This will be a phase I/II trial examining the safety and tolerability of pre-operative mFOLFIRINOX in combination with peri-operative oral hydroxychloroquine (FHQ) in the treatment of subjects with adenocarcinoma of the pancreas. Subjects will be staged prior to protocol entry by contrast-enhanced helical abdominal CT scan done using a pancreas mass protocol or EUS. Eligible subjects with biopsy-proven, resectable pancreatic adenocarcinoma without evidence of venous or arterial involvement on CT scan receive HCQ orally in combination with mFOLFIRINOX prior to surgery. Hydroxychloroquine will begin with the first dose of mFOLFIRINOX and continue for 2 weeks post-operatively. Three to six weeks after the last dose of mFOLFIRINOX, patients will undergo surgical exploration and pancreatectomy if technically feasible and all toxicities have resolved. Pathologic specimens will undergo detailed histopathologic and immunohistochemical evaluations with particular attention to the six surgical margins of resection: the bile duct margin (for Whipple specimens), the margin of pancreatic transection, the retroperitoneal margin, the proximal and distal duodenal margins (for Whipple specimens), and the portal vein margin along the pancreatic head (for Whipple specimens) or medial pancreas (for distal pancreatectomies). Tissue specimens will be stored at -80C for future correlative studies of autophagy and tumor response to protocol therapy. Ten to fourteen weeks following completion of successful surgical removal of their tumor, subjects will undergo repeat staging studies per standard of care. Subjects will pursue standard of care adjuvant therapy options at the discretion of their physician.
Subjects with biopsy-proven adenocarcinoma of the pancreas
Pancreatic protocol helical CT scan demonstrating absence of venous or arterial involvement, consistent with NCCN guidelines for resectable disease
ECOG performance status ≤ 1
No active second malignancy except for basal cell carcinoma of the skin
Subjects deemed surgically unresectable or subjects unwilling to undergo surgical resection.
Subjects who have received chemotherapy within 12 months prior to study entry.
Subjects who are found to have loss-of-function mutations in DPYD or UGTA1 by Oneome pharmacogenomic testing, resulting in increased risk of mFOLFIRINOX toxicity. DPYD mutations have been noted in 5% of the overall population. Homozygous UGT1A1 mutations have been noted in 10% of North Americans.
Prior use of radiotherapy or investigational agents for pancreatic cancer.
Single group
Hydroxychloroquine sulfate
DrugHydroxychloroquine, oral, dose escalated (400mg, 800mg, 1200mg) beginning concurrent with mFOLFIRINOX and extending 2 weeks post-operatively. Dose will be assigned to patients using 3+3 Algorithm to identify the Maximum Dose Tolerated.
Phase I - Establishing Maximum tolerated dose (MTD)
Maximum tolerated dose (MTD) for FHQ which is defined as the highest dose level in which the investigators have treated 6 patients with at most 1 experiencing dose limiting toxicities (DLT). A maximum of 18 patients (3x6) will be accrued for dose finding.
Phase II - Rate of grade IIb or better histopathological response
The number of patients that have a rate of grade IIb or better histopathological response.
Phase II - To establish the potential biological activity of FHQ by biochemical tumor response, as assessed by Ca 19-9.
Treatment response will be assessed by measuring the change in the tumor marker Ca 19-9 in the serum before and after FHQ.
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