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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)

NCT03281369

Description:

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.

Related Conditions:
  • Esophageal Adenocarcinoma
  • Esophageal Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief 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)
  • Official 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)

Clinical Trial IDs

  • ORG STUDY ID: YO39609
  • SECONDARY ID: 2016-004529-17
  • NCT ID: NCT03281369

Conditions

  • Gastric Adenocarcinoma or Gastroesophageal Junction Adenocarcinoma or Esophageal Carcinoma

Interventions

DrugSynonymsArms
5-Fluorouracil (5-FU)1L-A2: Atezo+mFOLFOX6 followed by Atezo+Cobi (Gastric Cancer)
LeucovorinFolinic acid1L-A2: Atezo+mFOLFOX6 followed by Atezo+Cobi (Gastric Cancer)
Oxaliplatin1L-A2: Atezo+mFOLFOX6 followed by Atezo+Cobi (Gastric Cancer)
AtezolizumabTecentriq1L-A2: Atezo+mFOLFOX6 followed by Atezo+Cobi (Gastric Cancer)
CobimetinibCotellic1L-A2: Atezo+mFOLFOX6 followed by Atezo+Cobi (Gastric Cancer)
Ramucirumab2L-Control: Ramucirumab + Paclitaxel (Gastric Cancer)
Paclitaxel2L-Control: Ramucirumab + Paclitaxel (Gastric Cancer)
PEGylated recombinant human hyaluronidase (PEGPH20)2L-2: Atezo + PEGPH20 (Gastric Cancer)
BL-80402L-3: Atezo + BL-8040 (Gastric Cancer)
Linagliptin2L-4: Atezo + Linagliptin (Gastric Cancer)
AtezolizumabTecentriq1L-1:Atezo+Tiragolumab+Cisplatin+5FU(Esophageal Cancer Cohort)
CobimetinibCotellic1L-A: mFOLFOX6 + Atezo + Cobi (Gastric Cancer)
Cisplatin1L-1:Atezo+Tiragolumab+Cisplatin+5FU(Esophageal Cancer Cohort)
TiragolumabRO70922841L-1:Atezo+Tiragolumab+Cisplatin+5FU(Esophageal Cancer Cohort)
5-Fluorouracil (5-FU)1L-1:Atezo+Tiragolumab+Cisplatin+5FU(Esophageal Cancer Cohort)

Purpose

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 Arms

NameTypeDescriptionInterventions
1L-Control: mFOLFOX6 (Gastric Cancer)Active ComparatorParticipants 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.
  • 5-Fluorouracil (5-FU)
  • Leucovorin
  • Oxaliplatin
1L-A: mFOLFOX6 + Atezo + Cobi (Gastric Cancer)ExperimentalParticipants 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.
  • 5-Fluorouracil (5-FU)
  • Leucovorin
  • Oxaliplatin
  • Atezolizumab
  • Cobimetinib
1L-A2: Atezo+mFOLFOX6 followed by Atezo+Cobi (Gastric Cancer)ExperimentalParticipants 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.
  • 5-Fluorouracil (5-FU)
  • Leucovorin
  • Oxaliplatin
  • Atezolizumab
  • Cobimetinib
1L-B: mFOLFOX6 + Atezo (Gastric Cancer)ExperimentalParticipants in the 1L-B Gastric Cancer arm will receive mFOLFOX6 treatment consisting of 5-FU, leucovorin and oxaliplatin in combination with atezolizumab. 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.
  • 5-Fluorouracil (5-FU)
  • Leucovorin
  • Oxaliplatin
  • Atezolizumab
2L-Control: Ramucirumab + Paclitaxel (Gastric Cancer)Active ComparatorParticipants 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.
  • Ramucirumab
  • Paclitaxel
2L-1: Atezo + Cobi (Gastric Cancer)ExperimentalParticipants in the 2L-1 Gastric Cancer arm received atezolizumab in combination with cobimetinib. Enrollment completed as of October 2019.
  • Atezolizumab
  • Cobimetinib
2L-2: Atezo + PEGPH20 (Gastric Cancer)ExperimentalParticipants 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.
  • PEGylated recombinant human hyaluronidase (PEGPH20)
  • Atezolizumab
2L-3: Atezo + BL-8040 (Gastric Cancer)ExperimentalParticipants 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.
  • BL-8040
  • Atezolizumab
2L-4: Atezo + Linagliptin (Gastric Cancer)ExperimentalParticipants 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.
  • Linagliptin
  • Atezolizumab
1L-1:Atezo+Tiragolumab+Cisplatin+5FU(Esophageal Cancer Cohort)ExperimentalParticipants in the 1L-1 Esophageal Cancer arm will receive atezolizumab in combination with tiragolumab and chemotherapy.
  • Atezolizumab
  • Cisplatin
  • Tiragolumab
  • 5-Fluorouracil (5-FU)
1L-2: Atezo+Cisplatin+5-FU (Esophageal Cancer Cohort)ExperimentalParticipants in the 1L-2 Esophageal Cancer arm will receive atezolizumab in combination with chemotherapy.
  • Atezolizumab
  • Cisplatin
  • 5-Fluorouracil (5-FU)
1L-Control: Cisplatin+5-FU (Esophageal Cancer Cohort)Active ComparatorParticipants in the 1L-Control Eophageal Cancer arm will receive chemotherapy.
  • Cisplatin
  • 5-Fluorouracil (5-FU)
1L-3: Atezo+Tiragolumab (Esophageal Cancer Cohort)ExperimentalParticipants 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.
  • Atezolizumab
  • Tiragolumab

