Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Avelumab

Crizotinib

Antineoplastic Agents, Immunological

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

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

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

PF-06463922

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

Pfizer CT.gov Call Center

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

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

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

Cmax of crizotinib in the presence of avelumab was observed directly from data.

Tmax of crizotinib in the presence of avelumab was observed directly from data as time of first occurrence.

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).

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.

Cmax of crizotinib metabolite PF-06260182 in the presence of avelumab was observed directly from data.

Tmax of crizotinib metabolite PF-06260182 in the presence of avelumab was observed directly from data as time of first occurrence.

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).

MRAUCtau of metabolite PF-06260182 in the presence of avelumab was calculated (MRAUCtau=Metabolite AUCtau/parent AUCtau). Parent=crizotinib, metabolite=PF-06260182

MRCmax of metabolite PF-06260182 in the presence of avelumab was calculated (MRCmax=Metabolite Cmax/parent Cmax). Parent=crizotinib, metabolite=PF-06260182

Cmax of lorlatinib in the presence of avelumab was observed directly from data.

Tmax of lorlatinib in the presence of avelumab was observed directly from data.

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).

AUClast 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.

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.

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.

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.

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.

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%.

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%.

Pfizer

The same event may appear as both an AE and an SAE. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study. Total number at risk below refers to the number of participants evaluable for SAEs or AEs.

Participants with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg (starting dose) orally twice a day (BID) on a continuous daily dosing schedule.

Group A: Avelumab + Crizotinib

Participants with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg (starting dose) orally once a day (QD) on a continuous daily dosing schedule.

Group B: Avelumab + Lorlatinib

Total

Age, Continuous

<65 years

65-<75 years

75-<85 years

Age, Customized

Sex: Female, Male

American Indian or Alaska Native

Asian

White

Race/Ethnicity, Customized

Hispanic or Latino

Not Hispanic or Latino

Not Reported

Age Range

The baseline analysis population included all participants who received at least one dose of study drug. Participants were classified according to the study treatment actually received. If a participant received more than one treatment the participant was classified according to the first treatment received.

Enrollment in the study was terminated early based on the changing landscape in treatment options for treatment naïve ALK positive NSCLC. This decision was not due to any safety concerns or regulatory interactions. All participants on active treatment at the time of the early enrollment termination could continue treatment and follow up per the protocol.

Pfizer ClinicalTrials.gov Call Center

The analysis population included all participants enrolled in Phase 1b who were in the safety analysis set (all participants who received at least one dose of study drug), and either experienced DLT during the first 2 cycles (1 cycle = 14 days), or completed the observation period for the first 2 cycles of treatment.

Number of Participants With Dose-limiting Toxicities (DLTs): Phase 1b

The analysis population included all participants who received at least one dose of study drug. Participants were classified according to the study treatment actually received. If a participant received more than one treatment the participant was classified according to the first treatment received.

Percentage of Participants With Objective Response (OR): Phase 2

The analysis population included all participants who received at least one dose of study drug in Group B. Participants were classified according to the study treatment actually received. If a participant received more than one treatment the participant was classified according to the first treatment received. Results for Group A are not reported for this outcome measure according to the protocol.

Percentage of Participants With CR for Group B: Phase 2

Participants with TEAEs

Participants with Grade >= 3 TEAEs

Participants with treatment-related TEAEs

Participants with Grade >= 3 treatment-related TEAEs

Participants with SAEs

Participants with treatment-related SAEs

Participants with TEAEs leading to discontinuation of avelumab

Participants with TEAEs leading to discontinuation of crizotinib

Participants with TEAEs leading to discontinuation of lorlatinib

Participants with TEAEs leading to discontinuation of any study drug

Participants with TEAEs leading to discontinuation of all study drugs

Participants with treatment-related TEAEs leading to discontinuation of avelumab

Participants with treatment-related TEAEs leading to discontinuation of crizotinib

Participants with treatment-related TEAEs leading to discontinuation of lorlatinib

Participants with TEAEs leading to death

Participants with treatment-related TEAEs leading to death

Participants with infusion-related reactions

The analysis population included all participants who received at least one dose of study drug. Participants were classified according to the study treatment actually received. If a participant received more than one study treatment, the participant were classified according to the first treatment received.

Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

Anemia

Lymphocyte count decreased

Lymphocyte count increased

Neutrophil count decreased

White blood cell decreased

Alanine aminotransferase increased

Aspartate aminotransferase increased

Blood bilirubin increased

Cholesterol high

CPK increased

GGT increased

Hypercalcemia

Hyperglycemia

Hypermagnesemia

Hypertriglyceridemia

Hypoalbuminemia

Hyponatremia

Lipase increased

Serum amylase increased

Hemoglobin increased

Platelet count decreased

Alkaline phosphatase increased

Creatinine increased

Hyperkalemia

Hypernatremia

Hypocalcemia

Hypoglycemia

Hypokalemia

Hypomagnesemia

Hypophosphatemia

The analysis population included all participants who received at least one dose of study drug and who could be evaluated for CTCAE criteria for each parameter in each treatment group. Participants were classified according to the study treatment actually received. If a participant received more than one study treatment, the participant was classified according to the first treatment received.

