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.
Brief Title
Combination Chemotherapy 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.
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.
Categories
Conditions
Pancreatic Adenocarcinoma
Borderline Resectable Adenocarcinoma of the Head of the Pancrease
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)
* 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)
Inclusion 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)
* 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)
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT02839343
Org Class
Other
Org Full Name
Alliance for Clinical Trials in Oncology
Org Study Id
A021501
Overall Status
Unknown status
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Preoperative Extended Chemotherapy vs. Chemotherapy Plus Hypofractionated Radiation Therapy for Borderline Resectable Adenocarcinoma of the Head of the Pancreas
Primary Outcomes
Outcome Description
Defined as the percentage 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.
Outcome Measure
Overall Survival (OS) Rate
Outcome Time Frame
18 months
Secondary Ids
Secondary Id
NCI-2016-00456
Secondary Outcomes
Outcome Description
Defined as the percentage of patients in whom an achieved R0 resection was achieved during surgery.
Outcome Time Frame
24 months
Outcome Measure
Residual Tumor (R)0 Resection Rate
Outcome 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.
Outcome Time Frame
4 years and 7 months
Outcome Measure
Event-free Survival
Outcome Description
Defined as the percentage 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.
Outcome Time Frame
24 months
Outcome Measure
Pathologic Complete Rate (pCR) Rate
Outcome 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).
Outcome Time Frame
1 year
Outcome 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
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Lakshmi Rajdev
Investigator Email
lrajdev@montefiore.org
Investigator Phone