed‬‭below:‬‭Wherever‬‭possible,‬‭timely‬‭confirmation‬‭of‬‭initial‬‭liver‬‭related‬‭laboratory‬
‭abnormalities‬ ‭should‬ ‭occur‬ ‭prior‬ ‭to‬ ‭the‬ ‭reporting‬ ‭of‬ ‭a‬ ‭potential‬ ‭DILI‬ ‭event.‬ ‭All‬ ‭occurrences‬ ‭of‬
‭potential DILIs, meeting the defined criteria, must be reported as SAEs.‬
‭Potential drug induced liver injury is defined as:‬
‭1.‬ ‭AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) AND‬
‭2.‬ ‭Total‬‭bilirubin‬‭>‬‭2‬‭times‬‭ULN,‬‭without‬‭initial‬‭findings‬‭of‬‭cholestasis‬‭(elevated‬‭serum‬‭alkaline‬
‭phosphatase) AND‬
‭3.‬ ‭No‬ ‭other‬ ‭immediately‬ ‭apparent‬ ‭possible‬ ‭causes‬ ‭of‬ ‭AT‬ ‭elevation‬ ‭and‬ ‭hyperbilirubinemia,‬
‭including,‬‭but‬‭not‬‭limited‬‭to,‬‭viral‬‭hepatitis,‬‭pre-existing‬‭chronic‬‭or‬‭acute‬‭liver‬‭disease,‬‭or‬‭the‬
‭administration of other drug(s) known to be hepatotoxic.‬
‭AEs‬ ‭of‬ ‭Special‬ ‭Interest‬ ‭(Product‬ ‭Specific‬ ‭Usually‬ ‭a‬ ‭regulatory‬ ‭requirement.‬
‭Remove‬ ‭if‬ ‭not‬
‭applicable)‬
‭Pregnancy‬
‭If,‬ ‭following‬ ‭initiation‬ ‭of‬ ‭the‬ ‭investigational‬ ‭product,‬ ‭it‬ ‭is‬ ‭subsequently‬ ‭discovered‬ ‭that‬ ‭a‬ ‭study‬
‭participant‬‭is‬‭pregnant‬‭or‬‭may‬‭have‬‭been‬‭pregnant‬‭at‬‭the‬‭time‬‭of‬‭investigational‬‭product‬‭exposure,‬
‭including‬‭during‬‭at‬‭least‬‭5‬‭half-lives‬‭after‬‭product‬‭administration,‬‭the‬‭investigational‬‭product‬‭will‬‭be‬
‭permanently discontinued in an appropriate manner (eg, dose tapering if necessary for participant).‬
‭The‬ ‭investigator‬ ‭must‬ ‭immediately‬‭notify‬‭Worldwide.Safety@bms.com‬‭of‬‭this‬‭event‬‭and‬‭complete‬
‭one‬ ‭of‬ ‭the‬ ‭following‬ ‭forms‬ ‭within‬ ‭24‬ ‭hours‬ ‭of‬ ‭awareness‬ ‭of‬ ‭the‬ ‭event‬ ‭via‬ ‭either‬ ‭the‬ ‭CIOMS,‬
‭MedWatch‬ ‭or‬ ‭appropriate‬ ‭Pregnancy‬ ‭Surveillance‬ ‭Form‬ ‭in‬ ‭accordance‬ ‭with‬ ‭SAE‬ ‭reporting‬
‭procedures.‬
‭Protocol-required‬ ‭procedures‬ ‭for‬ ‭study‬ ‭discontinuation‬ ‭and‬ ‭follow-up‬ ‭must‬ ‭be‬ ‭performed‬ ‭on‬ ‭the‬
‭participant.‬
‭Follow-up‬ ‭information‬ ‭regarding‬ ‭the‬ ‭course‬ ‭of‬ ‭the‬ ‭pregnancy,‬ ‭including‬ ‭perinatal‬ ‭and‬ ‭neonatal‬
‭outcome‬‭and,‬‭where‬‭applicable,‬‭offspring‬‭information‬‭must‬‭be‬‭reported‬‭on‬‭the‬‭CIOMS,‬‭MedWatch,‬
‭BMS‬ ‭Pregnancy‬ ‭Surveillance‬‭Form,‬‭or‬‭approved‬‭site‬‭SAE‬‭form.‬ ‭A‬‭BMS‬‭Pregnancy‬‭Surveillance‬
‭Form may be provided upon request.‬
‭Any‬‭pregnancy‬‭that‬‭occurs‬‭in‬‭a‬‭female‬‭partner‬‭of‬‭a‬‭male‬‭study‬‭participant‬‭should‬‭be‬‭reported‬‭to‬‭BMS.‬
‭Information‬ ‭on‬ ‭this‬‭pregnancy‬‭will‬‭be‬‭collected‬‭on‬‭the‬‭Pregnancy‬‭Surveillance‬‭Form.‬‭In‬‭order‬‭for‬
‭Sponsor‬‭or‬‭designee‬‭to‬‭collect‬‭any‬‭pregnancy‬‭surveillance‬‭information‬‭from‬‭the‬‭female‬‭partner,‬‭the‬
‭female partner must sign an informed consent form for disclosure of this information.‬
‭Other Safety Considerations‬
‭Any‬‭significant‬‭worsening‬‭noted‬‭during‬‭interim‬‭or‬‭final‬‭physical‬‭examinations,‬‭electrocardiograms,‬
‭X-rays,‬‭and‬‭any‬‭other‬‭potential‬‭safety‬‭assessments,‬‭whether‬‭or‬‭not‬‭these‬‭procedures‬‭are‬‭required‬‭by‬
‭the‬ ‭protocol,‬‭should‬‭also‬‭be‬‭recorded‬‭as‬‭a‬‭non-serious‬‭or‬‭serious‬‭AE,‬‭as‬‭appropriate,‬‭and‬‭reported‬
‭accordingly.‬
‭MFAR‬
‭Clinical‬
‭Research‬
‭on‬
‭behalf‬
‭of‬
‭GETNE‬
‭will‬
‭request‬
‭from‬
‭BMS‬ ‭GPV&E,‬
‭aepbusinessprocess@bms.com‬‭the‬‭SAE‬‭reconciliation‬‭report‬‭and‬‭include‬‭the‬‭BMS‬‭protocol‬‭number‬
‭every 3 months and prior to database lock or final data summary.‬
‭GPV&E‬‭will‬‭send‬‭the‬‭investigator‬‭the‬‭report‬‭to‬‭verify‬‭and‬‭confirm‬‭all‬‭SAEs‬‭have‬‭been‬‭transmitted‬‭to‬
‭BMS GPV&E.‬
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‭The‬ ‭data‬ ‭elements‬ ‭listed‬ ‭on‬ ‭the‬ ‭GPV&E‬ ‭reconciliation‬ ‭report‬ ‭will‬‭be‬‭used‬‭for‬‭case‬‭identification‬
‭purposes.‬‭If‬‭the‬‭Sponsor‬‭determines‬‭a‬‭case‬‭was‬‭not‬‭transmitted‬‭to‬‭BMS‬‭GPV&E,‬‭the‬‭case‬‭should‬‭be‬
‭sent immediately to BMS‬‭(‬‭Worldwide.Safety@bms.com‬‭).‬
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‭13.‬
‭Quality assurance‬
‭13.1.‬ ‭Control of data consistency‬
‭The‬ ‭investigator‬ ‭or‬ ‭qualified‬ ‭designee‬ ‭is‬ ‭responsible‬ ‭for‬ ‭recording‬ ‭and‬ ‭verifying‬ ‭the‬ ‭accuracy‬ ‭of‬
‭subject data.‬
‭●‬ ‭The‬‭study‬‭will‬‭use‬‭eCRFs.‬‭A‬‭designated‬‭CRO‬‭will‬‭review‬‭the‬‭data‬‭entered‬‭by‬‭investigational‬
‭staff‬‭for‬‭completeness‬‭and‬‭accuracy.‬‭Electronic‬‭data‬‭queries‬‭stating‬‭the‬‭nature‬‭of‬‭the‬‭problem‬
‭and‬‭requesting‬‭clarification‬‭will‬‭be‬‭created‬‭for‬‭discrepancies‬‭and‬‭missing‬‭values‬‭and‬‭sent‬‭to‬
‭the‬‭investigational‬‭site‬‭via‬‭the‬‭EDC‬‭system.‬‭Designated‬‭investigator‬‭site‬‭staff‬‭is‬‭required‬‭to‬
‭respond promptly to queries and to make any necessary changes to the data.‬
‭●‬ ‭Concomitant‬‭treatments‬‭and‬‭prior‬‭medications‬‭entered‬‭into‬‭the‬‭database‬‭will‬‭be‬‭coded‬‭using‬
‭the‬ ‭WHO‬ ‭Drug‬ ‭Reference‬ ‭List,‬ ‭which‬ ‭employs‬ ‭the‬ ‭Anatomical‬ ‭Therapeutic‬ ‭Chemical‬
‭classification system.‬
‭●‬ ‭Medical‬ ‭history/current‬ ‭medical‬ ‭conditions‬ ‭and‬ ‭adverse‬ ‭events‬ ‭will‬ ‭be‬ ‭coded‬ ‭using‬ ‭the‬
‭Medical dictionary for regulatory activities (MedDRA) terminology.‬
‭●‬ ‭The‬ ‭site‬ ‭staff‬ ‭designated‬ ‭by‬ ‭the‬ ‭investigator‬ ‭will‬ ‭enter‬ ‭the‬ ‭information‬ ‭required‬ ‭by‬ ‭the‬
‭protocol onto the eCRFs as well as onto the designated CRO’s requisition form.‬
‭13.2.‬ ‭On-site‬‭quality‬‭control‬‭(for‬‭multi-centre‬‭studies‬‭only‬‭when‬‭data‬‭are‬‭sent‬
‭to a Data Centre or similar)‬
‭●‬ ‭Before‬‭study‬‭initiation,‬‭at‬‭a‬‭site‬‭initiation‬‭visit‬‭or‬‭at‬‭an‬‭investigator’s‬‭meeting,‬‭the‬‭protocol‬
‭and CRFs will be reviewed with the investigators and their staff.‬
‭●‬ ‭During‬‭the‬‭study,‬‭the‬‭field‬‭monitor‬‭will‬‭visit‬‭the‬‭site‬‭regularly‬‭to‬‭check‬‭the‬‭completeness‬‭of‬
‭patient‬‭records,‬‭the‬‭accuracy‬‭of‬‭entries‬‭on‬‭the‬‭CRFs,‬‭the‬‭adherence‬‭to‬‭the‬‭protocol‬‭to‬‭Good‬
‭Clinical‬ ‭Practice,‬ ‭the‬ ‭progress‬ ‭of‬ ‭enrollment,‬ ‭and‬ ‭to‬ ‭ensure‬ ‭that‬ ‭study‬ ‭treatment‬ ‭is‬ ‭being‬
‭stored,‬‭dispensed,‬‭and‬‭accounted‬‭for‬‭according‬‭to‬‭specifications.‬‭Key‬‭study‬‭personnel‬‭must‬‭be‬
‭available to assist the field monitor during these visits.‬
‭●‬ ‭The‬‭investigator‬‭must‬‭maintain‬‭source‬‭documents‬‭for‬‭each‬‭patient‬‭in‬‭the‬‭study,‬‭consisting‬‭of‬
‭case‬‭and‬‭visit‬‭notes‬‭(hospital‬‭or‬‭clinic‬‭medical‬‭records)‬‭containing‬‭demographic‬‭and‬‭medical‬
‭information,‬ ‭laboratory‬ ‭data,‬ ‭electrocardiograms,‬ ‭and‬ ‭the‬ ‭results‬ ‭of‬ ‭any‬ ‭other‬ ‭tests‬ ‭or‬
‭assessments.‬‭All‬‭information‬‭recorded‬‭on‬‭CRFs‬‭must‬‭be‬‭traceable‬‭to‬‭source‬‭documents‬‭in‬‭the‬
‭patient's‬‭file.‬‭The‬‭investigator‬‭must‬‭also‬‭keep‬‭the‬‭original‬‭signed‬‭informed‬‭consent‬‭form‬‭(a‬
‭signed copy is given to the patient).‬
‭●‬ ‭The‬‭investigator‬‭must‬‭give‬‭the‬‭monitor‬‭access‬‭to‬‭all‬‭relevant‬‭source‬‭documents‬‭to‬‭confirm‬
‭their consistency with the CRF entries.‬
‭13.3.‬ ‭Audits‬‭(for‬‭multi-centre‬‭studies‬‭only‬‭when‬‭data‬‭are‬‭sent‬‭to‬‭Data‬‭Centre‬‭or‬
‭similar)‬
‭●‬ ‭To‬‭ensure‬‭quality‬‭of‬‭data,‬‭study‬‭integrity,‬‭and‬‭compliance‬‭with‬‭the‬‭protocol‬‭and‬‭the‬‭various‬
‭applicable‬ ‭regulations‬ ‭and‬‭guidelines,‬‭the‬‭“Sponsor”‬‭may‬‭conduct‬‭site‬‭visits‬‭to‬‭institutions‬
‭participating to protocols.‬
‭●‬ ‭The‬‭investigator,‬‭by‬‭accepting‬‭to‬‭participate‬‭to‬‭this‬‭protocol,‬‭agrees‬‭to‬‭cooperate‬‭fully‬‭with‬
‭any‬ ‭quality‬ ‭assurance‬ ‭visit‬ ‭undertaken‬ ‭by‬ ‭third‬ ‭parties,‬‭including‬‭representatives‬‭from‬‭the‬
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‭“Sponsor”,‬‭national‬‭and/or‬‭foreign‬‭regulatory‬‭authorities‬‭or‬‭company‬‭supplying‬‭the‬‭product‬
‭under‬ ‭investigation,‬ ‭as‬ ‭well‬ ‭as‬ ‭to‬ ‭allow‬ ‭direct‬ ‭access‬ ‭to‬ ‭documentation‬ ‭pertaining‬ ‭to‬ ‭the‬
‭clinical‬‭trial‬‭(including‬‭CRFs,‬‭source‬‭documents,‬‭hospital‬‭patient‬‭charts‬‭and‬‭other‬‭study‬‭files)‬
‭to these authorized individuals.‬
‭●‬ ‭The‬ ‭investigator‬ ‭must‬ ‭inform‬ ‭the‬ ‭“Sponsor”‬ ‭immediately‬ ‭in‬ ‭case‬ ‭a‬ ‭regulatory‬ ‭authority‬
‭inspection would be scheduled.‬
‭13.4.‬ ‭Central review of pathology‬
‭No central pathology review is planned.‬
‭13.5 Central review of Images‬
‭All‬‭images‬‭of‬‭patients‬‭will‬‭be‬‭uploaded‬‭to‬‭a‬‭platform‬‭in‬‭DICOM‬‭format‬‭and‬‭will‬‭be‬‭reviewed‬‭centrally‬
‭by‬ ‭a‬ ‭radiologist‬ ‭specialised‬ ‭in‬ ‭pathology‬ ‭to‬ ‭avoid‬ ‭bias.‬ ‭Information‬ ‭for‬ ‭test‬ ‭uploading‬ ‭and‬
‭management is provided in a central reviewing manual located at the ISF.‬
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‭14.‬
‭Ethical considerations‬
‭14.1.‬ ‭Patient protection‬
‭This‬ ‭protocol‬ ‭has‬ ‭been‬ ‭written,‬ ‭and‬ ‭the‬ ‭study‬ ‭will‬ ‭be‬ ‭conducted‬ ‭according‬ ‭to‬ ‭the‬ ‭ICH‬
‭Harmonized‬
‭Tripartite‬
‭Guideline‬
‭for‬
‭Good‬
‭Clinical‬
‭Practice‬
‭(ref:‬
‭http://www.ifpma.org/pdfifpma/e6.pdf‬‭)‬ ‭with‬ ‭applicable‬ ‭local‬ ‭regulations‬ ‭(including‬ ‭European‬
‭Directive‬‭2001/20/EC‬‭and‬‭US‬‭Code‬‭of‬‭Federal‬‭Regulations‬‭Title‬‭21),‬‭and‬‭with‬‭the‬‭ethical‬‭principles‬
‭laid down in the Declaration of Helsinki.‬
‭The‬‭protocol‬‭and‬‭the‬‭proposed‬‭informed‬‭consent‬‭form‬‭must‬‭be‬‭reviewed‬‭and‬‭approved‬‭by‬‭a‬
‭properly‬‭constituted‬‭Institutional‬‭Review‬‭Board/Independent‬‭Ethics‬‭Committee/Research‬‭required‬‭to‬
‭sign‬‭a‬‭protocol‬‭signature‬‭page‬‭confirming‬‭his/her‬‭agreement‬‭to‬‭conduct‬‭the‬‭study‬‭in‬‭accordance‬‭with‬
‭these‬‭documents‬‭and‬‭all‬‭of‬‭the‬‭instructions‬‭and‬‭procedures‬‭found‬‭in‬‭this‬‭protocol‬‭and‬‭to‬‭give‬‭access‬‭to‬
‭all‬ ‭relevant‬ ‭data‬ ‭and‬ ‭records‬ ‭to‬ ‭auditors,‬ ‭Quality‬‭Assurance‬‭representatives,‬‭IRBs/IECs/REBs‬‭and‬
‭regulatory authorities as required.‬
‭14.2.‬ ‭Subject identification‬
‭●‬ ‭The‬ ‭investigator‬‭must‬‭ensure‬‭anonymity‬‭of‬‭the‬‭patients;‬‭patients‬‭must‬‭not‬‭be‬‭identified‬‭by‬
‭names in any documents submitted to the Sponsor.‬
‭●‬ ‭Signed‬‭informed‬‭consent‬‭forms‬‭and‬‭patient‬‭enrollment‬‭log‬‭must‬‭be‬‭kept‬‭strictly‬‭confidential‬
‭to enable patient identification at the site.‬
‭●‬ ‭The‬‭investigator‬‭agrees‬‭that‬‭the‬‭IRB/ERC,‬‭or‬‭regulatory‬‭authority‬‭representatives‬‭may‬‭consult‬
‭and/or‬‭copy‬‭trial‬‭documents‬‭in‬‭order‬‭to‬‭verify‬‭worksheet/case‬‭report‬‭form‬‭data.‬‭By‬‭signing‬‭the‬
‭consent‬‭form,‬‭the‬‭subject‬‭agrees‬‭to‬‭this‬‭process.‬‭If‬‭trial‬‭documents‬‭will‬‭be‬‭photocopied‬‭during‬
‭the‬‭process‬‭of‬‭verifying‬‭worksheet/case‬‭report‬‭form‬‭information,‬‭the‬‭subject‬‭will‬‭be‬‭identified‬
‭by unique code only; full names/initials will be masked prior to transmission.‬
‭●‬ ‭By‬‭signing‬‭this‬‭protocol,‬‭the‬‭investigator‬‭agrees‬‭to‬‭treat‬‭all‬‭subject‬‭data‬‭used‬‭and‬‭disclosed‬‭in‬
‭connection‬ ‭with‬ ‭this‬ ‭trial‬ ‭in‬ ‭accordance‬ ‭with‬ ‭all‬ ‭applicable‬ ‭privacy‬ ‭laws,‬ ‭rules‬ ‭and‬
‭regulations.‬
‭14.3.‬ ‭Informed consent‬
‭●‬ ‭Eligible‬‭patients‬‭may‬‭only‬‭be‬‭included‬‭in‬‭the‬‭study‬‭after‬‭providing‬‭written‬‭(witnessed,‬‭where‬
‭required by law or regulation), IRB/IEC/REB-approved informed consent.‬
‭●‬ ‭Informed‬‭consent‬‭must‬‭be‬‭obtained‬‭before‬‭conducting‬‭any‬‭study-specific‬‭procedures‬‭(i.e.‬‭all‬
‭of‬ ‭the‬ ‭procedures‬ ‭described‬ ‭in‬ ‭the‬ ‭protocol).‬ ‭The‬ ‭process‬ ‭of‬ ‭obtaining‬ ‭informed‬ ‭consent‬
‭should be documented in the patient source documents.‬
‭●‬ ‭The‬‭date‬‭when‬‭a‬‭patient’s‬‭Informed‬‭Consent‬‭was‬‭actually‬‭obtained‬‭will‬‭be‬‭captured‬‭in‬‭their‬
‭CRFs.‬
‭●‬ ‭An‬‭informed‬‭consent‬‭form‬‭(ICF)‬‭that‬‭is‬‭considered‬‭appropriate‬‭for‬‭this‬‭study‬‭and‬‭complies‬
‭with the ICH GCP guideline and regulatory requirements will be provided with this protocol.‬
‭●‬ ‭Women‬‭of‬‭childbearing‬‭potential‬‭should‬‭be‬‭informed‬‭that‬‭taking‬‭the‬‭study‬‭medication‬‭may‬
‭involve‬‭unknown‬‭risks‬‭to‬‭the‬‭fetus‬‭if‬‭pregnancy‬‭were‬‭to‬‭occur‬‭during‬‭the‬‭study‬‭and‬‭agree‬‭that‬
‭in‬‭order‬‭to‬‭participate‬‭in‬‭the‬‭study‬‭they‬‭must‬‭adhere‬‭to‬‭the‬‭contraception‬‭requirement‬‭for‬‭the‬
‭duration‬‭of‬‭the‬‭study.‬‭If‬‭there‬‭is‬‭any‬‭question‬‭that‬‭the‬‭patient‬‭will‬‭not‬‭reliably‬‭comply,‬‭they‬
‭should not be entered in the study.‬
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‭Additional consent form‬
‭Sub-studies‬‭and‬‭studies‬‭with‬‭an‬‭optional‬‭biomarker‬‭component‬‭may‬‭have‬‭a‬‭separate‬‭consent‬
‭form‬‭covering‬‭those‬‭studies.‬‭This‬‭form‬‭will‬‭be‬‭adapted‬‭for‬‭each‬‭study.‬‭These‬‭informed‬‭consent‬‭forms‬
‭will‬‭be‬‭submitted‬‭for‬‭ethical‬‭approval‬‭together‬‭with‬‭the‬‭Study‬‭Protocol‬‭and‬‭the‬‭main‬‭informed‬‭consent‬
‭form‬‭of‬‭the‬‭study.‬‭If‬‭a‬‭patient‬‭opts‬‭not‬‭to‬‭participate‬‭in‬‭the‬‭optional‬‭assessments,‬‭this‬‭in‬‭no‬‭way‬‭will‬
‭affect the patient’s ability to participate in the main research study.‬
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‭15.‬
‭Publication policy‬
‭This‬‭trial‬‭is‬‭intended‬‭for‬‭publication,‬‭even‬‭if‬‭terminated‬‭prematurely.‬‭Publication‬‭may‬‭include‬‭any‬‭or‬
‭all‬ ‭of‬ ‭the‬ ‭following:‬ ‭posting‬ ‭of‬ ‭a‬ ‭synopsis‬ ‭online,‬ ‭abstract‬ ‭and/or‬ ‭presentation‬ ‭at‬ ‭a‬ ‭scientific‬
‭conference, or publication of a full manuscript.‬
‭The‬‭authors‬‭will‬‭work‬‭to‬‭submit‬‭a‬‭manuscript‬‭describing‬‭trial‬‭results‬‭within‬‭12‬‭months‬‭after‬‭the‬‭last‬
‭data become available.‬
‭A‬ ‭synopsis‬ ‭of‬ ‭trial‬ ‭results‬ ‭for‬ ‭approved‬ ‭products‬ ‭will‬ ‭be‬ ‭posted‬ ‭on‬ ‭www.clinicaltrials.gov‬ ‭by‬‭12‬
‭months‬ ‭after‬ ‭the‬ ‭last‬ ‭subject's‬ ‭last‬ ‭visit‬ ‭for‬ ‭the‬ ‭primary‬‭outcome,‬‭12‬‭months‬‭after‬‭the‬‭decision‬‭to‬
‭discontinue‬ ‭development,‬ ‭or‬ ‭product‬ ‭marketing‬ ‭(dispensed,‬ ‭administered,‬ ‭delivered‬ ‭or‬ ‭promoted),‬
‭whichever is later.‬
‭These‬ ‭timelines‬ ‭may‬ ‭be‬ ‭extended,‬ ‭if‬ ‭additional‬ ‭time‬‭is‬‭needed‬‭for‬‭analysis,‬‭to‬‭protect‬‭intellectual‬
‭property, or to comply with confidentiality agreements with other parties.‬
‭Authors‬ ‭of‬ ‭the‬ ‭primary‬‭results‬‭manuscript‬‭will‬‭be‬‭provided‬‭the‬‭complete‬‭results‬‭from‬‭the‬‭Clinical‬
‭Study Report, subject to the confidentiality agreement.‬
‭When‬‭a‬‭manuscript‬‭is‬‭submitted‬‭to‬‭a‬‭biomedical‬‭journal‬‭the‬‭protocol‬‭and‬‭statistical‬‭analysis‬‭plan‬‭will‬
‭also‬‭be‬‭submitted‬‭to‬‭facilitate‬‭the‬‭peer‬‭and‬‭editorial‬‭review‬‭of‬‭the‬‭manuscript.‬‭If‬‭the‬‭manuscript‬‭is‬
‭subsequently‬ ‭accepted‬ ‭for‬ ‭publication‬ ‭the‬ ‭journal‬ ‭will‬ ‭be‬ ‭allowed,‬ ‭to‬ ‭post‬ ‭on‬‭its‬‭website‬‭the‬‭key‬
‭sections‬‭of‬‭the‬‭protocol‬‭that‬‭are‬‭relevant‬‭to‬‭evaluating‬‭the‬‭trial,‬‭specifically‬‭those‬‭sections‬‭describing‬
‭the‬‭trial‬‭objectives‬‭and‬‭hypotheses,‬‭the‬‭subject‬‭inclusion‬‭and‬‭exclusion‬‭criteria,‬‭the‬‭trial‬‭design‬‭and‬
‭procedures,‬ ‭the‬ ‭efficacy‬ ‭and‬ ‭safety‬ ‭measures,‬ ‭the‬ ‭statistical‬ ‭analysis‬ ‭plan,‬ ‭and‬ ‭any‬ ‭amendments‬
‭relating to those sections.‬
‭The‬‭first‬‭author‬‭is‬‭responsible‬‭for‬‭defending‬‭the‬‭integrity‬‭of‬‭the‬‭data,‬‭method(s)‬‭of‬‭data‬‭analysis‬‭and‬
‭the scientific content of the manuscript.‬
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‭APPENDICES‬
‭Appendix A. Performance Status Criteria‬
‭WHO Performance Status Scale‬
‭Karnofsky Performance Scale‬
‭Grade‬
‭Descriptions‬
‭Percent‬
‭Description‬
‭0‬
‭Normal‬ ‭activity.‬ ‭Fully‬‭active,‬‭able‬‭to‬
‭carry‬ ‭on‬ ‭all‬ ‭pre-disease‬ ‭performance‬
‭without restriction.‬
‭100‬
‭Normal, no complaints, no evidence of disease.‬
‭90‬
‭Able‬ ‭to‬ ‭carry‬ ‭on‬ ‭normal‬ ‭activity;‬ ‭minor‬ ‭signs‬ ‭or‬
‭symptoms of disease.‬
‭1‬
‭Symptoms,‬
‭but‬
‭ambulatory.‬
‭Restricted‬ ‭in‬ ‭physically‬ ‭strenuous‬
‭activity,‬ ‭but‬ ‭ambulatory‬ ‭and‬ ‭able‬ ‭to‬
‭carry‬ ‭out‬‭work‬‭of‬‭a‬‭light‬‭or‬‭sedentary‬
‭nature‬ ‭(e.g.,‬ ‭light‬ ‭housework,‬ ‭office‬
‭work)‬
‭80‬
‭Normal‬ ‭activity‬ ‭with‬ ‭effort;‬ ‭some‬ ‭signs‬ ‭or‬
‭symptoms of disease.‬
‭70‬
‭Cares‬‭for‬‭self,‬‭unable‬‭to‬‭carry‬‭on‬‭normal‬‭activity‬‭or‬
‭to do active work.‬
‭2‬
‭In‬‭bed‬‭<50%‬‭of‬‭the‬‭time.‬ ‭Ambulatory‬
‭and‬‭capable‬‭of‬‭all‬‭self-care,‬‭but‬‭unable‬
‭to‬ ‭carry‬ ‭out‬ ‭any‬ ‭work‬ ‭activities.‬ ‭Up‬
‭and‬ ‭about‬ ‭more‬ ‭than‬ ‭50%‬ ‭of‬ ‭waking‬
‭hours.‬
‭60‬
‭Requires‬ ‭occasional‬ ‭assistance,‬ ‭but‬ ‭is‬ ‭able‬ ‭to‬ ‭care‬
‭for most of his/her needs.‬
‭50‬
‭Requires‬ ‭considerable‬ ‭assistance‬ ‭and‬ ‭frequent‬
‭medical care.‬
‭3‬
‭In‬ ‭bed‬ ‭>50%‬ ‭of‬ ‭the‬ ‭time.‬
‭Capable‬
‭of‬
‭only‬
‭limited‬
‭self-care,‬ ‭confined‬ ‭in‬ ‭bed‬ ‭or‬
‭chair‬ ‭more‬ ‭than‬ ‭50%‬‭of‬‭waking‬
‭hours.‬
‭40‬
‭Disabled, requires special care and assistance.‬
‭30‬
‭Severely‬ ‭disabled,‬‭hospitalization‬‭indicated.‬ ‭Death‬
‭not imminent.‬
‭4‬
‭100%‬ ‭bedridden.‬
‭Completely‬
‭disabled.‬ ‭Cannot‬ ‭carry‬ ‭on‬ ‭any‬
‭self-care.‬
‭Totally‬ ‭confined‬ ‭to‬
‭bed or chair‬
‭20‬
‭Very‬ ‭sick,‬ ‭hospitalization‬ ‭indicated.‬
‭Death‬ ‭not‬
‭imminent.‬
‭10‬
‭Moribund, fatal processes progressing rapidly.‬
‭5‬
‭Deceased.‬
‭0‬
‭Deceased.‬
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‭Appendix B. References‬
‭[i]‬
‭Garcia-Carbonero‬‭R‬‭,‬‭Capdevila‬‭J,‬‭Crespo-Herrero‬‭G‬‭et‬‭al.‬‭Incidence,‬‭patterns‬‭of‬‭care‬
‭and‬ ‭prognostic‬ ‭factors‬ ‭for‬‭outcome‬‭of‬‭gastroenteropancreatic‬‭neuroendocrine‬‭tumors‬‭(GEP-NETs):‬
‭results‬
‭from‬
‭the‬
‭National‬ ‭Cancer‬ ‭Registry‬ ‭of‬ ‭Spain‬ ‭(RGETNE).‬ ‭Ann‬ ‭Oncol.‬ ‭2010‬
‭Sep;21(9):1794-803.‬
‭[ii]‬
‭Yao‬‭JC,‬‭Hassan‬‭M,‬‭Phan‬‭A,‬‭et‬‭al.‬‭One‬‭hundred‬‭years‬‭after‬‭"carcinoid":‬‭epidemiology‬
‭of‬ ‭and‬ ‭prognostic‬ ‭factors‬ ‭for‬ ‭neuroendocrine‬ ‭tumors‬ ‭in‬ ‭35,825‬ ‭cases‬ ‭in‬ ‭the‬‭United‬‭States.‬‭J‬‭Clin‬
‭Oncol. 2008 Jun 20;26(18):3063-72‬
‭[iii]‬
‭Rindi‬ ‭G,‬ ‭Arnold‬ ‭R,‬ ‭Bosman‬ ‭FT,‬ ‭et‬ ‭al.‬ ‭Nomenclature‬ ‭and‬ ‭classification‬ ‭of‬
‭neuroendocrine‬‭neoplasms‬‭of‬‭the‬‭digestive‬‭system.‬‭WHO‬‭classification‬‭of‬‭tumours‬‭of‬‭the‬‭digestive‬
‭system. 4th ed Lyon: International Agency for Research on cancer (IARC); 2010.‬
‭[iv]‬
‭Sorbye‬ ‭H,‬ ‭Strosberg‬ ‭J,‬ ‭Baudin‬ ‭E,‬ ‭et‬ ‭al.‬ ‭Gastroenteropancreatic‬ ‭high-grade‬
‭neuroendocrine carcinoma. Cancer 2014;120: 2814-23.‬
‭[v]‬
‭Sorbye‬‭H,‬‭Welin‬‭S,‬‭Langer‬‭SW‬‭et‬‭al.‬‭Predictive‬‭and‬‭prognostic‬‭factors‬‭for‬‭treatment‬
‭and‬‭survival‬‭in‬‭305‬‭patients‬‭with‬‭advanced‬‭gastrointestinal‬‭neuroendocrine‬‭carcinoma‬‭(WHO‬‭G3):‬‭the‬
‭NORDIC NEC study. Ann Oncol, 2013. 24(1): p. 152-60.‬
‭[vi]‬
‭Moertel‬‭CG,‬‭Kvols‬‭LK,‬‭O'Connell‬‭MJ‬‭et‬‭al.‬‭Treatment‬‭of‬‭neuroendocrine‬‭carcinomas‬
‭with‬ ‭combined‬ ‭etoposide‬ ‭and‬ ‭cisplatin.‬ ‭Evidence‬ ‭of‬ ‭major‬ ‭therapeutic‬ ‭activity‬ ‭in‬ ‭the‬ ‭anaplastic‬
‭variants of these neoplasms. Cancer, 1991. 68(2): p. 227-232.‬
‭[vii]‬
‭Mitry‬ ‭E,‬ ‭Baudin‬ ‭E,‬ ‭Ducreux‬ ‭M‬ ‭et‬ ‭al.‬ ‭Treatment‬ ‭of‬ ‭poorly‬ ‭differentiated‬
‭neuroendocrine tumours with etoposide and cisplatin. Br J Cancer, 1999. 81(8): p. 1351.‬
‭[viii]‬
‭Iwasa‬ ‭S,‬ ‭Morizane‬ ‭C,‬ ‭Okusaka‬ ‭T‬ ‭et‬ ‭al.‬ ‭Cisplatin‬ ‭and‬ ‭etoposide‬ ‭as‬ ‭first-line‬
‭chemotherapy‬ ‭for‬ ‭poorly‬ ‭differentiated‬ ‭neuroendocrine‬ ‭carcinoma‬ ‭of‬ ‭the‬ ‭hepatobiliary‬ ‭tract‬ ‭and‬
‭pancreas. Jpn J Clin Oncol, 2010. 40(4): p. 313-318.‬
‭[ix]‬
‭Deutschbein‬‭T,‬‭Unger‬‭N,‬‭Yuece‬‭A‬‭et‬‭al.‬‭Chemotherapy‬‭in‬‭patients‬‭with‬‭progressive,‬
‭undifferentiated‬‭neuroendocrine‬‭tumors:‬‭a‬‭single-center‬‭experience.‬‭Horm‬‭metab‬‭Res,‬‭2011.‬‭43(12):‬‭p.‬
‭838-843.‬
‭[x]‬
‭Patta‬ ‭A,‬ ‭Fakih‬ ‭M.‬ ‭First-line‬ ‭cisplatin‬ ‭plus‬ ‭etoposide‬ ‭in‬ ‭high-grade‬ ‭metastatic‬
‭neuroendocrine‬‭tumors‬‭of‬‭colon‬‭and‬‭rectum‬‭(MCRC‬‭NET):‬‭review‬‭of‬‭8‬‭cases.‬‭Anticancer‬‭Research,‬
‭2011. 31(3): p. 975-978.‬
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‭Topalian‬ ‭SL,‬ ‭Bhatia‬ ‭S,‬ ‭Hollebecque‬ ‭A‬ ‭et‬ ‭al.‬ ‭Abstract‬ ‭CT074:‬ ‭Non-comparative,‬
‭open-label,‬ ‭multiple‬ ‭cohort,‬ ‭phase‬ ‭1/2‬ ‭study‬ ‭to‬ ‭evaluate‬ ‭nivolumab‬ ‭(NIVO)‬ ‭in‬ ‭patients‬ ‭with‬
‭virus-associated‬ ‭tumors‬ ‭(CheckMate‬ ‭358):‬ ‭Efficacy‬ ‭and‬ ‭safety‬ ‭in‬ ‭Merkel‬ ‭cell‬ ‭carcinoma‬ ‭(MCC).‬
‭Cancer Research 2017; 77: CT074-CT074‬
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SAP_001.pdf: 
‭A phase II study of Platinum-doublet‬
‭chemotherapy in combination with‬
‭nivolumab as first-line treatment, in‬
‭subjects with unresectable, locally‬
‭advanced or metastatic G3‬
‭Neuroendocrine Neoplasms (NENs) of‬
‭the gastroenteropancreatic (GEP) tract‬
‭or of unknown (UK) origin. (GETNE‬
‭T1913).‬
‭NICE-NEC STUDY‬
‭FINAL STATISTICAL REPORT (2022)‬
‭9‬‭th‬‭of November 2022‬
‭Page‬‭1‬‭of‬‭83‬


