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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Pancreatic Adenocarcinoma

Intervention / Treatment
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* Drug: Nab-Paclitaxel
* Drug: Gemcitabine
* Drug: Oxaliplatin
* Drug: Leucovorin
* Drug: Fluorouracil
* Drug: Atezolizumab
* Drug: Cobimetinib
* Drug: PEGPH20
* Drug: BL-8040
* Drug: Selicrelumab
* Drug: Bevacizumab
* Drug: RO6874281
* Drug: AB928
* Drug: Tiragolumab
* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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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: Uncontrolled pleural effusion, pericardial effusion, or ascites requiring drainage procedure (i.e., more than one time per month) 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort 1: Control (Nab-Paclitaxel and Gemcitabine)<br>Cohort 1: Participants will receive Nab-Paclitaxel 125 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28 day cycle; and Gemcitabine 1000 mg/m^2 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. | Drug: Nab-Paclitaxel<br>* Nab-Paclitaxel will be administered as per the schedule specified in the respective arm.<br>Drug: Gemcitabine<br>* Gemcitabine will be administered as per the schedule specified in the respective arm.<br>|
| Experimental: Cohort 1: Atezolizumab + Chemotherapy + Selicrelumab<br>Cohort 1: Participants will receive Atezolizumab 840 mg IV infusion on Days 1 and 15 of each 28 day cycle; Nab-paclitaxel 125 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28 day cycle; Gemcitabine 1000 mg/m^2 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. | Drug: Nab-Paclitaxel<br>* Nab-Paclitaxel will be administered as per the schedule specified in the respective arm.<br>Drug: Gemcitabine<br>* Gemcitabine will be administered as per the schedule specified in the respective arm.<br>Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in the respective arm.<br>Drug: Selicrelumab<br>* Selicrelumab will be administered as per the schedule specified in the respective arm.<br>|
| Experimental: Cohort 1: Atezolizumab + Chemotherapy + Bevacizumab<br>Cohort 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/m^2 IV infusion on Days 1, 8, and 15 of each 28 day cycle; Gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28 day cycle. | Drug: Nab-Paclitaxel<br>* Nab-Paclitaxel will be administered as per the schedule specified in the respective arm.<br>Drug: Gemcitabine<br>* Gemcitabine will be administered as per the schedule specified in the respective arm.<br>Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in the respective arm.<br>Drug: Bevacizumab<br>* Bevacizumab will be administered as per the schedule specified in the respective arm.<br>|
| Experimental: Cohort 1: Atezolizumab + Chemotherapy + AB928<br>Cohort 1: Participant will receive AB928 150 mg orally once daily on Days 1 to 28 of each 28 day cycle; Atezolizumab 840 mg IV infusion on Days 1 and 15 of each 28 day cycle; Nab-paclitaxel 125 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28 day cycle; Gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28 day cycle. | Drug: Nab-Paclitaxel<br>* Nab-Paclitaxel will be administered as per the schedule specified in the respective arm.<br>Drug: Gemcitabine<br>* Gemcitabine will be administered as per the schedule specified in the respective arm.<br>Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in the respective arm.<br>Drug: AB928<br>* AB928 will be administered as per the schedule specified in the respective arm.<br>|
| Experimental: Cohort 1: Atezolizumab + Chemotherapy + Tiragolumab<br>Cohort 1: Participants will receive Atezolizumab 840 mg IV infusion on Days 1 and 15 of each 28 day cycle; Tiragolumab 420 mg IV infusion on Days 1 and 15 of each 28 day cycle; Nab-paclitaxel 125 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28 day cycle; Gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28 day cycle. | Drug: Nab-Paclitaxel<br>* Nab-Paclitaxel will be administered as per the schedule specified in the respective arm.<br>Drug: Gemcitabine<br>* Gemcitabine will be administered as per the schedule specified in the respective arm.<br>Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in the respective arm.<br>Drug: Tiragolumab<br>* Tiragolumab will be administered as per the schedule specified in the respective arm.<br>|
