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

• ClinicalTrials.gov Identifier: NCT02839343
• Recruitment Status: Active, not recruiting
• First Posted: July 20, 2016
• Last Update Posted: May 16, 2019
• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI); Sky Foundation
• Information provided by (Responsible Party): Alliance for Clinical Trials in Oncology

Tracking Information

• First Submitted Date: July 14, 2016
• First Posted Date: July 20, 2016
• Last Update Posted Date: May 16, 2019
• Study Start Date: December 2016
• Estimated Primary Completion Date: March 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 6, 2017)

Overall survival (OS) rate [ Time Frame: 18 months ]

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.

• Original Primary Outcome Measures (submitted: July 18, 2016): overall survival [ Time Frame: Up to 18 months ]
• Change History: Complete list of historical versions of study NCT02839343 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: September 6, 2017)

• Residual tumor (R)0 resection rate [ Time Frame: 24 months ]
  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.
• Event-free survival [ Time Frame: 5 years ]
  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.
• Pathologic complete rate (pCR) rate [ Time Frame: 24 months ]
  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.
• 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 ]
  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).

Original Secondary Outcome Measures (submitted: July 18, 2016)

• Event-free survival [ Time Frame: Up to 5 years ]
• R0 resection rate [ Time Frame: Up to 24 months ]
• pathologic complete response rate [ Time Frame: Up to 24 months ]
• incidence of adverse events per Common Terminology Criteria for Adverse Events version 4 [ Time Frame: Up to 24 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• Brief Summary: 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• Radiation: radiation therapy
• Procedure: surgery
• Drug: mFOLFIRINOX
  oxaliplatin IV, irinotecan IV, leucovorin IV and 5-FU IV
• Drug: FOLFOX
  oxaliplatin IV, leucovorin IV and 5-FU IV

Study Arms

• Experimental: mFOLFIRINOX + surgery + FOLFOX
  Patients 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.
  Interventions:

  • Procedure: surgery
  • Drug: mFOLFIRINOX
  • Drug: FOLFOX
• Experimental: mFOLFIRINOX + radiation + surgery + FOLFOX
  Patients 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.
  Interventions:

  • Radiation: radiation therapy
  • Procedure: surgery
  • Drug: mFOLFIRINOX
  • Drug: FOLFOX

• Publications *: Katz MHG, Ou FS, Herman JM, Ahmad SA, Wolpin B, Marsh R, Behr S, Shi Q, Chuong M, Schwartz LH, Frankel W, Collisson E, Koay EJ, Hubbard JM, Leenstra JL, Meyerhardt J, O'Reilly E; Alliance for Clinical Trials on Oncology. Alliance for clinical trials in oncology (ALLIANCE) trial A021501: preoperative extended chemotherapy vs. chemotherapy plus hypofractionated radiation therapy for borderline resectable adenocarcinoma of the head of the pancreas. BMC Cancer. 2017 Jul 27;17(1):505. doi: 10.1186/s12885-017-3441-z.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: May 14, 2019): 126
• Original Estimated Enrollment (submitted: July 18, 2016): 124
• Study Completion Date: Not Provided
• Estimated Primary Completion Date: March 2020 (Final data collection date for primary outcome measure)

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT02839343
• Other Study ID Numbers: A021501; NCI-2016-00456 ( Registry Identifier: NCI Clinical Trial Reporting Program )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Alliance for Clinical Trials in Oncology
• Study Sponsor: Alliance for Clinical Trials in Oncology

Collaborators

• National Cancer Institute (NCI)
• Sky Foundation

Investigators

• Study Chair: Matthew Katz, MD, FACS; The University of Texas MD Anderson Cancer Center

• PRS Account: Alliance for Clinical Trials in Oncology
• Verification Date: May 2019