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A Study of Multiple Immunotherapy-Based Treatment Combinations in Participants With Metastatic Pancreatic Ductal Adenocarcinoma (Morpheus-Pancreatic Cancer)

NCT03193190

Description:

A Phase Ib/II, open-label, multicenter, randomized study designed to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of immunotherapy-based treatment combinations in participants with metastatic Pancreatic Ductal Adenocarcinoma (PDAC). Two cohorts will be enrolled in parallel in this study: Cohort 1 will consist of patients who have received no prior systemic therapy for metastatic PDAC, and Cohort 2 will consist of patients who have received one line of prior systemic therapy for PDAC. In each cohort, eligible patients will be assigned to one of several treatment arms.

Related Conditions:
  • Pancreatic Ductal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Multiple Immunotherapy-Based Treatment Combinations in Participants With Metastatic Pancreatic Ductal Adenocarcinoma (Morpheus-Pancreatic 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 Metastatic Pancreatic Ductal Adenocarcinoma (Morpheus-Pancreatic Cancer)

Clinical Trial IDs

  • ORG STUDY ID: WO39608
  • SECONDARY ID: 2016-004126-42
  • NCT ID: NCT03193190

Conditions

  • Pancreatic Adenocarcinoma

Interventions

DrugSynonymsArms
Nab-PaclitaxelCohort 1: Control (Nab-Paclitaxel and Gemcitabine)
GemcitabineCohort 1: Control (Nab-Paclitaxel and Gemcitabine)
OxaliplatinCohort 2: Control (Nab-Paclitaxel and Gemcitabine or mFOLFOX6)
LeucovorinCohort 2: Control (Nab-Paclitaxel and Gemcitabine or mFOLFOX6)
FluorouracilCohort 2: Control (Nab-Paclitaxel and Gemcitabine or mFOLFOX6)
AtezolizumabCohort 1: Atezolizumab + Chemotherapy + Selicrelumab
CobimetinibCohort 2: Atezolizumab + Cobimetinib
PEGPH20Cohort 2: Atezolizumab + PEGPH20
BL-8040Cohort 2: Atezolizumab + BL-8040
SelicrelumabCohort 1: Atezolizumab + Chemotherapy + Selicrelumab
BevacizumabCohort 1: Atezolizumab + Chemo + Selicrelumab + Bevacizumab
EmactuzumabCohort 1: Atezolizumab + Chemotherapy + Emactuzumab
RO6874281Cohort 2: Atezolizumab + RO6874281 every 2 weeks

Purpose

A Phase Ib/II, open-label, multicenter, randomized study designed to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of immunotherapy-based treatment combinations in participants with metastatic Pancreatic Ductal Adenocarcinoma (PDAC). Two cohorts will be enrolled in parallel in this study: Cohort 1 will consist of patients who have received no prior systemic therapy for metastatic PDAC, and Cohort 2 will consist of patients who have received one line of prior systemic therapy for PDAC. In each cohort, eligible patients will be assigned to one of several treatment arms.

