Evaluation of Efficacy and Safety of Neoadjuvant Treatment With Pamrevlumab in Combination With Chemotherapy (Either Gemcitabine Plus Nab-paclitaxel or FOLFIRINOX) in Participants With Locally Advanced Pancreatic Cancer

Study Overview
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Brief Summary
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This is a Phase 3, randomized, double-blind trial to evaluate the efficacy and safety of neoadjuvant treatment with pamrevlumab or placebo in combination with either gemcitabine plus nab-paclitaxel (G/NP) or FOLFIRINOX in the treatment of participants with locally advanced, unresectable pancreatic cancer.

Detailed Description
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Participants will be randomized in a 1:1 ratio to one of the two study treatment arms; pamrevlumab with either G/NP or FOLFIRINOX, placebo with G/NP or FOLFIRINOX. Each participant may receive up to 6 cycles of treatment (each treatment cycle is 28 days). Tumor tissue will be collected during resection to determine surgical outcome and for biomarker analysis. Tumor response will be evaluated by changes in CT scan, FDG-PET, CA 19-9, and NCCN® guidelines. All participants randomized will have a safety follow-up visit approximately 28 days after the last dose of study treatment and a final safety follow-up phone call at approximately 60 days after the last dose. Participants who complete study treatment will be evaluated for surgical exploration for possible R0 or R1 resection. Surgery will occur at least 4 weeks after the last dose (allowing for a wash-out period from treatment) and only after receipt of the recommendation from the central review board with regards to surgical eligibility. Surgery will occur no longer than 8 weeks after the last dose. Participants who undergo surgery will be evaluated for surgical complications for at least an additional 90 days following discharge from surgery. Participants who are ineligible for surgical exploration (i.e. participants who did not complete study treatment or do not meet any of the protocol defined criteria or had a contraindication to surgery) will continue in the Follow-up period and receive treatment as per standard of care (SOC) for each institution. All participants will be followed for disease progression (if not previously detected) or recurrence following resection (local progression or metastatic disease). Participants will also be followed for any additional anti-cancer therapy received for their pancreatic cancer. All participants will be followed for survival (until death) or until the last participant to complete treatment reaches 18 months post-treatment.

Official Title
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A Phase 3, Randomized, Double-Blind Study of Pamrevlumab or Placebo in Combination With Either Gemcitabine Plus Nab-paclitaxel or FOLFIRINOX as Neoadjuvant Treatment in Patients With Locally Advanced, Unresectable Pancreatic Cancer

Conditions
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Pancreatic Cancer Non-resectable

Intervention / Treatment
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* Drug: Pamrevlumab + Gemcitabine + Nab-paclitaxel or Pamrevlumab + FOLFIRINOX
* Drug: Placebo + Gemcitabine + Nab-paclitaxel or Placebo + FOLFIRINOX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Understand and sign informed consent; be willing to comply with study procedures, including surgery Age ≥ 18 years Be a male, or non-pregnant and non-lactating female Negative serum B-hCG pregnancy test at screening for women of childbearing potential Male participants with partners of childbearing potential and female participants of childbearing potential are required to use highly effective contraception methods during the conduct of the study and for 6 months after the last dose of study drug Histologically or cytologically proven diagnosis of pancreatic ductal adenocarcinoma (PDAC) Locally advanced pancreatic cancer considered unresectable according to NCCN Guidelines® Version 2.2018 as determined by central imaging Measurable disease as defined by RECIST 1.1 criteria as determined by central imaging Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Adequate liver function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 x upper limit of normal (ULN), alkaline phosphatase <2.5 x ULN, and bilirubin ≤1.5 x ULN or in participants with biliary stenting ≤2.0 x ULN Adequate bone marrow function: platelets >100,000 cells/mm3, hemoglobin >9.0 g/dl and absolute neutrophil count (ANC) >1,500 cells/mm3 Adequate renal function: creatinine < 1.5 x ULN, creatinine clearance ≥ 30 mL/min Less than grade 2 pre-existing peripheral neuropathy (per CTCAE) Exclusion Criteria: Prior chemotherapy or radiation for pancreatic cancer Previous (within the past 3 years) or concurrent malignancy diagnosis except non-melanoma skin cancer and in situ carcinomas (excluding in situ breast cancer) Major surgery within 4 weeks prior to signing informed consent form. Biliary stents are permitted. History of allergy or hypersensitivity to human, humanized or chimeric monoclonal antibodies History of allergy or hypersensitivity to any of the chemotherapy agents being prescribed or their excipients Any medical or surgical condition that may place the participant at increased risk while on study Any condition potentially decreasing compliance to study procedures Exposure to another investigational drug within 28 days of first dosing visit, or 5 half-lives of the investigational drug (whichever is longer) Uncontrolled intercurrent illness including, but not limited to, ongoing or active systemic infections, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Documented history of drug or alcohol abuse within 6 months of signing informed consent Any medical condition that, in the opinion of the investigator, may pose a safety risk to a participant in this trial, may confound the assessment of safety and efficacy, or may interfere with study participation Participants with a history of interstitial pulmonary disease, hepatitis C virus (HCV), hepatitis B virus (HBV) or human immunodeficiency virus (HIV) infection Participants who have been administered a live vaccine within 4 weeks prior to the first administration of therapy Participants who cannot stop chronic medications that inhibit or induce cytochrome P (CYP) 2C8 or CYP3A4 Participants with poorly controlled comorbid conditions, including; congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), uncontrolled diabetes mellitus (DM) or neurologic disorders (not acutely related to pancreatic cancer) or limited function

