Chemotherapy and Radiation Therapy Before Surgery Followed by Gemcitabine in Treating Patients With Pancreatic Cancer

Neoadjuvant FOLFIRINOX and Chemoradiation Followed by Definitive Surgery and Postoperative Gemcitabine for Patients With Borderline Resectable Pancreatic Adenocarcinoma: An Intergroup Single-Arm Pilot Study

This pilot clinical trial studies combination chemotherapy and radiation therapy before surgery followed by gemcitabine hydrochloride in treating patients with pancreatic cancer. Drugs used in chemotherapy, such as oxaliplatin, irinotecan hydrochloride, leucovorin calcium, fluorouracil, and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving combination chemotherapy and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving chemotherapy after surgery may kill any tumor cells that remain after surgery.

Study Overview

• Status: Completed
• Conditions: Acinar Cell Adenocarcinoma of the Pancreas; Duct Cell Adenocarcinoma of the Pancreas; Recurrent Pancreatic Cancer; Stage III Pancreatic Cancer; Stage II Pancreatic Cancer
• Intervention / Treatment: Procedure: surgery; Drug: 5-fluorouracil; Radiation: radiation; Drug: irinotecan; Drug: leucovorin; Drug: oxaliplatin; Drug: capecitabine; Drug: gemcitabine

Detailed Description

The purpose of this study is to evaluate a new treatment program for patients with borderline resectable pancreas cancer in order to determine what effects, good and bad, chemotherapy and chemoradiation have on your cancer and to see if it allows safe surgery.

Primary Objectives:

• To assess the accrual rate of this study.
• To assess the rate of treatment-related toxicity and treatment delay during preoperative therapy.
• To assess the rate of completion of all preoperative and operative therapy.

Secondary Objectives:

• To assess the macroscopic (R0/R1) resection rate.
• To estimate the rate of radiographic and histopathologic response to preoperative therapy.
• To estimate the time to locoregional and distant recurrence.
• To assess overall survival (OS).
• To retrieve nucleic acids from pretreatment pancreatic ductal adenocarcinoma biopsies and to assess the quality of these nucleic acids using a sequencing-based assessment of tumor DNA.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093
      • UC San Diego Moores Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Evanston, Illinois, United States, 60201
      • NorthShore University HealthSystem-Evanston Hospital
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • The James Graham Brown Cancer Center at University of Louisville
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center Jefferson
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
    • West Chester, Ohio, United States, 45069
      • University Pointe
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Pre-Registration Eligibility Criteria

• Documentation of Disease and Radiographic Staging

  • Cytologic or histologic proof of adenocarcinoma of the pancreatic head or uncinate process
  • Objective radiographic staging with a) contrast-enhanced, helical thin-cut computed tomography (CT)/magnetic resonance imaging (MRI) scan of the abdomen and b) CT scan/MRI of the chest
  • Note: echoendoscopic staging will be permitted as an adjunctive modality, but all stage definitions below will be determined using CT/MRI as outlined below. In the event echoendoscopic stage and CT/MRI stage are discordant, the CT/MRI stage will be used. Significant discordance should be discussed with the study principal investigator (PI) prior to enrollment

  • Borderline resectable primary tumor, defined by the presence of any one or more of the following on CT/MRI, and confirmed by central radiographic review:

    • An interface between the primary tumor and the superior mesenteric vein or portal vein (SMV-PV) measuring ≥ 180 degrees of the circumference of the vessel wall
    • Short-segment occlusion of the SMV-PV with normal vein above and below the level of obstruction that is amenable to resection and venous reconstruction
    • Short segment interface (of any degree) between tumor and hepatic artery with normal artery proximal and distal to the interface that is amenable to resection and reconstruction
    • An interface between the tumor and superior mesenteric artery (SMA) measuring < 180 degrees of the circumference of the vessel wall

  • No potentially resectable disease defined as primary tumors with all of the following:

    • An interface between the primary tumor and the superior mesenteric vein or portal vein (SMV-PV) measuring < 180 degrees of the circumference of the vessel wall
    • No radiographic interface between the tumor and the (superior mesenteric artery) SMA, hepatic artery or celiac axis
    • No radiographic evidence of metastatic disease

  • No metastatic disease defined as any one or more of the following:

    • Suspicious lymphadenopathy outside the standard surgical field (i.e., aortocaval nodes, distant abdominal nodes)
    • Radiographic evidence for metastatic disease in distant organs, such as masses in distant organs or ascites

  • No locally advanced and/or unresectable disease clearly defined by any one or more of the following by CT/MRI:

    • An interface between the tumor and the SMA measuring ≥ 180 degrees of the circumference of the vessel wall
    • No interface between the tumor and the aorta
    • Occlusion of the SMV or portal vein without a sufficient cuff of normal vein above and below the level of obstruction with which to perform venous reconstruction
    • Long-segment interface (of any degree) between the tumor and the common hepatic artery or its major tributaries with insufficient artery proximal and distal to the interface to perform reconstruction
• No prior chemotherapy or chemoradiation for pancreatic cancer
• No patients with a "currently active" second malignancy other than non-melanoma skin cancers. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for ≥ 3 years
• Baseline peripheral sensory neuropathy must be grade < 2
• No patients with known Gilbert's Syndrome or homozygosity for UGT1A1*28 polymorphism
• No history of pulmonary embolism in the past 6 months
• Age ≥ 18 years of age
• Eastern Cooperative Oncology Group (ECOG)/Zubrod performance status 0-1
• Pregnancy/Nursing Status: Non-pregnant and non-breast-feeding. Female participants of child-bearing potential must have a negative urine or serum pregnancy test prior to registration. Perimenopausal participants must be amenorrheic > 12 months to be considered not of childbearing potential.

