Testing the Use of the Usual Chemotherapy Before and After Surgery for Removable Pancreatic Cancer

• ClinicalTrials.gov Identifier: NCT04340141
• Recruitment Status: Recruiting
• First Posted: April 9, 2020
• Last Update Posted: April 9, 2024
• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Alliance for Clinical Trials in Oncology

Tracking Information

• First Submitted Date: April 7, 2020
• First Posted Date: April 9, 2020
• Last Update Posted Date: April 9, 2024
• Actual Study Start Date: July 1, 2020
• Estimated Primary Completion Date: January 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 7, 2020)

Overall survival (OS) [ Time Frame: Time between randomization and death from any cause, assessed up to 6 years. ]

Overall survival is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. The treatment arms will be compared using a stratified Cox regression model, and hazard ratios from each arm will be estimated.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 15, 2020)

• Disease-free survival (DFS) [ Time Frame: Time between randomization and progression prior to surgery, metastases detected during surgery, recurrence (locoregional and/or distant) after resection, and death due to all causes, assessed up to 6 years. ]
  Disease-free survival (DFS) is defined as the time from randomization to the date of progression prior to surgery, metastases detected during surgery, recurrence (locoregional and/or distant) after resection, and death due to all causes, whichever occurs first. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
• Time to locoregional recurrence (TLR) [ Time Frame: Time between randomization and locoregional recurrence after resection, assessed up to 6 years. ]
  Time to locoregional recurrence (TLR) is defined as the time from randomization to the date of locoregional recurrence after resection. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
• Time to distant metastases (TDM) [ Time Frame: Time between randomization and metastases prior to surgery, metastases detected during surgery, or distant recurrence after resection, assessed up to 6 years. ]
  Time to distant metastases (TDM) is defined as the time from randomization to the date of metastases prior to surgery, metastases detected during surgery, or distant recurrence after resection. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
• R0 resection rate [ Time Frame: At time of surgery. ]
  The rate (percentage) of patients with negative resection margins after undergoing surgery.
• Rate of unresectability [ Time Frame: At time of surgery or planned time of surgery. ]
  The rate (percentage) of patients who cannot undergo surgery due to adverse events, progressive disease, death, poor performance, or patient/physician decision, are deemed unresectable before surgery, or resection was not performed during surgery.
• Pathologic complete response (pCR) rate [ Time Frame: At time of surgery. ]
  The rate (percentage) of patients who achieve a pathologic complete response (pCR) confirmed by histopathologic review of the surgical specimen.
• Incidence of adverse events (AEs), assessed using National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) version 5.0 (v5.0) [ Time Frame: Up to 2 years. ]
  The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns within treatment arms and during the following three time points: during perioperative chemotherapy, surgical complications during surgery and post-operative period for 30 days, and during adjuvant chemotherapy.
• Fluorouracil, irinotecan hydrochloride, leucovorin calcium, and oxaliplatin (modified [m]FOLFIRINOX) dose intensity delivered [ Time Frame: 8 months ]
  Dose intensity is defined as the percentage of total cumulative dose the patient received divided by the total dose planned per protocol times 100.
• Fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin (modified [m]FOLFIRINOX) number of cycles received [ Time Frame: 8 months ]
  The number of cycles received is defined as the total number of cycles that the participant received at least one dose of any agent in mFOLFIRINOX.
• Quality of life as assessed by the physical functioning, nausea/vomiting, and diarrhea subscales in the Quality of Life Questionnaire-Core 30 (QLQ-C30) [ Time Frame: 8 weeks ]
  Quality of Life Questionnaire-Core 30 (QLQ-C30) is a 30-item questionnaire to assess the overall quality of life in cancer patients. QLQ-C30 includes functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting), and other (dyspnoea, appetite loss, insomnia, constipation/diarrhea, and financial difficulties). Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores are averaged, and transformed to 0-100 scale; higher score=better level of physical functioning, greater occurrence of nausea/vomiting, and greater occurrence of diarrhea.
• Influence of diet, body mass index, weight loss, physical activity, and other lifestyle habits on overall survival [ Time Frame: Time between randomization and death from any cause, assessed up to 6 years. ]
  Multivariate Cox proportional hazards models will be fit for overall survival (OS) endpoint (defined above) with covariates corresponding to baseline diet and lifestyle questionnaire responses and hazard ratios and 95% confidence intervals will be reported.
• Influence of diet, body mass index, weight loss, physical activity, and other lifestyle habits on disease-free survival (DFS) [ Time Frame: Time between randomization and progression prior to surgery, metastases detected during surgery, recurrence (locoregional and/or distant) after resection, and death due to all causes, assessed up to 6 years. ]
  Multivariate Cox proportional hazards models will be fit for disease-free survival (DFS) endpoint (defined above) with covariates corresponding to baseline diet and lifestyle questionnaire responses and hazard ratios and 95% confidence intervals will be reported.
• Influence of diet, body mass index, weight loss, physical activity, and other lifestyle habits on the risk of grade 3+ adverse event associated with chemotherapy [ Time Frame: Up to 2 years. ]
  Multivariate Logistic models will be fit for the binary endpoint of grade 3+ adverse event (patient experiences at least one grade 3 or higher adverse event during treatment)
• The ability of computed tomography (CT)-based radiomics to distinguish post-neoadjuvant chemotherapy (NAC) fibrosis from viable tumor as measured by comparison to histological evaluation [ Time Frame: At time of surgery. ]
  Comparison between computed tomography (CT)-based radiomics and histological tumor fibrosis proportions will be measured using Spearman's rank correlation coefficient.
• Computed tomography (CT)-based radiomics as non-invasive predictors of overall survival [ Time Frame: Time between randomization and death from any cause, assessed up to 6 years. ]
  Multivariate Cox proportional hazards model will be fit for overall survival (OS) endpoint (defined above) with covariates chosen from all available radiomics features using the least absolute shrinkage and selection operator (LASSO) method with 10-fold cross-validation (CV) and additionally adjusted for clinically important confounders. After the final model is selected the area under the receiver operating characteristic curve (AUC) will be reported to indicate the prediction performance of the radiomics model.

