A Phase Ib/II, Open-Label, Multicenter, Randomized, Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Cancer or Esophageal Cancer (Morpheus-Gastric and Esophageal Cancer)
Overview
- Phase
- Phase 1
- Intervention
- 5-Fluorouracil (5-FU)
- Conditions
- Gastric Adenocarcinoma or Gastroesophageal Junction Adenocarcinoma or Esophageal Carcinoma
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 214
- Locations
- 28
- Primary Endpoint
- For Arm 1L-A : Percentage of Participants with Serious and Non-serious Treatment-related AEs
- Status
- Completed
- Last Updated
- 4 months ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
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;
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;
Arms & Interventions
1L-Control: mFOLFOX6 (Gastric Cancer)
Participants in the 1L Gastric Cancer Control arm will receive modified FOLFOX6 (mFOLFOX6) treatment consisting of 5-fluorouracil (5-FU), leucovorin (folinic acid), and oxaliplatin. Participants who progressed on treatment may have the option of receiving Atezolizumab + Cobimetinib treatment, provided they meet the eligibility criteria. No longer enrolling participants as of June 2018.
Intervention: 5-Fluorouracil (5-FU)
1L-Control: mFOLFOX6 (Gastric Cancer)
Participants in the 1L Gastric Cancer Control arm will receive modified FOLFOX6 (mFOLFOX6) treatment consisting of 5-fluorouracil (5-FU), leucovorin (folinic acid), and oxaliplatin. Participants who progressed on treatment may have the option of receiving Atezolizumab + Cobimetinib treatment, provided they meet the eligibility criteria. No longer enrolling participants as of June 2018.
Intervention: Leucovorin
1L-Control: mFOLFOX6 (Gastric Cancer)
Participants in the 1L Gastric Cancer Control arm will receive modified FOLFOX6 (mFOLFOX6) treatment consisting of 5-fluorouracil (5-FU), leucovorin (folinic acid), and oxaliplatin. Participants who progressed on treatment may have the option of receiving Atezolizumab + Cobimetinib treatment, provided they meet the eligibility criteria. No longer enrolling participants as of June 2018.
Intervention: Oxaliplatin
1L-A: mFOLFOX6 + Atezo + Cobi (Gastric Cancer)
Participants in the 1L-A Gastric Cancer arm will receive mFOLFOX6 treatment consisting of 5-FU, leucovorin and oxaliplatin in combination with atezolizumab plus cobimetinib. No longer enrolling participants as of June 2018.
Intervention: 5-Fluorouracil (5-FU)
1L-A: mFOLFOX6 + Atezo + Cobi (Gastric Cancer)
Participants in the 1L-A Gastric Cancer arm will receive mFOLFOX6 treatment consisting of 5-FU, leucovorin and oxaliplatin in combination with atezolizumab plus cobimetinib. No longer enrolling participants as of June 2018.
Intervention: Leucovorin
1L-A: mFOLFOX6 + Atezo + Cobi (Gastric Cancer)
Participants in the 1L-A Gastric Cancer arm will receive mFOLFOX6 treatment consisting of 5-FU, leucovorin and oxaliplatin in combination with atezolizumab plus cobimetinib. No longer enrolling participants as of June 2018.
Intervention: Oxaliplatin
1L-A: mFOLFOX6 + Atezo + Cobi (Gastric Cancer)
Participants in the 1L-A Gastric Cancer arm will receive mFOLFOX6 treatment consisting of 5-FU, leucovorin and oxaliplatin in combination with atezolizumab plus cobimetinib. No longer enrolling participants as of June 2018.
Intervention: Atezolizumab
1L-A2: Atezo+mFOLFOX6 followed by Atezo+Cobi (Gastric Cancer)
Participants in the 1L-A2 Gastric Cancer arm will receive mFOLFOX6 treatment consisting of 5-FU, leucovorin and oxaliplatin in combination with atezolizumab during cycles 1 and 2 followed by atezolizumab plus cobimetinib during cycles 3 and beyond. No longer enrolling participants as of June 2018.
Intervention: Atezolizumab
1L-A: mFOLFOX6 + Atezo + Cobi (Gastric Cancer)
Participants in the 1L-A Gastric Cancer arm will receive mFOLFOX6 treatment consisting of 5-FU, leucovorin and oxaliplatin in combination with atezolizumab plus cobimetinib. No longer enrolling participants as of June 2018.
