Phase II Randomized Trial Of MFOLFIRINOX +/- Ramucirumab In Advanced Pancreatic Cancer

Study Overview

Phase II Randomized Trial of mFOLFIRINOX +/- Ramucirumab in Advanced Pancreatic Cancer

This is a phase II, multicenter, double-blinded, randomized, 2-arm trial evaluating the efficacy and safety of mFOLFIRINOX plus ramucirumab (Arm A) vs. mFOLFIRINOX plus placebo (Arm B) in 94 subjects with advanced pancreatic cancer, not amenable to curative treatment. Both arms will continue treatment until disease progression or unacceptable toxicity.

OUTLINE: This is a multi-center study. EXPERIMENTAL ARM A: * Oxaliplatin 85 mg/m^2 over 2-4 hours * Irinotecan 165 mg/m^2 over 90 minutes * 5-FU 2,400 mg/m^2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm A will receive ramucirumab (RAM) administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks. CONTROL ARM B : * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm B will receive a placebo infusion every 2 weeks. Due to the double-blinded nature of this study, the volume of placebo will be calculated as if it were RAM. In order to demonstrate adequate organ function, all screening labs must be obtained within 7 days prior to registration: Hematological: * Hemoglobin ≥ 9 g/dL * Absolute Neutrophil Count (ANC) ≥ 1,500/mm^3 * Platelet Count (PLT) ≥ 100,000/mm^3 Renal: * Creatinine ≤ 1.5 mg/dL or Creatinine clearance^1 ≥ 40 mL/min * Albumin ≥ 2.5 g/dL Hepatic: * Bilirubin ≤ 1.5 mg/dL * Aspartate aminotransferase (AST) ≤ 3 × ULN or < 5 xULN in the setting of liver metastases * Alanine aminotransferase (ALT) ≤ 3 × ULN or < 5 xULN in the setting of liver metastases Coagulation: * International Normalized Ratio (INR) (Patients receiving warfarin must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to first dose of protocol therapy) ≤1.5 and a partial thromboplastin time (PTT) (PTT/aPTT) < 1.5 x ULN

Pancreatic Cancer

DRUG: mFOLFIRINOX
DRUG: Ramucirumab
OTHER: Placebo

HCRN GI14-198

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2015-10-19	Results First Submitted 2024-11-19	Last Update Submitted that met QC Criteria 2024-12-19
First Submitted that Met QC Criteria 2015-10-19	Results First Submitted that Met QC Criteria 2024-12-19	Last Update Posted (ACTUAL) 2025-01-01
First Posted (ACTUAL) 2015-10-20	Results First Posted 2025-01-01	Last Verified 2024-12

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Randomized

Interventional Model:
Parallel

Masking:
Quadruple

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Arm A: Experimental Arm mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. *	DRUG: mFOLFIRINOX mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. DRUG: Ramucirumab Ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks.
PLACEBO_COMPARATOR: Arm B: Placebo Arm mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. *	DRUG: mFOLFIRINOX mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. OTHER: Placebo Placebo infusion with volume calculated as if it were ramucirumab every 2 weeks.

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Arm A: Experimental Arm

mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. *

DRUG: mFOLFIRINOX

mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia.

DRUG: Ramucirumab

Ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks.

PLACEBO_COMPARATOR: Arm B: Placebo Arm

DRUG: mFOLFIRINOX

mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia.

OTHER: Placebo

Placebo infusion with volume calculated as if it were ramucirumab every 2 weeks.

