A Study of Multiple Immunotherapy-Based Treatment Combinations in Patients With Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Cancer (G/GEJ) or Esophageal Cancer (Morpheus-Gastric and Esophageal Cancer)

Phase 2TerminatedNCT03281369

Hoffmann-La Roche219 enrolled

Overview

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

219

Conditions

Gastric Adenocarcinoma or Gastroesophageal Junction Adenocarcinoma or Esophageal Carcinoma

Interventions

5-Fluorouracil (5-FU)DRUG

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.

LeucovorinDRUG

Leucovorin: 100 mg/m\^2 IV over 2 hours on Days 1 and 15 of every 28-day cycle.

OxaliplatinDRUG

Oxaliplatin: 100 mg/m\^2 administered by IV infusion over 2 hours on Days 1 and 15 of every 28-day cycle.

AtezolizumabDRUG

Atezolizumab: 840 mg by IV infusion on Days 1 and 15 of every 28-day cycle.

CobimetinibDRUG

Cobimetinib: 60 mg by mouth once a day on Days 1-21 of every 28-day cycle

RamucirumabBIOLOGICAL

Ramucirumab: 8 mg/kg administered by IV infusion over 60 minutes on Days 1 and 15 of every 28-day cycle.

PaclitaxelDRUG

Paclitaxel: 80 mg/m\^2 administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.

PEGylated recombinant human hyaluronidase (PEGPH20)BIOLOGICAL

PEGPH20: 3 micrograms per kilogram (mcg/kg) administered by IV infusion on Days 1, 8, and 15 of every 21-day cycle.

BL-8040DRUG

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).

LinagliptinDRUG

Linagliptin: 5 mg orally once a day of every 21-day cycle.

AtezolizumabDRUG

Atezolizumab: 1200 mg administered by IV infusion on Day 1 of every 21-day cycle

CobimetinibDRUG

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.

CisplatinDRUG

Cisplatin: 80 mg/m\^2 administered by IV infusion on Day 1 of each 21 day cycle. Treatment will be capped after 6 doses.

TiragolumabDRUG

Tiragolumab: 600 mg administered by IV infusion on Day 1 of every 21 day cycle.

