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)

Phase 2TerminatedNCT02584634

Pfizer43 enrolled

Overview

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

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Non-Small Cell Lung Cancer

Interventions

AvelumabDRUG

Administered by IV once every two weeks in doses of either 5 mg/kg or 10 mg/kg

PF-06463922DRUG

Tablets taken orally once every day in doses of either 100mg, 75mg, or 50mg.

CrizotinibDRUG

Capsules. Taken orally once or twice every day in doses of either 200mg or 250mg.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

* 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.

Locations (20)

Emory University Hospital Midtown

Atlanta, Georgia, United States

Emory University Hospital

Atlanta, Georgia, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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).

Data from ClinicalTrials.gov

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Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.