‭1.‬‭T‬‭ABLE‬‭OF‬‭C‬‭ONTENTS‬
‭2.‬
‭PATIENTS RECRUITED AND STUDY POPULATIONS‬
‭5‬
‭2.1.‬
‭SCREENING FAILURES‬
‭5‬
‭2.2.‬
‭PATIENT POPULATIONS‬
‭6‬
‭3.‬
‭RESULTS‬
‭8‬
‭3.1.‬
‭EVALUABLE PATIENTS‬
‭8‬
‭3.2.‬
‭BASELINE CHARACTERISTICS‬
‭9‬
‭3.2.1.‬ ‭BASELINE - DEMOGRAPHIC DATA‬
‭9‬
‭3.2.2.‬ ‭BASELINE - CANCER HISTORY‬
‭11‬
‭3.3.‬
‭BASELINE - ANALYTICS‬
‭15‬
‭3.4.‬
‭Baseline - Hematology and Coagulation‬
‭15‬
‭3.5.‬
‭Baseline - Biochemistry, Thyroid Function and‬‭Serology‬
‭17‬
‭3.6.‬
‭Baseline - Other Determinations‬
‭22‬
‭4.‬
‭Treatment exposure‬
‭24‬
‭4.1.‬
‭Induction Phase‬
‭24‬
‭4.2.‬
‭Maintenance Phase‬
‭29‬
‭4.3.‬
‭Total duration of treatment with Nivolumab‬
‭35‬
‭4.4.‬
‭Cycles administered after progression‬
‭35‬
‭4.5.‬
‭END OF TREATMENT - END OF STUDY - FOLLOW-UP‬
‭36‬
‭4.5.1.‬ ‭End of treatment‬
‭36‬
‭4.5.2.‬ ‭End of Study‬
‭36‬
‭4.5.3.‬ ‭Follow-up (all patients)‬
‭37‬
‭4.5.4.‬ ‭Follow-up (only alive patients)‬
‭37‬
‭4.6.‬
‭PRIMARY ENDPOINT: OVERALL SUVIVAL (OS)‬
‭38‬
‭4.7.‬
‭SECONDARY ENDPOINTS‬
‭40‬
‭4.7.1.‬ ‭PROGRESSION FREE SURVIVAL (PFS)‬
‭40‬
‭4.7.2.‬ ‭Events: Progressions/Deaths‬
‭40‬
‭4.7.3.‬ ‭ORR: Objective Response Rate‬
‭42‬
‭4.7.4.‬ ‭Best Overall Response‬
‭42‬
‭4.7.5.‬ ‭Duration of Response‬
‭42‬
‭4.7.5.1.‬ ‭Figure: Waterfall plot. Maximum % total change‬‭with BOR‬
‭43‬
‭4.7.5.2‬
‭Figure: Waterfall plot. Maximum % total change‬‭VS BOR‬
‭44‬
‭Page‬‭2‬‭of‬‭83‬


