Study to Evaluate Safety, Efficacy, Pharmacokinetics And Pharmacodynamics Of Avelumab In Combination With Either Crizotinib Or PF-06463922 In Patients With NSCLC. (Javelin Lung 101)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of avelumab when combined with either crizotinib or PF-06463922.

Detailed Description
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This is a Phase 1b/2, open label, multi center, multiple dose, safety, pharmacokinetic and pharmacodynamic study of Group A and Group B in cohorts of adult patients with locally advanced or metastatic NSCLC.

Official Title
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A PHASE 1B/2, OPEN-LABEL, DOSE-FINDING STUDY TO EVALUATE SAFETY, EFFICACY, PHARMACOKINETICS AND PHARMACODYNAMICS OF AVELUMAB (MSB0010718C) IN COMBINATION WITH EITHER CRIZOTINIB OR PF-06463922 IN PATIENTS WITH ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Avelumab
* Drug: PF-06463922
* Drug: Crizotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Diagnosis of advanced or metastatic NSCLC. Group A must be ALK negative NSCLC and Group B must be ALK positive NSCLC Group A at least one prior regimen of therapy Group B any number of prior regimens. Mandatory tumor tissue available At least one measurable lesion ECOG Performance status 0 or 1 Adequate bone marrow, renal, liver and pancreatic function Negative pregnancy test for females of childbearing potential Group B Phase 2: No prior systemic treatment for advanced or metastatic disease (adjuvant and/or neoadjuvant therapies are allowed if completed at least 6 months prior to study entry. No prior tyrosine kinase inhibitor therapy is allowed at any time prior to study entry) Exclusion Criteria: No prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody. No Severe or Chronic medical conditions including gastrointestinal abnormalities or significant cardiac history No active infection requiring systemic therapy Prior organ transplantation including allogenic stem cell transplantation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>ALK negative Non-Small Cell Lung Cancer | Drug: Avelumab<br>* Administered by IV once every two weeks in doses of either 5 mg/kg or 10 mg/kg<br>* Other names: MSB0010718C;Drug: Crizotinib<br>* Capsules. Taken orally once or twice every day in doses of either 200mg or 250mg.<br>* Other names: PF-02341066;|
| Experimental: Group B<br>ALK positive Non-Small Cell Lung Cancer | Drug: Avelumab<br>* Administered by IV once every two weeks in doses of either 5 mg/kg or 10 mg/kg<br>* Other names: MSB0010718C;Drug: PF-06463922<br>* Tablets taken orally once every day in doses of either 100mg, 75mg, or 50mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities (DLTs): Phase 1b | Any of the following adverse events (AEs) occurring during the primary DLT observation period that are attributable to one, the other, or both study drugs were classified as DLTs: Grade 4 (life-threatening) neutropenia if >7 days in duration; febrile neutropenia; Grade >=3 (severe or life threatening) neutropenic infection; Grade >=3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia >7 days; Grade 4 anemia; any Grade >=3 toxicity, except for any of the following: transient (<=6 hours) Grade 3 (severe) flu like symptoms or fever; transient (<=24 hours) Grade 3 fatigue, local reactions, or headache that resolved to Grade <=1 (no AE or mild AE); Grade 3 nausea and/or vomiting, diarrhea or skin toxicity that resolved to Grade <=1 within 7 days; any Grade >=3 amylase or lipase abnormality; tumor flare phenomenon; single laboratory values out of normal range that were not related to treatment, did not have any clinical correlate, and resolve to Grade <=1 within 7 days. | First 2 cycles (1 cycle = 14 days) | 
| Percentage of Participants With Objective Response (OR): Phase 2 | OR is defined as complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 from start date (the date of first dose of study treatment) until disease progression or death due to any cause. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. Per RECIST v1.1: CR is defined as the disappearance of all target or non-target lesions; any pathological lymph nodes (whether target or non target) must have reduction in short axis to <10 mm and all lymph nodes must be non-pathological in size (<10 mm short axis). PR is defined as a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. | Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years) | 
| Percentage of Participants With CR for Group B: Phase 2 | Per RECIST v1.1: CR is defined as the disappearance of all target or non-target lesions; any pathological lymph nodes (whether target or non target) must have reduction in short axis to <10 mm and all lymph nodes must be non-pathological in size (<10 mm short axis). | Baseline up to 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs are those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event is during the on-treatment period. Treatment-related AEs was any untoward medical occurrence attributed to study drug in a participant who received study drug. Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03: Grade 3 (Severe) events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment; Grade 4 (Life-threatening) events caused participant to be in imminent danger of death; Grade 5 (Death) events=death related to an AE. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in participant hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | Baseline up to 30 days after last dose of study treatment or the day before start day of new anti-cancer therapy (maximum of 5 years) | 
