TerminatedNCT03281369Updated Aug 3, 2026Results posted

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)

A Phase 1/2 interventional study of 5-Fluorouracil (5-FU) and Leucovorin in Gastric Adenocarcinoma or Gastroesophageal Junction Adenocarcinoma or Esophageal Carcinoma, sponsored by Hoffmann-La Roche. Terminated at 28 sites in 7 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-08-03.

Sponsored by Hoffmann-La Roche · Phase 1/2, Interventional, and Treatment

Why this study was terminated

The study was closed because the sponsor decided not to continue the development of certain treatment combinations.

Phase: Phase 1/2
Study type: Interventional
Enrollment: 219
Allocation: Randomized
Ages: 18 Years and older
Sex: All

Study 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 studied

Gastric Adenocarcinoma or Gastroesophageal Junction Adenocarcinoma or Esophageal Carcinoma

Browse trials for

Esophageal Neoplasms 1,591

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

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:

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.

Study design

Phase: Phase 1 / Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 219 participants (actual)

Study arms

Active comparator
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.
Drug: 5-Fluorouracil (5-FU) · Drug: Leucovorin · Drug: Oxaliplatin
Experimental
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.
Drug: 5-Fluorouracil (5-FU) · Drug: Leucovorin · Drug: Oxaliplatin · Drug: Atezolizumab · Drug: Cobimetinib
Experimental
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.
Drug: 5-Fluorouracil (5-FU) · Drug: Leucovorin · Drug: Oxaliplatin · Drug: Atezolizumab · Drug: Cobimetinib
Active comparator
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.
Biological: Ramucirumab · Drug: Paclitaxel
Experimental
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.
Drug: Atezolizumab · Drug: Cobimetinib
Experimental
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.
Biological: PEGylated recombinant human hyaluronidase (PEGPH20) · Drug: Atezolizumab
Experimental
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.
Drug: BL-8040 · Drug: Atezolizumab
Experimental
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.
Drug: Linagliptin · Drug: Atezolizumab
Experimental
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.
Drug: Atezolizumab · Drug: Cisplatin · Drug: Tiragolumab · Drug: 5-Fluorouracil (5-FU)
Experimental
1L-2: Atezo+Cisplatin+5-FU (Esophageal Cancer Cohort)
Participants in the 1L-2 Esophageal Cancer arm will receive atezolizumab in combination with chemotherapy.
Drug: Atezolizumab · Drug: Cisplatin · Drug: 5-Fluorouracil (5-FU)
Active comparator
1L-Control: Cisplatin+5-FU (Esophageal Cancer Cohort)
Participants in the 1L-Control Eophageal Cancer arm will receive chemotherapy.
Drug: Cisplatin · Drug: 5-Fluorouracil (5-FU)
Experimental
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.
Drug: Atezolizumab · Drug: Tiragolumab

Interventions

Drug5-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.
DrugLeucovorin
Leucovorin: 100 mg/m\^2 IV over 2 hours on Days 1 and 15 of every 28-day cycle.
Also known as: Folinic acid
DrugOxaliplatin
Oxaliplatin: 100 mg/m\^2 administered by IV infusion over 2 hours on Days 1 and 15 of every 28-day cycle.
DrugAtezolizumab
Atezolizumab: 840 mg by IV infusion on Days 1 and 15 of every 28-day cycle.
Also known as: Tecentriq
DrugCobimetinib
Cobimetinib: 60 mg by mouth once a day on Days 1-21 of every 28-day cycle
Also known as: Cotellic
BiologicalRamucirumab
Ramucirumab: 8 mg/kg administered by IV infusion over 60 minutes on Days 1 and 15 of every 28-day cycle.
DrugPaclitaxel
Paclitaxel: 80 mg/m\^2 administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.
BiologicalPEGylated 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.
DrugBL-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).
DrugLinagliptin
Linagliptin: 5 mg orally once a day of every 21-day cycle.
DrugAtezolizumab
Atezolizumab: 1200 mg administered by IV infusion on Day 1 of every 21-day cycle
Also known as: Tecentriq
DrugCobimetinib
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.
Also known as: Cotellic
DrugCisplatin
Cisplatin: 80 mg/m\^2 administered by IV infusion on Day 1 of each 21 day cycle. Treatment will be capped after 6 doses.
DrugTiragolumab
Tiragolumab: 600 mg administered by IV infusion on Day 1 of every 21 day cycle.
Also known as: RO7092284
Drug5-Fluorouracil (5-FU)
5-FU 800 mg/m\^2 administerd by IV infusion on Days 1-5 of each 21 day cycle.