‭4.7.5.3‬
‭Figure: Waterfall plot. Maximum % total change‬‭VS pRIMARY‬
‭LOCATION‬
‭45‬
‭4.7.5.4‬
‭Figure: Waterfall plot. Maximum % total change‬‭VS KI67‬
‭46‬
‭4.7.5.4‬
‭Figure: Waterfall plot. Maximum % total change‬‭VS‬
‭DIFFERENTATION TUMOUR‬
‭47‬
‭4.7.5.2.‬ ‭Figure: Spider plot. Maximum % total change‬
‭48‬
‭4.7.5.5‬
‭Figure: Spider plot. Maximum % total change‬‭VS‬
‭DIFFERENTIATION‬
‭49‬
‭4.7.5.6‬
‭Figure: Spider plot. Maximum % total change‬‭VS BOR‬
‭50‬
‭4.7.5.7‬
‭Figure: Spider plot. Maximum % total change‬‭VS CGA‬
‭51‬
‭4.7.5.8‬
‭Figure: Spider plot. Maximum % total change‬‭VS NSE‬
‭52‬
‭4.8.‬
‭OS STRATIFIED BY FACTORS OF INTEREST: DIFFERENTIATED/‬‭Ki67/‬
‭PRIMARY TUMOUR LOCATION / CGA / NSE‬
‭53‬
‭4.8.1.‬ ‭OS vs Differentiation‬
‭53‬
‭4.8.1.1.‬ ‭Figure: OS vs Differentiation. Kaplan Meier‬‭graph‬
‭54‬
‭4.8.2.‬ ‭OS vs Ki67‬
‭55‬
‭4.8.2.1.‬ ‭Figure: OS vs Ki67. Kaplan Meier graph‬
‭56‬
‭4.8.3.‬ ‭OS vs Location‬
‭57‬
‭4.8.3.1.‬ ‭Figure: OS vs Location. Kaplan Meier graph‬
‭58‬
‭4.8.4.‬ ‭OS vs CGA‬
‭59‬
‭4.8.4.1.‬ ‭Figure: OS vs CGA Kaplan Meier graph‬
‭60‬
‭4.8.5.‬ ‭OS vs NSE‬
‭61‬
‭4.8.5.1.‬ ‭Figure: OS vs NSE Kaplan Meier graph‬
‭62‬
‭4.9.‬
‭PFS STRATIFIED BY FACTORS OF INTEREST: DIFFERENTIATED/‬
‭Ki67/ PRIMARY TUMOUR LOCATION / CGA / ENOLASE‬
‭63‬
‭4.9.1.‬ ‭PFS vs Differentiation‬
‭63‬
‭4.9.1.1.‬ ‭Figure: PFS vs Differentiation. Kaplan Meier‬‭graph‬
‭64‬
‭4.9.2.‬ ‭PFS vs Ki67‬
‭65‬
‭4.9.2.1.‬ ‭Figure: PFS vs Ki67. Kaplan Meier graph‬
‭66‬
‭4.9.3.‬ ‭PFS vs Location‬
‭67‬
‭4.9.3.1.‬ ‭Figure: PFS vs Location. Kaplan Meier graph‬
‭68‬
‭4.9.4.‬ ‭PFS vs CGA‬
‭69‬
‭4.9.4.1.‬ ‭PFS vs CGA (2)‬
‭69‬
‭4.9.4.2.‬ ‭Figure: PFS vs CGA Kaplan Meier graph (2)‬
‭70‬
‭4.9.4.3.‬ ‭PFS vs CGA (3)‬
‭71‬
‭4.9.4.4.‬ ‭Figure: PFS vs CGA Kaplan Meier graph (3)‬
‭72‬
‭Page‬‭3‬‭of‬‭83‬