| Number of Participants With Baseline Laboratory Abnormalities Grade <=2 and Post-Baseline Laboratory Abnormalities of Grades 3 or 4 Per NCI CTCAE v4.03 | The laboratory results were graded according to the NCI CTCAE v4.03 severity grade. Grade 1=mild AE. Grade 2=moderate AE. Grade 3=severe AE. Grade 4=life-threatening consequences; urgent intervention indicated. Shift tables were provided to examine the distribution of laboratory toxicities. The following parameters had met the criteria of CTCAE grade shift change from Grade <=2 at baseline to Grade 3 or 4 post baseline: anemia, lymphocyte count decreased, lymphocyte count decreased, neutrophil count decreased, white blood cell decreased, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, cholesterol high, Creatine phosphokinase (CPK) increased, Gamma glutamyl transferase (GGT) increased, hypercalcemia, hyperglycemia, hypermagnesemia, hypertriglyceridemia, hypoalbuminemia, hyponatremia, lipase increased, serum amylase increased. Baseline is defined as the last assessment prior to the date/time of the first dose of study treatment. | Screening up to end of treatment/withdrawal (maximum of 5 years) | 
| Number of Participants With Vital Signs Meeting Pre-defined Criteria | Pre-defined criteria in vital signs: pulse rate <50 beats per minute, pulse rate >120 bpm, sitting diastolic blood pressure (DBP) increase and decrease in change from baseline of >= 20 millimeter of mercury (mmHg), sitting systolic blood pressure(SBP) < 90 mmHg, increase and decrease in change from baseline of >= 30mmHg. Baseline is defined as the last assessment prior to the date/time of the first dose of study treatment. | Screening up to end of treatment/withdrawal (maximum of 5 years) | 
| Disease Control Rate (DCR) | DC is defined as objective response (CR or PR) or stable disease (SD) per RECIST v.1.1 from the date of first dose of study treatment until disease progression or death due to any cause. The DCR is the proportion of patients with DC. Per RECIST v1.1: CR is defined as the disappearance of all target or non-target lesions; any pathological lymph nodes (whether target or non target) must have reduction in short axis to <10 mm. PR is defined as a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD is defined as a >=20% increase in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of one or more new lesions. | Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years) | 
| Duration of Response (DR) | DR: time from first documented occurrence of response (PR or CR) until date of first documented PD or death due to underlying cancer. Per RECIST 1.1: CR: disappearance of all non-nodal target lesions and of all non-target lesions; any pathological lymph nodes assigned as target lesions/non-target lesions have a reduction in short axis to <10 mm. PR: at least a >=30% decrease in sum of diameter of all target lesions, taking as reference baseline sum of diameters. PD: at least a >=20% increase in sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of existing non-target lesions. Appearance of new lesions. Participants with no PD and were still alive by 02 Feb 2020, were censored at last adequate tumor assessment. Kaplan-Meier method was used for DR analysis. | Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years) | 
| Time to Tumor Response (TTR) | TTR is defined, for participants with an objective response (CR or PR), as the time from the start date (the date of first dose of treatment) to the first documentation of objective response (CR or PR) which is subsequently confirmed. Per RECIST v1.1: CR: disappearance of all non-nodal target lesions and of all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions/ non-target lesions must have a reduction in short axis to <10 mm. PR: at least a 30% decrease in sum of diameter of all target lesions, taking as reference baseline sum of diameters. | Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years) | 
| Progression-free Survival (PFS) | PFS is defined as the time from start date (the date of first dose of treatment) to the date of the first documentation of PD per RECIST v1.1 or death due to any cause, whichever occurs first. Per RECIST v1.1: PD: a >=20% increase in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years) | 
| Kaplan-Meier Estimates of Overall Survival (OS) | OS is defined as the time from start date (the date of first dose of treatment) to the date of death due to any cause. | Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years) | 
| Maximum Plasma Concentration (Cmax) of Crizotinib in The Presence of Avelumab | Cmax of crizotinib in the presence of avelumab was observed directly from data. | Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2 | 
| Time to Cmax (Tmax) of Crizotinib in The Presence of Avelumab | Tmax of crizotinib in the presence of avelumab was observed directly from data as time of first occurrence. | Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2 | 
| Area Under The Plasma Concentration-Time Curve During The Dosing Interval Time Course (AUCtau) of Crizotinib in The Presence of Avelumab | AUCtau of crizotinib in the presence of avelumab was calculated by Linear/Log trapezoidal method. Dose interval is defined as after single dose from time zero to the next dose (after single dose and at steady state). | Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2 | 