Original Secondary Outcome Measures (submitted: April 7, 2020)

• Disease-free survival (DFS) [ Time Frame: Time between randomization and progression prior to surgery, metastases detected during surgery, recurrence (locoregional and/or distant) after resection, and death due to all causes, assessed up to 6 years. ]
  Disease-free survival (DFS) is defined as the time from randomization to the date of progression prior to surgery, metastases detected during surgery, recurrence (locoregional and/or distant) after resection, and death due to all causes, whichever occurs first. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
• Time to locoregional recurrence (TLR) [ Time Frame: Time between randomization and locoregional recurrence after resection, assessed up to 6 years. ]
  Time to locoregional recurrence (TLR) is defined as the time from randomization to the date of locoregional recurrence after resection. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
• Time to distant metastases (TDM) [ Time Frame: Time between randomization and metastases prior to surgery, metastases detected during surgery, or distant recurrence after resection, assessed up to 6 years. ]
  Time to distant metastases (TDM) is defined as the time from randomization to the date of metastases prior to surgery, metastases detected during surgery, or distant recurrence after resection. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
• R0 resection rate [ Time Frame: At time of surgery. ]
  The rate (percentage) of patients with negative resection margins after undergoing surgery.
• Rate of unresectability [ Time Frame: At time of surgery or planned time of surgery. ]
  The rate (percentage) of patients who cannot undergo surgery due to adverse events, progressive disease, death, poor performance, or patient/physician decision, are deemed unresectable before surgery, or resection was not performed during surgery.
• Pathologic complete response (pCR) rate [ Time Frame: At time of surgery. ]
  The rate (percentage) of patients who achieve a pathologic complete response (pCR) confirmed by histopathologic review of the surgical specimen.
• Incidence of adverse events (AEs), assessed using National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) version 5.0 (v5.0) [ Time Frame: Up to 2 years. ]
  The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns within treatment arms and during the following three time points: during perioperative chemotherapy, surgical complications during surgery and post-operative period for 30 days, and during adjuvant chemotherapy.
• Fluorouracil, irinotecan hydrochloride, leucovorin calcium, and oxaliplatin (modified [m]FOLFIRINOX) dose intensity delivered [ Time Frame: 8 months ]
  Dose intensity is defined as the percentage of total cumulative dose the patient received divided by the total dose planned per protocol times 100.
• Fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin (modified [m]FOLFIRINOX) number of cycles received [ Time Frame: 8 months ]
  The number of cycles received is defined as the total number of cycles that the participant received at least one dose of any agent in mFOLFIRINOX.
• Quality of life as assessed by the physical functioning, nausea/vomiting, and diarrhea subscales in the Quality of Life Questionnaire-Core 30 (QLQ-C30) [ Time Frame: 8 weeks ]
  Quality of life (QOL) as assessed by the physical functioning, nausea/vomiting, and diarrhea subscale scores from the Quality of Life Questionnaire-Core 30 (QLQ-C30) questionnaire. The mean change in score and 95% confidence interval of the change from baseline and 8 weeks will be reported.
• Influence of diet, body mass index, weight loss, physical activity, and other lifestyle habits on overall survival [ Time Frame: Time between randomization and death from any cause, assessed up to 6 years. ]
  Multivariate Cox proportional hazards models will be fit for overall survival (OS) endpoint (defined above) with covariates corresponding to baseline diet and lifestyle questionnaire responses and hazard ratios and 95% confidence intervals will be reported.
• Influence of diet, body mass index, weight loss, physical activity, and other lifestyle habits on disease-free survival (DFS) [ Time Frame: Time between randomization and progression prior to surgery, metastases detected during surgery, recurrence (locoregional and/or distant) after resection, and death due to all causes, assessed up to 6 years. ]
  Multivariate Cox proportional hazards models will be fit for disease-free survival (DFS) endpoint (defined above) with covariates corresponding to baseline diet and lifestyle questionnaire responses and hazard ratios and 95% confidence intervals will be reported.
• Influence of diet, body mass index, weight loss, physical activity, and other lifestyle habits on the risk of grade 3+ adverse event associated with chemotherapy [ Time Frame: Up to 2 years. ]
  Multivariate Logistic models will be fit for the binary endpoint of grade 3+ adverse event (patient experiences at least one grade 3 or higher adverse event during treatment)
• The ability of computed tomography (CT)-based radiomics to distinguish post-neoadjuvant chemotherapy (NAC) fibrosis from viable tumor as measured by comparison to histological evaluation [ Time Frame: At time of surgery. ]
  Comparison between computed tomography (CT)-based radiomics and histological tumor fibrosis proportions will be measured using Spearman's rank correlation coefficient.
• Computed tomography (CT)-based radiomics as non-invasive predictors of overall survival [ Time Frame: Time between randomization and death from any cause, assessed up to 6 years. ]
  Multivariate Cox proportional hazards model will be fit for overall survival (OS) endpoint (defined above) with covariates chosen from all available radiomics features using the least absolute shrinkage and selection operator (LASSO) method with 10-fold cross-validation (CV) and additionally adjusted for clinically important confounders. After the final model is selected the area under the receiver operating characteristic curve (AUC) will be reported to indicate the prediction performance of the radiomics model.