‭4.9.4.5.‬ ‭PFS vs CGA (5)‬
‭73‬
‭4.9.4.6.‬ ‭Figure: PFS vs CGA Kaplan Meier graph (5)‬
‭74‬
‭4.9.5.‬ ‭PFS vs Enolase‬
‭75‬
‭4.9.5.1.‬ ‭Figure: PFS vs NSE Kaplan Meier graph‬
‭76‬
‭4.10.‬
‭ORR STRATIFIED BY FACTORS OF INTEREST: DIFFERENTIATED/‬
‭Ki67/ PRIMARY TUMOUR LOCATION / CGA / NSE‬
‭77‬
‭4.10.1.‬
‭MULTIVARIATE ANALYSIS OF PFS AND OS‬
‭81‬
‭4.10.1.1.‬ ‭Factors included in the multivariate analysis‬‭of the PFS (1)‬
‭81‬
‭4.10.1.2.‬ ‭Factors included in the multivariate analysis‬‭of the PFS (2)‬
‭85‬
‭4.10.1.3.‬ ‭Factors included in the multivariate analysis‬‭of the OS (1)‬
‭89‬
‭4.10.1.4.‬ ‭Factors included in the multivariate analysis‬‭of the OS (2)‬
‭94‬
‭5.‬
‭Safety analysis‬
‭99‬
‭5.1.‬
‭Induction‬
‭100‬
‭5.2.‬
‭Maintenance‬
‭110‬
‭5.3.‬
‭General‬
‭115‬
‭Page‬‭4‬‭of‬‭83‬


‭NICE-NEC‬‭a‬‭phase‬‭II‬‭study‬‭of‬‭Platinum-doublet‬‭chemotherapy‬‭in‬‭combination‬‭with‬
‭nivolumab‬‭as‬‭first-line‬‭treatment,‬‭in‬‭subjects‬‭with‬‭unresectable,‬‭locally‬‭advanced‬‭or‬
‭metastatic‬ ‭G3‬ ‭Neuroendocrine‬ ‭Neoplasms‬ ‭(NENs)‬‭of‬‭the‬‭gastroenteropancreatic‬
‭(GEP) tract or of unknown (UK) origin. (GETNE T1913).‬
‭Primary endpoint is 12 m OS.‬
‭Secondary endpoints include ORR, and PFS by RECIST 1.1 and safety.‬
‭The‬‭database‬‭for‬‭the‬‭results‬‭of‬‭the‬‭following‬‭report‬‭was‬‭locked‬‭down‬‭on‬‭the‬
‭XX‬‭th‬‭of XX 202X.‬
‭Page‬‭5‬‭of‬‭83‬


‭2.‬‭PATIENTS RECRUITED AND STUDY‬
‭POPULATIONS‬
‭2.1.‬ ‭SCREENING FAILURES‬
‭Table 2: List of patients: screening Failure Reasons‬
‭Patient number‬
‭Screening failure‬
‭Reason Screening failure‬
‭Page‬‭6‬‭of‬‭83‬


‭2.2.‬ ‭PATIENT POPULATIONS‬
‭Enrolled‬
‭All participants who signed informed consent and were registered.‬
‭Table 3: Enrolled population‬
‭Overall (N=)‬
‭Enrolled‬
‭Yes‬
‭No‬
‭Treated‬
‭All‬‭participants‬‭who‬‭received‬‭at‬‭least‬‭one‬‭dose‬‭of‬‭any‬‭study‬‭medication.‬‭This‬‭is‬‭the‬
‭primary dataset for dosing and safety analysis.‬
‭Table 4: Treated population‬
‭Overall (N=)‬
‭Treated‬
‭Yes‬
‭No‬
‭Table 5: Treated population: Reason excluded‬
‭Patient number‬
‭Treated population‬
‭Reason excluded from Treated population‬
‭Response-Evaluable‬
‭All‬ ‭treated‬ ‭subjects‬ ‭who‬ ‭have‬ ‭a‬‭baseline‬‭and‬‭at‬‭least‬‭one‬‭on-treatment‬‭imaging‬
‭evaluation or had progression or death prior to the first on-treatment scan.‬
‭REASON FOR EVALUATION‬
‭Table 6: Response-Evaluable population‬
‭Overall (N=)‬
‭Response-Evaluable analysis‬
‭set‬
‭Yes‬
‭No‬
‭Page‬‭7‬‭of‬‭83‬


‭Table 7: Response-Evaluable population: Reason excluded‬
‭Patient‬
‭number‬
‭Response-‬
‭Evaluable‬
‭population‬
‭Response‬
‭reason‬
‭1st Tumor‬
‭assessment‬
‭measurement‬
‭(lesions)‬
‭PD‬
‭dat‬
‭e‬
‭First‬
‭FU‬
‭EOS‬
‭reason‬
‭EO‬
‭S‬
‭date‬
‭First‬
‭treatment‬
‭admin‬
‭Page‬‭8‬‭of‬‭83‬


‭3.‬‭RESULTS‬
‭The‬‭database‬‭for‬‭the‬‭results‬‭of‬‭the‬‭following‬‭report‬‭was‬‭locked‬‭down‬‭on‬‭the‬
‭XX‬‭th‬‭of XXX 202X.‬
‭3.1.‬ ‭EVALUABLE PATIENTS‬
‭Regarding‬ ‭the‬ ‭efficacy‬ ‭analysis‬ ‭the‬‭Response-Evaluable‬‭population‬‭will‬‭be‬‭used‬
‭(n=).‬
‭Table 8: Populations and Hospital‬
‭Overall‬
‭Overall (N=)‬
‭Enrolled‬
‭Yes‬
‭No‬
‭Treated‬
‭ Yes‬
‭No‬
‭Response-Evaluable analysis set‬
‭Yes‬
‭No‬
‭Hospital‬
‭   CENTRO ONCOLÓGICO MD ANDERSON INTERNATIONAL ESPAÑA‬
‭   HOSPITAL RAMÓN Y CAJAL‬
‭   HOSPITAL UNIVERSITARI VALL D’HEBRON(*)‬
‭   HOSPITAL UNIVERSITARIO 12 DE OCTUBRE‬
‭   HOSPITAL UNIVERSITARIO CENTRAL DE ASTURIAS‬
‭   HOSPITAL UNIVERSITARIO LA PAZ‬
‭   HOSPITAL UNIVERSITARIO MIGUEL SERVET‬
‭   HOSPITAL VIRGEN DE LA VICTORIA‬
‭   HOSPITAL VIRGEN DEL ROCÍO‬
‭   INSTITUT CATALÀ D’ONCOLOGIA L’HOSPITALET (ICO)‬
‭Page‬‭9‬‭of‬‭83‬


‭3.2.‬ ‭BASELINE CHARACTERISTICS‬
‭3.2.1.‬‭BASELINE - DEMOGRAPHIC DATA‬
‭Table 9: Baseline - Demographic Data‬
‭Overall‬
‭Overall (N=)‬
‭Gender‬
‭   Female‬
‭   Male‬
‭Age at registration (year)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Race‬
‭   Caucasian‬
‭   Latin‬
‭   Unknown‬
‭Weight (Kg)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Height (cm)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Systolic Blood Pressure‬
‭(mmHg)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Diastolic Blood Pressure‬
‭(mmHg)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Temperature (ºC)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭Page‬‭10‬‭of‬‭83‬


‭Overall‬
‭Overall (N=)‬
‭   Range‬
‭Respiratory rate (bpm)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Pulse Rate (bpm)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭ECOG‬
‭   0‬
‭   1‬
‭   2‬
‭Physical examination‬
‭   Normal‬
‭   Clinically relevant findings‬
‭Page‬‭11‬‭of‬‭83‬


‭3.2.2.‬‭BASELINE - CANCER HISTORY‬
‭Table 10: Baseline - Cancer History (I)‬
‭Overall‬
‭Overall (N=)‬
‭Cancer Type‬
‭   Gastroenteropancreatic tract‬
‭   Primary Unknown‬
‭Primary location‬
‭   Esophagus‬
‭   Gastric‬
‭   Pancreas‬
‭   Right colon‬
‭   Left colon‬
‭   Rectum‬
‭   Duodenum‬
‭   Ileum‬
‭   Prostate‬
‭   Inguinal‬
‭   Unknown‬
‭Primary location (grouped)‬
‭   Duodenum/Ileum‬
‭   Esophagus/Gastric‬
‭   Pancreas‬
‭   Colon/Rectum‬
‭   Not specified/Others‬
‭Primary location (Colon/Rectum vs‬
‭Others)‬
‭   Colon/Rectum‬
‭   Others‬
‭Initial T Stage‬
‭   T0‬
‭   T1‬
‭   T2‬
‭   T3‬
‭   T4‬
‭   Tx‬
‭Initial N Stage‬
‭   N0‬
‭   N1‬
‭   N2‬
‭   Nx‬
‭Initial M Stage‬
‭   M0‬
‭   M1‬
‭Cancer Stage at diagnosis‬
‭   I‬
‭   III‬
‭   IV‬
‭Histological grade‬
‭   3‬
‭Ki-67 Index‬
‭   N‬
‭Page‬‭12‬‭of‬‭83‬


‭Overall‬
‭Overall (N=)‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Ki-67 categorised‬
‭   <=20‬
‭   >20‬
‭Ki-67 categorised‬
‭   <=50‬
‭   >50‬
‭Ki-67 categorised‬
‭   <=55‬
‭   >55‬
‭Mitotic Rate‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Differentiation‬
‭   Well differentiated‬
‭   Poorly differentiated‬
‭Functional status‬
‭   Functioning‬
‭   Non-functioning‬
‭   Unknown‬
‭Table 11: Baseline - Cancer History (II)‬
‭Overall‬
‭Overall (N=)‬
‭Primary surgery‬
‭   Yes‬
‭   No‬
‭   Unknown‬
‭Time since Primary surgery to treatment initiation (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Primary Surgery Outcome‬
‭   Missing data‬
‭   R0‬
‭   R2‬
‭   UK‬
‭Radiotherapy‬
‭   Yes‬
‭   No‬
‭Other cancer history‬
‭   Yes‬
‭Page‬‭13‬‭of‬‭83‬


‭Overall‬
‭Overall (N=)‬
‭   No‬
‭   Unknown‬
‭Other cancer history specify‬
‭   NA‬
‭   Breast‬
‭   Colorectal adenoma‬
‭   Prostate adenocarcinoma‬
‭Table 12: Baseline - Current NEN‬
‭Overall‬
‭Overall (N=)‬
‭Current NEN T‬
‭Stage‬
‭   T0‬
‭   T1‬
‭   T2‬
‭   T3‬
‭   T4‬
‭   Tx‬
‭Current NEN N‬
‭Stage‬
‭   N0‬
‭   N1‬
‭   N2‬
‭   Nx‬
‭Current NEN M‬
‭Stage‬
‭   M0‬
‭   M1‬
‭Current NEN Stage‬
‭   III‬
‭   IV‬
‭Table 13: Baseline - Metastatic disease location‬
‭Overall‬
‭Overall (N=)‬
‭Affected Organ Liver‬
‭   No‬
‭   Yes‬
‭Affected Organ Lung‬
‭   No‬
‭   Yes‬
‭Affected Organ Nodules‬
‭   No‬
‭   Yes‬
‭Affected Organ Peritoneal‬
‭   No‬
‭   Yes‬
‭Affected Organ Bone‬
‭Page‬‭14‬‭of‬‭83‬


‭Overall‬
‭Overall (N=)‬
‭   No‬
‭   Yes‬
‭Affected Organ Spleen‬
‭   No‬
‭   Yes‬
‭Affected Organ Soft tissue‬
‭   No‬
‭   Yes‬
‭Affected Organ Others‬
‭   No‬
‭   Yes‬
‭Affected Organs Number‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Affected Organs Number‬
‭(categorised)‬
‭   1 Organ‬
‭   2 Organs‬
‭   3 Organs‬
‭   4 Organs‬
‭   5 Organs‬
‭   6 Organs‬
‭Page‬‭15‬‭of‬‭83‬


‭3.3.‬ ‭BASELINE - ANALYTICS‬
‭3.4.‬ ‭B‬‭ASELINE‬‭- H‬‭EMATOLOGY‬‭AND‬‭C‬‭OAGULATION‬
‭Table 14: Baseline - Hematology and Coagulation‬
‭Overall‬
‭Overall (N=)‬
‭PTT Value‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Basophils (x 10e9/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Eosinophils (x 10e9/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Hematocrit (%)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Hemoglobine (g/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭INR Value‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Lymphocytes (x 10e9/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Monocytes (x 10e3/µL)‬
‭   N‬
‭   Mean (95%CI)‬
‭Page‬‭16‬‭of‬‭83‬


‭Overall‬
‭Overall (N=)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Neutrophils (x 10e3/µL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Platelets (x 10e9/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭PT Value‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Red Blood Count (10e6/µL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭White Blood Count‬
‭(10e3/µL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Page‬‭17‬‭of‬‭83‬


‭3.5.‬ ‭B‬‭ASELINE‬‭- B‬‭IOCHEMISTRY‬‭, T‬‭HYROID‬‭F‬‭UNCTION‬‭AND‬
‭S‬‭EROLOGY‬
‭Table 15: Baseline - Biochemistry, Thyroid Function and Serology‬
‭Overall‬
‭Overall (N=)‬
‭Albumin (g/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭ALT (U/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Amylase (U/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭AST (U/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭BUN (mg/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭CGA (ng/mL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭CGA <> 2 x ULN‬
‭   Missing data‬
‭   CGA >= 2*ULN‬
‭   CGA < 2*ULN‬
‭Calcium (mg/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Page‬‭18‬‭of‬‭83‬


‭Overall‬
‭Overall (N=)‬
‭Creatinine Kinase (U/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Creatinine (mg/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Direct Bilirubin (mg/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Free T3 (pmol/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Free T4 (ng/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭GGT (U/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Glucose (mg/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Indirect Bilirubin (mg/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭IFNy (ng/mL)‬
‭   N‬
‭   Mean (95%CI)‬
‭Page‬‭19‬‭of‬‭83‬


‭Overall‬
‭Overall (N=)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭IL1 (pg/mL)‬
‭   N‬
‭   Mean‬
‭   SD‬
‭   Median‬
‭   Range‬
‭IL6 (pg/mL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭LDH (U/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Lipase (U/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Magnesium (mg/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Neuron-Specific Enolase‬
‭(ng/mL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭NSE catgorised >2 x ULN‬
‭   Missing data‬
‭   NSE >= 2*ULN‬
‭   NSE < 2*ULN‬
‭Phosphorus (mg/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Phosphatase (U/L)‬
‭   N‬
‭Page‬‭20‬‭of‬‭83‬


‭Overall‬
‭Overall (N=)‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Potassium (mmol/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Sodium (mmol/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭TNF-α Value‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Total Bilirubin (mg/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Total Protein (g/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭TSH (mUI/L)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Urea (mg/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Uric Acid (mg/dL)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭Page‬‭21‬‭of‬‭83‬