Trial Arms

NameTypeDescriptionInterventions
Cohort 1: Control (Nab-Paclitaxel and Gemcitabine)Active ComparatorCohort 1: Participants will receive Nab-Paclitaxel 125 mg/m2 IV infusion on Days 1, 8, and 15 of each 28 day cycle; and Gemcitabine 1000 mg/m2 IV infusion on Days 1, 8, and 15 of each 28 day cycle. Participants in the Cohort 1 control arm who experience disease progression will be given the option of enrolling into Cohort 2 (if open for enrollment), provided they meet eligibility criteria.
  • Nab-Paclitaxel
  • Gemcitabine
Cohort 1: Atezolizumab + Chemotherapy + SelicrelumabExperimentalCohort 1: Participants will receive Atezolizumab 840 mg IV infusion on Days 1 and 15 of each 28 day cycle; Nab-paclitaxel 125 mg/m2 IV infusion on Days 1, 8, and 15 of each 28 day cycle; Gemcitabine 1000 mg/m2 IV infusion on Days 1, 8, and 15 of each 28 day cycle; and Selicrelumab 16 mg subcutaneous injection on Day 1 of Cycles 1−4 and every third cycle thereafter (i.e. Cycles 7, 10, 13 etc.) of each 28-day cycle.
  • Nab-Paclitaxel
  • Gemcitabine
  • Atezolizumab
  • Selicrelumab
Cohort 1: Atezolizumab + Chemo + Selicrelumab + BevacizumabExperimentalCohort 1: Participants will receive Atezolizumab 840 mg IV infusion on Days 1 and 15 of each 28 day cycle; Bevacizumab 10 mg/kg IV infusion on Days 1 and 15 of each 28 day cycle; Nab-paclitaxel 125 mg/m2 IV infusion on Days 1, 8, and 15 of each 28 day cycle; Gemcitabine 1000 mg/m2 IV infusion on Days 1, 8, and 15 of each 28 day cycle; and Selicrelumab 16 mg subcutaneous on Day 1 of Cycles 1−4 and every third cycle thereafter (i.e. Cycles 7, 10, 13 etc.) of each 28-day cycle.
  • Nab-Paclitaxel
  • Gemcitabine
  • Atezolizumab
  • Selicrelumab
  • Bevacizumab
Cohort 1: Atezolizumab + Chemotherapy + BevacizumabExperimentalCohort 1: Participants will receive Atezolizumab 840 mg IV infusion on Days 1 and 15 of each 28 day cycle; Bevacizumab 10 mg/kg IV infusion on Days 1 and 15 of each 28 day cycle; Nab-paclitaxel 125 mg/m2 IV infusion on Days 1, 8, and 15 of each 28 day cycle; Gemcitabine 1000 mg/m2 IV infusion on Days 1, 8, and 15 of each 28 day cycle.
  • Nab-Paclitaxel
  • Gemcitabine
  • Atezolizumab
  • Bevacizumab
Cohort 1: Atezolizumab + Chemotherapy + EmactuzumabExperimentalCohort 1: Participants will receive Emactuzumab 1000 mg IV infusion on Days 1 and 15 of each 28 day cycle; Atezolizumab 840 mg IV infusion on Days 1 and 15 of each 28 day cycle; Nab-paclitaxel 125 mg/m2 IV infusion on Days 1, 8, and 15 of each 28 day cycle; Gemcitabine 1000 mg/m2 IV infusion on Days 1, 8, and 15 of each 28 day cycle.
  • Nab-Paclitaxel
  • Gemcitabine
  • Atezolizumab
  • Emactuzumab
Cohort 2: Atezolizumab + CobimetinibExperimentalCohort 2: Participants will receive Cobimetinib 60 milligrams (mg) once daily orally on Days 1-21 of each 28-day cycle; and Atezolizumab 840 mg IV infusion on Days 1 and 15 of each 28-day cycle. Participants who progressed on treatment may have the option of receiving Atezolizumab + RO6874281 treatment, provided they meet the eligibility criteria and the arm is open for enrollment.
  • Atezolizumab
  • Cobimetinib
Cohort 2: Atezolizumab + PEGPH20ExperimentalCohort 2: Participants will receive PEGPH20 3 micrograms per kilogram (mcg/kg) IV infusion on Days 1, 8 and 15 of each 21-day cycle; and Atezolizumab 1200 mg IV infusion on Day 1 of each 21-day cycle. Participants who progressed on treatment, may have the option of receiving Atezolizumab + Cobimetinib or Atezolizumab + RO6874281 treatment, provided they meet the eligibility criteria and the arms are open for enrollment.
  • Atezolizumab
  • PEGPH20
Cohort 2: Atezolizumab + BL-8040ExperimentalCohort 2: Participants will receive BL-8040 1.25 milligrams per kilogram (mg/kg) subcutaneously (SC) on Days 1-5 of the first week, followed by combination treatment consisting of BL-8040 1.25 mg/kg SC three times a week on non-consecutive days and Atezolizumab 1200 mg IV infusion on Day 1 of each 21-day cycle. Participants who progressed on treatment may have the option of receiving Atezolizumab + Cobimetinib or Atezolizumab + RO6874281 treatment, provided they meet the eligibility criteria and the arms are open for enrollment.
  • Atezolizumab
  • BL-8040
Cohort 2: Atezolizumab + RO6874281 every 2 weeksExperimentalCohort 2: Participants will receive Atezolizumab 840 mg IV infusion on days 1 and 15 of each 28 day cycle; RO6874281 will be administered 10 mg by IV infusion on day 1 and 15 mg on days 8, 15, and 22 for cycle 1 (28 day cycle). RO6874281 will be administered 15 mg by IV infusion on days 1 and 15 of each subsequent 28 day cycle. Participants who progressed on treatment may have the option of receiving Atezolizumab + Cobimetinib, provided they meet the eligibility criteria and the arm is open for enrollment.
  • Atezolizumab
  • RO6874281
Cohort 2: Atezolizumab + RO6874281 every 3 weeksExperimentalCohort 2: Participants will receive Atezolizumab 1200 mg IV infusion on Day 1 of each 21 day cycle; and RO6874281 10 mg by IV infusion on day 1 of each 21 day cycle. Participants who progressed on treatment may have the option of receiving Atezolizumab + Cobimetinib, provided they meet the eligibility criteria and the arm is open for enrollment.
  • Atezolizumab
  • RO6874281
Cohort 2: Atezolizumab + EmactuzumabExperimentalCohort 2: Participants will receive Emactuzumab 1000 mg IV infusion on day 1 of each 21 day cycle; and Atezolizumab 1200 mg IV infusion on Day 1 of each 21 day cycle. Participants who progressed on treatment, may have the option of receiving Atezolizumab + Cobimetinib or Atezolizumab + RO6874281 treatment, provided they meet the eligibility criteria and the arms are open for enrollment.
  • Atezolizumab
  • Emactuzumab
Cohort 2: Control (Nab-Paclitaxel and Gemcitabine or mFOLFOX6)Active ComparatorCohort 2: Participants who progressed on a prior fluoropyrimidine-based regimen will receive Nab-paclitaxel 125 mg/m2 IV infusion on Days 1, 8, and 15 of each 28 day cycle; and Gemcitabine 1000 mg/m2 IV infusion on Days 1, 8, and 15 of each 28 day cycle. Participants who progressed on a prior gemcitabine-based regimen will receive 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6). Participants will receive Oxaliplatin 85 mg/m2 IV on Days 1 and 15 of each 28 day cycle; Leucovorin 400 mg/m2 IV on Days 1 and 15 of each 28 day cycle; Fluorouracil 400 mg/m2 IV push on Days 1 and 15 of each 28 day cycle; and Fluorouracil 2400 mg/m2 IV continuous infusion over 46 hours on Days 1 and 2 and on Days 15 and 16 of each 28 day cycle. Participants who progressed on treatment, may have the option of receiving Atezolizumab + Cobimetinib or Atezolizumab + RO6874281 treatment, provided they meet the eligibility criteria and the arms are open for enrollment.
  • Nab-Paclitaxel
  • Gemcitabine
  • Oxaliplatin
  • Leucovorin
  • Fluorouracil