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

Descriptive Information

• Brief Title: Testing the Use of the Usual Chemotherapy Before and After Surgery for Removable Pancreatic Cancer
• Official Title: A Phase III Trial of Perioperative Versus Adjuvant Chemotherapy for Resectable Pancreatic Cancer
• Brief Summary: This phase III trial compares perioperative chemotherapy (given before and after surgery) versus adjuvant chemotherapy (given after surgery) for the treatment of pancreatic cancer that can be removed by surgery (removable/resectable). Chemotherapy drugs, such as fluorouracil, irinotecan, leucovorin, and oxaliplatin, 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. Giving chemotherapy before and after surgery (perioperatively) may work better in treating patients with pancreatic cancer compared to giving chemotherapy after surgery (adjuvantly).

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate and compare overall survival (OS) in patients with resectable pancreatic adenocarcinoma treated with perioperative fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin (modified [m]FOLFIRINOX) and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

SECONDARY OBJECTIVES:

I. To evaluate and compare disease-free survival (DFS) in patients with resectable pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

II. To evaluate and compare time to locoregional recurrence (TLR) in patients with resectable pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

III. To evaluate and compare time to distant metastases (TDM) in patients with resectable pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

IV. To evaluate and compare the R0 resection rate in patients with resectable pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

V. To evaluate and compare rate of unresectability in patients with resectable pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

VI. To evaluate rate of pathologic complete response in patients randomized to the perioperative therapy arm.

VII. To evaluate and compare mFOLFIRINOX dose intensity delivered and number of cycles received in patients with resectable pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

VIII. To evaluate and compare adverse event profile in patients with resectable pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

IX. To compare physical functioning, nausea/vomiting, and diarrhea, as measured with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) between patients with resectable pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

X. To prospectively assess the influence of diet, body mass index, weight loss, physical activity, and other lifestyle habits on the disease-free survival and overall survival among patients with localized pancreatic cancers.

XI. To assess the influence of diet, obesity, physical activity, and other lifestyle habits on the risk of toxicity associated with chemotherapy.

XII. To evaluate the ability of computed tomography (CT)-based radiomics in distinguishing post-neoadjuvant chemotherapy (NAC) fibrosis from viable tumor in patients randomized to the perioperative therapy arm.