Eligibility Criteria

        Inclusion Criteria:

        Gastric Cancer Cohorts Inclusion Criteria:

          -  Age >/= 18 years;

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1;

          -  Life expectancy >/= 3 months, as determined by the investigator;

          -  Histologically or cytologically confirmed locally advanced unresectable or metastatic
             adenocarcinoma of gastric or gastroesophageal junction; (for the 1L Gastric Cancer
             Cohort: no prior systemic therapy for the locally advanced or metastatic disease; for
             the 2L Gastric Cancer Cohort: disease progression during or following a first-line
             platinum-containing or fluoropyrimidine-containing chemotherapy regimen);

          -  Availability of a representative tumor specimen that is suitable for determination of
             PD-L1 and TIGIT levels by IHC and/or additional biomarker status by means of
             retrospective central testing;

          -  Only for the 1L Gastric Cancer Cohort: human epidermal growth factor receptor 2
             (HER2)-negative tumors;

          -  Measurable disease (at least one target lesion) according to Response Evaluation
             Criteria in Solid Tumors, Version 1.1 (RECIST v1.1);

          -  Adequate hematologic and end organ function based on laboratory results obtained
             within 14 days prior to initiation of study treatment;

          -  For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use contraceptive measures as outlined for each specific
             treatment arm;

          -  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 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;

          -  Active EBV infection and known or suspected chronic active EBV infection 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 and 5 months after the final
             dose of tiragolumab.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants With Objective Response, as Determined by Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1)
Time Frame:From Randomization until disease progression or loss of clinical benefit (up to approximately 3-6 years)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Progression-Free Survival (PFS), as Determined by Investigator According to RECIST v1.1
Time Frame:From randomization up to the first occurrence of disease (up to approximately 3-6 years)
Safety Issue:
Description:
Measure:Overall Survival (OS)
Time Frame:From randomization up to death from any cause (up to approximately 3-6 years)
Safety Issue:
Description:
Measure:Percentage of Participants Who Are Alive at Month 6 and at Month 12
Time Frame:Month 6, Month 12
Safety Issue:
Description:
Measure:Duration of Response, as Determined by Investigator According to RECIST v1.1
Time Frame: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)
Safety Issue:
Description:
Measure:Percentage of Participants With Disease Control, as Determined by the Investigator per RECIST v1.1
Time Frame:From randomization until disease progression or loss of clinical benefit (up to approximately 3-6 years)
Safety Issue:
Description:
Measure:Serum Concentration of Atezolizumab
Time Frame: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)
Safety Issue:
Description:
Measure:Plasma Concentration of Cobimetinib
Time Frame:Prior to cobimetinib dose, 2-4 hr after cobimetinib dose on Day 15 of Cycle 1 (cycle length=28 days)
Safety Issue:
Description:
Measure:Plasma Concentration of PEGPH20
Time Frame: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)
Safety Issue:
Description:Pre-infusion (0 hr), 5 min and 1-3 hrs post infusion (infusion duration=10-12 min) on Day 1 of Cycle 1; pre-infusion (0 hr) on Days 8 and 15 of Cycle 1, Day 1 of Cycles 3, 4, 8, 12, 16; pre-infusion (0 hr) and 5 min post-infusion on Day 1 of Cycle 2 (each cycle=21 days); 30 days and 120 days after last dose (up to approximately 3-6 years)
Measure:Plasma Concentration of BL-8040
Time Frame: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)
Safety Issue:
Description:Pre-dose (0 hr) on Day 1 of priming period (1 week prior to Day 1 of Cycle 1); 1 hr post-dose on Days 1, 5 of priming period; pre-dose (0 hr), 1 hour post-dose on Day 15 of Cycle 1 and Day 1 of Cycles 2, 3, 4, 8, 12, 16; pre-dose (0 hr) on Day 1 of Cycle 20 and every 4 cycles thereafter (each cycle=21 days) (up to approximately 3-6 years); 30 days after last dose (up to approximately 3-6 years)
Measure:Plasma Concentration of Linagliptin
Time Frame: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
Safety Issue:
Description:
Measure:Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab
Time Frame: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)
Safety Issue:
Description:
Measure:Percentage of Participants With ADA to PEGPH20
Time Frame: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)
Safety Issue:
Description:
Measure:Percentage of Participants With ADA to BL-8040
Time Frame: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)
Safety Issue:
Description:Pre-dose (0 hr) on Day 1 of priming period (1 week prior to Cycle 1 Day 1), Day 15 of Cycle 1 and Day 1 of Cycles 2, 3, 4, 8, 12, 16, 20 and every 4 cycles thereafter (each cycle=21 days) (up to approximately 3-6 years); 30 days after last dose (up to approximately 3-6 years)
Measure:Percentage of Participants With Objective Response, in Participants with TIGIT-Positive Tumors by IHC (Esophageal Cancer Cohort Only)
Time Frame:From Randomization until disease progression or loss of clinical benefit (up to approximately 2 years)
Safety Issue:
Description:
Measure:Percentage of Participants With Objective Response, in Participants With PD-L1 IC/TC-Positive Tumors by IHC (Esophageal Cancer Cohort Only)
Time Frame:From Randomization until disease progression or loss of clinical benefit (up to approximately 2 years)
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

Last Updated

April 2, 2020