Eligibility Criteria

        Inclusion Criteria:

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Histologically or cytologically confirmed metastatic pancreatic ductal adenocarcinoma

          -  For patients in Cohort 1: no prior systemic treatment for PDAC

          -  For patients in Cohort 2: disease progression during administration of either 5-FU− or
             gemcitabine-based first-line chemotherapy

          -  Life expectancy greater than or equal to 3 months

          -  Availability of a representative tumor specimen that is suitable for determination of
             programmed death-ligand 1 (PD-L1) and/or additional biomarker status via central
             testing

          -  Measurable disease (at least one target lesion) according to RECIST v1.1

          -  Adequate hematologic and end-organ function test results

          -  Tumor accessible for biopsy

          -  For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use contraceptive measures, and agreement to refrain from
             donating eggs, 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:

          -  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, drug-induced
             pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening
             chest computed tomography (CT) scan

          -  Positive human immunodeficiency (HIV) test at screening or at any time prior to
             screening

          -  Active hepatitis B or C virus infection or active tuberculosis

          -  Severe infection within 4 weeks prior to initiation of study treatment

          -  Prior allogeneic stem cell or solid organ transplantation

          -  History of malignancy other than pancreatic carcinoma within 2 years prior to
             screening, with the exception of those with a negligible risk of metastasis or death
      
