Phase 3 Study of FOLFIRINOX (mFFX) +/- SBRT in Locally Advanced Pancreatic Cancer

Study Overview
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Brief Summary
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The goal of this study is to determine the safety and efficacy of a chemotherapy regimen known as Modified FOLFIRINOX (mFFX) alone or with the addition of Stereotactic Body Radiotherapy (SBRT). We hope to learn if this new treatment combination helps to control the disease and improve survival for patients with locally advanced pancreatic cancer.

Detailed Description
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Primary Objective: To determine progression free survival for mFFX +/- SBRT. Secondary Objectives: To determine metastasis free survival following mFFX chemotherapy alone or with SBRT. To determine the overall survival in pancreatic cancer patients treated with chemotherapy +/- SBRT. To determine local progression-free survival in pancreatic cancer patients after chemotherapy +/- SBRT. To evaluate acute (within 3 months of treatment) grade 2 or greater gastritis, fistula, enteritis, or ulcer and any other grade 3-4 gastrointestinal toxicity within 3 months of treatment. To evaluate the utility of FDG-PET for treatment planning and estimation of progression free survival. To identify new biomarkers in pancreatic cancer. To evaluate the quality of life of patients before and after either chemotherapy or chemotherapy and SBRT.

Official Title
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A Randomized Phase III Study Evaluating Modified FOLFIRINOX (mFFX) With or Without Stereotactic Body Radiotherapy (SBRT) in the Treatment of Locally Advanced Pancreatic Cancer: A Pancreatic Cancer Radiotherapy Study Group (PanCRS) Trial

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: Oxaliplatin
* Drug: Irinotecan
* Drug: Leucovorin
* Drug: 5FU
* Radiation: Stereotactic Body Radiotherapy (SBRT)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Histologically-confirmed adenocarcinoma of the pancreas Determined unresectable by a pancreatic cancer surgeon or a multi-disciplinary or gastrointestinal oncology Tumor Board. Stable or better disease on re-staging scans Typically, tumors < 8.0 cm in greatest axial dimension but final determination of eligibility based upon radiation normal tissue constraints Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1, or 2 Leukocytes (white blood cells, WBC) ≥ 3,000/mL Absolute neutrophil count (ANC) ≥ 1,500/mL Platelets ≥ 50,000/mL Total bilirubin ≤ 1.5 X institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 2.5 X institutional ULN Creatinine within normal institutional limits Ability to understand and the willingness to sign an informed consent form Life expectancy > 6 months EXCLUSION CRITERIA Metastatic disease Prior radiotherapy to the upper abdomen/liver. Prior chemotherapy for pancreatic cancer, other than up to 4 cycles of modified FOLFIRINOX. Age < 18 years Uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection (or infections requiring systemic antibiotic treatment) Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness/social situations that would limit compliance with study requirements. Any concurrent malignancy other than non-melanoma skin cancer, non-invasive bladder cancer, or carcinoma in situ of the cervix. Patients with a previous malignancy without evidence of disease for > 5 years will be allowed to enter the trial. Pregnant or lactating Women of child-bearing potential who are unwilling or unable to use an acceptable method of birth control (hormonal or barrier method of birth control; abstinence) for duration of the study Women who are not post-menopausal (as defined in Appendix III) and have a positive urine or serum pregnancy test or refuse to take a pregnancy test Male subjects who are unwilling or unable to use effective contraception for duration of the study

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: Modified FOLFIRINOX<br>Modified FOLFIRINOX (mFFX), a chemotherapeutic treatment regimen of 5FU, leucovorin, irinotecan, and oxaliplatin. | Drug: Oxaliplatin<br>* Oxaliplatin 85 mg/m² IV over 2 hours on Day 1 of a 14-day cycle.<br>* Other names: Eloxatin;Drug: Irinotecan<br>* Irinotecan 180 mg/m² IV over 90 minutes on Day 1 of a 14-day cycle.<br>* Other names: Onivyde;Drug: Leucovorin<br>* Leucovorin 400 mg/m² IV over 2 hours on Day 1 of a 14-day cycle.<br>* Other names: Citrovorum Factor;Drug: 5FU<br>* 5FU 2,400 mg/m² IV over 46 to 48 hours starting on Day 1 of a 14-day cycle.<br>* Other names: Adrucil;|
| Experimental: Modified FOLFIRINOX plus Stereotactic Body Radiotherapy<br>Modified FOLFIRINOX (mFFX), a chemotherapeutic treatment regimen of 5FU, leucovorin, irinotecan, and oxaliplatin, in combination with stereotactic body radiotherapy (SBRT) | Drug: Oxaliplatin<br>* Oxaliplatin 85 mg/m² IV over 2 hours on Day 1 of a 14-day cycle.<br>* Other names: Eloxatin;Drug: Irinotecan<br>* Irinotecan 180 mg/m² IV over 90 minutes on Day 1 of a 14-day cycle.<br>* Other names: Onivyde;Drug: Leucovorin<br>* Leucovorin 400 mg/m² IV over 2 hours on Day 1 of a 14-day cycle.<br>* Other names: Citrovorum Factor;Drug: 5FU<br>* 5FU 2,400 mg/m² IV over 46 to 48 hours starting on Day 1 of a 14-day cycle.<br>* Other names: Adrucil;Radiation: Stereotactic Body Radiotherapy (SBRT)<br>* Radiotherapy treatment starting about 8 weeks after modified FOLFIRINOX induction chemotherapy, administered as 5 fractions of 8 Grey (Gy) each, on 5 separate days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Progression-free survival (PFS) means the period of time that a participant remains alive without tumor progression either locally or at a distant site in the body (metastasis). The effect of the study treatments was assessed as the median PFS of participants in the treatment groups. The outcome is reported as the median PFS with standard deviation. | 38 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Progression-free Survival (Local PFS) | Local progression-free survival (PFS) means the period of time that a participant remains alive without recurrence or advancement of the disease at the baseline sites of the tumor (local progression). The effect of the study treatments was assessed as the median local PFS of participants in the treatment groups. The outcome is reported as the median local PFS with standard deviation. | 38 months | 
| Progression-free Survival (PFS) at 1 Year | Progression-free survival (PFS) means the period of time that a participant remains alive without tumor progression either locally or at a distant site in the body (metastasis). The effect of the study treatments was assessed as the number of participants in each treatment group that remained alive without tumor progression, at 1 year after treatment. The outcome is reported as a number without dispersion. | 1 year | 
| Metastasis-free Survival (MFS) | Metastasis-free survival (MFS) means the period of time that a participant remains alive without the appearance of new tumor lesions a distant site in the body (metastasis). The effect of the study treatments was assessed as the median MFS of participants in the treatment groups. The outcome is reported as the median PFS with standard deviation. | 62 months | 
| Overall Survival (OS) | The effect of the study treatments was assessed as the length of time participants in each treatment group that remained alive. The outcome is reported as the median OS with standard deviation. | 62 months | 
| Grade 2 or Greater Gastrointestinal (GI) Toxicity | Toxicity means an adverse event related to the study treatment. Toxicity was assessed between treatment groups as the number of treatment-related , ≥ grade 2 events of gastritis, fistula, enteritis, or ulcer; plus any other Grade 3 to 5 gastrointestinal (GI) toxicity. The outcome is reported as the number of defined adverse events by preferred term for each treatment group, occurring within 3 months of the start of treatment. These adverse events by definition are all within the Common Terminology Criteria for Adverse Events (CTCAE) version 4.01 Gastrointestinal Body System. The outcome is reported as numbers without dispersion. All-cause Mortality mFFX 7 SBRT 8 | 3 months |