‭Overall‬
‭Overall (N=)‬
‭   Range‬
‭Page‬‭22‬‭of‬‭83‬


‭3.6.‬ ‭B‬‭ASELINE‬‭- O‬‭THER‬‭D‬‭ETERMINATIONS‬
‭Table 16: Baseline - Other Determinations‬
‭Overall‬
‭Overall (N=)‬
‭Protein‬
‭   Negative‬
‭   +1‬
‭   Traces‬
‭   +2‬
‭   +3‬
‭   Unknown‬
‭Bilirubin‬
‭   Negative‬
‭   Positive‬
‭   Unknown‬
‭   ND‬
‭Blood‬
‭   Negative‬
‭   Positive‬
‭   Unknown‬
‭   ND‬
‭Color/appearence‬
‭   Normal‬
‭   Abnormal‬
‭   ND‬
‭   Unknown‬
‭Glucose‬
‭   Normal‬
‭   Abnormal‬
‭   Unknown‬
‭Leukocytes esterase‬
‭   Negative‬
‭   Positive‬
‭   ND‬
‭   Unknown‬
‭Nitrite‬
‭   Negative‬
‭   Positive‬
‭   Unknown‬
‭Urobilinogen‬
‭   Negative‬
‭   Positive‬
‭   ND‬
‭   Unknown‬
‭Ketones‬
‭   Negative‬
‭   Positive‬
‭   Unknown‬
‭Urine Analysis pH‬
‭   N‬
‭   Mean (95%CI)‬
‭Page‬‭23‬‭of‬‭83‬


‭Overall‬
‭Overall (N=)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Urine Analysis Specific‬
‭gravity‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭ECG‬
‭   Normal‬
‭   Clinically relevant findings‬
‭   Unknown‬
‭Ecg QTc Value‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Page‬‭24‬‭of‬‭83‬


‭4.‬‭T‬‭REATMENT‬‭EXPOSURE‬
‭Table 17: Patients in each phase‬
‭Overall‬
‭Overall (N=)‬
‭Starting Induction Phase‬
‭   No‬
‭   Yes‬
‭Starting Maintenance‬
‭Phase‬
‭   No‬
‭   Yes‬
‭4.1.‬ ‭I‬‭NDUCTION‬‭P‬‭HASE‬
‭Table 18: Adherence to Carboplatin, Etoposide and Nivolumab (Induction Phase)‬
‭Carboplatin (N=)‬
‭Etoposide (N=)‬
‭Nivolumab (N=)‬
‭Time duration of in induction (months)‬
‭N‬
‭Mean (95%CI)‬
‭SD‬
‭Median (95%CI)‬
‭Range‬
‭Number of cycles administered (Induction‬
‭phase)‬
‭0‬
‭1‬
‭2‬
‭3‬
‭4‬
‭5‬
‭6‬
‭Number of cycles administered (Induction‬
‭phase)‬
‭N‬
‭Mean (95%CI)‬
‭SD‬
‭Median (95%CI)‬
‭Range‬
‭Omission (Induction phase)‬
‭Yes‬
‭No‬
‭Omissions number (Induction phase)‬
‭N‬
‭Mean (95%CI)‬
‭SD‬
‭Median (95%CI)‬
‭Page‬‭25‬‭of‬‭83‬


‭Carboplatin (N=)‬
‭Etoposide (N=)‬
‭Nivolumab (N=)‬
‭Range‬
‭Omissions number (Induction phase)‬
‭0‬
‭1‬
‭2‬
‭3‬
‭Delay (Induction phase)‬
‭Yes‬
‭No‬
‭Delay number (Induction phase)‬
‭N‬
‭Mean (95%CI)‬
‭SD‬
‭Median (95%CI)‬
‭Range‬
‭Delay number (Induction phase)‬
‭0‬
‭1‬
‭2‬
‭3‬
‭4‬
‭Table 19: Delay time Carboplatin (Induction Phase)‬
‭Patient‬
‭Number‬
‭Carboplatin‬
‭delay time -‬
‭Induction‬
‭phase C2‬
‭(days)‬
‭Carboplatin‬
‭delay time -‬
‭Induction‬
‭phase C3‬
‭(days)‬
‭Carboplatin‬
‭delay time -‬
‭Induction‬
‭phase C4‬
‭(days)‬
‭Carboplatin‬
‭delay time -‬
‭Induction‬
‭phase C5‬
‭(days)‬
‭Carboplatin‬
‭delay time -‬
‭Induction‬
‭phase C6‬
‭(days)‬
‭Carboplatin‬
‭delay time -‬
‭Induction‬
‭phase C7‬
‭(days)‬
‭Carboplatin‬
‭delay time -‬
‭Induction‬
‭phase C8‬
‭(days)‬
‭Carboplatin‬
‭total delay‬
‭time -‬
‭Induction‬
‭phase(days)‬
‭Table 20: Delay time Etoposide (Induction Phase)‬
‭Patient‬
‭Number‬
‭Etoposide‬
‭delay time -‬
‭Induction‬
‭phase C2‬
‭(days)‬
‭Etoposide‬
‭delay time -‬
‭Induction‬
‭phase C3‬
‭(days)‬
‭Etoposide‬
‭delay time -‬
‭Induction‬
‭phase C4‬
‭(days)‬
‭Etoposide‬
‭delay time -‬
‭Induction‬
‭phase C5‬
‭(days)‬
‭Etoposide‬
‭delay time -‬
‭Induction‬
‭phase C6‬
‭(days)‬
‭Etoposide‬
‭delay time -‬
‭Induction‬
‭phase C7‬
‭(days)‬
‭Etoposide‬
‭delay time -‬
‭Induction‬
‭phase C8‬
‭(days)‬
‭Etoposide‬
‭total delay‬
‭time -‬
‭Induction‬
‭phase(days‬
‭)‬
‭Page‬‭26‬‭of‬‭83‬


‭Table 21: Delay time Nivolumab (Induction Phase)‬
‭Patient‬
‭Number‬
‭Nivolumab‬
‭delay time -‬
‭Induction‬
‭phase C2‬
‭(days)‬
‭Nivolumab‬
‭delay time -‬
‭Induction‬
‭phase C3‬
‭(days)‬
‭Nivolumab‬
‭delay time -‬
‭Induction‬
‭phase C4‬
‭(days)‬
‭Nivolumab‬
‭delay time -‬
‭Induction‬
‭phase C5‬
‭(days)‬
‭Nivolumab‬
‭delay time -‬
‭Induction‬
‭phase C6‬
‭(days)‬
‭Nivolumab‬
‭delay time -‬
‭Induction‬
‭phase C7‬
‭(days)‬
‭Nivolumab‬
‭delay time -‬
‭Induction‬
‭phase C8‬
‭(days)‬
‭Nivolumab‬
‭total delay‬
‭time -‬
‭Induction‬
‭phase(days)‬
‭Page‬‭27‬‭of‬‭83‬


‭4.2.‬ ‭M‬‭AINTENANCE‬‭P‬‭HASE‬
‭The‬ ‭following‬ ‭results‬ ‭are‬ ‭analyzed‬ ‭only‬ ‭in‬‭patients‬‭that‬‭started‬‭the‬‭maintenance‬
‭phase.‬
‭Table 22: Adherence to Nivolumab (Maintenance Phase)‬
‭Overall‬
‭Overall (N=)‬
‭Time duration of Nivolumab in Maintenance (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Nivolumab number of cycles administered (Maintenance phase)‬
‭   0‬
‭   1‬
‭   2‬
‭   3‬
‭   4‬
‭   5‬
‭   6‬
‭   7‬
‭   8‬
‭   9‬
‭   10‬
‭   11‬
‭   12‬
‭   13‬
‭   14‬
‭   15‬
‭   16‬
‭   17‬
‭   18‬
‭   19‬
‭   20‬
‭   21‬
‭   22‬
‭   23‬
‭   24‬
‭   25‬
‭   26‬
‭   27‬
‭Nivolumab number of cycles administered (Maintenance phase)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Nivolumab omission (Maintenance phase)‬
‭   No‬
‭   Yes‬
‭Page‬‭28‬‭of‬‭83‬


‭Overall‬
‭Overall (N=)‬
‭Nivolumab omissions number (Maintenance phase)‬
‭   0‬
‭   1‬
‭Nivolumab omissions number (Maintenance phase)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Nivolumab delay (Maintenance phase)‬
‭   No‬
‭   Yes‬
‭Nivolumab delay number (Maintenance phase)‬
‭   0‬
‭   1‬
‭   2‬
‭   3‬
‭Nivolumab delay number (Maintenance phase)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Page‬‭29‬‭of‬‭83‬


‭Table 23: Delay time Nivolumab (Maintenance Phase)‬
‭Patient‬
‭Number‬
‭Nivolumab delay time – Maintenance phase‬
‭C2‬
‭(days)‬
‭C3‬
‭(days)‬
‭C4‬
‭(days)‬
‭C5‬
‭(days)‬
‭C6‬
‭(days)‬
‭C7‬
‭(days)‬
‭C8‬
‭(days)‬
‭C9‬
‭(days)‬
‭C10‬
‭(days)‬
‭C11‬
‭(days)‬
‭C12‬
‭(days)‬
‭C13‬
‭(days)‬
‭C14‬
‭(days)‬
‭C15‬
‭(days)‬
‭C16‬
‭(days)‬
‭C17‬
‭(days)‬
‭C18‬
‭(days)‬
‭C19‬
‭(days)‬
‭C20‬
‭(days)‬
‭C21‬
‭(days)‬
‭C22‬
‭(days)‬
‭C23‬
‭(days)‬
‭C24‬
‭(days)‬
‭C25‬
‭(days)‬
‭C26‬
‭(days)‬
‭C27‬
‭(days)‬
‭(da‬
‭ys)‬
‭Page‬‭30‬‭of‬‭83‬


‭Table 24: List of administered dates Nivolumab (Maitenance Phase)‬
‭Patient‬
‭Number‬
‭1‬
‭2‬
‭3‬
‭4‬
‭5‬
‭6‬
‭7‬
‭8‬
‭9‬
‭10‬
‭11‬
‭12‬
‭13‬
‭14‬
‭15‬
‭16‬
‭17‬
‭18‬
‭19‬
‭20‬
‭21‬
‭22‬
‭23‬
‭24‬
‭25‬
‭26‬
‭27‬
‭Page‬‭31‬‭of‬‭83‬


‭4.3.‬ ‭T‬‭OTAL‬‭DURATION‬‭OF‬‭TREATMENT‬‭WITH‬‭N‬‭IVOLUMAB‬
‭Overall‬
‭Overall (N=)‬
‭Time duration of Nivolumab Induction + Maintenance (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭4.4.‬ ‭C‬‭YCLES‬‭ADMINISTERED‬‭AFTER‬‭PROGRESSION‬
‭Table 25: Cycles administered after progression‬
‭Nivolumab (N=)‬
‭Cycles after progression Nivolumab (Maintenance phase)‬
‭Yes‬
‭No‬
‭Number of cycles after progression Nivolumab (Maintenance phase)‬
‭0‬
‭1‬
‭2‬
‭Number of cycles after progression Nivolumab (Maintenance phase)‬
‭N‬
‭Mean (95%CI)‬
‭SD‬
‭Median (95%CI)‬
‭Range‬
‭Page‬‭32‬‭of‬‭83‬


‭4.5.‬ ‭END OF TREATMENT - END OF STUDY -‬
‭FOLLOW-UP‬
‭4.5.1.‬‭E‬‭ND‬‭OF‬‭TREATMENT‬
‭Table 26: End of Treatment reasons‬
‭Overall‬
‭Overall (N=)‬
‭Reason for End Of Treatment‬
‭   Progression‬
‭   Unnacceptable toxicity‬
‭   Investigator decision‬
‭   Study treatment completion‬
‭   Other‬
‭Other reason for End Of Treatment‬
‭specified‬
‭   Clinical impairment and death‬
‭   Death‬
‭   Esophageal mucositis‬
‭   Not applicable‬
‭   Not specified‬
‭4.5.2.‬‭E‬‭ND‬‭OF‬‭S‬‭TUDY‬
‭Table 27: End of Study reasons‬
‭Overall‬
‭Overall (N=)‬
‭Reason for End Of Study‬
‭   Lost of follow-up‬
‭   Exitus‬
‭   Others‬
‭Other reason for End Of Study‬
‭specified‬
‭   End of study‬
‭   Not applicable‬
‭Page‬‭33‬‭of‬‭83‬


‭4.5.3.‬‭F‬‭OLLOW‬‭-‬‭UP‬‭(‬‭ALL‬‭PATIENTS‬‭)‬
‭Table 28: Median follow-up (all patients)‬
‭Overall‬
‭Overall (N=)‬
‭Time since treatment started (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Time since treatment started (months) [> 24 months of‬
‭follow-up]‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭4.5.4.‬‭F‬‭OLLOW‬‭-‬‭UP‬‭(‬‭ONLY‬‭ALIVE‬‭PATIENTS‬‭)‬
‭Table 29: Median follow-up (only alive patients)‬
‭Overall‬
‭Overall (N=)‬
‭Time since treatment started (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Time since treatment started (months) [> 24 months of‬
‭follow-up]‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Page‬‭34‬‭of‬‭83‬


‭The‬ ‭efficacy‬ ‭analyses‬ ‭are‬ ‭reported‬ ‭in‬ ‭those‬ ‭patients‬ ‭belonging‬ ‭to‬ ‭the‬
‭response population as defined previously (n=).‬
‭4.6.‬ ‭PRIMARY ENDPOINT: OVERALL SURVIVAL (OS)‬
‭As‬ ‭specified‬ ‭in‬ ‭the‬ ‭protocol‬ ‭the‬ ‭Primary‬ ‭endpoint‬ ‭is‬ ‭one‬ ‭year‬ ‭OS‬ ‭rate‬ ‭with‬
‭nivolumab‬ ‭plus‬ ‭chemotherapy.‬ ‭This‬ ‭is‬ ‭defined‬ ‭as‬ ‭the‬ ‭proportion‬ ‭of‬‭patients‬‭that‬
‭remain‬‭alive‬‭at‬‭12‬‭months‬‭since‬‭the‬‭beginning‬‭of‬‭treatment.‬‭OS‬‭will‬‭be‬‭censored‬‭on‬
‭the last date a participant was known to be alive.‬
‭Table 30: Events type OS‬
‭OS‬
‭N‬
‭%‬
‭95%CI‬
‭Alive‬
‭Death‬
‭Total‬
‭Reason of death‬
‭N‬
‭%‬
‭95%CI‬
‭Clinical deterioration‬
‭Clinical worsening.‬
‭Not applicable‬
‭Progression disease‬
‭Sepsis‬
‭Unknown‬
‭Total‬
‭Table 31: Median/mean OS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Overall survival‬
‭Table 32: OS estimated survival ratio‬
‭OS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 6 months‬
‭At 12 months‬
‭At 18 months‬
‭At 24 months‬
‭At 30 months‬
‭At 36 months‬
‭Page‬‭35‬‭of‬‭83‬