What researchers measure

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

Results

Posted Aug 3, 2026

Participant flow

A total of 219 participants with metastatic gastric or esophageal cancer took part in the study from 13 Oct 2017 to 09 Oct 2025. The study enrolled participants with gastric cancer (GC) in 2 cohorts: Cohort 1: received no prior systemic therapy for GC \& Cohort 2: received 1 prior line of systemic therapy for GC and participants with esophageal cancer in 1 cohort (received no prior systemic treatment).

Stage 1

Participant flow — Stage 1
Milestone	Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1 Cohort 2: Atezolizumab + BL-8040	Stage 1 Cohort 2: Atezolizumab + Linagliptin	Stage 1: Cisplatin + 5-FU (Control)	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU
Started	5	16	15	15	16	24	65	63
Safety-evaluable (se) population	5	12	13	13	14	23	65	62
Efficacy population	5	12	13	13	14	23	65	62
Completed	4	11	13	12	11	23	61	57
Not completed	1	5	2	3	5	1	4	6
Withdrew: Progression of disease	1	0	0	0	0	0	0	0
Withdrew: Protocol violation	0	0	1	0	0	0	0	0
Withdrew: Death	0	1	0	0	2	0	1	3
Withdrew: Withdrawal by subject	0	3	1	1	0	1	1	0
Withdrew: Reason not specified	0	1	0	0	1	0	0	0
Withdrew: Physician decision	0	0	0	1	1	0	0	1
Withdrew: Study terminated by sponsor	0	0	0	1	1	0	2	1
Withdrew: Adverse event	0	0	0	0	0	0	0	1

Stage 2

Participant flow — Stage 2
Milestone	Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1 Cohort 2: Atezolizumab + BL-8040	Stage 1 Cohort 2: Atezolizumab + Linagliptin	Stage 1: Cisplatin + 5-FU (Control)	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU	Stage 2: Atezolizumab + Tiragolumab
Started	0	0	0	0	0	0	0	0	15
Se population	0	0	0	0	0	0	0	0	14
Efficacy population	0	0	0	0	0	0	0	0	14
Completed	0	0	0	0	0	0	0	0	15
Not completed	0	0	0	0	0	0	0	0	0

Long-term Survival Follow Up (LTSFU)

Participant flow — Long-term Survival Follow Up (LTSFU)
Milestone	Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1 Cohort 2: Atezolizumab + BL-8040	Stage 1 Cohort 2: Atezolizumab + Linagliptin	Stage 1: Cisplatin + 5-FU (Control)	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU	Stage 2: Atezolizumab + Tiragolumab
Started	4	11	13	12	11	8	61	57	15
Completed	0	0	0	0	0	0	0	0	0
Not completed	4	11	13	12	11	8	61	57	15
Withdrew: Study terminated by sponsor	0	0	0	0	0	0	5	11	4
Withdrew: Death	3	11	13	10	10	7	55	42	11
Withdrew: Lost to follow-up	1	0	0	1	0	0	1	1	0
Withdrew: Symptomatic deterioration	0	0	0	1	0	0	0	0	0
Withdrew: Withdrawal by subject	0	0	0	0	1	1	0	3	0

Outcome measures

PrimaryStage 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
Reported as:: Number · percentage of participants

Stage 1: Percentage of Participants With Objective Response (OR), as Determined by Investigator According to RECIST v1.1
percentage of participants	Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1 Cohort 2: Atezolizumab + BL-8040	Stage 1 Cohort 2: Atezolizumab + Linagliptin	Stage 1: Cisplatin + 5-FU (Control)	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU
Stage 1: Percentage of Participants With Objective Response (OR), as Determined by Investigator According to RECIST v1.1	40.0 (5.27 to 85.34)	16.7 (2.09 to 48.41)	0 (0.00 to 24.71)	15.4 (1.92 to 45.45)	21.4 (4.66 to 50.80)	47.8 (26.82 to 69.41)	53.8 (41.03 to 66.30)	67.7 (54.66 to 79.06)

