Clinical Trials /

Combination Chemotherapy With or Without Hypofractionated Radiation Therapy Before Surgery in Treating Patients With Pancreatic Cancer

NCT02839343

Description:

This randomized phase II trial studies how well combination chemotherapy (mFOLFIRINOX) with or without hypofractionated radiation therapy before surgery works in patients with pancreatic cancer that can be removed by surgery. Drugs used in combination chemotherapy, such as oxaliplatin, leucovorin calcium, fluorouracil, and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. It is not yet known if combination chemotherapy is more effective with or without hypofractionated radiation therapy before surgery in treating patients with pancreatic cancer.

Related Conditions:
  • Pancreatic Ductal Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination Chemotherapy With or Without Hypofractionated Radiation Therapy Before Surgery in Treating Patients With Pancreatic Cancer
  • Official Title: Preoperative Extended Chemotherapy vs. Chemotherapy Plus Hypofractionated Radiation Therapy for Borderline Resectable Adenocarcinoma of the Head of the Pancreas

Clinical Trial IDs

  • ORG STUDY ID: A021501
  • SECONDARY ID: NCI-2016-00456
  • NCT ID: NCT02839343

Conditions

  • Pancreatic Adenocarcinoma
  • Borderline Resectable Adenocarcinoma of the Head of the Pancrease

Interventions

DrugSynonymsArms
mFOLFIRINOXmFOLFIRINOX + radiation + surgery + FOLFOX
FOLFOXmFOLFIRINOX + radiation + surgery + FOLFOX

Purpose

This randomized phase II trial studies how well combination chemotherapy (mFOLFIRINOX) with or without hypofractionated radiation therapy before surgery works in patients with pancreatic cancer that can be removed by surgery. Drugs used in combination chemotherapy, such as oxaliplatin, leucovorin calcium, fluorouracil, and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. It is not yet known if combination chemotherapy is more effective with or without hypofractionated radiation therapy before surgery in treating patients with pancreatic cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate and estimate 18 months overall survival (OS) rate of patients with borderline
      resectable pancreatic ductal adenocarcinoma (PDAC) receiving neoadjuvant therapy.

      SECONDARY OBJECTIVES:

      I. To evaluate and estimate the R0 resection rates in patients receiving each of the two
      multimodality treatment regimens.

      II. To evaluate and estimate the event-free survival in patients receiving each of the two
      multimodality treatment regimens.

      III. To evaluate and estimate the pathologic compete response (pCR) rates in patients
      receiving each of the two multimodality treatment regimens.

      IV. To assess the adverse events (AE) profile and safety of each treatment arm.

      TERTIARY OBJECTIVES:

      I. To test the effect of the rs2853564 vitamin D receptor (VDR) variant on OS rate and
      discover novel candidate genes associated with OS and severe toxicity of chemotherapy by
      using genome-wide genotyping approaches.

      II. To evaluate risk classification previously developed by Koay et al using normalized area
      under the enhancement curve (NAUC).

      III. To access prognostic value of NAUC ratio defined as post-neoadjuvant NAUC divided by
      pre-neoadjuvant therapy NAUC.

      IV. To evaluate risk classification previously developed by Koay et al using delta measure.

      OUTLINE: Patients are randomized to 1 of 2 treatment arms.

      ARM A: Patients receive oxaliplatin intravenously (IV) over 2 hours, irinotecan IV over 90
      minutes, and leucovorin calcium IV over 2 hours on day 1. Patients also receive fluorouracil
      IV continuously over 46-48 hours on days 1-2. Treatment repeats every 14 days for 8 courses
      in the absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive oxaliplatin intravenously (IV) over 2 hours, irinotecan IV over 90
      minutes, and leucovorin calcium IV over 2 hours on day 1. Patients also receive fluorouracil
      IV continuously over 46-48 hours on days 1-2. Treatment repeats every 14 days for 7 courses
      in the absence of disease progression or unacceptable toxicity. Patients receive either
      stereotactic body radiation therapy (SBRT) or hypofractionated image guided radiation therapy
      (HIGRT) on days 1-5 of course 8.

      SURGERY Within 4 to 8 weeks after the last dose of chemotherapy (arm A) or of radiation (arm
      B), patients considered surgical candidates for resection (after central review) will undergo
      surgery at the registering institution.

