A Phase Ib/II, open label, multi-center, randomized study designed to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of immunotherapy-based treatment combinations in patients with locally advanced unresectable or metastatic G/GEJ cancer (hereafter referred to as gastric cancer) and esophageal cancer. Two cohorts of patients with gastric cancer have been enrolled in parallel in this study: the second-line (2L) Gastric Cancer Cohort consists of patients with gastric cancer who have progressed after receiving a platinum-containing or fluoropyrimide-containing chemotherapy regimen in the first-line setting, and the first-line (1L) Gastric Cancer Cohort consists of patients with gastric cancer who have not received prior chemotherapy in this setting. In each cohort, eligible patients will be assigned to one of several treatment arms. Additionally, a cohort of patients with esophageal cancer who have not received prior systemic treatment for their disease will be enrolled in this study. Eligible patients will be randomized to chemotherapy or the combination of chemotherapy with checkpoint inhibitor immunotherapy.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
214
5-FU 2400 milligrams per square meter (mg/m\^2) by continuous intravenous (IV) infusion over 46 hours on Days 1 and 2 and Days 15 and 16 of every 28-day cycle.
Leucovorin: 100 mg/m\^2 IV over 2 hours on Days 1 and 15 of every 28-day cycle.
Oxaliplatin: 100 mg/m\^2 administered by IV infusion over 2 hours on Days 1 and 15 of every 28-day cycle.
Atezolizumab: 840 mg by IV infusion on Days 1 and 15 of every 28-day cycle.
Cobimetinib: 60 mg by mouth once a day on Days 1-21 of every 28-day cycle
Ramucirumab: 8 mg/kg administered by IV infusion over 60 minutes on Days 1 and 15 of every 28-day cycle.
Paclitaxel: 80 mg/m\^2 administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.
PEGPH20: 3 micrograms per kilogram (mcg/kg) administered by IV infusion on Days 1, 8, and 15 of every 21-day cycle.
BL-8040: 1.25 mg/kg administered by subcutaneous (SC) injection on Days 1-5 during the 5-day priming period prior to Cycle 1; 1.25 mg/kg administered by SC injection three times a week (Days 1, 3, 5, 8, 10, 12, 15, 17, and 19 of every 21-day cycle).
Linagliptin: 5 mg orally once a day of every 21-day cycle.
Atezolizumab: 1200 mg administered by IV infusion on Day 1 of every 21-day cycle
Cobimetinib: 40 or 60 mg (depending on the recommended dose determined during the safety run-in phase) by mouth once a day on Days 1-21 of every 28-day cycle.
Cisplatin: 80 mg/m\^2 administered by IV infusion on Day 1 of each 21 day cycle. Treatment will be capped after 6 doses.
Tiragolumab: 600 mg administered by IV infusion on Day 1 of every 21 day cycle.
5-FU 800 mg/m\^2 administerd by IV infusion on Days 1-5 of each 21 day cycle.