Statistical analysis

Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + PEGPH20 · Difference in overall response rates: -16.67 · 95% CI -45.77 to 12.43
Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + BL-8040 · Difference in overall response rates: -1.28 · 95% CI -38.09 to 35.53
Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + Linagliptin · Difference in overall response rates: 4.76 · 95% CI -33.09 to 42.61

SecondaryStage 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)
Reported as:: Median · months

Stage 1: Progression Free Survival (PFS) After Randomization, as Determined by Investigator According to RECIST v1.1
months	Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1 Cohort 2: Atezolizumab + BL-8040	Stage 1 Cohort 2: Atezolizumab + Linagliptin	Stage 1: Cisplatin + 5-FU (Control)	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU
Stage 1: Progression Free Survival (PFS) After Randomization, as Determined by Investigator According to RECIST v1.1	14.93 (10.64 to NA)	6.06 (3.68 to 8.77)	1.84 (1.48 to 2.10)	1.97 (1.71 to 7.92)	1.95 (1.64 to 4.93)	5.98 (2.69 to 8.11)	7.03 (5.55 to 8.28)	6.90 (5.95 to 9.89)

Statistical analysis

Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + PEGPH20 · Hazard ratio (hr): 6.74 · 95% CI 2.06 to 22.00
Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + BL-8040 · Hazard ratio (hr): 0.97 · 95% CI 0.41 to 2.27
Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + Linagliptin · Hazard ratio (hr): 1.31 · 95% CI 0.58 to 2.97
Stage 1: Cisplatin + 5-FU (Control) vs Stage 1: Atezolizumab + Cisplatin + 5-FU · Hazard ratio (hr): 0.79 · 95% CI 0.48 to 1.31
Stage 1: Cisplatin + 5-FU (Control) vs Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU · Hazard ratio (hr): 0.56 · 95% CI 0.33 to 0.94

SecondaryStage 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)
Reported as:: Median · months

Stage 1: Overall Survival (OS) After Randomization
months	Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1 Cohort 2: Atezolizumab + BL-8040	Stage 1 Cohort 2: Atezolizumab + Linagliptin	Stage 1: Cisplatin + 5-FU (Control)	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU
Stage 1: Overall Survival (OS) After Randomization	16.99 (14.65 to NA)	8.33 (6.37 to 10.94)	7.00 (5.26 to 8.87)	10.64 (3.71 to 39.06)	8.57 (4.27 to 28.12)	10.09 (7.59 to 23.20)	12.98 (11.17 to 15.70)	16.56 (12.22 to 21.03)

Statistical analysis

Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + PEGPH20 · Hazard ratio (hr): 1.16 · 95% CI 0.52 to 2.61
Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + BL-8040 · Hazard ratio (hr): 0.63 · 95% CI 0.26 to 1.51
Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + Linagliptin · Hazard ratio (hr): 0.60 · 95% CI 0.25 to 1.43
Stage 1: Cisplatin + 5-FU (Control) vs Stage 1: Atezolizumab + Cisplatin + 5-FU · Hazard ratio (hr): 0.99 · 95% CI 0.58 to 1.68
Stage 1: Cisplatin + 5-FU (Control) vs Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU · Hazard ratio (hr): 0.75 · 95% CI 0.43 to 1.29

SecondaryStage 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
Reported as:: Number · percentage of participants

Stage 1: OS at Month 6 and Month 12
percentage of participants	Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1 Cohort 2: Atezolizumab + BL-8040	Stage 1 Cohort 2: Atezolizumab + Linagliptin	Stage 1: Cisplatin + 5-FU (Control)	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU
Month 6	100.00 (100.00 to 100.00)	75.00 (50.50 to 99.50)	53.85 (26.75 to 80.95)	51.28 (23.10 to 79.47)	56.25 (29.80 to 82.70)	78.02 (60.98 to 95.06)	87.52 (79.43 to 95.61)	88.65 (80.73 to 96.57)
Month 12	100.00 (100.00 to 100.00)	25.00 (0.50 to 49.50)	23.08 (0.17 to 45.98)	42.74 (14.71 to 70.76)	40.18 (13.51 to 66.85)	36.71 (16.54 to 56.89)	57.83 (45.73 to 69.92)	65.36 (53.36 to 77.36)

