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

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ClinicalTrials.gov Identifier: NCT04340141
Recruitment Status : Recruiting
First Posted : April 9, 2020
Last Update Posted : October 5, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology

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).

Condition or disease Intervention/treatment Phase
Pancreatic Adenosquamous Carcinoma Resectable Pancreatic Adenocarcinoma Pancreatic Cancer Drug: Oxaliplatin Drug: Irinotecan Hydrochloride Drug: Leucovorin Calcium Drug: Fluorouracil Procedure: Resection Other: Questionnaire Administration Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 352 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase III Trial of Perioperative Versus Adjuvant Chemotherapy for Resectable Pancreatic Cancer
Actual Study Start Date : July 1, 2020
Estimated Primary Completion Date : January 2026
Estimated Study Completion Date : November 2030

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
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

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.
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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. R0 resection rate [ Time Frame: At time of surgery. ]
    The rate (percentage) of patients with negative resection margins after undergoing surgery.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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)

  14. 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.

  15. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04340141


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

Locations
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Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
Investigators
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Study Chair: Cristina R. Ferrone, MD Massachusetts General Hospital
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Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT04340141    
Other Study ID Numbers: A021806
NCI-2020-01560 ( Registry Identifier: NCI Clinical Trial Reporting Program )
U10CA180821 ( U.S. NIH Grant/Contract )
First Posted: April 9, 2020    Key Record Dates
Last Update Posted: October 5, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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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
Additional relevant MeSH terms:
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Pancreatic Neoplasms
Carcinoma, Adenosquamous
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Neoplasms, Complex and Mixed
Leucovorin
Fluorouracil
Oxaliplatin
Irinotecan
Calcium
Levoleucovorin
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors