Safety And Efficacy Study Of Avelumab Plus Chemotherapy With Or Without Other Anti-Cancer Immunotherapy Agents In Patients With Advanced Malignancies

Phase 2TerminatedNCT03317496

Pfizer67 enrolled

Overview

This is a Phase 1b/2, open label, multicenter, safety and clinical activity study of avelumab in combination with chemotherapy as first-line treatment of adult patients with locally advanced or metastatic solid tumors. Initially, avelumab will be evaluated in combination with pemetrexed and carboplatin in patients with advanced non-squamous non-small cell lung cancer (NSCLC) (Cohort A1) and in combination with gemcitabine and cisplatin in patients with cisplatin-eligible urothelial (bladder) cancer (UC) (Cohort A2). As more information is learned about other anti-cancer immunotherapy agents, in future portions of the study, avelumab may be combined with chemotherapy and other anti-cancer immunotherapy agents in patients with these same or different tumor types.

This is a Phase 1b/2, open label, multicenter, safety, clinical activity, pharmacokinetic (PK), and pharmacodynamics (PD) study of avelumab in combination with chemotherapy with or without other anti-cancer immunotherapies, as first-line treatment of adult patients with locally advanced or metastatic solid tumors. Initially, avelumab will be evaluated in combination with pemetrexed and carboplatin in patients with advanced non-squamous non-small cell lung cancer (NSCLC) (Cohort A1) and with gemcitabine and cisplatin in patients with cisplatin-eligible urothelial cancer (UC) (Cohort A2). Given the growing preclinical and clinical indications that combinations of anti-cancer immunotherapies potentially improve patient outcomes compared to results seen with single agents, in portions of the study to be added in the future, avelumab will be evaluated in combination with both standard-of-care chemotherapy and other anti-cancer immunotherapies in patients with advanced malignancies. Each cohort in the study will consist of a Phase 1b lead-in portion to evaluate safety and a Phase 2 cohort expansion to evaluate safety and efficacy. In the Phase 1b safety lead-in portion, up to 12 patients will be enrolled into each cohort and evaluated for dose-limiting toxicities (DLT) during the first 2 cycles of treatment. If investigational products administration in a cohort is deemed safe in the Phase 1b lead-in, enrollment may be expanded into the Phase 2 cohort expansion. Up to approximately 40 patients in each cohort (including those enrolled in the Phase 1b lead-in and those enrolled in the Phase 2 cohort expansion) will be enrolled and treated with avelumab plus chemotherapy in the initial portion of the study and, in future portions of the study, with avelumab plus chemotherapy with or without other anti-cancer immunotherapies. In the Phase 1b lead-in portions of NSCLC Cohort A1 and UC Cohort A2, avelumab is dosed at 800 mg fixed dose every 3 weeks. Under Protocol Amendment 4, avelumab is dosed at 1200 mg fixed dose every 3 weeks in the Phase 1b lead-in portions of NSCLC Cohort A3 and in UC Cohort A4, in combination with the same standard-of-care chemotherapy doublets used in Cohort A1 and Cohort A2, respectively. For each tumor type, the study treatment combination with the highest avelumab dose determined to be safe may be advanced into Phase 2 cohort expansion.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumor that is not amenable for treatment with curative intent as follows: * For all groups: * Measurable disease by RECIST v1.1 with at least 1 measurable lesion, and availability of tumor specimen 18 months or less old. * No prior systemic treatment for unresectable locally advanced or metastatic disease for the tumor type under study. If prior systemic chemotherapy treatment was given in the adjuvant or neo-adjuvant setting or as part of radiotherapy chemotherapy treatment, disease-free interval after stop of systemic treatment must be more than 6 months for non-squamous NSCLC and more than 12 months for UC; * Cohort A1 and Cohort A3: Non-squamous NSCLC, with no activating EGFR mutations, ALK or ROS1 translocations/rearrangements. If monotherapy pembrolizumab is available as a standard of care treatment option, patients must have a tumor proportion score (TPS) \<50% for PD L1 (via the 22C3 pharmDx or the Ventana (SP263) PD L1 IHC assay). * Cohort A2 and Cohort A4: Transitional cell carcinoma of the urothelium including the bladder, urethra, renal pelvis, and ureter. 2. ECOG performance status 0 or 1 3. Estimated life expectancy of at least 90 days 4. Adequate bone marrow, renal, and liver function 5. Negative serum pregnancy test at screening 6. Signed and dated informed consent Exclusion Criteria: 1. Prior immunotherapy with any antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways. 2. Patients with known symptomatic central nervous system metastases requiring steroids. 3. Diagnosis of other malignancy within 2 years prior to enrollment except adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the bladder, breast, or cervix, or low grade (Gleason ≤6) prostate cancer 4. Use of immunosuppressive medication at the time of enrollment 5. Active or prior autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. 6. Prior organ transplantation including allogenic stem cell transplantation 7. Active infection requiring systemic therapy 8. Known history of HIV or AIDS 9. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening 10. Administration of live vaccine within 4 weeks prior to study entry 11. Known prior severe hypersensitivity to the investigational products or any component in their formulations, 12. Known prior severe hypersensitivity to platinum-related compounds for all cohorts, to pemetrexed for patients enrolled in Cohort A1 and Cohort A3, and to gemcitabine for patients enrolled in Cohort A2 and Cohort A4 13. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade \> 1) 14. Known history of colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis. 15. Ongoing cardiac dysrhythmias of NCI CTCAE v4.03 Grade 2 or prolongation of the QTcF interval to \>480 msec. 16. Clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke (\<6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure, or serious cardiac arrhythmia requiring medication. 17. Major surgery ≤28 days or major radiation therapy ≤14 days prior to enrollment. 18. Participation in other studies involving investigational drug(s) within 28 days prior to study entry. 19. Concurrent treatment with a prohibited medication. 20. Other acute or chronic medical or psychiatric condition 21. Pregnant female patients; breastfeeding female patients; fertile male patients and female patients of childbearing potential who are unwilling or unable to use at least 1 highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 90 days after the last dose of chemotherapy (for male and female patients) or at least 30 days after the last dose of avelumab (for female patients), whichever is longer.

