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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) (Morpheus-Gastric 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). Two cohorts will be enrolled in parallel in this study: the second-line (2L) Cohort will consist 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) Cohort will consist 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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Gastric Adenocarcinoma
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) (Morpheus-Gastric 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 (Morpheus-Gastric Cancer)

Clinical Trial IDs

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

Conditions

  • Gastric Adenocarcinoma or Gastroesophageal Junction Adenocarcinoma

Interventions

DrugSynonymsArms
5-Fluorouracil (5-FU)1L-Control: mFOLFOX6
LeucovorinFolinic acid1L-Control: mFOLFOX6
Oxaliplatin1L-Control: mFOLFOX6
AtezolizumabTecentriq1L-A: mFOLFOX6 + Atezo + Cobi
CobimetinibCotellic1L-A2: Atezo + mFOLFOX6 followed by Atezo + Cobi
Ramucirumab2L-Control: Ramucirumab + Paclitaxel
Paclitaxel2L-Control: Ramucirumab + Paclitaxel
PEGylated recombinant human hyaluronidase (PEGPH20)2L-2: Atezo + PEGPH20
BL-80402L-3: Atezo + BL-8040
Linagliptin2L-4: Atezo + Linagliptin
AtezolizumabTecentriq2L-2: Atezo + PEGPH20
CobimetinibCotellic1L-A: mFOLFOX6 + Atezo + Cobi

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). Two cohorts will be enrolled in parallel in this study: the second-line (2L) Cohort will consist 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) Cohort will consist 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.

Trial Arms

NameTypeDescriptionInterventions
1L-Control: mFOLFOX6Active ComparatorParticipants in the 1L 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.
  • 5-Fluorouracil (5-FU)
  • Leucovorin
  • Oxaliplatin
1L-A: mFOLFOX6 + Atezo + CobiExperimentalParticipants in the 1L-A arm will receive mFOLFOX6 treatment consisting of 5-FU, leucovorin and oxaliplatin in combination with atezolizumab plus cobimetinib.
  • 5-Fluorouracil (5-FU)
  • Leucovorin
  • Oxaliplatin
  • Atezolizumab
  • Cobimetinib
1L-A2: Atezo + mFOLFOX6 followed by Atezo + CobiExperimentalParticipants in the 1L-A2 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.
  • 5-Fluorouracil (5-FU)
  • Leucovorin
  • Oxaliplatin
  • Atezolizumab
  • Cobimetinib
1L-B: mFOLFOX6 + AtezoExperimentalParticipants in the 1L-B 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.
  • 5-Fluorouracil (5-FU)
  • Leucovorin
  • Oxaliplatin
  • Atezolizumab
2L-Control: Ramucirumab + PaclitaxelActive ComparatorParticipants in the 2L Control arm will receive ramucirumab plus paclitaxel. Participants who progressed on treatment may have the option of receiving Atezolizumab + Cobimetinib treatment, provided they meet the eligibility criteria.
  • Ramucirumab
  • Paclitaxel
2L-1: Atezo + CobiExperimentalParticipants in the 2L-1 arm will receive atezolizumab in combination with cobimetinib.
  • Atezolizumab
  • Cobimetinib
2L-2: Atezo + PEGPH20ExperimentalParticipants in the 2L-2 arm will receive atezolizumab in combination with PEGylated recombinant human hyaluronidase (PEGPH20). Participants who progressed on treatment may have the option of receiving Atezolizumab + Cobimetinib treatment, provided they meet the eligibility criteria.
  • PEGylated recombinant human hyaluronidase (PEGPH20)
  • Atezolizumab
2L-3: Atezo + BL-8040ExperimentalParticipants in the 2L-3 arm will receive atezolizumab in combination with BL-8040. Participants who progressed on treatment may have the option of receiving Atezolizumab + Cobimetinib treatment, provided they meet the eligibility criteria.
  • BL-8040
  • Atezolizumab
2L-4: Atezo + LinagliptinExperimentalParticipants in the 2L-4 arm will receive atezolizumab in combination with linagliptin. Participants who progressed on treatment may have the option of receiving Atezolizumab + Cobimetinib treatment, provided they meet the eligibility criteria.
  • Linagliptin
  • Atezolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Age >/= 18 years;

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

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

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

          -  Only for the 1L 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.

        Exclusion Criteria:

        Exclusion criteria for the 2L 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.

        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.
      
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 3-5 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 3-5 years)
Safety Issue:
Description:
Measure:Overall Survival (OS)
Time Frame:From randomization up to death from any cause (up to approximately 3-5 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 3-5 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 3-5 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 3-5 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 3-5 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 3-5 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 3-5 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 3-5 years); 30 days after last dose (up to approximately 3-5 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 3-5 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 3-5 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 3-5 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 3-5 years); 30 days after last dose (up to approximately 3-5 years)

Details

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

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