5-Fluorouracil (5-FU)DRUG

5-FU 800 mg/m\^2 administerd by IV infusion on Days 1-5 of each 21 day cycle.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: Gastric Cancer Cohorts Inclusion Criteria: * Age \>/= 18 years; * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1; * Life expectancy \>/= 3 months, as determined by the investigator; * Histologically or cytologically confirmed locally advanced unresectable or metastatic adenocarcinoma of gastric or gastroesophageal junction; (for the 1L Gastric Cancer Cohort: no prior systemic therapy for the locally advanced or metastatic disease; for the 2L Gastric Cancer Cohort: disease progression during or following a first-line platinum-containing or fluoropyrimidine-containing chemotherapy regimen); * Availability of a representative tumor specimen that is suitable for determination of PD-L1 and TIGIT levels by IHC and/or additional biomarker status by means of retrospective central testing; * Only for the 1L Gastric Cancer Cohort: human epidermal growth factor receptor 2 (HER2)-negative tumors; * Measurable disease (at least one target lesion) according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1); * Adequate hematologic and end organ function based on laboratory results obtained within 14 days prior to initiation of study treatment; * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures as outlined for each specific treatment arm; * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as outlined for each specific treatment arm. Esophageal Cancer Cohort Inclusion Criteria: * Histologically or cytologically confirmed diagnosis of squamous cell carcinoma or adenocarcinoma of the esophagus in locally advanced or metastatic disease; * No prior systemic treatment for esophageal cancer, with the following exception: For patients treated with chemotherapy in the locally advanced setting: occurrence of metastasis after 6 months from the last dose of chemotherapy; * For patients with adenocarcinoma: absence of HER2 expression; * Life expectancy \>/=3 months as determined by the investigator; * Measurable disease per RECIST v1.1; * Adequate hematologic and end-organ function; * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating eggs; * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm; * ECOG Performance Status of 0, 1, or 2. Exclusion Criteria: Exclusion criteria for the 2L Gastric Cancer Cohort: * Urinary protein is \> 1 + on dipstick and the required following 24-hour urine collection shows urinary protein \> 2000 mg; * Serious or non-healing wound, peptic ulcer, or bone fracture within 28 days prior to initiation of study treatment; * History of gastrointestinal perforation and/or fistulae within 6 months prior to initiation of study treatment; * Presence of a bowel obstruction, history or presence of inflammatory enteropathy, or extensive intestinal resection, Crohn disease, ulcerative colitis, or chronic diarrhea; * Uncontrolled arterial hypertension \>/= 150/ \>/= 90 millimeter of mercury (mmHg) despite standard medical management; * Chronic therapy with non-steroidal anti-inflammatory agents or other anti-platelet agents. Gastric Cancer Exclusion Criteria: * Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy; * Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases; * History of leptomeningeal disease; * Active or history of autoimmune disease or immune deficiency; * History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan; * Positive test for human immunodeficiency virus (HIV) at screening; * Active hepatitis B virus (HBV) or hepatitis C (HCV) infection; * Severe infection within 4 weeks prior to initiation of study treatment; * Significant cardiovascular disease; * Significant bleeding disorder; * Prior allogeneic stem cell or solid organ transplantation; * Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study; * Treatment with anticoagulation with warfarin, low-molecular-weight heparin, or similar agents for therapeutic purposes; * History of malignancy other than gastric or gastroesophageal junction carcinoma within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death; * Known allergy or hypersensitivity to any of the study drugs or their excipients. Esophageal Cancer Cohort Exclusion Criteria: * High risk for developing esophageal fistula by clinical assessment or imaging; * Symptomatic, untreated, or actively progressing central nervous system (CNS) Metastases; * Positive EBV viral capsid antigen IgM test at screening; * History of leptomeningeal disease; * Active or history of autoimmune disease or immune deficiency; * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan; * Active tuberculosis; * Significant cardiovascular disease within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina; * History of malignancy other than esophageal cancer within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death; * Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of atezolizumab or within 90 days after the final dose of tiragolumab.

Outcomes

Primary Outcomes

Stage 1: Percentage of Participants With Objective Response (OR), as Determined by Investigator According to RECIST v1.1

OR was defined as a complete response (CR) or partial response (PR) on two consecutive occasions ≥ 4 weeks apart during Stage 1, as determined by the investigator using RECIST v.1.1. Objective response rate (ORR) was defined as the percentage of participants with OR. CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of all target lesions, taking as reference the baseline SOD, in the absence of CR. 95% confidence intervals (CI) for rates were constructed using Clopper-Pearson method. Percentages have been rounded off.

Time frame: From randomization up to approximately 84.2 months

Secondary Outcomes

Stage 1: Progression Free Survival (PFS) After Randomization, as Determined by Investigator According to RECIST v1.1

PFS was defined as the time from randomization to the first occurrence of documented PD, as determined by the investigator according to RECIST v1.1 or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum in the study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm or unequivocal progression of existing non-target lesions. Participants who did not have documented PD or death, PFS was censored at the day of the last tumor assessment. Kaplan-Meier (K-M) method was used to estimate PFS.

Time frame: From randomization to the first occurrence of PD or death (up to approximately 84.2 months)

Stage 1: Overall Survival (OS) After Randomization

OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. K-M methodology was used to estimate the median OS.

Time frame: From randomization to death (up to approximately 84.2 months)

Stage 1: OS at Month 6 and Month 12

OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. The K-M approach was used to estimate the percentage of participants who were event-free for OS at Month 6 and Month 12. Percentages have been rounded off.

Time frame: At Months 6 and 12

Stage 1: Duration of Response (DOR), as Determined by Investigator According to RECIST v1.1

DOR was defined as time from first occurrence of a documented OR until the time of documented PD as determined by investigator assessment using RECIST v1.1 or death from any cause, whichever occurs first. CR was defined as the disappearance of all target \& non-target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. PD=at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on the study including baseline (nadir). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm or unequivocal progression of existing non-target lesions. Participants who did not have documented PD or death, DOR was censored at the day of the last tumor assessment. K-M method was used to estimate DOR.

