Randomized Phase II Trial of Pre-Operative Gemcitabine and Nab Paclitacel With or With Out Hydroxychloroquine

Randomized Phase II Trial of Pre-Operative Gemcitabine and Nab Paclitacel With or With Out Hydroxychloroquine

This is a randomized phase II trial that will examine the ability of the hydroxychloroquine to improve the clinical activity of a pre-operative regimen of gemcitabine and nab-paclitaxel in subjects with potentially resectable adenocarcinoma of the pancreas. Eligible subjects will receive 2 cycles of gemcitabine and nab-paclitaxel (day 1, 8, 15) with or without hydrocychloroquine followed by surgical resection. Primary endpoint will be histologic response as graded by Evans criteria. Secondary endpoints will be CA19-9 response and PET response. Pre and post treatment tissue biopsies will be obtained to assess for levels of autophagy in tumor, liver and peripheral blood.

Inclusion Criteria:

• Subjects with biopsy-proven potentially resectable or borderline adenocarcinoma of the pancreas as determined by National Comprehensive Cancer Network (NCCN) criteria
• Karnofsky performance status of 70-100%
• No active second malignancy except for basal cell carcinoma of the skin
• Patient has adequate biological parameters as demonstrated by the following blood counts at screening
• Absolute neutrophil count (ANC) ≥1.5 × 109/L;
• Platelet count ≥100,000/mm3 (100 × 109/L);
• Hemoglobin (Hgb) ≥9 g/dL.
• Patient has the following blood chemistry levels at Baseline
• aspartate aminotransferase (AST) (SGOT), Alanine transaminase (SGPT) ≤2.5 × upper limit of normal range (ULN)
• Total bilirubin ≤ULN
• Serum Creatinine ≤ 1.5mg/dl OR calculated creatinine clearance ≥ 50 for those patients with creatinine greater than 1.5
• Prothrombin time (PT)within normal limits (WNL). If patient is on warfarin for prophylactic clot presentation for indwelling catheter, Partial PT/PTT may be +/- 15 %
• thromboplastin time (PTT) WNL. If patient on warfarin for prophylactic clot presentation for indwelling catheter, PT/PTT may be +/- 15 %
• Age >18 years.
• Patient must be able to swallow enteral medications with no requirement for a feeding tube. Patient's must not have intractable nausea or vomiting which prohibits the patient from oral medications
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Subjects deemed surgically unresectable or subjects unwilling to undergo surgical resection.
• Subjects who have received chemotherapy within 12 months prior to randomization.
• Prior use of radiotherapy or investigational agents for pancreatic cancer.
• Any evidence of metastasis to distant organs (liver, lung, peritoneum).
• Symptomatic evidence of gastric outlet obstruction
• Inability to adhere to study and/or follow-up procedures
• History of allergic reactions or hypersensitivity to the study drugs (hydroxychloroquine, gemcitabine, abraxane).
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. All females of childbearing potential must have a blood test or urine study within two weeks prior to randomization to rule out pregnancy.
• Patients with porphyria are ineligible.
• Patients with psoriasis are ineligible unless the disease is well controlled and they are under the care of a specialist who agrees to monitor the patient for exacerbations.
• Patients requiring the use of enzyme-inducing anti-epileptic medication that includes: phenytoin, carbamazepine, phenobarbital, primidone or oxcarbazepine are excluded.
• Patients with previously documented macular degeneration or diabetic retinopathy are excluded.
• Baseline electrocardiogram (EKG) with corrected QT interval (QTc) >470 msec (including subjects on medication). Subjects with ventricular pacemaker for whom QT interval is not measurable will be eligible on a case-by-case basis.
• Patient with a history of interstitial lung disease, history of slowly progressive dyspnea, sarcoidosis, silicosis, idiopathic pulmonary fibrosis or pulmonary hypersensitivity pneumonitis
• Patient with known active infection with HIV, Hepatitis B or Hepatitis C
• Patients requiring use of warfarin for therapeutic purposes.