Primary Outcome Measures	Measure Description	Time Frame
Progression Free Survival (PFS) at 9 Month	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) >= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. PFS is defined as time of registration until disease progression met by RECIST 1.1 or death from any cause.	9 months

Secondary Outcome Measures	Measure Description	Time Frame
Overall Survival (OS)	Overall survival is defined by the date of randomization to date of death from any cause.	Up to a maximum of 53 months
Response Rate (RR)	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) >= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Overall Response (OR) = CR + PR.	Up to 44 months
Number of Participants With Adverse Events	Adverse events will be assessed to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.	From date of first dose until 30 days after the last treatment, assessed up to 44 months

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information. .
Age ≥ 18 years at the time of consent.
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 within 7 days prior to registration.
Histologic or cytological diagnosis of recurrent or metastatic pancreas adenocarcinoma (PCA) who present for first line chemotherapy treatment.
No prior first line systemic treatment (prior adjuvant or neoadjuvant treatment is permitted). Subjects whose disease has progressed after 6 months of last systemic chemotherapy or chemo-radiation in the adjuvant or neoadjuvant setting are eligible.
Measurable disease determined using guidelines of Response Evaluation Criteria In Solid Tumors (RECIST 1.1). Baseline tumor assessment should be performed using high resolution computed tomography (CT) scans or magnetic resonance imaging (MRI).
Urine protein < 1+ on dipstick test or routine urinalysis. If the proteinuria on these tests is ≥2+, then a 24-hour urine test must be collected and must demonstrate < 1g proteins in 24 hours to allow participation.
Estimated life expectancy of >12 weeks, as assessed by the site investigator.
If sexually active, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods) due to unknown risk of teratogenicity of ramucirumab

Subjects with histology other than adenocarcinoma; Examples include: neuroendocrine tumors, acinar cell cancer, sarcoma or lymphoma of the pancreas.
Ongoing or active infection.
Symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia. Symptomatic heart failure per New York Heart Association (NYHA) Class II-IV.
Uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) despite standard medical management.
Acute or sub-acute intestinal obstruction.
Interstitial pneumonia or interstitial fibrosis of the lung, which in the opinion of the site investigator could compromise the subject or the study.
Pleural effusion or ascites that causes > grade 1 dyspnea.
Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) with a history of hepatic encephalopathy or clinical meaningful ascites resulting from cirrhosis; clinically meaningful ascites is defined as ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis.
Grade 3 or higher bleeding event ≤ 3 months prior to randomization.
Experience of any arterial thrombotic or arterial thromboembolic events, including, but not limited to myocardial infarction, transient ischemic attack, or cerebrovascular accident, ≤ 6 months prior to randomization.
History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to randomization.
Documented and/or symptomatic or known brain or leptomeningeal metastases.
GI perforation/fistula
Documented and/or symptomatic or known brain or leptomeningeal metastases.
Severely immune-compromised (other than being on steroids), including known HIV infection.
Concurrent active malignancy other than adequately treated non-melanoma skin cancer, other noninvasive carcinoma, or in situ neoplasm. A subject with previous history of malignancy is eligible, provided that he/she has been disease free for > 3 years.
Breast-feeding or pregnant.
Prior autologous or allogeneic organ or tissue transplantation.
Known allergy to any of the treatment components.
Major surgery within 28 days prior to the first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 2 days prior to first dose of protocol therapy. The patient has elective or planned major surgery to be performed during the course of the clinical trial.
Any condition that does not permit compliance with the study schedule including psychological, geographical or medical.
Receiving medications that can effect clotting ability: warfarin, aspirin (once-daily aspirin use- maximum dose 325 mg/day is permitted), nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents. .
Serious or non-healing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Eli Lilly and Company
Hoosier Cancer Research Network

Investigators

PRINCIPAL_INVESTIGATOR: Walid Shaib, MD, Emory University

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Shaib WL, Manali R, Liu Y, El-Rayes B, Loehrer P, O'Neil B, Cohen S, Khair T, Robin E, Huyck T, Bekaii-Saab T. Phase II randomised, double-blind study of mFOLFIRINOX plus ramucirumab versus mFOLFIRINOX plus placebo in advanced pancreatic cancer patients (HCRN GI14-198). Eur J Cancer. 2023 Aug;189:112847. doi: 10.1016/j.ejca.2023.02.030. Epub 2023 Mar 11.

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