Time frame: Up to approximately 84.2 months

Stage 1: Percentage of Participants With Disease Control (DC), as Determined by Investigator According to RECIST v1.1

DC was defined as stable disease (SD) for ≥16 weeks for GC cohort or ≥ 12 weeks for esophageal cancer cohort, or CR/PR, as determined by investigator per RECIST v1.1. Disease control rate (DCR) was defined as percentage of participants with DC. CR was defined as disappearance of all target \& non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least 30% decrease in SOD of target lesions, taking as reference baseline SOD. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD was defined as at least 20% increase in SOD of target lesions, taking as reference smallest sum on study including baseline (nadir). Additionally, the sum must also demonstrate absolute increase of at least 5 mm or unequivocal progression of existing non-target lesions. Percentages have been rounded off.

Time frame: Up to approximately 84.2 months

Stages 1 and 2: Percentage of Participants With Adverse Events (AEs)

An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptoms, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product.

Time frame: Stage 1: Up to 84.2 months; Stage 2: Up to 42.6 months

Stage 1: Serum Concentration of Atezolizumab

1 cycle = 21 days for the all three reported arms: Stage 1 Cohort 2: Atezolizumab + PEGPH20, Stage 1: Atezolizumab + Cisplatin + 5-FU" cohorts and Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU" cohort. The protocol pre-specified that PK assessments could be conducted only for treatment combinations selected by the sponsor for further development. As the sponsor decided not to continue further development of the mFOLFOX6 + atezolizumab + cobimetinib, atezolizumab + linagliptin, and atezolizumab + BL-8040 combinations, PK data were not reported for these cohorts.

Time frame: Pre-dose, 30 minutes (min) post-dose (infusion=60 min) on Day 1 of Cycle 1; pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12, 16, 20, 24, & 28; Stage 1 treatment discontinuation (TD) (up to approximately 82.7 months)

Stage 1: Serum Concentration of Tiragolumab

Time frame: Pre-dose, 30 min post-dose on Day 1 of Cycle 1; pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12, 16, 20, 24, & 28 (1 Cycle=28 days); Stage 1 TD (up to approximately 46.7 months)

Stage 1: Plasma Concentration of PEGPH20

1 Cycle=21 days

Time frame: Pre-dose: Day 1 of Cycles 1, 2, 3, 4 & Days 8, 15 of Cycle 1; 5 minutes & 1-3 hours post-dose: Day 1 Cycle 1; 5 min post-dose: Day 1 Cycle 2; Stage 1: TD (up to approx 3.3 months) & Day 120 post last dose of atezo (up to approx 6.8 months)

Stage 1: Number of Participants With Treatment-emergent Anti-drug Antibodies (ADAs) to Atezolizumab

Participants who received atezolizumab were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following atezolizumab exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units (t.u.) greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants with a positive post-baseline sample have been reported here. The protocol pre-specified that ADA assessments could be conducted only for treatment combinations selected by the sponsor for further development. As the sponsor decided not to continue further development of the mFOLFOX6 + atezolizumab + cobimetinib, atezolizumab + linagliptin, and atezolizumab + BL-8040 combinations, ADA data were not reported for these cohorts.

Time frame: Up to approximately 82.7 months

Stage 1: Number of Participants With Treatment-emergent ADAs to Tiragolumab

Participants who received tiragolumab were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following tiragolumab exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 t.u. greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants with a positive post-baseline sample has been reported here.

Time frame: Up to approximately 46.7 months

Stage 1: Number of Participants With Treatment-emergent ADAs to PEGPH20

Participants who received PEGPH20 were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following PEGPH20 exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 t.u. greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants with a positive post-baseline sample has been reported here.

Time frame: Up to approximately 3.3 months