Locations (46)

University of Arizona Cancer Center - North Campus

Tucson, Arizona, United States

Banner-University Medical Center Tucson

Tucson, Arizona, United States

Stony Brook Cancer Center

Stony Brook, New York, United States

Stony Brook University

Stony Brook, New York, United States

Montefiore Medical Center - Einstein Center for Cancer Care

The Bronx, New York, United States

Outcomes

Primary Outcomes

Phase 1b Lead-in: Number of Participants With Dose-Limiting Toxicities (DLT)

DLTs=occurrence of any AEs attributable to study treatment in first 2 treatment cycles:Hematologic: grade(G)4 neutropenia lasting \>7days;febrile neutropenia with body temperature \>=38 degree Celsius for \>1hour; G\>=3 neutropenic infection(absolute neutrophil count \<1.0\*10\^9/L),G\>=3 thrombocytopenia (platelet count\<50.0-25.0\*10\^9/L)with bleeding;G4 thrombocytopenia(PC\<25.0\*10\^9/L),G4 anemia(life-threatening).Non-hematologic: any G4 toxicities;G3 toxicities persisting for \>3days despite medical treatment(nausea,vomiting,diarrhea)except endocrinopathies controlled with hormonal therapy;ALT/AST \>3\*upper limit of normal(ULN)if normal at baseline or 2\*Baseline(\>ULN at baseline)with total bilirubin \>2\*ULN and alkaline phosphatase \<2\*ULN;G3 QTcF prolongation after correction of any reversible cause(electrolyte abnormalities/hypoxia).Delay of \>=3weeks in scheduled administration/failure to deliver 75% of doses due to toxicities attributable to any study treatment. DLT-evaluable analysis set.

Time frame: Day 1 up to Week 6 (first 2 treatment cycles; 1 cycle = 21 days)

Percentage of Participants With Confirmed Objective Response (OR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment

OR: complete response(CR) or partial response(PR)determined by investigator according to RECIST v1.1 from date of first dose of study treatment until date of first documentation of progressive disease(PD),confirmed by repeat assessments performed no less than 4 weeks after first response. CR: disappearance of target and non-target lesions, with exception of nodal disease and normalization of tumor markers. All nodes, target and non-target must have short axis measures less than (\<)10 millimeter(mm). PR: \>=30% decrease in sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference baseline sum of diameters. Non-target lesions must be non-PD. PD: \>=20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5mm, appearance of one or more new lesions was considered PD.

Time frame: From start of the treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 3.5 years approximately)

Secondary Outcomes

Serum Concentration of Avelumab

The lower limit of quantification (LLOQ) for avelumab was 0.2 micrograms per milliliter. Pharmacokinetic concentration analysis set was subset of safety analysis set and included participants who had at least one concentration measurement for avelumab or other study drugs which they were assigned to receive. Treatment groups with same dose and administration frequency were combined as pre-specified in reporting and analysis plan.