Intervention: Cobimetinib
1L-A2: Atezo+mFOLFOX6 followed by Atezo+Cobi (Gastric Cancer)
Participants in the 1L-A2 Gastric Cancer arm will receive mFOLFOX6 treatment consisting of 5-FU, leucovorin and oxaliplatin in combination with atezolizumab during cycles 1 and 2 followed by atezolizumab plus cobimetinib during cycles 3 and beyond. No longer enrolling participants as of June 2018.
Intervention: 5-Fluorouracil (5-FU)
1L-A2: Atezo+mFOLFOX6 followed by Atezo+Cobi (Gastric Cancer)
Participants in the 1L-A2 Gastric Cancer arm will receive mFOLFOX6 treatment consisting of 5-FU, leucovorin and oxaliplatin in combination with atezolizumab during cycles 1 and 2 followed by atezolizumab plus cobimetinib during cycles 3 and beyond. No longer enrolling participants as of June 2018.
Intervention: Leucovorin
1L-A2: Atezo+mFOLFOX6 followed by Atezo+Cobi (Gastric Cancer)
Participants in the 1L-A2 Gastric Cancer arm will receive mFOLFOX6 treatment consisting of 5-FU, leucovorin and oxaliplatin in combination with atezolizumab during cycles 1 and 2 followed by atezolizumab plus cobimetinib during cycles 3 and beyond. No longer enrolling participants as of June 2018.
Intervention: Oxaliplatin
1L-A2: Atezo+mFOLFOX6 followed by Atezo+Cobi (Gastric Cancer)
Participants in the 1L-A2 Gastric Cancer arm will receive mFOLFOX6 treatment consisting of 5-FU, leucovorin and oxaliplatin in combination with atezolizumab during cycles 1 and 2 followed by atezolizumab plus cobimetinib during cycles 3 and beyond. No longer enrolling participants as of June 2018.
Intervention: Cobimetinib
2L-Control: Ramucirumab + Paclitaxel (Gastric Cancer)
Participants in the 2L Gastric Cancer Control arm received ramucirumab plus paclitaxel. Participants who progressed on treatment had the option of receiving Atezolizumab + Cobimetinib treatment, provided they met the eligibility criteria. Enrollment completed as of October 2019.
Intervention: Ramucirumab
2L-Control: Ramucirumab + Paclitaxel (Gastric Cancer)
Participants in the 2L Gastric Cancer Control arm received ramucirumab plus paclitaxel. Participants who progressed on treatment had the option of receiving Atezolizumab + Cobimetinib treatment, provided they met the eligibility criteria. Enrollment completed as of October 2019.
Intervention: Paclitaxel
2L-1: Atezo + Cobi (Gastric Cancer)
Participants in the 2L-1 Gastric Cancer arm received atezolizumab in combination with cobimetinib. Enrollment completed as of October 2019.
Intervention: Atezolizumab
2L-1: Atezo + Cobi (Gastric Cancer)
Participants in the 2L-1 Gastric Cancer arm received atezolizumab in combination with cobimetinib. Enrollment completed as of October 2019.
Intervention: Cobimetinib
2L-2: Atezo + PEGPH20 (Gastric Cancer)
Participants in the 2L-2 Gastric Cancer arm received atezolizumab in combination with PEGylated recombinant human hyaluronidase (PEGPH20). Participants who progressed on treatment had the option of receiving Atezolizumab + Cobimetinib treatment, provided they met the eligibility criteria. Enrollment completed as of October 2019.
Intervention: PEGylated recombinant human hyaluronidase (PEGPH20)
2L-2: Atezo + PEGPH20 (Gastric Cancer)
Participants in the 2L-2 Gastric Cancer arm received atezolizumab in combination with PEGylated recombinant human hyaluronidase (PEGPH20). Participants who progressed on treatment had the option of receiving Atezolizumab + Cobimetinib treatment, provided they met the eligibility criteria. Enrollment completed as of October 2019.
Intervention: Atezolizumab
2L-3: Atezo + BL-8040 (Gastric Cancer)
Participants in the 2L-3 Gastric Cancer arm received atezolizumab in combination with BL-8040. Participants who progressed on treatment had the option of receiving Atezolizumab + Cobimetinib treatment, provided they met the eligibility criteria. Enrollment completed as of October 2019.
Intervention: BL-8040
2L-3: Atezo + BL-8040 (Gastric Cancer)
Participants in the 2L-3 Gastric Cancer arm received atezolizumab in combination with BL-8040. Participants who progressed on treatment had the option of receiving Atezolizumab + Cobimetinib treatment, provided they met the eligibility criteria. Enrollment completed as of October 2019.
