Exploratory Platform Trial to Evaluate Immunotherapy Combinations With Chemotherapy for the Treatment of Patients With Previously Untreated Metastatic Pancreatic Adenocarcinoma

Study Overview
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Brief Summary
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This trial is designed to evaluate multiple clinical hypotheses and mechanistically-defined combinations to evaluate the safety and efficacy of first-line chemo-immunotherapy combinations in participants with metastatic pancreatic ductal adenocarcinoma (mPDAC).

Detailed Description
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This is an open-label, non-randomized, exploratory platform trial designed to assess the safety and antitumor activity of immunotherapy, in combination with standard of care chemotherapy, in participants with mPDAC who have not received prior therapy. Where supportive mechanistic data are available, immunotherapy may also be combined with other treatment modalities (eg, radiation). Each cohort of this platform trial will test a different immunotherapy combination and consist of up to 2 stages: an initial stage (Stage 1) to evaluate safety, biomarkers, and/or clinical activity of the combination and an expanded cohort (Stage 2), when warranted, based on the safety, clinical activity, and/or biomarker results from Stage 1. The Sponsor intends to modify and/or add new combinations to the protocol as data emerge from scientific findings, in this and other trials. This trial will be conducted in participants with histologically or cytologically documented diagnosis of mPDAC, with measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, who have not received prior systemic therapy for their disease in the metastatic setting. Participants must have adequate organ and hematologic function and acceptable performance status. Participants must consent to tumor biopsies, including a pre-treatment (baseline) and on-treatment samples.

Official Title
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A Multicenter, Open-label, ExploRatory Platform Trial to EValuate ImmunOtherapy Combinations With Chemotherapy for the Treatment of Patients With PreviousLy UnTreated MetastatIc Pancreatic AdenOcarciNoma (REVOLUTION)

Conditions
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Metastatic Pancreatic Adenocarcinoma

Intervention / Treatment
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* Drug: Nivolumab (Cohort A)
* Drug: Ipilimumab (Cohort A, B and C)
* Drug: Hydroxychloroquine (HCQ) (Cohort B)
* Drug: Nab-paclitaxel (nP) (Cohort A, B and C)
* Drug: Gemcitabine (gem) (Cohort A, B and C)
* Drug: NG350A (Cohort C)


