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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT03281369




Registration number
NCT03281369
Ethics application status
Date submitted
11/09/2017
Date registered
13/09/2017
Date last updated
1/05/2024

Titles & IDs
Public title
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)
Scientific title
A Phase Ib/II, Open-Label, Multicenter, Randomized, Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Cancer or Esophageal Cancer (Morpheus-Gastric and Esophageal Cancer)
Secondary ID [1] 0 0
2016-004529-17
Secondary ID [2] 0 0
YO39609
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Gastric Adenocarcinoma or Gastroesophageal Junction Adenocarcinoma or Esophageal Carcinoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Oesophageal (gullet)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - 5-Fluorouracil (5-FU)
Treatment: Drugs - Leucovorin
Treatment: Drugs - Oxaliplatin
Treatment: Drugs - Atezolizumab
Treatment: Drugs - Cobimetinib
Other interventions - Ramucirumab
Treatment: Drugs - Paclitaxel
Other interventions - PEGylated recombinant human hyaluronidase (PEGPH20)
Treatment: Drugs - BL-8040
Treatment: Drugs - Linagliptin
Treatment: Drugs - Atezolizumab
Treatment: Drugs - Cobimetinib
Treatment: Drugs - Cisplatin
Treatment: Drugs - Tiragolumab
Treatment: Drugs - 5-Fluorouracil (5-FU)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Active Comparator: 1L-Control: Cisplatin+5-FU (Esophageal Cancer Cohort) - Participants in the 1L-Control Eophageal Cancer arm will receive chemotherapy.

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.


Treatment: Drugs: 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.

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

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

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

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

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

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

Other interventions: 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.

Treatment: Drugs: 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).

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

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

Treatment: Drugs: 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.

Treatment: Drugs: 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.

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

Treatment: Drugs: 5-Fluorouracil (5-FU)
5-FU 800 mg/m^2 administerd by IV infusion on Days 1-5 of each 21 day cycle.
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Participants With Objective Response, as Determined by Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1)
Timepoint [1] 0 0
From Randomization until disease progression or loss of clinical benefit (up to approximately 3-6 years)
Primary outcome [2] 0 0
Percentage of Participants with Adverse Events (AEs)
Timepoint [2] 0 0
From first study treatment administration until 30 days after the last dose or until initiation of new systemic anti-cancer therapy, whichever occurs first (up to approximately 3-6 years)
Primary outcome [3] 0 0
For Arm 1L-A : Percentage of Participants with Serious and Non-serious Treatment-related AEs
Timepoint [3] 0 0
During the safety run-in phase up to 28 days
Secondary outcome [1] 0 0
Progression-Free Survival (PFS), as Determined by Investigator According to RECIST v1.1
Timepoint [1] 0 0
From randomization up to the first occurrence of disease (up to approximately 3-6 years)
Secondary outcome [2] 0 0
Overall Survival (OS)
Timepoint [2] 0 0
From randomization up to death from any cause (up to approximately 3-6 years)
Secondary outcome [3] 0 0
Percentage of Participants Who Are Alive at Month 6 and at Month 12
Timepoint [3] 0 0
Month 6, Month 12
Secondary outcome [4] 0 0
Duration of Response, as Determined by Investigator According to RECIST v1.1
Timepoint [4] 0 0
From the date of first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to approximately 3-6 years)
Secondary outcome [5] 0 0
Percentage of Participants With Disease Control, as Determined by the Investigator per RECIST v1.1
Timepoint [5] 0 0
From randomization until disease progression or loss of clinical benefit (up to approximately 3-6 years)
Secondary outcome [6] 0 0
Serum Concentration of Atezolizumab
Timepoint [6] 0 0
Pre-infusion (0 hour [hr]), 30 minutes (min) post-infusion (infusion=60 min) on Day 1 of Cycle 1; pre-infusion (0 hr) on Day 1 of Cycles 2, 3, 4, 8, 12, 16 (each cycle=28 days); 30 days and 120 days after last dose (up to approximately 3-6 years)
Secondary outcome [7] 0 0
Plasma Concentration of Cobimetinib
Timepoint [7] 0 0
Prior to cobimetinib dose, 2-4 hr after cobimetinib dose on Day 15 of Cycle 1 (cycle length=28 days)
Secondary outcome [8] 0 0
Plasma Concentration of PEGPH20
Timepoint [8] 0 0
Pre-infusion (0 hr) on Day 1 of Cycle 1 up to 30 days and 120 days after last dose (up to approximately 3-6 years) (Detailed timeframe is provided in outcome measure description)
Secondary outcome [9] 0 0
Plasma Concentration of BL-8040
Timepoint [9] 0 0
Pre-dose (0 hr) on Day 1 of priming period (1 week prior to Day 1 of Cycle 1) up to 30 days after last dose (up to approximately 3-6 years) (Detailed timeframe is provided in outcome measure description)
Secondary outcome [10] 0 0
Plasma Concentration of Linagliptin
Timepoint [10] 0 0
2 hr postdose oral linagliptin on Day 1 of Cycle 1, prior to atezolizumab infusion and predose oral linagliptin on Day 15 of Cycle 1 as well as on Day 1 of Cycles 2, 3, and 4
Secondary outcome [11] 0 0
Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab
Timepoint [11] 0 0
Pre-infusion (0 hr) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (each cycle=28 days); 30 days and 120 days after last dose (up to approximately 3-6 years)
Secondary outcome [12] 0 0
Percentage of Participants With ADA to PEGPH20
Timepoint [12] 0 0
Pre-infusion (0 hr) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (each cycle=21 days); 30 days and 120 days after last dose (up to approximately 3-6 years)
Secondary outcome [13] 0 0
Percentage of Participants With ADA to BL-8040
Timepoint [13] 0 0
Pre-dose (0 hr) on Day 1 of priming period (1 week prior to Day 1 of Cycle 1) up to 30 days after last dose (up to approximately 3-6 years) (Detailed timeframe is provided in outcome measure description)