• Required Pre-Registration Laboratory Values:

  • Granulocytes ≥ 2,000/ul
  • Hemoglobin > 9 g/dL
  • Platelets ≥ 100,000/ul
  • Albumin > 3.0 g/dL
  • Creatinine ≤1.5 x upper limit of normal (ULN)

Registration Eligibility Criteria

• Confirmation of pre-registration eligibility criteria as described under "Documentation of Disease and Radiographic Staging" by the Alliance Central Radiographic Review

• Required Registration Laboratory Values:

  • Bilirubin ≤2 mg/dl
  • AST (SGOT) & ALT (SGPT) ≤ 2.5 x ULN

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: mFOLFIRINOX, chemoradiation, surgery and gemcitabine; Each patient will receive mFOLFIRINOX therapy administered every other week for a total of 4 cycles. Each treatment cycle is a total of 14 days. This treatment program consists of four drugs (oxaliplatin 85 mg/m^2 IV over 2 hours on day 1 followed by irinotecan 180 mg/m^2 IV over 90 minutes on day 1 followed by, leucovorin 400 mg/m^2 IV over 2 hours on day 1 followed by 5-FU 2400 mg/m^2 IV over 46-48 hours). Two to six weeks following treatment with the mFOLFIRINOX, if the tumor has not spread to other parts of the body then the patient will receive capecitabine 825 mg/m^2, twice daily for 28 days along with radiation therapy. Patients will have surgery within 4-10 weeks of the last dose of chemoradiation if the tumor has gotten smaller or stayed the same. Within 6-8 weeks following surgery, patients will receive gemcitabine for 2 cycles (1 cycle is 28 days). Gemcitabine will be given IV on days 1, 8 and 15 of every 28 day cycle.

Procedure: surgery; Drug: 5-fluorouracil; IV; Radiation: radiation; Drug: irinotecan; IV; Drug: leucovorin; IV; Drug: oxaliplatin; IV; Drug: capecitabine; PO; Drug: gemcitabine; IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Accrual rate, calculated by total number of patients accrued divided by number of months from the date the study is opened at the fifth site to the evaluation date	Up to 3 years
Rate of treatment-related toxicity during preoperative therapy assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4	Up to 30 days after completion of study treatment
Rate of treatment delay (greater than 4 weeks) during preoperative therapy	Up to 28 weeks
Completion rate of all preoperative and operative therapy	Up to 30 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Macroscopic (R0/R1) resection rate defined as number of patients achieved R0 or R1 resection during surgery divided by number of evaluable patients	At the time of surgery
Radiographic response rate defined as number of patients who achieved complete response (CR) or partial response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 during pre-operative therapy divided by the number of evaluable patients	Up to 18 weeks
Histopathologic response rate defined as number of patients who achieved CR or PR determined according to histopathologic examination during pre-operative therapy divided by the number of evaluable patients	Up to 18 weeks
Time to locoregional recurrence	From the date of registration to the date of the first documented locoregional recurrence, assessed up to 3 years
Time to distant recurrence	From the date of registration to the date of the first documented distant recurrence, assessed up to 3 years
Overall survival	From the date of registration to the date of the death due to all causes, assessed up to 3 years

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Matthew Katz, M.D., M.D. Anderson Cancer Center

Publications and helpful links

General Publications

• Katz MH, Shi Q, Ahmad SA, Herman JM, Marsh Rde W, Collisson E, Schwartz L, Frankel W, Martin R, Conway W, Truty M, Kindler H, Lowy AM, Bekaii-Saab T, Philip P, Talamonti M, Cardin D, LoConte N, Shen P, Hoffman JP, Venook AP. Preoperative Modified FOLFIRINOX Treatment Followed by Capecitabine-Based Chemoradiation for Borderline Resectable Pancreatic Cancer: Alliance for Clinical Trials in Oncology Trial A021101. JAMA Surg. 2016 Aug 17;151(8):e161137. doi: 10.1001/jamasurg.2016.1137. Epub 2016 Aug 17.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2013
• Primary Completion (Actual): September 5, 2014
• Study Completion (Actual): June 15, 2018

Study Registration Dates

• First Submitted: March 25, 2013
• First Submitted That Met QC Criteria: March 29, 2013
• First Posted (Estimate): April 1, 2013

Study Record Updates

• Last Update Posted (Actual): September 4, 2018
• Last Update Submitted That Met QC Criteria: August 30, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Adenocarcinoma; Pancreatic Neoplasms; Carcinoma, Acinar Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Gemcitabine; Fluorouracil; Capecitabine; Oxaliplatin; Leucovorin; Irinotecan
• Other Study ID Numbers: A021101; U10CA031946 (U.S. NIH Grant/Contract)