‭Figure 1: Overall survival‬
‭Page‬‭36‬‭of‬‭83‬


‭4.7.‬ ‭SECONDARY ENDPOINTS‬
‭4.7.1.‬‭PROGRESSION FREE SURVIVAL (PFS)‬
‭As‬‭specified‬‭in‬‭the‬‭protocol‬‭PFS‬‭is‬‭defined‬‭as‬‭the‬‭time‬‭from‬‭the‬‭enrollment‬‭date‬‭to‬
‭the‬‭date‬‭of‬‭the‬‭first‬‭documented‬‭tumor‬‭progression‬‭per‬‭RECIST‬‭1.1,‬‭or‬‭death‬‭due‬
‭to‬‭any‬‭cause.‬‭Participants‬‭who‬‭did‬‭not‬‭progress‬‭or‬‭die‬‭will‬‭be‬‭censored‬‭on‬‭the‬‭date‬
‭of‬ ‭their‬ ‭last‬ ‭evaluable‬ ‭tumor‬ ‭assessment.‬ ‭Participants‬ ‭who‬ ‭did‬‭not‬‭have‬‭any‬‭on‬
‭study‬‭tumor‬‭assessments‬‭will‬‭be‬‭censored‬‭on‬‭the‬‭beginning‬‭of‬‭treatment‬‭date.‬‭PFS‬
‭curves,‬‭PFS‬‭medians‬‭with‬‭95%‬‭CIs,‬‭and‬‭PFS‬‭rates‬‭at‬‭6,‬‭12,‬‭18,‬‭24,‬‭36,‬‭and‬‭48‬
‭months‬ ‭with‬ ‭95%‬ ‭CIs‬ ‭will‬ ‭be‬ ‭estimated‬ ‭using‬ ‭Kaplan-Meier‬ ‭methodology‬ ‭if‬
‭follow-up requirements are met.‬
‭4.7.2.‬‭E‬‭VENTS‬‭: P‬‭ROGRESSIONS‬‭/D‬‭EATHS‬
‭Table 33: Events type PFS‬
‭PFS (PD REcist 1.1 or Death)‬
‭N‬
‭%‬
‭95%CI‬
‭No‬
‭PD (Recist 1.1)‬
‭Death (without previous PD)‬
‭Total‬
‭Table 34: Median/mean PFS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Progression free survival‬
‭Table 35: PFS estimated survival ratio‬
‭PFS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 6 months‬
‭At 12 months‬
‭At 18 months‬
‭At 24 months‬
‭At 30 months‬
‭At 36 months‬
‭Page‬‭37‬‭of‬‭83‬


‭Figure 2: Progression free survival‬
‭Page‬‭38‬‭of‬‭83‬


‭4.7.3.‬‭ORR: O‬‭BJECTIVE‬‭R‬‭ESPONSE‬‭R‬‭ATE‬
‭BOR‬‭and‬‭ORR‬‭are determined based on RECIST 1.1.‬
‭4.7.4.‬‭B‬‭EST‬‭O‬‭VERALL‬‭R‬‭ESPONSE‬
‭Table 36: ORR‬
‭Overall Response Rate‬
‭N‬
‭%‬
‭95%CI‬
‭PR‬
‭SD‬
‭PD‬
‭NE‬
‭Total‬
‭Table 37: BOR: Best Overall Response‬
‭Overall‬
‭Overall (N=)‬
‭Best Overall‬
‭Response‬
‭   PR‬
‭   SD‬
‭   PD‬
‭   NE‬
‭+‬‭The X patients with‬‭NE‬‭had XXX‬
‭4.7.5.‬‭D‬‭URATION‬‭OF‬‭R‬‭ESPONSE‬
‭The‬‭duration‬‭of‬‭response‬‭is‬‭calculated‬‭in‬‭those‬‭patients‬‭with‬‭Best‬‭Response‬‭CR‬‭or‬
‭PR.‬
‭Table 38: BOR: Best Overall Response‬
‭Overall‬
‭Overall (N=)‬
‭Duration of response‬
‭(months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭4.7.5.1.‬
‭F‬‭IGURE‬‭: W‬‭ATERFALL‬‭PLOT‬‭. M‬‭AXIMUM‬‭%‬‭TOTAL‬‭CHANGE‬‭WITH‬‭BOR‬
‭Page‬‭39‬‭of‬‭83‬


‭4.7.5.2‬
‭FIGURE: WATERFALL PLOT. MAXIMUM % TOTAL‬
‭CHANGE VS BOR‬
‭4.7.5.3‬
‭FIGURE: WATERFALL PLOT. MAXIMUM % TOTAL‬
‭CHANGE VS PRIMARY LOCATION‬
‭4.7.5.4‬
‭FIGURE: WATERFALL PLOT. MAXIMUM % TOTAL‬
‭CHANGE VS KI67‬
‭4.7.5.4‬
‭FIGURE: WATERFALL PLOT. MAXIMUM % TOTAL‬
‭CHANGE VS DIFFERENTATION TUMOUR‬
‭4.7.5.2.‬
‭FIGURE: SPIDER PLOT. MAXIMUM % TOTAL CHANGE‬
‭Page‬‭40‬‭of‬‭83‬


‭4.7.5.5‬
‭F‬‭IGURE‬‭: S‬‭PIDER‬‭PLOT‬‭. M‬‭AXIMUM‬‭%‬‭TOTAL‬‭CHANGE‬‭VS DIFFERENTIATION‬
‭4.7.5.6‬
‭F‬‭IGURE‬‭: S‬‭PIDER‬‭PLOT‬‭. M‬‭AXIMUM‬‭%‬‭TOTAL‬‭CHANGE‬‭VS BOR‬
‭4.7.5.7‬
‭F‬‭IGURE‬‭: S‬‭PIDER‬‭PLOT‬‭. M‬‭AXIMUM‬‭%‬‭TOTAL‬‭CHANGE‬‭VS CGA‬
‭4.7.5.8‬
‭F‬‭IGURE‬‭: S‬‭PIDER‬‭PLOT‬‭. M‬‭AXIMUM‬‭%‬‭TOTAL‬‭CHANGE‬‭VS NSE‬
‭4.8.‬ ‭OS STRATIFIED BY FACTORS OF INTEREST:‬
‭DIFFERENTIATED/ K‬‭I‬‭67/ PRIMARY TUMOUR‬
‭LOCATION / CGA / NSE‬
‭4.8.1.‬‭OS‬‭VS‬‭D‬‭IFFERENTIATION‬
‭Two groups are defined (as reported in eCRD): Well and Poorly differientated‬
‭Table 39: OS vs Differentiation: Median estimation‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Well differentiated‬
‭Poorly differentiated‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭2‬‭Log rank test to compare categories: p-value=X‬
‭Table 40: OS vs Differentiation: Survival ratio estimation‬
‭SG‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭Well differentiated‬
‭At 6 months‬
‭At 12 months‬
‭Poorly‬
‭differentiated‬
‭At 6 months‬
‭At 12 months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭4.8.1.1.‬
‭F‬‭IGURE‬‭: OS‬‭VS‬‭D‬‭IFFERENTIATION‬‭. K‬‭APLAN‬‭M‬‭EIER‬‭GRAPH‬
‭Page‬‭41‬‭of‬‭83‬


‭4.8.2.‬‭OS‬‭VS‬‭K‬‭I‬‭67‬
‭Two groups are defined from the Ki67 values recorded at the eCRF:‬
‭55 and >55‬
≤
‭Table 41: OS vs Ki67: Median estimation‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Ki67<=55‬
‭Ki67>55‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭2‬‭Log rank test to compare categories: p-value=X‬
‭Table 42: OS vs Ki67: Survival ratio estimation‬
‭SG‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭Ki67<=55‬
‭At 6 months‬
‭At 12‬
‭months‬
‭Ki67>55‬
‭At 6 months‬
‭At 12‬
‭months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭4.8.2.1.‬
‭F‬‭IGURE‬‭: OS‬‭VS‬‭K‬‭I‬‭67. K‬‭APLAN‬‭M‬‭EIER‬‭GRAPH‬
‭Page‬‭42‬‭of‬‭83‬


‭4.8.3.‬‭OS‬‭VS‬‭L‬‭OCATION‬
‭Six‬
‭groups‬
‭are‬
‭defined‬
‭from‬
‭the‬
‭Location‬
‭recorded‬
‭at‬
‭the‬
‭eCRF:‬
‭Esophagus/Gastric,‬
‭Pancreas,‬
‭Colon/Rectum,‬
‭Duodenum/Ileum‬
‭and‬
‭Not‬
‭specified/Others.‬
‭Table 43: OS vs Location: Median estimation‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Duodenum/Ileum‬
‭Esophagus/Gastric‬
‭Pancreas‬
‭Colon/Rectum‬
‭Not specified/Others‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭2‬‭Log rank test to compare categories: p-value=X‬
‭Table 44: OS vs Location Survival ratio estimation‬
‭SG‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭Duodenum/Ileum‬
‭At 6 months‬
‭At 12 months‬
‭Esophagus/Gastri‬
‭c‬
‭At 6 months‬
‭At 12 months‬
‭Pancreas‬
‭At 6 months‬
‭At 12 months‬
‭Colon/Rectum‬
‭At 6 months‬
‭At 12 months‬
‭Not‬
‭specified/Others‬
‭At 6 months‬
‭At 12 months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭4.8.3.1.‬
‭F‬‭IGURE‬‭: OS‬‭VS‬‭L‬‭OCATION‬‭. K‬‭APLAN‬‭M‬‭EIER‬‭GRAPH‬
‭Page‬‭43‬‭of‬‭83‬


‭4.8.4.‬‭OS‬‭VS‬‭CGA‬
‭Two‬‭groups‬‭are‬‭defined‬‭from‬‭the‬‭CGA‬‭recorded‬‭at‬‭the‬‭eCRF:‬‭CGA‬‭<‬‭2*‬‭ULN‬‭and‬
‭CGA >= 2*‬‭ULN.‬
‭Table 45: OS vs CGA: Median estimation‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭CGA < 2*ULN‬
‭CGA >= 2*ULN‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭2‬‭Log rank test to compare categories: p-value=X‬
‭Table 46: OS vs CGA Survival ratio estimation‬
‭SG‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭CGA < 2*ULN‬
‭At 6 months‬
‭At 12 months‬
‭CGA >=‬
‭2*ULN‬
‭At 6 months‬
‭At 12 months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭4.8.4.1.‬
‭F‬‭IGURE‬‭: OS‬‭VS‬‭CGA K‬‭APLAN‬‭M‬‭EIER‬‭GRAPH‬
‭Page‬‭44‬‭of‬‭83‬


‭4.8.5.‬‭OS‬‭VS‬‭NSE‬
‭Two‬‭groups‬‭are‬‭defined‬‭from‬‭the‬‭Location‬‭recorded‬‭at‬‭the‬‭eCRF:‬‭NSE‬‭<‬‭2*ULN,‬
‭NSE >= 2*ULN‬
‭Table 47: OS vs NSE: Median estimation‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭NSE < 2*ULN‬
‭NSE >= 2*ULN‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭2‬‭Log rank test to compare categories: p-value=X‬
‭Table 48: OS vs NSE Survival ratio estimation‬
‭SG‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭NSE < 2*ULN‬
‭At 6 months‬
‭At 12 months‬
‭NSE >=‬
‭2*ULN‬
‭At 6 months‬
‭At 12 months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭4.8.5.1.‬
‭F‬‭IGURE‬‭: OS‬‭VS‬‭NSE K‬‭APLAN‬‭M‬‭EIER‬‭GRAPH‬
‭Page‬‭45‬‭of‬‭83‬


‭4.9.‬ ‭PFS STRATIFIED BY FACTORS OF INTEREST:‬
‭DIFFERENTIATED/ K‬‭I‬‭67/ PRIMARY TUMOUR‬
‭LOCATION / CGA / ENOLASE‬
‭4.9.1.‬‭PFS‬‭VS‬‭D‬‭IFFERENTIATION‬
‭Two groups are defined (as reported in eCRD): Well and Poorly differentiated‬
‭Table 49: PFS vs Differentiation: Median estimation‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Well differentiated‬
‭Poorly differentiated‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭2‬‭Log rank test to compare categories: p-value=X‬
‭Table 50: PFS vs Differentiation: Survival ratio estimation‬
‭SG‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭Well differentiated‬
‭At 6 months‬
‭At 12 months‬
‭Poorly‬
‭differentiated‬
‭At 6 months‬
‭At 12 months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭4.9.1.1.‬
‭F‬‭IGURE‬‭: PFS‬‭VS‬‭D‬‭IFFERENTIATION‬‭. K‬‭APLAN‬‭M‬‭EIER‬‭GRAPH‬
‭Page‬‭46‬‭of‬‭83‬


‭4.9.2.‬‭PFS‬‭VS‬‭K‬‭I‬‭67‬
‭Two groups are defined from the Ki67 values recorded at the eCRF: <=55 and >55‬
‭Table 51: PFS vs Ki67: Median estimation‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Ki67<=55‬
‭Ki67>55‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭2‬‭Log rank test to compare categories: p-value=X‬
‭Table 52: PFS vs Ki67: Survival ratio estimation‬
‭SG‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭Ki67<=55‬
‭At 6 months‬
‭At 12‬
‭months‬
‭Ki67>55‬
‭At 6 months‬
‭At 12‬
‭months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭4.9.2.1.‬
‭F‬‭IGURE‬‭: PFS‬‭VS‬‭K‬‭I‬‭67. K‬‭APLAN‬‭M‬‭EIER‬‭GRAPH‬
‭Page‬‭47‬‭of‬‭83‬


‭4.9.3.‬‭PFS‬‭VS‬‭L‬‭OCATION‬
‭Six‬
‭groups‬
‭are‬
‭defined‬
‭from‬
‭the‬
‭Location‬
‭recorded‬
‭at‬
‭the‬
‭eCRF:‬
‭Esophagus/Gastric,‬
‭Pancreas,‬
‭Colon/Rectum,‬
‭Duodenum/Ileum‬
‭and‬
‭Not‬
‭specified/Others.‬
‭Table 53: PFS vs Location: Median estimation‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Duodenum/Ileum‬
‭Esophagus/Gastric‬
‭Pancreas‬
‭Colon/Rectum‬
‭Not specified/Others‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭2‬‭Log rank test to compare categories: p-value= X‬
‭Table 54: PFS vs Location Survival ratio estimation‬
‭SG‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭Duodenum/Ileum‬
‭At 6 months‬
‭At 12 months‬
‭Esophagus/Gastri‬
‭c‬
‭At 6 months‬
‭At 12 months‬
‭Pancreas‬
‭At 6 months‬
‭At 12 months‬
‭Colon/Rectum‬
‭At 6 months‬
‭At 12 months‬
‭Not‬
‭specified/Others‬
‭At 6 months‬
‭At 12 months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭4.9.3.1.‬
‭F‬‭IGURE‬‭: PFS‬‭VS‬‭L‬‭OCATION‬‭. K‬‭APLAN‬‭M‬‭EIER‬‭GRAPH‬
‭Page‬‭48‬‭of‬‭83‬


