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)

Non-Small Cell Lung Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02584634
• Other study ID #: B9991005
• Secondary ID: 2015-001879-43JA
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: December 18, 2015
• Est. completion date: July 13, 2022

Study information

• Verified date: June 2023
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 43
• Est. completion date: July 13, 2022
• Est. primary completion date: February 2, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

• 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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-Small Cell Lung Cancer

Intervention

Drug:
• Avelumab
Administered by IV once every two weeks in doses of either 5 mg/kg or 10 mg/kg
• PF-06463922
Tablets taken orally once every day in doses of either 100mg, 75mg, or 50mg.
• Crizotinib
Capsules. Taken orally once or twice every day in doses of either 200mg or 250mg.

Locations

Country	Name	City	State
Australia	Chris O'Brien Lifehouse	Camperdown	New South Wales
Australia	The Prince Charles Hospital	Chermside	Queensland
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	Royal Melbourne Hospital	Parkville	Victoria
Japan	National Hospital Organization Kyushu Cancer Center	Fukuoka
Japan	The Cancer Institute Hospital of JFCR	Koto-ku, Tokyo
Japan	Aichi cancer center central hospital	Nagoya	Aichi
Korea, Republic of	National Cancer Center	Goyang-Si	Gyeonggi-do
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Spain	Institut Catala d'Oncologia de Badalona	Badalona	Barcelona
Spain	Hospital Quiron Barcelona	Barcelona
Spain	Hospital Universitari de la Vall d'Hebron	Barcelona
United States	Emory University Hospital	Atlanta	Georgia
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	The Emory Clinic	Atlanta	Georgia
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Ophthalmic Consultants of Boston Inc (OCB)	Boston	Massachusetts
United States	Tennessee Oncology, PLLC	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Australia,  Japan,  Korea, Republic of,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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)
Secondary	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
Secondary	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

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