Statistical analysis

Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + PEGPH20 · Difference in event-free rate: -21.15 · 95% CI -57.69 to 15.38
Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + PEGPH20 · Difference in event-free rate: -1.92 · 95% CI -35.46 to 31.61
Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + BL-8040 · Difference in event-free rate: -23.72 · 95% CI -61.06 to 13.63
Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + BL-8040 · Difference in event-free rate: 17.74 · 95% CI -19.49 to 54.96
Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + Linagliptin · Difference in event-free rate: -18.75 · 95% CI -54.80 to 17.30
Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + Linagliptin · Difference in event-free rate: 15.18 · 95% CI -21.03 to 51.39
Stage 1: Cisplatin + 5-FU (Control) vs Stage 1: Atezolizumab + Cisplatin + 5-FU · Difference in event-free rate: 9.50 · 95% CI -9.36 to 28.37
Stage 1: Cisplatin + 5-FU (Control) vs Stage 1: Atezolizumab + Cisplatin + 5-FU · Difference in event-free rate: 21.11 · 95% CI -2.41 to 44.64
Stage 1: Cisplatin + 5-FU (Control) vs Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU · Difference in event-free rate: 10.63 · 95% CI -8.16 to 29.42
Stage 1: Cisplatin + 5-FU (Control) vs Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU · Difference in event-free rate: 28.65 · 95% CI 5.17 to 52.12

SecondaryStage 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
Reported as:: Median · months

Stage 1: Duration of Response (DOR), as Determined by Investigator According to RECIST v1.1
months	Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1 Cohort 2: Atezolizumab + BL-8040	Stage 1 Cohort 2: Atezolizumab + Linagliptin	Stage 1: Cisplatin + 5-FU (Control)	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU
Stage 1: Duration of Response (DOR), as Determined by Investigator According to RECIST v1.1	NA (NA to NA)	3.32 (2.89 to 3.75)	—	NA (58.84 to NA)	14.46 (3.55 to NA)	5.91 (2.83 to 14.06)	6.90 (5.32 to 8.77)	7.16 (4.40 to 15.31)

Statistical analysis

Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + Linagliptin · Hazard ratio (hr): 0.24 · 95% CI 0.02 to 2.67
Stage 1: Cisplatin + 5-FU (Control) vs Stage 1: Atezolizumab + Cisplatin + 5-FU · Hazard ratio (hr): 0.85 · 95% CI 0.41 to 1.76
Stage 1: Cisplatin + 5-FU (Control) vs Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU · Hazard ratio (hr): 0.57 · 95% CI 0.27 to 1.19
Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control) vs Stage 1 Cohort 2: Atezolizumab + BL-8040 · Hazard ratio (hr): 0.009

SecondaryStage 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
Reported as:: Number · percentage of participants

Stage 1: Percentage of Participants With Disease Control (DC), as Determined by Investigator According to RECIST v1.1
percentage of participants	Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1 Cohort 2: Atezolizumab + BL-8040	Stage 1 Cohort 2: Atezolizumab + Linagliptin	Stage 1: Cisplatin + 5-FU (Control)	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU
Stage 1: Percentage of Participants With Disease Control (DC), as Determined by Investigator According to RECIST v1.1	80.0 (28.36 to 99.49)	66.7 (34.89 to 90.08)	0 (0.00 to 24.71)	23.1 (5.04 to 53.81)	21.4 (4.66 to 50.80)	56.5 (34.49 to 76.81)	78.5 (66.51 to 87.69)	83.9 (72.33 to 91.98)

SecondaryStages 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
Reported as:: Number · percentage of participants

Stages 1 and 2: Percentage of Participants With Adverse Events (AEs)
percentage of participants	Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1 Cohort 2: Atezolizumab + BL-8040	Stage 1 Cohort 2: Atezolizumab + Linagliptin	Stage 1: Cisplatin + 5-FU (Control)	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU	Stage 2: Atezolizumab + Tiragolumab
Stages 1 and 2: Percentage of Participants With Adverse Events (AEs)	100	100	100	100	100	100	100	100	100