‭4.9.4.‬‭PFS‬‭VS‬‭CGA‬
‭4.9.4.1.‬
‭PFS‬‭VS‬‭CGA (2)‬
‭Two‬‭groups‬‭are‬‭defined‬‭from‬‭the‬‭CGA‬‭at‬‭the‬‭eCRF:‬‭CGA‬‭<‬‭2*ULN‬‭and‬‭CGA‬‭>=‬
‭2*ULN.‬
‭Table 55: PFS vs CGA: Median estimation‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭CGA < 2*ULN‬
‭CGA >= 2*ULN‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭2‬‭Log rank test to compare categories: p-value=X‬
‭Table 56: PFS vs CGA: Survival ratio estimation‬
‭SG‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭CGA < 2*ULN‬
‭At 6 months‬
‭At 12 months‬
‭CGA >=‬
‭2*ULN‬
‭At 6 months‬
‭At 12 months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭4.9.4.2.‬
‭F‬‭IGURE‬‭: PFS‬‭VS‬‭CGA K‬‭APLAN‬‭M‬‭EIER‬‭GRAPH‬‭(2)‬
‭Page‬‭49‬‭of‬‭83‬


‭4.9.4.3.‬
‭PFS‬‭VS‬‭CGA (3)‬
‭Two‬‭groups‬‭are‬‭defined‬‭from‬‭the‬‭CGA‬‭at‬‭the‬‭eCRF:‬‭CGA‬‭<‬‭3‬‭ULN‬‭and‬‭CGA‬‭>=‬‭3‬
·
·
‭ULN.‬
‭Table 57: PFS vs CGA: Median estimation‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭CGA < 3*ULN‬
‭CGA >= 3*ULN‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭2‬‭Log rank test to compare categories: p-value=X‬
‭Table 58: PFS vs CGA: Survival ratio estimation‬
‭SG‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭CGA < 3*ULN‬
‭At 6 months‬
‭At 12 months‬
‭CGA >=‬
‭3*ULN‬
‭At 6 months‬
‭At 12 months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭4.9.4.4.‬
‭F‬‭IGURE‬‭: PFS‬‭VS‬‭CGA K‬‭APLAN‬‭M‬‭EIER‬‭GRAPH‬‭(3)‬
‭Page‬‭50‬‭of‬‭83‬


‭4.9.4.5.‬
‭PFS‬‭VS‬‭CGA (5)‬
‭Two‬‭groups‬‭are‬‭defined‬‭from‬‭the‬‭CGA‬‭at‬‭the‬‭eCRF:‬‭CGA‬‭<‬‭5*ULN‬‭and‬‭CGA‬‭>=‬
‭5*ULN.‬
‭Table 59: PFS vs CGA: Median estimation‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭CGA < 5*ULN‬
‭CGA >= 5*ULN‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭2‬‭Log rank test to compare categories: p-value=X‬
‭Table 60: PFS vs CGA: Survival ratio estimation‬
‭SG‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭CGA < 5*ULN‬
‭At 6 months‬
‭At 12 months‬
‭CGA >=‬
‭5*ULN‬
‭At 6 months‬
‭At 12 months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭4.9.4.6.‬
‭F‬‭IGURE‬‭: PFS‬‭VS‬‭CGA K‬‭APLAN‬‭M‬‭EIER‬‭GRAPH‬‭(5)‬
‭Page‬‭51‬‭of‬‭83‬


‭4.9.5.‬‭PFS‬‭VS‬‭E‬‭NOLASE‬
‭Two‬ ‭groups‬ ‭are‬ ‭defined‬ ‭from‬ ‭the‬ ‭Enolase‬ ‭values:‬ ‭NSE‬ ‭<‬ ‭2*ULN‬ ‭and‬ ‭NSE‬ ‭>=‬
‭2*ULN‬
‭Table 61: PFS vs Enolase: Median estimation‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭NSE < 2*ULN‬
‭NSE >= 2*ULN‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭2‬‭Log rank test to compare categories: p-value=X‬
‭Table 62: PFS vs NSE: Survival ratio estimation‬
‭SG‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭NSE < 2*ULN‬
‭At 6 months‬
‭At 12 months‬
‭NSE >=‬
‭2*ULN‬
‭At 6 months‬
‭At 12 months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭4.9.5.1.‬
‭F‬‭IGURE‬‭: PFS‬‭VS‬‭NSE K‬‭APLAN‬‭M‬‭EIER‬‭GRAPH‬
‭Page‬‭52‬‭of‬‭83‬


‭4.10.‬‭ORR STRATIFIED BY FACTORS OF INTEREST:‬
‭DIFFERENTIATED/ K‬‭I‬‭67/ PRIMARY TUMOUR‬
‭LOCATION / CGA / NSE‬
‭Table 63: ORR vs Differentiation‬
‭Well differentiated‬
‭(N=)‬
‭Poorly differentiated‬
‭(N=)‬
‭Total (N=)‬
‭p‬
‭value‬
‭Best Overall Response‬
‭   PR‬
‭   SD‬
‭   PD‬
‭   NE‬
‭Objective Response Rate‬
‭(ORR): CR or PR (BOR)‬
‭   Yes (CR/PR)‬
‭   No‬
‭1.‬
‭Fisher’s Exact Test for Count Data‬
‭2.‬
‭Pearson’s Chi-squared test‬
‭Page‬‭53‬‭of‬‭83‬


‭Table 64: ORR vs Ki67‬
‭<=55 (N=)‬
‭>55 (N=)‬
‭Total (N=)‬
‭p‬
‭value‬
‭Best Overall Response‬
‭   PR‬
‭   SD‬
‭   PD‬
‭   NE‬
‭Objective Response Rate (ORR): CR or PR‬
‭(BOR)‬
‭   Yes (CR/PR)‬
‭   No‬
‭1.‬
‭Fisher’s Exact Test for Count Data‬
‭2.‬
‭Pearson’s Chi-squared test‬
‭Page‬‭54‬‭of‬‭83‬


‭Table 65: ORR vs Location‬
‭Esophagus/‬
‭Gastric (N=)‬
‭Pancrea‬
‭s (N=)‬
‭Colon/Rectu‬
‭m (N=)‬
‭Duodenum/‬
‭Ileum (N=)‬
‭Not‬
‭specified/Others‬
‭(N=)‬
‭Total (N=)‬
‭p‬
‭value‬
‭BOR‬
‭   PR‬
‭   SD‬
‭   PD‬
‭   NE‬
‭Objective Response Rate‬
‭(ORR): CR or PR (BOR)‬
‭   Yes (CR/PR)‬
‭   No‬
‭1.‬
‭Fisher’s Exact Test for Count Data‬
‭Table 66: ORR vs Location‬
‭Colon/Rectum‬
‭(N=)‬
‭Others‬
‭(N=)‬
‭Total (N=)‬
‭p‬
‭value‬
‭Best Overall Response‬
‭   PR‬
‭   SD‬
‭   PD‬
‭   NE‬
‭Objective Response Rate (ORR): CR‬
‭or PR (BOR)‬
‭   Yes (CR/PR)‬
‭   No‬
‭1.‬
‭Fisher’s Exact Test for Count Data‬
‭Page‬‭55‬‭of‬‭83‬


‭Table 67: ORR vs CGA‬
‭CGA < 2*ULN‬
‭(N=)‬
‭CGA >= 2*ULN‬
‭(N=)‬
‭Total (N=)‬
‭p‬
‭value‬
‭Best Overall Response‬
‭   PR‬
‭   SD‬
‭   PD‬
‭   NE‬
‭Objective Response Rate (ORR):‬
‭CR or PR (BOR)‬
‭   Yes (CR/PR)‬
‭   No‬
‭1.‬
‭Fisher’s Exact Test for Count Data‬
‭2.‬
‭Pearson’s Chi-squared test‬
‭Table 68: ORR vs Enolase‬
‭NSE < 2*ULN‬
‭(N=)‬
‭NSE >= 2*ULN‬
‭(N=)‬
‭Total (N=)‬
‭p‬
‭value‬
‭Best Overall Response‬
‭   PR‬
‭   SD‬
‭   PD‬
‭   NE‬
‭Objective Response Rate (ORR):‬
‭CR or PR (BOR)‬
‭   Yes (CR/PR)‬
‭   No‬
‭1.‬
‭Fisher’s Exact Test for Count Data‬
‭2.‬
‭Pearson’s Chi-squared test‬
‭Page‬‭56‬‭of‬‭83‬


‭4.10.1.‬
‭MULTIVARIATE ANALYSIS OF PFS AND OS‬
‭4.10.1.1.‬
‭F‬‭ACTORS‬‭INCLUDED‬‭IN‬‭THE‬‭MULTIVARIATE‬‭ANALYSIS‬‭OF‬‭THE‬‭PFS (1)‬
‭Table 69: Factors included in the multivariate analysis of the PFS‬
‭PD/Exitus‬
‭No (N=)‬
‭Yes (N=)‬
‭Total (N=)‬
‭p value‬
‭CGA <> 2 x ULN‬
‭   Missing data‬
‭   CGA < 2*ULN‬
‭   CGA >= 2*ULN‬
‭Enolase <> 2 x ULN‬
‭   Missing data‬
‭   NSE < 2*ULN‬
‭   NSE >= 2*ULN‬
‭Primary neuroendocrine tumour‬
‭   Duodenum/Ileum‬
‭   Esophagus/Gastric‬
‭   Pancreas‬
‭   Colon/Rectum‬
‭   Not specified/Others‬
‭Differentiation‬
‭   Well differentiated‬
‭   Poorly differentiated‬
‭Ki-67 categorised‬
‭   <=55‬
‭   >55‬
‭ECOG‬
‭   0‬
‭   1‬
‭   2‬
‭Gender‬
‭   Female‬
‭   Male‬
‭Age categorised by median (61 years)‬
‭   <=61y‬
‭   >61y‬
‭LDH‬
‭   <= 2ULN‬
‭   > 2ULN‬
‭1.‬
‭Fisher’s Exact Test for Count Data‬
‭Page‬‭57‬‭of‬‭83‬


‭Table 70: PFS univariate and multivariate Cox model‬
‭Univariate Cox Regression‬
‭Multivariate Cox Regression‬
‭Characteristic‬
‭N‬
‭Event N‬
‭HR‬‭1‬
‭95% CI‬‭1‬
‭p-value‬
‭N‬
‭Event N‬
‭HR‬‭1‬
‭95% CI‬‭1‬
‭p-value‬
‭CGA <> 2 x ULN‬
‭CGA < 2*ULN‬
‭CGA >= 2*ULN‬
‭Enolase <> 2 x ULN‬
‭NSE < 2*ULN‬
‭NSE >= 2*ULN‬
‭Primary neuroendocrine tumour‬
‭Duodenum/Ileum‬
‭Esophagus/Gastric‬
‭Pancreas‬
‭Colon/Rectum‬
‭Not specified/Others‬
‭Differentiation‬
‭Well differentiated‬
‭Poorly differentiated‬
‭Ki-67 categorised‬
‭<=55‬
‭>55‬
‭ECOG‬
‭0‬
‭1‬
‭2‬
‭Gender‬
‭Female‬
‭Male‬
‭Age categorised by median (61 years)‬
‭<=61y‬
‭>61y‬
‭LDH‬
‭<= 2ULN‬
‭Page‬‭58‬‭of‬‭83‬


‭Univariate Cox Regression‬
‭Multivariate Cox Regression‬
‭Characteristic‬
‭N‬
‭Event N‬
‭HR‬‭1‬
‭95% CI‬‭1‬
‭p-value‬
‭N‬
‭Event N‬
‭HR‬‭1‬
‭95% CI‬‭1‬
‭p-value‬
‭> 2ULN‬
‭1‬‭HR = Hazard Ratio, CI = Confidence Interval‬
‭Note:‬‭Los p-valores marcados en negrita indican que‬‭el valor es estadísticamente significativo <0.05‬
‭Page‬‭59‬‭of‬‭83‬


‭Figure 3: Forest plot PFS Multivariate Cox Regression‬
‭Page‬‭60‬‭of‬‭83‬


‭4.10.1.2.‬
‭F‬‭ACTORS‬‭INCLUDED‬‭IN‬‭THE‬‭MULTIVARIATE‬‭ANALYSIS‬‭OF‬‭THE‬‭PFS (2)‬
‭Table 71: Factors included in the multivariate analysis of the PFS‬
‭PD/Exitus‬
‭No (N=)‬
‭Yes (N=)‬
‭Total (N=)‬
‭p value‬
‭CGA <> 2 x ULN‬
‭   Missing data‬
‭   CGA < 2*ULN‬
‭   CGA >= 2*ULN‬
‭Enolase <> 2 x ULN‬
‭   Missing data‬
‭   NSE < 2*ULN‬
‭   NSE >= 2*ULN‬
‭Primary neuroendocrine tumour‬
‭   Colon/Rectum‬
‭   Others‬
‭Differentiation‬
‭   Well differentiated‬
‭   Poorly differentiated‬
‭Ki-67 categorised‬
‭   <=55‬
‭   >55‬
‭ECOG‬
‭   0‬
‭   1‬
‭   2‬
‭Gender‬
‭   Female‬
‭   Male‬
‭Age categorised by median (x years)‬
‭   <=xy‬
‭   >xy‬
‭LDH‬
‭   <= 2ULN‬
‭   > 2ULN‬
‭1.‬
‭Fisher’s Exact Test for Count Data‬
‭Page‬‭61‬‭of‬‭83‬


‭Table 72: PFS univariate and multivariate Cox model‬
‭Univariate Cox Regression‬
‭Multivariate Cox Regression‬
‭Characteristic‬
‭N‬
‭Event N‬
‭HR‬‭1‬
‭95% CI‬‭1‬
‭p-value‬
‭N‬
‭Event N‬
‭HR‬‭1‬
‭95% CI‬‭1‬
‭p-value‬
‭CGA <> 2 x ULN‬
‭CGA < 2*ULN‬
‭CGA >= 2*ULN‬
‭Enolase <> 2 x ULN‬
‭NSE < 2*ULN‬
‭NSE >= 2*ULN‬
‭Primary neuroendocrine tumour‬
‭Colon/Rectum‬
‭Others‬
‭Differentiation‬
‭Well differentiated‬
‭Poorly differentiated‬
‭Ki-67 categorised‬
‭<=55‬
‭>55‬
‭ECOG‬
‭0‬
‭1‬
‭2‬
‭Gender‬
‭Female‬
‭Male‬
‭Age categorised by median (x years)‬
‭<=61y‬
‭>61y‬
‭LDH‬
‭<= 2ULN‬
‭> 2ULN‬
‭1‬‭HR = Hazard Ratio, CI = Confidence Interval‬
‭Page‬‭62‬‭of‬‭83‬