XIII. To determine whether CT-based radiomics retrieved from baseline examination may act as non-invasive predictors of survival outcome in patients randomized to the adjuvant therapy arm.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive oxaliplatin intravenously (IV) over 2 hours, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-3. Treatment repeats every 14 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Within 2-8 weeks of completing neoadjuvant chemotherapy, patients undergo surgical resection. Patients then receive oxaliplatin IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-3. Treatment repeats every 14 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo surgical resection. Beginning 3-12 weeks after surgery, patients then receive oxaliplatin IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-3. Treatment repeats every 14 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 6 years.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Pancreatic Adenosquamous Carcinoma
• Resectable Pancreatic Adenocarcinoma
• Pancreatic Cancer

Intervention

• Drug: Oxaliplatin
  Given IV
• Drug: Irinotecan Hydrochloride
  Given IV
• Drug: Leucovorin Calcium
  Given IV
• Drug: Fluorouracil
  Given IV
• Procedure: Resection
  Undergo surgical resection
• Other: Questionnaire Administration
  Ancillary studies

Study Arms

• Experimental: Arm I (perioperative chemotherapy, surgery)
  Patients receive oxaliplatin intravenously (IV) over 2 hours, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-3. Treatment repeats every 14 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Within 2-8 weeks of completing neoadjuvant chemotherapy, patients undergo surgical resection. Patients then receive oxaliplatin IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-3. Treatment repeats every 14 days for 4 cycles in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Oxaliplatin
  • Drug: Irinotecan Hydrochloride
  • Drug: Leucovorin Calcium
  • Drug: Fluorouracil
  • Procedure: Resection
  • Other: Questionnaire Administration
• Active Comparator: Arm II (surgery, adjuvant chemotherapy)
  Patients undergo surgical resection. Beginning 3-12 weeks after surgery, patients then receive oxaliplatin IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-3. Treatment repeats every 14 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Oxaliplatin
  • Drug: Irinotecan Hydrochloride
  • Drug: Leucovorin Calcium
  • Drug: Fluorouracil
  • Procedure: Resection
  • Other: Questionnaire Administration

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 7, 2020): 352
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: November 2030
• Estimated Primary Completion Date: January 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

PRE-REGISTRATION:

• Pathology: Histologic or cytologic proof of pancreatic adenocarcinoma or adenosquamous carcinoma
• TNM Stage: Tx-4, N0-1, M0 (M0 disease does not include spread to distant lymph nodes and organs)

• Resectable Primary Tumor: Local radiographic reading must be consistent with resectable disease defined as the following on 1) arterial and venous phase contrast-enhanced abdominal/pelvic CT scan or abdominal/pelvic magnetic resonance imaging (MRI) scan and 2) chest CT:

  • No involvement or abutment of the celiac artery, common hepatic artery, superior mesenteric artery, or replaced right hepatic artery (if applicable)
  • Less than 180 degree interface between tumor and vessel wall of the portal vein or superior mesenteric vein, and patent portal vein/splenic vein confluence
  • No evidence of metastatic disease
• Measurable disease or non-measurable disease o Non-measurable disease is defined as cytologic or histologic confirmation of adenocarcinoma of adenosquamous carcinoma by fine needle aspiration or core-biopsy of the pancreas without measurable disease by radiographic imaging

REGISTRATION:

• Confirmation of resectable disease by real-time central imaging review by the Alliance Imaging Core Lab at Imaging and Radiation Oncology Core (IROC) Ohio
• Determined to be appropriate candidate for curative-intent pancreatectomy by surgeon intending to perform the resection
• No prior radiation therapy, chemotherapy, targeted therapy, investigational therapy, or surgery for pancreatic cancer
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic, and teratogenic effects.
• Therefore, for women of childbearing potential only, a negative pregnancy test done =< 14 days prior to registration is required
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Total Neuropathy Score < 2
• Absolute neutrophil count (ANC) >= 1,500/uL
• Platelet count >= 100,000/uL
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (If obstructive jaundice is present, then biliary drainage must be initiated and total bilirubin =< 3.0)
• Creatinine =< 1.5 x ULN OR calculated (Calc.) creatinine clearance >= 30 mL/min (Calculated using the Cockcroft-Gault equation)
• No known Gilbert's Syndrome or known homozygosity for UGAT1A1*28 polymorphism
• No comorbid conditions that would prohibit curative-intent pancreatectomy
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug prior to registration
• Chronic concomitant treatment with strong inducers of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inducers must discontinue the drug prior to registration

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Cristina R. Ferrone, MD; 617-643-6189; cferrone@mgh.harvard.edu

• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT04340141
• Other Study ID Numbers: A021806; NCI-2020-01560 ( Registry Identifier: NCI Clinical Trial Reporting Program ); U10CA180821 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes

• Current Responsible Party: Alliance for Clinical Trials in Oncology
• Original Responsible Party: Same as current
• Current Study Sponsor: Alliance for Clinical Trials in Oncology
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Study Chair: Cristina R. Ferrone, MD; Massachusetts General Hospital

• PRS Account: Alliance for Clinical Trials in Oncology
• Verification Date: April 2024