SecondaryStage 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)
Reported as:: Geometric mean · micrograms per milliliter (μg/mL)

Stage 1: Serum Concentration of Atezolizumab
micrograms per milliliter (μg/mL)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU
Pre-dose on Day 1 of Cycle 1	NA ± NA	NA ± NA	NA ± NA
30 min post-dose on Day 1 of Cycle 1	362 ± 39.2	375 ± 21.6	379 ± 22.2
Pre-dose on Day 1 of Cycle 2	64.4 ± 28.0	70.9 ± 48.8	60.8 ± 43.9
Pre-dose on Day 1 of Cycle 3	95.6 ± 37.2	113 ± 54.3	87.3 ± 77.3
Pre-dose on Day 1 of Cycle 4	117 ± NA	137 ± 47.6	108 ± 56.8
Pre-dose on Day 1 of Cycle 8	—	216 ± 37.1	185 ± 44.6
Pre-dose on Day 1 of Cycle 12	—	204 ± 29.1	159 ± 46.7
Pre-dose on Day 1 of Cycle 16	—	289 ± 29.2	206 ± 34.2
Pre-dose on Day 1 of Cycle 20	—	—	273 ± 15.5
Pre-dose on Day 1 of Cycle 24	—	—	239 ± 35.1
Pre-dose on Day 1 of Cycle 28	—	—	209 ± NA
Stage 1 TD	93.7 ± 58.5	195 ± 55.9	89.8 ± 130.7

SecondaryStage 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)
Reported as:: Geometric mean · μg/mL

Stage 1: Serum Concentration of Tiragolumab
μg/mL	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU
Pre-dose on Day 1 of Cycle 1	NA ± NA
30 min post-dose on Day 1 of Cycle 1	223 ± 20.8
Pre-dose on Day 1 of Cycle 2	31.4 ± 45.6
Pre-dose on Day 1 of Cycle 3	43.3 ± 85.1
Pre-dose on Day 1 of Cycle 4	50.5 ± 62.1
Pre-dose on Day 1 of Cycle 8	83.4 ± 39.1
Pre-dose on Day 1 of Cycle 12	76.1 ± 58.2
Pre-dose on Day 1 of Cycle 16	87.6 ± 30.9
Pre-dose on Day 1 of Cycle 20	102 ± 15.9
Pre-dose on Day 1 of Cycle 24	97.8 ± 38.3
Pre-dose on Day 1 of Cycle 28	90.0 ± NA
Stage 1 TD	39.8 ± 166.4

SecondaryStage 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)
Reported as:: Geometric mean · μg/mL

Stage 1: Plasma Concentration of PEGPH20
μg/mL	Stage 1 Cohort 2: Atezolizumab + PEGPH20
Pre-dose on Day 1 of Cycle 1	NA ± NA
5 min post-dose on Day 1 of Cycle 1	31.4 ± 1290.5
1-3 h post-dose on Day 1 of Cycle 1	25.8 ± 1086.5
Pre-dose on Day 8 of Cycle 1	0.529 ± NA
Pre-dose on Day 15 of Cycle 1	0.485 ± NA
Pre-dose on Day 1 of Cycle 2	0.647 ± NA
5 min post-dose on Day 1 of Cycle 2	56.3 ± 42.8
Pre-dose on Day 1 of Cycle 3	1.92 ± 1992.5
Pre-dose on Day 1 of Cycle 4	10.2 ± NA
Stage 1 TD	2.12 ± 1276.5
Stage 1 Day 120 post last dose	0.0375 ± NA

SecondaryStage 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
Reported as:: Count of participants · Participants

Stage 1: Number of Participants With Treatment-emergent Anti-drug Antibodies (ADAs) to Atezolizumab
Participants	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU
Stage 1: Number of Participants With Treatment-emergent Anti-drug Antibodies (ADAs) to Atezolizumab	3	5	8

SecondaryStage 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
Reported as:: Count of participants · Participants

Stage 1: Number of Participants With Treatment-emergent ADAs to Tiragolumab
Participants	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU
Stage 1: Number of Participants With Treatment-emergent ADAs to Tiragolumab	0

SecondaryStage 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
Reported as:: Count of participants · Participants