      ADJUVANT CHEMOTHERAPY Within 4-12 weeks from the date of surgery, patients will receive
      oxaliplatin IV over 2 hours and leucovorin IV over 2 hours on day 1. Patients also receive
      fluorouracil IV continuously over 46-48 hours on days 1-2. Treatment repeats every 14 days
      for 4 courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 16 weeks for 2 years,
      then every 6 months for 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
mFOLFIRINOX + surgery + FOLFOXExperimentalPatients receive 8 cycles of mFOLFIRINOX. One cycle is 14 days. mFOLFIRINOX consists of oxaliplatin, irinotecan, leucovorin and 5-FU. Patients undergo surgery and receive 4 cycles of FOLFOX 4-12 weeks after surgery. FOLFOX consists of oxaliplatin, leucovorin and 5-FU.
  • mFOLFIRINOX
  • FOLFOX
mFOLFIRINOX + radiation + surgery + FOLFOXExperimentalPatients receive 7 cycles of mFOLFIRINOX. One cycle is 14 days. mFOLFIRINOX consists of oxaliplatin, irinotecan, leucovorin and 5-FU. Patients receive radiation therapy then undergo surgery and receive 4 cycles of FOLFOX 4-12 weeks after surgery. FOLFOX consists of oxaliplatin, leucovorin and 5-FU.
  • mFOLFIRINOX
  • FOLFOX

Eligibility Criteria

        Inclusion Criteria:

          -  Confirmation of radiographic stage as borderline resectable disease by real-time
             Alliance central radiographic review

          -  No prior chemotherapy or radiation for pancreatic cancer

          -  No definitive resection of pancreatic cancer

          -  Chronic concomitant treatment with strong inhibitors of cytochrome p450, family 3,
             subfamily a, polypeptide 4 gene (CYP3A4) is not allowed on this study; patients on
             strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration
             on the study

          -  Chronic concomitant treatment with strong CYP3A4 inducers is not allowed; patients
             must discontinue the drug 14 days prior to the start of study treatment

          -  No grade >= 2 neuropathy

          -  No known Gilbert's syndrome or known homozygosity for UGAT1A1*28 polymorphism

          -  No uncontrolled gastric ulcer disease (grade 3 gastric ulcer disease) within 28 days
             of registration

          -  Not pregnant and not nursing; for women of childbearing potential only, a negative
             pregnancy test done =< 7 days prior to registration is required

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

          -  Absolute neutrophil count (ANC) >= 1,500/mm^3

          -  Platelet count >= 100,000/mm^3

          -  Creatinine =< 1.5 x upper limit of normal (ULN) or

          -  Calculated (calc.) creatinine clearance > 45 mL/min

          -  Total bilirubin =< 2.0 mg/dL

          -  Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =< 2.5 X upper limit
             of normal (ULN)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival (OS) rate
Time Frame:18 months
Safety Issue:
Description:Defined as the number of patients who are alive at 18 months after randomization divided by the total number of evaluable patients in each arm. An evaluable patient is defined as any patient who signed informed consent, deemed eligible by central review and received any protocol-defined treatment. 95% confidence interval will be estimated based on standard method. Chi-squared test (or Fisher's exact test if the data in contingency table is sparse) will be used to compare 18 month OS rates among treatment arms. OS within each arm will be summarized by Kaplan-Meier method. Median, 1-year and 2-year rates will be estimated based on Kaplan-Meier curves.

Secondary Outcome Measures

Measure:Residual tumor (R)0 resection rate
Time Frame:24 months
Safety Issue:
Description:Defined as the proportion of patients in whom an achieved R0 resection was achieved during surgery. Chi-square test (or Fisher's exact test if the data in contingency table is sparse) will be used to compare R0 resection rate between treatment arms. Sensitivity analysis will be conducted among patients in cohort 1) and cohort 2). The association between R0 resection rate and OS/progression-free survival will be assessed by log-rank test and Cox model.
Measure:Event-free survival
Time Frame:5 years
Safety Issue:
Description:Defined as time from randomization to the first documentation of event where events considered are 1) disease progression, per RECIST, prior to surgery, 2) surgery with R2 resection, 3) recurrent disease following surgery, or 4) death due to any cause. Will be estimated using the method of Kaplan-Meier in each arm and compared between treatment groups using the log-rank test. The correlation between pathologic complete response (pCR) status and event-free survival time will be assessed by Cox model with landmark approach.
Measure:Pathologic complete rate (pCR) rate
Time Frame:24 months
Safety Issue:
Description:Defined as the proportion of patients in whom a pCR was confirmed by histopathologic review of the surgical specimen. Chi-square test (or Fisher's exact test if the data in contingency table is sparse) will be used to compare pCR resection rate between two treatment arms. Sensitivity analysis will be conducted among patients in cohort 1) and cohort 2). The association between pCR rate and OS/progression free survival (PFS) will be assessed by log-rank test and Cox model.
Measure:Incidence of adverse events assessed per Common Terminology Criteria for Adverse Events (CTCAE) version 4 and the Patient-Reported Outcomes version of the CTCAE
Time Frame:24 months
Safety Issue:
Description:Overall adverse event rates will be compared between treatment groups using Chi-square test (or Fisher's exact test if the data in contingency table is sparse).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Alliance for Clinical Trials in Oncology

Last Updated

July 24, 2020