Participation Criteria
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Eligibility Criteria
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Core Inclusion Criteria Participant has histologically or cytologically documented diagnosis of pancreatic adenocarcinoma with metastatic disease. Participants with locally advanced disease are not eligible. a. Participants with recurrent locally advanced disease are eligible, provided: i. the last dose of chemotherapy and/or radiotherapy occurred > 4 months prior to the first dose of study intervention, and; ii. no systemic or radiotherapy has been administered in the metastatic setting. Participant must have measurable disease by RECIST v1.1. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. A baseline tumor tissue sample is mandatory for enrollment. If archival tumor tissue is not available, then a fresh tumor biopsy must be provided. Participant must be age 18 years or older. Participant must have adequate organ function. Core Exclusion Criteria Participant must not have received any prior treatment, including chemotherapy, biological therapy, or targeted therapy for mPDAC, with the following exceptions and notes: Participants who have received prior neoadjuvant or adjuvant therapy for pancreatic adenocarcinoma are eligible if neoadjuvant and adjuvant therapy (including chemotherapy and/or radiotherapy) was completed more than 4 months before the start of study intervention. Prior surgical resection is permitted. Participants who have received treatment with any other enadenotucirev-based therapy or anti-CD40 antibody at any time are not eligible for the study (cohort C only). Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast. Participants with an active, known or suspected autoimmune disease. Participants with: type I diabetes mellitus; hypothyroidism only requiring hormone replacement; a history of Hashimoto syndrome, within 3 years of the first dose of study intervention, which resolved to hypothyroidism alone; skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment; or conditions not expected to recur in the absence of an external trigger are permitted to enroll.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Nivolumab + Ipilimumab + nP/gem<br> | Drug: Nivolumab (Cohort A)<br>* Nivolumab will be administered intravenously at 360 mg every 3 weeks for up to 2 years.<br>* Other names: Opdivo;Drug: Ipilimumab (Cohort A, B and C)<br>* For Cohort A and B, ipilimumab will be administered intravenously at 1mg/kg every 6 weeks for up to 2 cycles. For Cohort C, ipilimumab will be administered intravenously at 1mg/kg on C2D1 and C4D1.<br>* Other names: Yervoy;Drug: Nab-paclitaxel (nP) (Cohort A, B and C)<br>* Nab-paclitaxel will be administered intravenously at 125 mg/m2 for 2 weeks on and 1 week off, for at least 24 weeks, unless treatment discontinuation criteria are met.<br>* Other names: Abraxane;Drug: Gemcitabine (gem) (Cohort A, B and C)<br>* Gemcitabine will be administered intravenously at 1000 mg/m2 for 2 weeks on and 1 week off, for at least 24 weeks, unless treatment discontinuation criteria are met.<br>* Other names: Gemzar;|
| Experimental: Cohort B: Hydroxychloroquine + Ipilimumab + nP/gem<br> | Drug: Ipilimumab (Cohort A, B and C)<br>* For Cohort A and B, ipilimumab will be administered intravenously at 1mg/kg every 6 weeks for up to 2 cycles. For Cohort C, ipilimumab will be administered intravenously at 1mg/kg on C2D1 and C4D1.<br>* Other names: Yervoy;Drug: Hydroxychloroquine (HCQ) (Cohort B)<br>* Hydroxychloroquine will be administered orally daily for up to 2 years.<br>* Other names: Plaquenil;Drug: Nab-paclitaxel (nP) (Cohort A, B and C)<br>* Nab-paclitaxel will be administered intravenously at 125 mg/m2 for 2 weeks on and 1 week off, for at least 24 weeks, unless treatment discontinuation criteria are met.<br>* Other names: Abraxane;Drug: Gemcitabine (gem) (Cohort A, B and C)<br>* Gemcitabine will be administered intravenously at 1000 mg/m2 for 2 weeks on and 1 week off, for at least 24 weeks, unless treatment discontinuation criteria are met.<br>* Other names: Gemzar;|
| Experimental: Cohort C: NG-350A + Ipilimumab + nP/gem<br> | Drug: Ipilimumab (Cohort A, B and C)<br>* For Cohort A and B, ipilimumab will be administered intravenously at 1mg/kg every 6 weeks for up to 2 cycles. For Cohort C, ipilimumab will be administered intravenously at 1mg/kg on C2D1 and C4D1.<br>* Other names: Yervoy;Drug: Nab-paclitaxel (nP) (Cohort A, B and C)<br>* Nab-paclitaxel will be administered intravenously at 125 mg/m2 for 2 weeks on and 1 week off, for at least 24 weeks, unless treatment discontinuation criteria are met.<br>* Other names: Abraxane;Drug: Gemcitabine (gem) (Cohort A, B and C)<br>* Gemcitabine will be administered intravenously at 1000 mg/m2 for 2 weeks on and 1 week off, for at least 24 weeks, unless treatment discontinuation criteria are met.<br>* Other names: Gemzar;Drug: NG350A (Cohort C)<br>* NG-350A will be administered intravenously on Cycle 1 Days 15 (1e12 viral particles), 17 (3e12 viral particles), and 19 (3e12 viral particles).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events |  | Up to 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | Defined as the proportion of participants who achieve a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. | Up to 2.5 years | 
| Disease control rate (DCR) | Defined as the proportion of participants who achieve confirmed CR or PR or stable disease (SD) lasting at least 16 weeks | At 9 months | 
| Duration of response (DOR) | Defined as the time from first documentation of response (CR or PR) to first radiographic documentation of progressive disease (PD) or death due to any cause. | Up to 2.5 years | 
| Progression-free survival (PFS) | Defined as the time from initiation of study intervention to date of first documented radiographic progression of disease or death due to any cause. | Up to 2.5 years | 
| Overall survival (OS) | Defined as the time from initiation of study intervention until death due to any cause. | Up to 2.5 years | 
| Overall survival (OS) at 12 months | Defined as the time from initiation of study intervention until death due to any cause. | At 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Pancreatic Adenocarcinoma, Immunotherapy, Platform study, Nivolumab, Ipilimumab, Gemcitabine, nab-paclitaxel, hydroxychloroquine, NG-350A