Stage 1: Number of Participants With Treatment-emergent ADAs to PEGPH20
Participants	Stage 1 Cohort 2: Atezolizumab + PEGPH20
Stage 1: Number of Participants With Treatment-emergent ADAs to PEGPH20	0

Adverse events

Collected over Stage 1: Up to 84.2 months; Stage 2: Up to 42.6 months. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	4/5 (80%)	2/5 (40%)	5/5 (100%)
Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	12/16 (75%)	6/12 (50%)	12/12 (100%)
Stage 1 Cohort 2: Atezolizumab + PEGPH20	13/15 (86.7%)	1/13 (7.7%)	13/13 (100%)
Stage 1 Cohort 2: Atezolizumab + BL-8040	11/15 (73.3%)	5/13 (38.5%)	13/13 (100%)
Stage 1 Cohort 2: Atezolizumab + Linagliptin	13/16 (81.3%)	4/14 (28.6%)	14/14 (100%)
Stage 1: Cisplatin + 5-FU (Control)	8/24 (33.3%)	11/23 (47.8%)	23/23 (100%)
Stage 1: Atezolizumab + Cisplatin + 5-FU	56/65 (86.2%)	34/65 (52.3%)	65/65 (100%)
Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU	45/63 (71.4%)	38/62 (61.3%)	62/62 (100%)
Stage 2: Atezolizumab + Tiragolumab	11/15 (73.3%)	7/14 (50%)	14/14 (100%)

Most frequent serious events

Showing 10 of 134

Most frequent serious events
Event	Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1 Cohort 2: Atezolizumab + BL-8040	Stage 1 Cohort 2: Atezolizumab + Linagliptin	Stage 1: Cisplatin + 5-FU (Control)	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU	Stage 2: Atezolizumab + Tiragolumab
Gastrointestinal haemorrhageGastrointestinal disorders	1/5	0/12	0/13	0/13	0/14	1/23	1/65	1/62	1/14
Small intestinal obstructionGastrointestinal disorders	1/5	0/12	0/13	0/13	0/14	0/23	0/65	0/62	0/14
Cerebrovascular accidentNervous system disorders	1/5	0/12	0/13	0/13	0/14	0/23	0/65	0/62	0/14
PyrexiaGeneral disorders	0/5	0/12	0/13	2/13	0/14	0/23	2/65	4/62	0/14
DyspnoeaRespiratory, thoracic and mediastinal disorders	0/5	0/12	0/13	2/13	0/14	0/23	1/65	1/62	0/14
PneumoniaInfections and infestations	0/5	0/12	0/13	0/13	0/14	0/23	5/65	3/62	2/14
DysphagiaGastrointestinal disorders	0/5	0/12	1/13	0/13	0/14	2/23	5/65	5/62	0/14
IleusGastrointestinal disorders	0/5	1/12	0/13	0/13	0/14	1/23	0/65	0/62	1/14
NauseaGastrointestinal disorders	0/5	1/12	0/13	1/13	0/14	0/23	2/65	2/62	0/14
Obstruction gastricGastrointestinal disorders	0/5	1/12	0/13	0/13	0/14	0/23	1/65	0/62	0/14

Most frequent other events

Showing 10 of 242

Most frequent other events
Event	Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1 Cohort 2: Atezolizumab + BL-8040	Stage 1 Cohort 2: Atezolizumab + Linagliptin	Stage 1: Cisplatin + 5-FU (Control)	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU	Stage 2: Atezolizumab + Tiragolumab
Decreased appetiteMetabolism and nutrition disorders	5/5	6/12	6/13	5/13	6/14	15/23	34/65	33/62	1/14
FatigueGeneral disorders	4/5	4/12	3/13	3/13	3/14	8/23	31/65	19/62	2/14
NauseaGastrointestinal disorders	1/5	3/12	3/13	4/13	2/14	18/23	51/65	49/62	2/14
Injection related reactionInjury, poisoning and procedural complications	0/5	0/12	0/13	9/13	0/14	0/23	0/65	0/62	0/14
AnaemiaBlood and lymphatic system disorders	3/5	4/12	1/13	4/13	3/14	6/23	27/65	20/62	4/14
DiarrhoeaGastrointestinal disorders	3/5	3/12	1/13	2/13	1/14	5/23	18/65	31/62	1/14
VomitingGastrointestinal disorders	3/5	2/12	3/13	1/13	1/14	3/23	16/65	20/62	0/14
Back painMusculoskeletal and connective tissue disorders	3/5	1/12	2/13	0/13	2/14	2/23	11/65	9/62	3/14
Peripheral sensory neuropathyNervous system disorders	3/5	2/12	2/13	0/13	1/14	8/23	7/65	4/62	0/14
Dermatitis acneiformSkin and subcutaneous tissue disorders	3/5	0/12	0/13	0/13	0/14	0/23	1/65	0/62	0/14