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
Interventional Model Description: Participants will be randomized in a 1:1 ratio to one of the two study treatment arms; pamrevlumab with G/NP or FOLFIRINOX or placebo with G/NP or FOLFIRINOX.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Pamrevlumab + Gemcitabine + Nab-paclitaxel or Pamrevlumab + FOLFIRINOX | Drug: Pamrevlumab + Gemcitabine + Nab-paclitaxel or Pamrevlumab + FOLFIRINOX<br>* Drug: Pamrevlumab is administered on Days 1, 8 and 15 of Treatment Cycle 1 and on Day 1 and 15 of each subsequent treatment cycle via IV infusion. Drug: Gemcitabine is administered on Days 1, 8 and 15 of each 28 day treatment cycle via IV infusion. Drug: Nab-paclitaxel is administered on Days 1, 8 and 15 of each 28 day treatment cycle via IV infusion. Drug: FOLFIRINOX is a combination of several agents administered on Days 1 and 15 of each 28 day treatment cycle via IV infusion. The specific agents are Oxaliplatin, Folinic Acid, Irinotecan, and Fluorouracil.<br>* Other names: Efudex;|
| Placebo Comparator: Arm B<br>Placebo + Gemcitabine + Nab-paclitaxel or Placebo + FOLFIRINOX | Drug: Placebo + Gemcitabine + Nab-paclitaxel or Placebo + FOLFIRINOX<br>* Drug: Placebo is administered on Days 1, 8 and 15 of Treatment Cycle 1 and on Day 1 and 15 of each subsequent treatment cycle via IV infusion. Drug: Gemcitabine is administered on Days 1, 8 and 15 of each 28 day treatment cycle via IV infusion. Drug: Nab-paclitaxel is administered on Days 1, 8 and 15 of each 28 day treatment cycle via IV infusion. Drug: FOLFIRINOX is a combination of several agents administered on Days 1 and 15 of each 28 day treatment cycle via IV infusion. The specific agents are Oxaliplatin, Folinic Acid, Irinotecan, and Fluorouracil.<br>* Other names: Efudex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) |  | Randomization to death due to any cause or until the last participant to complete treatment reaches 18 months post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) |  | Randomization until one of the following events, whichever occurs first: resection failure or progression that precludes surgery, local or distant recurrence, death (assessed up to 6 years) | 
| Progression-free survival (PFS) |  | Randomization until disease progression or death, whichever occurs first (assessed up to 6 years) | 
| Best Overall Objective Response Rate (ORR), as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | Best ORR is defined as the percentage of participants who achieve complete response (CR) or partial response (PR) during treatment period. | Randomization until centrally-assessed progressive disease (PD), death, or first administration of anti-tumor treatment (other than study medication), whichever occurs first (assessed up to 6 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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locally advanced pancreatic cancer, unresectable pancreatic cancer