Gastric Adenocarcinoma or Gastroesophageal Junction Adenocarcinoma or Esophageal Carcinoma
Conditions
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.
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.
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.
DRUGCobimetinib
Cobimetinib: 60 mg by mouth once a day on Days 1-21 of every 28-day cycle
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.
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.
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.
Sponsors
Hoffmann-La Roche
Halozyme Therapeutics
BioLineRx, Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1: Percentage of Participants With Objective Response (OR), as Determined by Investigator According to RECIST v1.1 | From randomization up to approximately 84.2 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1: Progression Free Survival (PFS) After Randomization, as Determined by Investigator According to RECIST v1.1 | From randomization to the first occurrence of PD or death (up to approximately 84.2 months) | 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. |
| Stage 1: Overall Survival (OS) After Randomization | From randomization to death (up to approximately 84.2 months) | 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. |
| Stage 1: OS at Month 6 and Month 12 | At Months 6 and 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. |
| Stage 1: Duration of Response (DOR), as Determined by Investigator According to RECIST v1.1 | Up to approximately 84.2 months | 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. |
| Stage 1: Percentage of Participants With Disease Control (DC), as Determined by Investigator According to RECIST v1.1 | Up to approximately 84.2 months | 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. |
| Stages 1 and 2: Percentage of Participants With Adverse Events (AEs) | Stage 1: Up to 84.2 months; Stage 2: Up to 42.6 months | 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. |
| Stage 1: Serum Concentration of Atezolizumab | 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) | 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. |
| Stage 1: Serum Concentration of Tiragolumab | 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 | 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) | 1 Cycle=21 days |
| Stage 1: Number of Participants With Treatment-emergent Anti-drug Antibodies (ADAs) to Atezolizumab | Up to approximately 82.7 months | 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. |
| Stage 1: Number of Participants With Treatment-emergent ADAs to Tiragolumab | Up to approximately 46.7 months | 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. |
| Stage 1: Number of Participants With Treatment-emergent ADAs to PEGPH20 | Up to approximately 3.3 months | 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. |
Countries
Australia, Israel, South Korea, Spain, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
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).
Pre-assignment details
Eligible participants were assigned to one of several treatment arms in Stage 1. Cohort 2 participants with disease progression (PD), loss of clinical benefit, or unacceptable toxicity in Stage 1 were eligible for a different treatment combination in Stage 2. Results include only those cohorts that enrolled participants. Planned cohorts that did not enroll participants or were never opened are not presented.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized Stage 1: 85 years and over | 1 Participants |
| Age, Customized Stage 1: Adults (18-64 years) | 137 Participants |
| Age, Customized Stage 1: From 65-84 years | 81 Participants |
| Age, Customized Stage 2: 85 years and over | 0 Participants |
| Age, Customized Stage 2: Adults (18-64 years) | 11 Participants |
| Age, Customized Stage 2: From 65-84 years | 3 Participants |
| Ethnicity (NIH/OMB) Stage 1 Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Stage 1 Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Stage 1 Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Stage 2 Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Stage 2 Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Stage 2 Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) Stage 1 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Stage 1 Asian | 18 Participants |
| Race (NIH/OMB) Stage 1 Black or African American | 1 Participants |
| Race (NIH/OMB) Stage 1 More than one race | 0 Participants |
| Race (NIH/OMB) Stage 1 Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Stage 1 Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) Stage 1 White | 7 Participants |
| Race (NIH/OMB) Stage 2 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Stage 2 Asian | 12 Participants |
| Race (NIH/OMB) Stage 2 Black or African American | 0 Participants |
| Race (NIH/OMB) Stage 2 More than one race | 0 Participants |
| Race (NIH/OMB) Stage 2 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Stage 2 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Stage 2 White | 3 Participants |
| Sex: Female, Male Stage 1 Female | 28 Participants |
| Sex: Female, Male Stage 1 Male | 24 Participants |
| Sex: Female, Male Stage 2 Female | 0 Participants |
| Sex: Female, Male Stage 2 Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 5 | 12 / 16 | 13 / 15 | 11 / 15 | 13 / 16 | 8 / 24 | 56 / 65 | 45 / 63 | 11 / 15 |
| other Total, other adverse events | 5 / 5 | 12 / 12 | 13 / 13 | 13 / 13 | 14 / 14 | 23 / 23 | 65 / 65 | 62 / 62 | 14 / 14 |
| serious Total, serious adverse events | 2 / 5 | 6 / 12 | 1 / 13 | 5 / 13 | 4 / 14 | 11 / 23 | 34 / 65 | 38 / 62 | 7 / 14 |
Outcome results
None listed