| Apparent Plasma Clearance (CL/F) of Crizotinib in The Presence of Avelumab | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2 | 
| Cmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab | Cmax of crizotinib metabolite PF-06260182 in the presence of avelumab was observed directly from data. | Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2 | 
| Tmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab | Tmax of crizotinib metabolite PF-06260182 in the presence of avelumab was observed directly from data as time of first occurrence. | Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2 | 
| AUCtau of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab | AUCtau of crizotinib metabolite PF-06260182 in the presence of avelumab was calculated by Linear/Log trapezoidal method. Dose interval: single dose from time zero to the next dose (after single dose and at steady state). | Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2 | 
| Metabolite to Parent Ratio for AUCtau (MRAUCtau) of PF-06260182 in The Presence of Avelumab | MRAUCtau of metabolite PF-06260182 in the presence of avelumab was calculated (MRAUCtau=Metabolite AUCtau/parent AUCtau). Parent=crizotinib, metabolite=PF-06260182 | Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2 | 
| Metabolite to Parent Ratio for Cmax (MRCmax) of PF-06260182 in The Presence of Avelumab | MRCmax of metabolite PF-06260182 in the presence of avelumab was calculated (MRCmax=Metabolite Cmax/parent Cmax). Parent=crizotinib, metabolite=PF-06260182 | Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2 | 
| Cmax of Lorlatinib in The Presence of Avelumab | Cmax of lorlatinib in the presence of avelumab was observed directly from data. | Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2 | 
| Tmax of Lorlatinib in The Presence of Avelumab | Tmax of lorlatinib in the presence of avelumab was observed directly from data. | Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2 | 
| AUCtau of Lorlatinib in The Presence of Avelumab | AUCtau of lorlatinib in the presence of avelumab was calculated by Linear/Log trapezoidal method. Dose interval: single dose from time zero to the next dose (after single dose and at steady state). | Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2 | 
| Area Under The Plasma Concentration Time Curve From Time of Dosing to The Last Collection Time Point (AUClast) of Lorlatinib in The Presence of Avelumab | AUClast of lorlatinib in the presence of avelumab. | Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2 | 
| CL/F of Lorlatinib in The Presence of Avelumab | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2 | 
| Cmax of Avelumab in The Presence of Crizotinib (Group A) or Lorlatinib (Group B) After Single Dose of Avelumab | Cmax of avelumab in the presence of crizotinib was observed directly from the data in Group A. Cmax of avelumab in the presence of lorlatinib was observed directly from the data in Group B. | Pre-dose, 1, and 168 hours post dose of avelumab on Cycle 1 Day 1. | 
| Cmax of Avelumab in The Presence of Crizotinib (Group A) or Lorlatinib (Group B) After Multiple Doses of Avelumab | Cmax of avelumab in the presence of crizotinib was observed directly from the data in Group A. Cmax of avelumab in the presence of lorlatinib was observed directly from the data in Group B. | Pre-dose, 1, and 168 hours post dose of avelumab on Cycle 2 Day 1 | 
| Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Crizotinib (Group A) Following Multiple Doses of Avelumab | Ctrough is defined as predose concentration following multiple doses. Ctrough of avelumab in the presence of crizotinib was observed directly from the data in Group A. | Pre-dose on Day 1 of Cycles 2-5, 11, 17, 23, 29, 35, and 47. | 
| Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Lorlatinib (Group B) Following Multiple Doses of Avelumab | Ctrough is defined as predose concentration following multiple doses. Ctrough of avelumab in the presence of lorlatinib was observed directly from the data in Group B. | Pre-dose on Day 1 of Cycles 2-5, 11, 17, 23, 29, 35, 41, and 47. | 
| Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status | ADA never-positive was defined as no positive ADA results at any time point. ADA ever-positive was defined as at least one positive ADA result at any time point. Baseline is defined as the last assessment on or prior to the date/time of the first dose of avelumab. | Day 1 of Cycles 1-5, then every 12 weeks thereafter, end of treatment/withdrawal, and 30 days after last avelumab dose (up to a maximum of 5 years) | 
| Number of Participants With Positive Programmed Death Ligand-1 (PD-L1) Biomarker Expression | PD-L1 protein expression is determined by using Combined Positive Score (CPS), which is the percentage of viable tumor and tumor-infiltrated immune cells (restricted to lymphocytes and macrophages) within or directly associated with tumor cell strands showing partial or complete membrane staining using the SP263 antibody. Positive is defined as CPS>=1% and negative is defined as CPS <1%. | Baseline | 
| Number of Participants With Positive Tumor Infiltrating CD8+ Lymphocytes | Tumor infiltrating CD8+ lymphocytes is defined as the number of CD8+ cells per unit area and the percent of counted cells. Positive is defined as >=1% and negative is defined as <1%. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, Non-Small Cell Lung Cancer, ALK, avelumab, crizotinib, PF-06463922