Intervention: Atezolizumab
2L-4: Atezo + Linagliptin (Gastric Cancer)
Participants in the 2L-4 Gastric Cancer arm received atezolizumab in combination with linagliptin. Participants who progressed on treatment had the option of receiving Atezolizumab + Cobimetinib treatment, provided they met the eligibility criteria. Enrollment completed as of October 2019.
Intervention: Linagliptin
2L-4: Atezo + Linagliptin (Gastric Cancer)
Participants in the 2L-4 Gastric Cancer arm received atezolizumab in combination with linagliptin. Participants who progressed on treatment had the option of receiving Atezolizumab + Cobimetinib treatment, provided they met the eligibility criteria. Enrollment completed as of October 2019.
Intervention: Atezolizumab
1L-1:Atezo+Tiragolumab+Cisplatin+5FU(Esophageal Cancer Cohort)
Participants in the 1L-1 Esophageal Cancer arm will receive atezolizumab in combination with tiragolumab and chemotherapy.
Intervention: Atezolizumab
1L-1:Atezo+Tiragolumab+Cisplatin+5FU(Esophageal Cancer Cohort)
Participants in the 1L-1 Esophageal Cancer arm will receive atezolizumab in combination with tiragolumab and chemotherapy.
Intervention: Cisplatin
1L-1:Atezo+Tiragolumab+Cisplatin+5FU(Esophageal Cancer Cohort)
Participants in the 1L-1 Esophageal Cancer arm will receive atezolizumab in combination with tiragolumab and chemotherapy.
Intervention: Tiragolumab
1L-1:Atezo+Tiragolumab+Cisplatin+5FU(Esophageal Cancer Cohort)
Participants in the 1L-1 Esophageal Cancer arm will receive atezolizumab in combination with tiragolumab and chemotherapy.
Intervention: 5-Fluorouracil (5-FU)
1L-2: Atezo+Cisplatin+5-FU (Esophageal Cancer Cohort)
Participants in the 1L-2 Esophageal Cancer arm will receive atezolizumab in combination with chemotherapy.
Intervention: Atezolizumab
1L-2: Atezo+Cisplatin+5-FU (Esophageal Cancer Cohort)
Participants in the 1L-2 Esophageal Cancer arm will receive atezolizumab in combination with chemotherapy.
Intervention: Cisplatin
1L-Control: Cisplatin+5-FU (Esophageal Cancer Cohort)
Participants in the 1L-Control Eophageal Cancer arm will receive chemotherapy.
Intervention: Cisplatin
1L-2: Atezo+Cisplatin+5-FU (Esophageal Cancer Cohort)
Participants in the 1L-2 Esophageal Cancer arm will receive atezolizumab in combination with chemotherapy.
Intervention: 5-Fluorouracil (5-FU)
1L-Control: Cisplatin+5-FU (Esophageal Cancer Cohort)
Participants in the 1L-Control Eophageal Cancer arm will receive chemotherapy.
Intervention: 5-Fluorouracil (5-FU)
1L-3: Atezo+Tiragolumab (Esophageal Cancer Cohort)
Participants in the 1L-3 Esophageal Cancer arm will receive atezolizumab + tiragolumab treatment. Participants from the cisplatin + 5-FU esophageal cancer cohort arm may be permitted to enroll in this arm if they progress after receiving chemotherapy.
Intervention: Atezolizumab
1L-3: Atezo+Tiragolumab (Esophageal Cancer Cohort)
Participants in the 1L-3 Esophageal Cancer arm will receive atezolizumab + tiragolumab treatment. Participants from the cisplatin + 5-FU esophageal cancer cohort arm may be permitted to enroll in this arm if they progress after receiving chemotherapy.
Intervention: Tiragolumab
Outcomes
Primary Outcomes
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
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)
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)
Secondary Outcomes
- Progression-Free Survival (PFS), as Determined by Investigator According to RECIST v1.1(From randomization up to the first occurrence of disease (up to approximately 3-6 years))
- Percentage of Participants With Disease Control, as Determined by the Investigator per RECIST v1.1(From randomization until disease progression or loss of clinical benefit (up to approximately 3-6 years))
- Plasma Concentration of Cobimetinib(Prior to cobimetinib dose, 2-4 hr after cobimetinib dose on Day 15 of Cycle 1 (cycle length=28 days))
- Overall Survival (OS)(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(Month 6, Month 12)
- Duration of Response, as Determined by Investigator According to RECIST v1.1(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))
- Serum Concentration of Atezolizumab(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 PEGPH20(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))
- Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab(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))
- Plasma Concentration of BL-8040(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))
- Percentage of Participants With ADA to PEGPH20(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))
- Plasma Concentration of Linagliptin(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 ADA to BL-8040(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))