‭Note:‬‭Los p-valores marcados en negrita indican que el valor es estadísticamente significativo <0.05‬
‭Page‬‭63‬‭of‬‭83‬


‭Figure 4: Forest plot PFS Multivariate Cox Regression‬
‭Page‬‭64‬‭of‬‭83‬


‭4.10.1.3.‬
‭F‬‭ACTORS‬‭INCLUDED‬‭IN‬‭THE‬‭MULTIVARIATE‬‭ANALYSIS‬‭OF‬‭THE‬‭OS (1)‬
‭Table 73: Factors included in the multivariate analysis of the OS‬
‭OS‬
‭Alive (N=)‬
‭Death (N=)‬
‭Total (N=)‬
‭p value‬
‭CGA <> 2 x ULN‬
‭   Missing data‬
‭   CGA < 2*ULN‬
‭   CGA >= 2*ULN‬
‭Enolase <> 2 x ULN‬
‭   Missing data‬
‭   NSE < 2*ULN‬
‭   NSE >= 2*ULN‬
‭Primary neuroendocrine tumour‬
‭   Duodenum/Ileum‬
‭   Esophagus/Gastric‬
‭   Pancreas‬
‭   Colon/Rectum‬
‭   Not specified/Others‬
‭Differentiation‬
‭   Well differentiated‬
‭   Poorly differentiated‬
‭Ki-67 categorised‬
‭   <=55‬
‭   >55‬
‭ECOG‬
‭   0‬
‭   1‬
‭   2‬
‭Gender‬
‭   Female‬
‭   Male‬
‭Age categorised by median (x years)‬
‭   <=61y‬
‭   >61y‬
‭LDH‬
‭Page‬‭65‬‭of‬‭83‬


‭OS‬
‭Alive (N=)‬
‭Death (N=)‬
‭Total (N=)‬
‭p value‬
‭   <= 2ULN‬
‭   > 2ULN‬
‭1.‬
‭Fisher’s Exact Test for Count Data‬
‭2.‬
‭Pearson’s Chi-squared test‬
‭Page‬‭66‬‭of‬‭83‬


‭Table 74: OS univariate and multivariate Cox model‬
‭Univariate Cox Regression‬
‭Multivariate Cox Regression‬
‭Characteristic‬
‭N‬
‭Event‬
‭N‬
‭HR‬‭1‬
‭95% CI‬‭1‬
‭p-valu‬
‭e‬
‭N‬
‭Event‬
‭N‬
‭HR‬‭1‬
‭95% CI‬‭1‬
‭p-valu‬
‭e‬
‭CGA <> 2 x ULN‬
‭CGA < 2*ULN‬
‭CGA >= 2*ULN‬
‭Enolase <> 2 x ULN‬
‭NSE < 2*ULN‬
‭NSE >= 2*ULN‬
‭Primary neuroendocrine tumour‬
‭Duodenum/Ileum‬
‭Esophagus/Gastric‬
‭Pancreas‬
‭Colon/Rectum‬
‭Not specified/Others‬
‭Differentiation‬
‭Well differentiated‬
‭Poorly differentiated‬
‭Ki-67 categorised‬
‭<=55‬
‭>55‬
‭ECOG‬
‭0‬
‭1‬
‭2‬
‭Gender‬
‭Female‬
‭Male‬
‭Age categorised by median (x years)‬
‭<=61y‬
‭>61y‬
‭LDH‬
‭Page‬‭67‬‭of‬‭83‬


‭Univariate Cox Regression‬
‭Multivariate Cox Regression‬
‭Characteristic‬
‭N‬
‭Event‬
‭N‬
‭HR‬‭1‬
‭95% CI‬‭1‬
‭p-valu‬
‭e‬
‭N‬
‭Event‬
‭N‬
‭HR‬‭1‬
‭95% CI‬‭1‬
‭p-valu‬
‭e‬
‭<= 2ULN‬
‭> 2ULN‬
‭1‬‭HR = Hazard Ratio, CI = Confidence Interval‬
‭Note:‬‭Los p-valores marcados en negrita indican que el valor es estadísticamente significativo <0.05‬
‭Page‬‭68‬‭of‬‭83‬


‭Figure 5: Forest plot OS Multivariate Cox Regression‬
‭Page‬‭69‬‭of‬‭83‬


‭4.10.1.4.‬
‭F‬‭ACTORS‬‭INCLUDED‬‭IN‬‭THE‬‭MULTIVARIATE‬‭ANALYSIS‬‭OF‬‭THE‬‭OS (2)‬
‭Table 75: Factors included in the multivariate analysis of the OS‬
‭OS‬
‭Alive (N=)‬
‭Death (N=)‬
‭Total (N=)‬
‭p value‬
‭CGA <> 2 x ULN‬
‭   Missing data‬
‭   CGA < 2*ULN‬
‭   CGA >= 2*ULN‬
‭Enolase <> 2 x ULN‬
‭   Missing data‬
‭   NSE < 2*ULN‬
‭   NSE >= 2*ULN‬
‭Primary neuroendocrine tumour‬
‭   Colon/Rectum‬
‭   Others‬
‭Differentiation‬
‭   Well differentiated‬
‭   Poorly differentiated‬
‭Ki-67 categorised‬
‭   <=55‬
‭   >55‬
‭ECOG‬
‭   0‬
‭   1‬
‭   2‬
‭Gender‬
‭   Female‬
‭   Male‬
‭Age categorised by median (61 years)‬
‭   <=61y‬
‭   >61y‬
‭LDH‬
‭   <= 2ULN‬
‭   > 2ULN‬
‭Page‬‭70‬‭of‬‭83‬


‭1.‬
‭Fisher’s Exact Test for Count Data‬
‭2.‬
‭Pearson’s Chi-squared test‬
‭Page‬‭71‬‭of‬‭83‬


‭Table 76: OS univariate and multivariate Cox model‬
‭Univariate Cox Regression‬
‭Multivariate Cox Regression‬
‭Characteristic‬
‭N‬
‭Event N‬
‭HR‬‭1‬
‭95% CI‬‭1‬
‭p-value‬
‭N‬
‭Event N‬
‭HR‬‭1‬
‭95% CI‬‭1‬
‭p-value‬
‭CGA <> 2 x ULN‬
‭CGA < 2*ULN‬
‭CGA >= 2*ULN‬
‭Enolase <> 2 x ULN‬
‭NSE < 2*ULN‬
‭NSE >= 2*ULN‬
‭Primary neuroendocrine tumour‬
‭Colon/Rectum‬
‭Others‬
‭Differentiation‬
‭Well differentiated‬
‭Poorly differentiated‬
‭Ki-67 categorised‬
‭<=55‬
‭>55‬
‭ECOG‬
‭0‬
‭1‬
‭2‬
‭Gender‬
‭Female‬
‭Male‬
‭Age categorised by median (61 years)‬
‭<=61y‬
‭>61y‬
‭LDH‬
‭<= 2ULN‬
‭> 2ULN‬
‭1‬‭HR = Hazard Ratio, CI = Confidence Interval‬
‭Note:‬‭Los p-valores marcados en negrita indican que el valor es estadísticamente significativo <0.05‬
‭Page‬‭72‬‭of‬‭83‬


‭Figure 6: Forest plot OS Multivariate Cox Regression‬
‭Page‬‭73‬‭of‬‭83‬


‭5.‬‭S‬‭AFETY‬‭ANALYSIS‬
‭Table 77: Overall safety‬
‭Induction (N=)‬
‭Maintenance (N=)‬
‭General (N=)‬
‭Any AE‬
‭Yes‬
‭No‬
‭AE grade >=3‬
‭Yes‬
‭No‬
‭Toxicity: AE related to any treatment‬
‭Yes‬
‭No‬
‭Toxicity: AE related to nivolumab‬
‭Yes‬
‭No‬
‭Toxicity: AE related to carboplatin‬
‭Yes‬
‭No‬
‭Toxicity: AE related to etoposide‬
‭Yes‬
‭No‬
‭Toxicity: AE related to all treatments (induction)‬
‭Yes‬
‭No‬
‭Toxicity grade >=3‬
‭Yes‬
‭No‬
‭Toxicity related to nivolumab grade >=3‬
‭Yes‬
‭No‬
‭Toxicity related to carboplatin grade >=3‬
‭Yes‬
‭No‬
‭Toxicity related to etoposide grade >=3‬
‭Yes‬
‭No‬
‭Toxicity related to all treatments grade >=3‬
‭(induction)‬
‭Yes‬
‭No‬
‭SAE‬
‭Yes‬
‭No‬
‭Page‬‭74‬‭of‬‭83‬


‭5.1.‬ ‭I‬‭NDUCTION‬
‭Table 78: Most frequent Toxicity with 5% threshold (induction)‬
‭Toxicity‬
‭Frequency‬
‭Percentage (%)‬
‭Table 79: Grade of most frequent toxicities with 5% threshold overall (induction)‬
‭Toxicity‬
‭No‬
‭G-UK‬
‭G-1‬
‭G-2‬
‭G-3‬
‭G-4‬
‭G-5‬
‭Table 80: List of toxicities grade >=3 in all patients (induction)‬
‭Patient Number‬
‭AE CTCAE‬
‭AE Grade‬
‭AE Related to‬
‭Page‬‭75‬‭of‬‭83‬


‭Table 81: Most frequent AEs with 5% threshold (induction)‬
‭AE‬
‭Frequency‬
‭Percentage (%)‬
‭Page‬‭76‬‭of‬‭83‬


‭Table 82: Grade of most frequent AEs with 5% threshold overall (induction)‬
‭AE‬
‭No‬
‭G-UK‬
‭G-1‬
‭G-2‬
‭G-3‬
‭G-4‬
‭G-5‬
‭Page‬‭77‬‭of‬‭83‬


‭Table 83: List of all SAEs (induction)‬
‭Patient‬
‭Number‬
‭AE CTCAE‬
‭AE CTCAE‬
‭Other‬
‭AE‬
‭Grade‬ ‭AE Start Date‬ ‭AE Stop Date‬
‭AE‬
‭Related‬ ‭AE Intensity‬
‭AE Related to‬
‭Page‬‭78‬‭of‬‭83‬


‭Table 84: List of all toxicities (induction)‬
‭Patient‬
‭Number‬
‭AE CTCAE‬
‭AE CTCAE‬
‭Other‬
‭AE‬
‭Grade‬
‭AE Start‬
‭Date‬
‭AE Stop‬
‭Date‬
‭AE‬
‭SAE‬
‭AE‬
‭Intensity‬
‭AE Related to‬
‭Page‬‭79‬‭of‬‭83‬


‭5.2.‬ ‭M‬‭AINTENANCE‬
‭Table 85: Most frequent Toxicity with 5% threshold (maintenance)‬
‭Toxicity‬
‭Frequency‬
‭Percentage (%)‬
‭Table 86: Grade of most frequent toxicities with 5% threshold overall (maintenance)‬
‭Toxicity‬
‭No‬
‭G-UK‬
‭G-1‬
‭G-2‬
‭G-3‬
‭G-4‬
‭G-5‬
‭Table 87: List of toxicities grade >=3 in all patients (maintenance)‬
‭Patient Number‬
‭AE CTCAE‬
‭AE Grade‬
‭AE Related to‬
‭Table 88: Most frequent AEs with 5% threshold (maintenance)‬
‭AE‬
‭Frequency‬
‭Percentage (%)‬
‭Table 89: Grade of most frequent AEs with 5% threshold overall (maintenance)‬
‭AE‬
‭No‬
‭G-UK‬
‭G-1‬
‭G-2‬
‭G-3‬
‭G-4‬
‭G-5‬
‭Table 90: List of all SAEs (maintenance)‬
‭Page‬‭80‬‭of‬‭83‬


‭Patient‬
‭Number‬
‭AE CTCAE‬
‭AE CTCAE‬
‭Other‬
‭AE‬
‭Grade‬
‭AE Start‬
‭Date‬
‭AE Stop‬
‭Date‬
‭AE‬
‭Related‬ ‭AE Intensity‬
‭AE‬
‭Related‬
‭to‬
‭Table 91: List of all toxicities (maintenance)‬
‭Patient‬
‭Number‬
‭AE CTCAE‬
‭AE CTCAE Other‬
‭AE‬
‭Grade‬
‭AE Start‬
‭Date‬
‭AE Stop‬
‭Date‬
‭AE‬
‭SAE‬
‭AE Intensity‬
‭AE Related to‬
‭Page‬‭81‬‭of‬‭83‬


‭5.3.‬ ‭G‬‭ENERAL‬
‭Table 92: Most frequent Toxicity with 5% threshold‬
‭Toxicity‬
‭Frequency‬
‭Percentage (%)‬
‭Table 93: Grade of most frequent toxicities with 5% threshold overall‬
‭Toxicity‬
‭No‬
‭G-UK‬
‭G-1‬
‭G-2‬
‭G-3‬
‭G-4‬
‭G-5‬
‭Table 94: List of toxicities grade >=3 in all patients‬
‭Patient Number‬
‭AE CTCAE‬
‭AE Grade‬
‭AE Related to‬
‭Table 95: Most frequent AEs with 5% threshold‬
‭AE‬
‭Frequency‬
‭Percentage (%)‬
‭Table 96: Grade of most frequent AEs with 5% threshold overall‬
‭AE‬
‭No‬
‭G-UK‬
‭G-1‬
‭G-2‬
‭G-3‬
‭G-4‬
‭G-5‬
‭Page‬‭82‬‭of‬‭83‬


‭Table 97: List of all SAEs‬
‭Patient‬
‭Number‬
‭AE CTCAE‬
‭AE CTCAE‬
‭Other‬
‭AE‬
‭Grade‬ ‭AE Start Date‬ ‭AE Stop Date‬
‭AE‬
‭Related‬ ‭AE Intensity‬ ‭AE Related to‬
‭Table 98: List of all toxicities‬
‭Patient‬
‭Number‬
‭AE CTCAE‬
‭AE CTCAE Other‬
‭AE‬
‭Grade‬
‭AE Start‬
‭Date‬
‭AE Stop‬
‭Date‬
‭AE‬
‭SAE‬
‭AE Intensity‬
‭AE Related to‬
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