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
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
Time Frame:Month 6
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 Investigator According to 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]) 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 hour [hr]), 30 minutes (min) post-infusion (infusion duration=60 min) on Day 1 of Cycle 1; pre-infusion (0 hr) on Day 1 of Cycles 2, 3, 4, 8, 12, 16 (21 or 28 day cycles); 30 days and 120 days after last dose (up to approximately 3-5 years)
Measure:Plasma Concentration of Cobimetinib
Time Frame:Pre-dose (0 hr) and 2-4 hrs post-dose on Day 15 of Cycle 1 (cycle length=28 days)(up to approximately 3-5 years).
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, and 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); 30 days after last dose (up to approximately 3-5 years).
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 (21 or 28 day cycles); 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)
Measure:Serum Concentration of RO6874281
Time Frame:Pre-infusion (0 hr) on 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:For RO6874281 Q2W: Pre-infusion (0 hour [hr]), at end of infusion, and 4 hours after infusion on Day 1 of Cycle 1; pre-infusion (0 hr) and at end of infusion on Day 15 of Cycle 1; pre-infusion (0 hr) and at end of infusion on day 1 of Cycles 2, 3, 4, 6, 8, 10, 12, 15 and 18 and every third cycle thereafter (each cycle=28 days); and 30 days after last dose (up to approximately 3-5 years). For RO6874281 Q3W: Pre-infusion (0 hour [hr]), at end of infusion, 2 hours after infusion and 4 hours after infusion on Day 1 of Cycles 1 and 3; 24 hours after the Day 1 infusion for Cycles 1 and 3; 48 hours after the Day 1 infusion for Cycles 1 and 3; 168 hours after the Day 1 infusion for Cycles 1 and 3; 1 hour after initiation of infusion on Day 1 of Cycle 1; pre-infusion (0 hr) and at end of infusion on day 1 of Cycles 2, 4, 6, 8, 10, 12, 14, 16 and 19 and every third cycle thereafter (each cycle=21 days); and 30 days after last dose (up to approximately 3-5 years).
Measure:Serum Concentration of Emactuzumab
Time Frame:Pre-dose (0 hour [hr]) on 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:Cohort 1: Pre-dose (0 hour [hr]) on Day 1 and 8 of Cycle 1; pre-dose (0 hr) and at end of Emactuzumab infusion on day 1 of Cycles 2, 3, 4, 8, 12 and 16 (each cycle = 28 days); and 30 days after last dose (up to approximately 3-5 years). Cohort 2: Pre-dose (0 hour [hr]) on Day 1 of Cycle 1; on Day 15 of Cycle 1; pre-dose (0 hr) and at end of Emactuzumab infusion on day 1 of Cycles 2, 3, 4, 8, 12 and 16 (each cycle = 21 days); and 30 days after last dose (up to approximately 3-5 years).
Measure:Serum Concentration of Selicrelumab
Time Frame:Pre-dose (0 hour [hr]) on Days 1 and 8 of Cycle 1, 4, 8, 12 and 16; pre-dose (0 hr) on day 1 of Cycle 2 (each cycle = 28 days); and 30 days after last dose (up to approximately 3-5 years).
Safety Issue:
Description:
Measure:Serum Concentration of Bevacizumab
Time Frame:Pre-dose (0 hour [hr]) on Days 1 of Cycle 1 and 4 (each cycle = 28 days); and 30 days after last dose (up to approximately 3-5 years).
Safety Issue:
Description:
Measure:Percentage of Participants With ADA to RO6874281
Time Frame:Pre-infusion (0 hr) on 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:RO6874281 Q2W arm: Pre-infusion (0 hour [hr]) on Days 1 and 15 of Cycle 1; pre-infusion (0 hour [hr]) on Day 1 of Cycles 2, 3, 4, 6, 8, 10, 12, 15 and 18 and every third cycle thereafter (each cycle=28 days); and 30 days after last dose (up to approximately 3-5 years). RO6874281 Q3W arm: Pre-infusion (0 hour [hr]) on Day 1 of cycles 1, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 19 and every third cycle thereafter (each cycle=21 days); and 30 days after last dose (up to approximately 3-5 years).
Measure:Percentage of Participants With ADA to Emactuzumab
Time Frame:Pre-dose (0 hour [hr]) on Day 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:Cohort 1: Pre-dose (0 hour [hr]) on Day 1 and 8 of Cycle 1; pre-dose (0 hr) on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (each cycle = 28 days); and 30 days after last dose (up to approximately 3-5 years). Cohort 2: Pre-dose (0 hour [hr]) on Day 1 of Cycle 1; on Day 15 of Cycle 1; pre-dose (0 hr) on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (each cycle = 21 days); and 30 days after last dose (up to approximately 3-5 years).
Measure:Percentage of Participants With ADA to Selicrelumab
Time Frame:Pre-dose (0 hour [hr]) on Day 1 of cycles 1, 2, 4, 8, 12 and 16 (each cycle = 28 days); and 30 days after last dose (up to approximately 3-5 years).
Safety Issue:
Description:
Measure:Percentage of Participants With ADA to Bevacizumab
Time Frame:Pre-dose (0 hour [hr]) on Day 1 of Cycles 1 and 4 (each cycle = 28 days); and 30 days after last dose (up to approximately 3-5 years).
Safety Issue:
Description:

Details

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

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