Mayo Clinic Cancer Center
Scottsdale, Arizona, United States
Uni of Southern California
Los Angeles, California, United States
UCLA Jonsson Comprehensive Cancer Center
Santa Monica, California, United States
Columbia University Medical Center
New York, New York, United States
Tennessee Oncology - Nashville
Nashville, Tennessee, United States
Percentage of Participants With Objective Response, as Determined by Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1)
Time frame: From Randomization until disease progression or loss of clinical benefit (up to approximately 3-6 years)
Percentage of Participants with Adverse Events (AEs)
Time frame: From first study treatment administration until 30 days after the last dose or until initiation of new systemic anti-cancer therapy, whichever occurs first (up to approximately 3-6 years)
For Arm 1L-A : Percentage of Participants with Serious and Non-serious Treatment-related AEs
Time frame: During the safety run-in phase up to 28 days
Progression-Free Survival (PFS), as Determined by Investigator According to RECIST v1.1
Time frame: From randomization up to the first occurrence of disease (up to approximately 3-6 years)
Overall Survival (OS)
Time frame: From randomization up to death from any cause (up to approximately 3-6 years)
Percentage of Participants Who Are Alive at Month 6 and at Month 12
Time frame: Month 6, Month 12
Duration of Response, as Determined by Investigator According to RECIST v1.1
Time frame: From the date of first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to approximately 3-6 years)
Percentage of Participants With Disease Control, as Determined by the Investigator per RECIST v1.1
Time frame: From randomization until disease progression or loss of clinical benefit (up to approximately 3-6 years)
Serum Concentration of Atezolizumab
Time frame: Pre-infusion (0 hour [hr]), 30 minutes (min) post-infusion (infusion=60 min) on Day 1 of Cycle 1; pre-infusion (0 hr) on Day 1 of Cycles 2, 3, 4, 8, 12, 16 (each cycle=28 days); 30 days and 120 days after last dose (up to approximately 3-6 years)
Plasma Concentration of Cobimetinib
Time frame: Prior to cobimetinib dose, 2-4 hr after cobimetinib dose on Day 15 of Cycle 1 (cycle length=28 days)
Plasma Concentration of PEGPH20
Pre-infusion (0 hr), 5 min and 1-3 hrs post infusion (infusion duration=10-12 min) on Day 1 of Cycle 1; pre-infusion (0 hr) on Days 8 and 15 of Cycle 1, Day 1 of Cycles 3, 4, 8, 12, 16; pre-infusion (0 hr) and 5 min post-infusion on Day 1 of Cycle 2 (each cycle=21 days); 30 days and 120 days after last dose (up to approximately 3-6 years)
Time frame: Pre-infusion (0 hr) on Day 1 of Cycle 1 up to 30 days and 120 days after last dose (up to approximately 3-6 years) (Detailed timeframe is provided in outcome measure description)
Plasma Concentration of BL-8040
Pre-dose (0 hr) on Day 1 of priming period (1 week prior to Day 1 of Cycle 1); 1 hr post-dose on Days 1, 5 of priming period; pre-dose (0 hr), 1 hour post-dose on Day 15 of Cycle 1 and Day 1 of Cycles 2, 3, 4, 8, 12, 16; pre-dose (0 hr) on Day 1 of Cycle 20 and every 4 cycles thereafter (each cycle=21 days) (up to approximately 3-6 years); 30 days after last dose (up to approximately 3-6 years)
Time frame: Pre-dose (0 hr) on Day 1 of priming period (1 week prior to Day 1 of Cycle 1) up to 30 days after last dose (up to approximately 3-6 years) (Detailed timeframe is provided in outcome measure description)
Plasma Concentration of Linagliptin
Time frame: 2 hr postdose oral linagliptin on Day 1 of Cycle 1, prior to atezolizumab infusion and predose oral linagliptin on Day 15 of Cycle 1 as well as on Day 1 of Cycles 2, 3, and 4
Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab
Time frame: Pre-infusion (0 hr) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (each cycle=28 days); 30 days and 120 days after last dose (up to approximately 3-6 years)
Percentage of Participants With ADA to PEGPH20
Time frame: Pre-infusion (0 hr) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (each cycle=21 days); 30 days and 120 days after last dose (up to approximately 3-6 years)
Percentage of Participants With ADA to BL-8040
Pre-dose (0 hr) on Day 1 of priming period (1 week prior to Cycle 1 Day 1), Day 15 of Cycle 1 and Day 1 of Cycles 2, 3, 4, 8, 12, 16, 20 and every 4 cycles thereafter (each cycle=21 days) (up to approximately 3-6 years); 30 days after last dose (up to approximately 3-6 years)
Time frame: Pre-dose (0 hr) on Day 1 of priming period (1 week prior to Day 1 of Cycle 1) up to 30 days after last dose (up to approximately 3-6 years) (Detailed timeframe is provided in outcome measure description)
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The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Blacktown Hospital
Blacktown, New South Wales, Australia
Monash Medical Centre-Moorabbin Campus
Clayton, Victoria, Australia
Peter MacCallum Cancer Centre
Melbourne, Victoria, Australia
Rambam Health Care Campus
Haifa, Israel
...and 18 more locations