A subject is deemed evaluable if they have received at least 3 of 4 cycles of chemotherapy and at least 80% of the expected HCQ doses and undergo successful surgical extirpation their disease. Patients will receive daily oral HCQ concurrently with neoadjuvant mFOLFIRINOX, planned for 4 cycles. Each cycle of mFOLFIRINOX is 14 days, therefore 4 cycles will occur over a period of 56 days. Oral HCQ will continue after completion of neoadjuvant chemotherapy and extend 2 weeks post-operatively. Patients will undergo restaging scans after completion of 4 cycles of mFOLFIRINOX. Within 3 to 6 weeks after completion of cycle 4 of mFOLFIRINOX, patients will proceed for surgical resection. Patients will receive surveillance scans 10 to 14 weeks after completion of surgery.

Patients will receive HCQ every day starting at the first dose of mFOLFIRINOX. Capsules of HCQ are available in 200 mg strengths. HCQ will be administered in divided doses (BID) for doses to minimize nausea. Patients should be told to swallow the whole capsule in rapid succession without chewing. The starting phase I dose for HCQ is 400 mg. Before accrual to the next dose level may begin, all patients in a given cohort must complete the 2 months of combination treatment (HCQ + mFOLFIRINOX), permitting toxicities to be assessed.

Dose will be assigned to patients using 3+3 Algorithm to identify the MTD. Dose level 1 is 400 mg hydroxychloroquine, dose level 2 is 800 mg hydroxychloroquine, and dose level 3 is 1200 mg hydroxychloroquine. If 0 first-dose DLTs are observed out of 3 patients treated with the first dose-level, the next cohort of 3 patients may be enrolled and treated at the next dose-level. If 1 out of the 3 patients treated with a dose-level experience a first-dose DLT, up to 3 additional patients (6 total) will be enrolled at that dose-level. If only 1 out of these 6 patients experiences a first-dose DLT, then the next cohort of 3 patients may be enrolled and treated at the next dose-level. If ≥2 out of these 6 patients experience first-dose DLTs, then dose escalation is stopped. Additional patients will be enrolled at the prior lower dose-level to achieve a total of 6 patients. If ≥2 out of 3 patients in a cohort experience a first-dose DLT, dose escalation will be stopped. Additional patients will be enrolled at the prior lower dose-level, to achieve a total of 6 patients. If 0 or 1 out of 3 patients at the highest dose-level (1200 mg) experiences a DLT, additional patients will be enrolled to achieve a total of 6 patients. If ≤1 out of these 6 patients experiences a DLT, the 1200mg dose-level will be declared the maximal safe dose administered in this Phase 1 study. If ≥2 patients experience a DLT, additional patients will be enrolled at the prior lower dose-level, for a total of 6 patients. If a DLT occurs in the first patient enrolled in the trial, the first cohort of six patients will be assigned to Level 1. If a cohort of six patients at Level 1 experiences more than one DLT, accrual to the trial will be paused, and the trial will be referred to the GI DSMB for appropriate action. At the conclusion of the dose escalation phase, the DSMB will meet to perform an interim review of safety data prior to establishing the maximum tolerated dose for the phase 2 phase of the trial. The maximum sample size of the study is 40 patients. Cohorts will be accrued until a new cohort would exceed the maximum study size; therefore, the final sample size will be between 35 and 40 patients.