Baseline characteristics

All randomized population included all randomized participants.

Age, Customized
Age, Customized(Participants)	Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1 Cohort 2: Atezolizumab + BL-8040	Stage 1 Cohort 2: Atezolizumab + Linagliptin	Stage 1: Cisplatin + 5-FU (Control)	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU	Stage 2: Atezolizumab + Tiragolumab	Total
Stage 1: Adults (18-64 years)	2	9	11	11	14	21	38	31	—	137
Stage 1: From 65-84 years	3	7	4	4	2	2	27	32	—	81
Stage 1: 85 years and over	0	0	0	0	0	1	0	0	—	1
Stage 2: Adults (18-64 years)	—	—	—	—	—	—	—	—	11	11
Stage 2: From 65-84 years	—	—	—	—	—	—	—	—	3	3
Stage 2: 85 years and over	—	—	—	—	—	—	—	—	0	0

Sex: Female, Male
Sex: Female, Male(Participants)	Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1 Cohort 2: Atezolizumab + BL-8040	Stage 1 Cohort 2: Atezolizumab + Linagliptin	Stage 1: Cisplatin + 5-FU (Control)	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU	Stage 2: Atezolizumab + Tiragolumab	Total
Stage 1 — Female	1	4	3	2	2	0	6	10	—	28
Stage 1 — Male	4	12	12	13	14	24	59	53	—	191
Stage 2 — Female	—	—	—	—	—	—	—	—	0	0
Stage 2 — Male	—	—	—	—	—	—	—	—	15	15

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1 Cohort 2: Atezolizumab + BL-8040	Stage 1 Cohort 2: Atezolizumab + Linagliptin	Stage 1: Cisplatin + 5-FU (Control)	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU	Stage 2: Atezolizumab + Tiragolumab	Total
Stage 1 — Hispanic or Latino	0	0	0	2	0	1	2	0	—	5
Stage 1 — Not Hispanic or Latino	5	16	15	11	16	22	61	62	—	208
Stage 1 — Unknown or Not Reported	0	0	0	2	0	1	2	1	—	6
Stage 2 — Hispanic or Latino	—	—	—	—	—	—	—	—	0	0
Stage 2 — Not Hispanic or Latino	—	—	—	—	—	—	—	—	14	14
Stage 2 — Unknown or Not Reported	—	—	—	—	—	—	—	—	1	1

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Stage 1 Cohort 1: mFOLFOX6 + Atezolizumab + Cobimetinib	Stage 1 Cohort 2: Ramucirumab + Paclitaxel (Control)	Stage 1 Cohort 2: Atezolizumab + PEGPH20	Stage 1 Cohort 2: Atezolizumab + BL-8040	Stage 1 Cohort 2: Atezolizumab + Linagliptin	Stage 1: Cisplatin + 5-FU (Control)	Stage 1: Atezolizumab + Cisplatin + 5-FU	Stage 1: Atezolizumab +Tiragolumab + Cisplatin +5-FU	Stage 2: Atezolizumab + Tiragolumab	Total
Stage 1 — American Indian or Alaska Native	0	0	0	0	0	0	0	0	—	0
Stage 1 — Asian	3	10	8	7	11	18	37	43	—	137
Stage 1 — Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	1	0	—	1
Stage 1 — Black or African American	0	0	0	0	0	0	0	1	—	1
Stage 1 — White	2	6	7	6	4	6	26	18	—	75
Stage 1 — More than one race	0	0	0	0	0	0	0	0	—	0
Stage 1 — Unknown or Not Reported	0	0	0	2	1	0	1	1	—	5
Stage 2 — American Indian or Alaska Native	—	—	—	—	—	—	—	—	0	0
Stage 2 — Asian	—	—	—	—	—	—	—	—	12	12
Stage 2 — Native Hawaiian or Other Pacific Islander	—	—	—	—	—	—	—	—	0	0
Stage 2 — Black or African American	—	—	—	—	—	—	—	—	0	0
Stage 2 — White	—	—	—	—	—	—	—	—	3	3
Stage 2 — More than one race	—	—	—	—	—	—	—	—	0	0
Stage 2 — Unknown or Not Reported	—	—	—	—	—	—	—	—	0	0

