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)

NCT ID: NCT03281369

Last Updated: 2025-12-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 214 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-13
• Study Completion Date: 2025-10-09

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.

Conditions

Gastric Adenocarcinoma or Gastroesophageal Junction Adenocarcinoma or Esophageal Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

5-Fluorouracil (5-FU)

Intervention Type: 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.

Leucovorin

Intervention Type: DRUG

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

Oxaliplatin

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

5-Fluorouracil (5-FU)

Intervention Type: 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.

Leucovorin

Intervention Type: DRUG

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

Oxaliplatin

Intervention Type: DRUG

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

Atezolizumab

Intervention Type: DRUG

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

Cobimetinib

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

5-Fluorouracil (5-FU)

Intervention Type: 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.

Leucovorin

Intervention Type: DRUG

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

Oxaliplatin

Intervention Type: DRUG

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

Atezolizumab

Intervention Type: DRUG

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

Cobimetinib

Intervention Type: DRUG

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

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.

Group Type: ACTIVE_COMPARATOR

Ramucirumab

Intervention Type: BIOLOGICAL

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

Paclitaxel

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Atezolizumab

Intervention Type: DRUG

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

Cobimetinib

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

PEGylated recombinant human hyaluronidase (PEGPH20)

Intervention Type: BIOLOGICAL

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

Atezolizumab

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

BL-8040

Intervention Type: DRUG

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).

Atezolizumab

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Linagliptin

Intervention Type: DRUG

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

Atezolizumab

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Atezolizumab

Intervention Type: DRUG

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

Cisplatin

Intervention Type: DRUG

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

Intervention Type: DRUG

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

5-Fluorouracil (5-FU)

Intervention Type: DRUG

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

1L-2: Atezo+Cisplatin+5-FU (Esophageal Cancer Cohort)

Participants in the 1L-2 Esophageal Cancer arm will receive atezolizumab in combination with chemotherapy.

Group Type: EXPERIMENTAL

Atezolizumab

Intervention Type: DRUG

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

Cisplatin

Intervention Type: DRUG

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

5-Fluorouracil (5-FU)

Intervention Type: DRUG

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

1L-Control: Cisplatin+5-FU (Esophageal Cancer Cohort)

Participants in the 1L-Control Eophageal Cancer arm will receive chemotherapy.

Group Type: ACTIVE_COMPARATOR

Cisplatin

Intervention Type: DRUG

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

5-Fluorouracil (5-FU)

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Atezolizumab

Intervention Type: DRUG

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

Tiragolumab

Intervention Type: DRUG

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

Interventions

5-Fluorouracil (5-FU)

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.

Intervention Type: DRUG

Leucovorin

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

Intervention Type: DRUG

Oxaliplatin

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

Intervention Type: DRUG

Atezolizumab

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

Intervention Type: DRUG

Cobimetinib

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

Intervention Type: DRUG

Ramucirumab

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

Intervention Type: BIOLOGICAL

Paclitaxel

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

Intervention Type: DRUG

PEGylated recombinant human hyaluronidase (PEGPH20)

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

Intervention Type: BIOLOGICAL

BL-8040

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).

Intervention Type: DRUG

Linagliptin

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

Intervention Type: DRUG

Atezolizumab

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

Intervention Type: DRUG

Cobimetinib

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.

Intervention Type: DRUG

Cisplatin

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

Intervention Type: DRUG

Tiragolumab

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

Intervention Type: DRUG

5-Fluorouracil (5-FU)

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

Intervention Type: DRUG

Other Intervention Names

Folinic acid; Tecentriq; Cotellic; Tecentriq; Cotellic; RO7092284

Eligibility Criteria

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.

• 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

• 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.

• 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.

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Halozyme Therapeutics

INDUSTRY

Sponsor Role: collaborator

BioLineRx, Ltd.

INDUSTRY

Sponsor Role: collaborator

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

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

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

Sourasky Medical Centre

Tel Aviv, , Israel

Seoul National University Bundang Hospital

Gyeonggi-do, , South Korea

Korea University Anam Hospital

Seoul, , South Korea

Seoul National University Hospital (SNUH) - Medical Oncology Center

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

Yonsei University College of Medicine (YUCM)-Yonsei Cancer Center

Seoul, , South Korea

University of Ulsan College of Medicine - Asan Medical Center (AMC) - Asan Cancer Center (ACC)

Songpa-gu, , South Korea

The Catholic University of Korea St. Vincent's Hospital

Suwon, , South Korea

Universidad de Navarra - Clinica Universitaria de Navarra (CUN)

Pamplona, Navarre, Spain

Hospital Universitari Vall dHebron

Barcelona, , Spain

National Cheng Kung University Hospital

Tainan, , Taiwan

Taipei Veterans General Hospital

Taipei, , Taiwan

National Taiwan University Hospital (NTUH) - Cancer Research Center

Zhongzheng Dist., , Taiwan

Beatson West of Scotland Cancer Centre

Glasgow, , United Kingdom

Barts and The London School of Medicine and Dentistry - Barts Cancer Institute (BCI)-CECM

London, , United Kingdom

The Royal Marsden

London, , United Kingdom

The Christie NHS Foundation Trust

Manchester, , United Kingdom

The Royal Marsden NHS Foundation Trust - Royal Marsden Hospital (RMH) - Sutton

Sutton, , United Kingdom

Countries

United States; Australia; Israel; South Korea; Spain; Taiwan; United Kingdom

References

Ko AH, Kim KP, Siveke JT, Lopez CD, Lacy J, O'Reilly EM, Macarulla T, Manji GA, Lee J, Ajani J, Alsina Maqueda M, Rha SY, Lau J, Al-Sakaff N, Allen S, Lu D, Shemesh CS, Gan X, Cha E, Oh DY. Atezolizumab Plus PEGPH20 Versus Chemotherapy in Advanced Pancreatic Ductal Adenocarcinoma and Gastric Cancer: MORPHEUS Phase Ib/II Umbrella Randomized Study Platform. Oncologist. 2023 Jun 2;28(6):553-e472. doi: 10.1093/oncolo/oyad022.

Reference Type: DERIVED

PMID: 36940261 (View on PubMed)

Other Identifiers

2016-004529-17

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

YO39609

Identifier Type: -

Identifier Source: org_study_id