Number of Participants With Baseline Laboratory Abnormalities Grade <=2 and Post-Baseline Laboratory Abnormalities of Grades 3 or 4 Per NCI CTCAE v4.03

Pulse rate <50 bpm

Pulse rate >120 bpm

Sitting DBP change >= 20 mmHg increase

Sitting DBP change >= 20 mmHg decrease

Sitting SBP <90 mmHg

Sitting SBP change >= 30 mmHg increase

Sitting SBP change >= 30 mmHg decrease

The analysis population included all participants who received at least one dose of study drug. Participants were classified according to the study treatment actually received. If a participant received more than one study treatment, the participant was classified according to the first treatment received.

Number of Participants With Vital Signs Meeting Pre-defined Criteria

Disease Control Rate (DCR)

The analysis population included all participants who received at least one dose of study drug and who had confirmed complete response or partial response. Participants were classified according to the study treatment actually received. If a participant received more than one treatment the participant was classified according to the first treatment received.

Duration of Response (DR)

Time to Tumor Response (TTR)

Progression-free Survival (PFS)

Kaplan-Meier Estimates of Overall Survival (OS)

The analysis population included participants who received at least one dose of study drug and who had at least one of the pharmacokinetic (PK) parameters of interest for crizotinib in Group A. Group B was not evaluable for this outcome measure.

Maximum Plasma Concentration (Cmax) of Crizotinib in The Presence of Avelumab

The analysis population included participants who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this outcome measure.

Time to Cmax (Tmax) of Crizotinib in The Presence of Avelumab

Area Under The Plasma Concentration-Time Curve During The Dosing Interval Time Course (AUCtau) of Crizotinib in The Presence of Avelumab

Apparent Plasma Clearance (CL/F) of Crizotinib in The Presence of Avelumab

Cmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab

Tmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab

AUCtau of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab

Metabolite to Parent Ratio for AUCtau (MRAUCtau) of PF-06260182 in The Presence of Avelumab

Metabolite to Parent Ratio for Cmax (MRCmax) of PF-06260182 in The Presence of Avelumab

The analysis population included participants who received at least one dose of study drug and who had at least one of the PK parameters of interest for lorlatinib in Group B. Group A is not evaluable for this outcome measure.

Cmax of Lorlatinib in The Presence of Avelumab

Tmax of Lorlatinib in The Presence of Avelumab

AUCtau of Lorlatinib in The Presence of Avelumab

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

CL/F of Lorlatinib in The Presence of Avelumab

The analysis population included participants who received at least one dose of study drug and who had at least one post-dose concentration measurement above the lower limit of quantification for avelumab.

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 (Group A) or Lorlatinib (Group B) After Multiple Doses of Avelumab

Cycle 2 Day 1

Cycle 3 Day 1

Cycle 4 Day 1

Cycle 5 Day 1

Cycle 11 Day 1

Cycle 17 Day 1

Cycle 23 Day 1

Cycle 29 Day 1

Cycle 35 Day 1

Cycle 47 Day 1

The analysis population included participants who received at least one dose of study drug and who had least one observation. Number of Participants Analyzed represents the total number of participants in the analysis population for this outcome measure. Number Analyzed represents the number of participants with concentration measurement above lower limit of quantification at each visit. Group B was not evaluable for this outcome measure.

Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Crizotinib (Group A) Following Multiple Doses of Avelumab

Cycle 41 Day 1

The analysis population included participants who received at least one dose of study drug and who had least one observation. Number of Participants Analyzed represents the total number of participants in the analysis population for this outcome measure. Number Analyzed represents the number of participants with concentration measurement above lower limit of quantification at each visit. Group A was not evaluable for this outcome measure.

Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Lorlatinib (Group B) Following Multiple Doses of Avelumab

ADA never-positive

ADA ever-positive

Including all the participants from Group A and Group B.

All Participants

The analysis population was a subset of the safety analysis set (all participants who received at least one dose of study drug) and included participants who had at least one ADA sample collected for avelumab.

Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status

Positive

The analysis population was a subset of the safety analysis set (all participants who received at least one dose of study drug) and included participants who had at least one biomarker parameter of PD-L1 from the corresponding assay sample with at least one baseline biomarker measurement.

Spots Global Cancer Trial Database for 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)

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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