Study locations

28 sites

Mayo Clinic Cancer Center
Scottsdale, Arizona 85259, United States
Uni of Southern California
Los Angeles, California 90033, United States
UCLA Jonsson Comprehensive Cancer Center
Santa Monica, California 90404, United States
Columbia University Medical Center
New York, New York 10032, United States
Tennessee Oncology - Nashville
Nashville, Tennessee 37203, United States
The University of Texas MD Anderson Cancer Center
Houston, Texas 77030-4000, United States
Blacktown Hospital
Blacktown, New South Wales 2148, Australia
Monash Medical Centre-Moorabbin Campus
Clayton, Victoria 3168, Australia
Peter MacCallum Cancer Centre
Melbourne, Victoria 3000, Australia
Rambam Health Care Campus
Haifa, 3109601, Israel
Sourasky Medical Centre
Tel Aviv, 64239, Israel
Seoul National University Bundang Hospital
Gyeonggi-do, 13620, South Korea
Korea University Anam Hospital
Seoul, 02841, South Korea
Seoul National University Hospital
Seoul, 110-744, South Korea
Samsung Medical Center
Seoul, 135-710, 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, 05505, South Korea
The Catholic University of Korea St. Vincent's Hospital
Suwon, 442-723, South Korea
Universidad de Navarra - Clinica Universitaria de Navarra (CUN)
Pamplona, Navarre 31008, Spain
Hospital Universitari Vall dHebron
Barcelona, 08035, Spain
National Cheng Kung University Hospital
Tainan, 70457, Taiwan
National Taiwan University Hospital
Taipei, 100, Taiwan
Taipei Veterans General Hospital
Taipei, 11217, Taiwan
Beatson West of Scotland Cancer Centre
Glasgow, G12 0YN, United Kingdom
Barts and The London School of Medicine and Dentistry - Barts Cancer Institute (BCI)-CECM
London, 0, United Kingdom
The Royal Marsden
London, SW7 3RP, United Kingdom
The Christie NHS Foundation Trust
Manchester, M20 4BX, United Kingdom
The Royal Marsden NHS Foundation Trust - Royal Marsden Hospital (RMH) - Sutton
Sutton, SM2 5PT, United Kingdom

References and documents

Publications

Sun JM, Chao Y, Kim SB, Rha SY, Evans TRJ, Strickland AH, Wainberg Z, Chau I, Pelles-Avraham S, Ajani J, Malhotra R, Liu Q, Li S, Cha E, Kalaitzidou M, Huang X, Allen S, Hsu CH. First-line tiragolumab plus atezolizumab and chemotherapy in patients with previously untreated, locally advanced unresectable or metastatic oesophageal cancer (MORPHEUS-EC): a randomised, open-label, phase 1b/2 trial. Lancet Oncol. 2026 Jan;27(1):90-102. doi: 10.1016/S1470-2045(25)00402-4. PubMed 41449151 ↗
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. PubMed 36940261 ↗

Study documents

Protocol and statistical analysis plan · Sep 27, 2023

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data\_sharing

Registry details

Key details

Study ID: NCT03281369
Lead sponsor: Hoffmann-La Roche
Collaborators: Halozyme Therapeutics, BioLineRx, Ltd.
Responsible party: Sponsor
First posted: Sep 13, 2017
Start date: Oct 13, 2017
Primary completion: Oct 9, 2025
Completion: Oct 9, 2025
Results posted: Aug 3, 2026
Last update: Aug 3, 2026

Study contacts

Clinical Trials

study director · Hoffmann-La Roche

Oversight

FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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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)

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