Eligibility
Key inclusion criteria
Gastric Cancer Cohorts

- 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

- 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

- 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

- 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
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1/Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
13/10/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/04/2025
Actual
Sample size
Target
410
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Blacktown Hospital - Blacktown
Recruitment hospital [2] 0 0
Monash Medical Centre-Moorabbin Campus - Clayton
Recruitment hospital [3] 0 0
Peter MacCallum Cancer Centre; Medical Oncology - Melbourne
Recruitment postcode(s) [1] 0 0
2148 - Blacktown
Recruitment postcode(s) [2] 0 0
3168 - Clayton
Recruitment postcode(s) [3] 0 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Illinois
Country [4] 0 0
United States of America
State/province [4] 0 0
Kentucky
Country [5] 0 0
United States of America
State/province [5] 0 0
Minnesota
Country [6] 0 0
United States of America
State/province [6] 0 0
New York
Country [7] 0 0
United States of America
State/province [7] 0 0
Tennessee
Country [8] 0 0
United States of America
State/province [8] 0 0
Texas
Country [9] 0 0
United States of America
State/province [9] 0 0
Wisconsin
Country [10] 0 0
Israel
State/province [10] 0 0
Beer Sheva
Country [11] 0 0
Israel
State/province [11] 0 0
Haifa
Country [12] 0 0
Israel
State/province [12] 0 0
Jerusalem
Country [13] 0 0
Israel
State/province [13] 0 0
Petach Tikva
Country [14] 0 0
Israel
State/province [14] 0 0
Tel-Aviv
Country [15] 0 0
Korea, Republic of
State/province [15] 0 0
Seodaemun-Gu
Country [16] 0 0
Korea, Republic of
State/province [16] 0 0
Seongnam-si
Country [17] 0 0
Korea, Republic of
State/province [17] 0 0
Seoul
Country [18] 0 0
Korea, Republic of
State/province [18] 0 0
Songpa-gu
Country [19] 0 0
Korea, Republic of
State/province [19] 0 0
Suwon-si
Country [20] 0 0
Spain
State/province [20] 0 0
Navarra
Country [21] 0 0
Spain
State/province [21] 0 0
Barcelona
Country [22] 0 0
Taiwan
State/province [22] 0 0
Tainan
Country [23] 0 0
Taiwan
State/province [23] 0 0
Taipei City
Country [24] 0 0
Taiwan
State/province [24] 0 0
Zhongzheng Dist.
Country [25] 0 0
United Kingdom
State/province [25] 0 0
Glasgow
Country [26] 0 0
United Kingdom
State/province [26] 0 0
London
Country [27] 0 0
United Kingdom
State/province [27] 0 0
Manchester
Country [28] 0 0
United Kingdom
State/province [28] 0 0
Sutton

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Hoffmann-La Roche
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Halozyme Therapeutics
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/Industry
Name [2] 0 0
BioLineRx, Ltd.
Address [2] 0 0
Country [2] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT03281369
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT03281369