Time frame: Pre-dose, 1 hour post-dose on Day 1 of Cycle 1, 2, 3, 6, 10, 14; 336 hours post-dose on Day 15 of Cycle 1, 2, 3 (each cycle of 21 days)

Absolute Value of Tumor Mutational Burden (TMB) in Tumor Tissue

Mutational load within tumor tissue was defined as number per megabase of the genome, coding, base substitution, and indel mutations present in the sample. Mutational load was determined in whole blood samples using next generation deoxyribonucleic acid (DNA) sequencing followed by computational analysis.

Time frame: Pre-dose on Day 1 of Cycle 1

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs

Adverse event (AE) was any untoward medical occurrence in a participants who received any study drug without regard to possibility of causal relationship. Serious adverse event was any untoward medical occurrence that at any dose resulted in any of following outcomes/deemed significant for any other reason: death; initial /prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first.

Time frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5 years approximately)

Number of Participants With Treatment Related TEAEs

A treatment related AE included AEs related to at least one study drug in the combination. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Relatedness to study drug was assessed by the investigator.

Number of Participants With Grade 3 or Higher TEAEs Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v 4.03

AE was any untoward medical occurrence in a participant who received any study drug without regard to possibility of causal relationship. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. TEAEs were graded by the investigator using NCI CTCAE v 4.03 as Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death. In this outcome measure, number of participants with grade 3 or higher TEAEs were reported.

Time frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5 years approximately)

Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade

Participants with laboratory abnormalities of any Grade as per NCI CTCAE toxicity grading v4.03 were summarized:hematology(anemia,hemoglobin increased,lymphocyte count decreased,lymphocyte count increased, neutrophil count decreased,platelet count decreased and white blood cell decreased)and clinical chemistry(alanine aminotransferase increased,alkaline phosphatase,increased,aspartate,aminotransferase increased,blood bilirubin increased,cholesterol high,creatinine phosphokinase\[cpk\] increased,creatinine increased,gamma-glutamyl transferase\[ggt\] increased,hypercalcemia,hyperglycemia,hyperkalemia, hypermagnesemia,hypernatremia,hypertriglyceridemia,hypoalbuminemia,hypocalcemia,hypoglycemia,hypokalemia,hypomagnesemia,hyponatremia, hypophosphatemia,serum amylase increased and lipase increased).As per NCI CTCAE toxicity grading v4.03, Grade1=mild;Grade2=moderate;Grade3=severe;Grade4=life-threatening;Grade 5=death.Parameters with at least 1 participant with abnormal value are reported.

Time frame: From screening up to 90 days after last dose of study drug (maximum up to 5 years approximately)

Progression Free Survival (PFS) as Per RECIST v 1.1 by Investigator Assessment

PFS was defined as the time from the date of first dose of study treatment to the date of the first documentation of PD per RECIST v1.1 or death due to any cause, whichever occurred first. PD: \>=20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5mm, appearance of one or more new lesions was considered PD. The median duration of PFS was not derived for less than (\<) 10 participants.

Time frame: From start of treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 5 years approximately)

Duration of Response (DOR) as Per RECIST v 1.1 by Investigator Assessment

DOR was defined as time from first documentation of objective response (confirmed CR or PR) to the date of first PD documentation or death due to any cause, whichever occurs first. CR: disappearance of target and non-target lesions, with exception of nodal disease and normalization of tumor markers. All nodes, target and non-target must have short axis measures less than (\<)10 millimeter(mm). PR: \>=30% decrease in sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference baseline sum of diameters. Non-target lesions must be non-PD. PD: \>=20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5mm, appearance of one or more new lesions was considered PD. Median DOR was not derived for \< 5 participants.

Time frame: From date of first documented response to date of first documented PD or death due to any cause, whichever occurred first (maximum up to 5 years approximately)

Time-to-Tumor Response (TTR) as Per RECIST v 1.1 by Investigator Assessment

TTR was defined as the time from the date of first dose of study treatment to the first documentation of objective response (CR or PR) as assessed by investigator according to RECIST v 1.1. CR: disappearance of target and non-target lesions, with exception of nodal disease and normalization of tumor markers. All nodes, target and non-target must have short axis measures less than (\<)10 millimeter(mm). PR: \>=30% decrease in sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference baseline sum of diameters. Non-target lesions must be non-PD.

Time frame: From first dose of study treatment until first documentation of CR or PR (maximum up to 5 years approximately)