| Experimental: Cohort 2: Atezolizumab + Cobimetinib<br>Cohort 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. | Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in the respective arm.<br>Drug: Cobimetinib<br>* Cobimetinib will be administered as per the schedule specified in the respective arm.<br>|
| Experimental: Cohort 2: Atezolizumab + PEGPH20<br>Cohort 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. | Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in the respective arm.<br>Drug: PEGPH20<br>* PEGPH20 will be administered as per the schedule specified in the respective arm.<br>|
| Experimental: Cohort 2: Atezolizumab + BL-8040<br>Cohort 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. | Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in the respective arm.<br>Drug: BL-8040<br>* BL-8040 will be administered as per the schedule specified in the respective arm.<br>|
| Experimental: Cohort 2: Atezolizumab + RO6874281 every 2 weeks<br>Cohort 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. | Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in the respective arm.<br>Drug: RO6874281<br>* RO6874281 will be administered as per the schedule specified in the respective arm<br>|
| Experimental: Cohort 2: Atezolizumab + RO6874281 every 3 weeks<br>Cohort 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. | Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in the respective arm.<br>Drug: RO6874281<br>* RO6874281 will be administered as per the schedule specified in the respective arm<br>|
| Active Comparator: Cohort 2: Control (Nab-Paclitaxel and Gemcitabine or mFOLFOX6)<br>Cohort 2: Participants who progressed on a prior fluoropyrimidine-based regimen will receive Nab-paclitaxel 125 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28 day cycle; and Gemcitabine 1000 mg/m^2 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/m^2 IV on Days 1 and 15 of each 28 day cycle; Leucovorin 400 mg/m^2 IV on Days 1 and 15 of each 28 day cycle; Fluorouracil 400 mg/m^2 IV push on Days 1 and 15 of each 28 day cycle; and Fluorouracil 2400 mg/m^2 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. | Drug: Nab-Paclitaxel<br>* Nab-Paclitaxel will be administered as per the schedule specified in the respective arm.<br>Drug: Gemcitabine<br>* Gemcitabine will be administered as per the schedule specified in the respective arm.<br>Drug: Oxaliplatin<br>* Oxaliplatin will be administered as per the schedule specified in the respective arm.<br>Drug: Leucovorin<br>* Leucovorin will be administered as per the schedule specified in the respective arm.<br>Drug: Fluorouracil<br>* Fluorouracil will be administered as per the schedule specified in the respective arm.<br>|
| Experimental: Cohort 1: Atezolizumab + Chemotherapy + Tocilizumab<br>Cohort 1: Participants will receive Tocilizumab 8 mg/kg IV infusion on Day 1 of each 28 day cycle; Atezolizumab 1680 mg IV infusion on Day 1 of each 28 day cycle; Nab-paclitaxel 125 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28 day cycle; and Gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28 day cycle. | Drug: Nab-Paclitaxel<br>* Nab-Paclitaxel will be administered as per the schedule specified in the respective arm.<br>Drug: Gemcitabine<br>* Gemcitabine will be administered as per the schedule specified in the respective arm.<br>Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in the respective arm.<br>Drug: Tocilizumab<br>* Tocilizumab will be administered as per the schedule specified in the respective arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Objective Response, as Determined by Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) |  | From randomization until disease progression or loss of clinical benefit (up to approximately 7-9 years) | 
| Percentage of Participants With Adverse Events (AEs) |  | 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 7-9 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS), as Determined by Investigator According to RECIST v1.1 |  | From randomization up to the first occurrence of disease (up to approximately 7-9 years) | 
| Overall Survival |  | From randomization up to death from any cause (up to approximately 7-9 years) | 
| Percentage of Participants who are Alive at Month 6 |  | Month 6 | 
| Duration of Response, as Determined by Investigator According to RECIST v1.1 |  | 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 7-9 years) | 
| Percentage of Participants With Disease Control, as Determined by Investigator According to RECIST v1.1 |  | From randomization until disease progression or loss of clinical benefit (up to approximately 7-9 years) |