Study of Pre-surgery Gemcitabine + Hydroxychloroquine (GcHc) in Stage IIb or III Adenocarcinoma of the Pancreas

Phase 1

Completed

Conditions: Pancreatic Cancer

Interventions: Drug: Hydroxychloroquine
Drug: Gemcitabine

Registration Number: NCT01128296

Lead Sponsor: Amer Zureikat

Brief Summary: The primary goal of the research study is to determine whether treating pancreatic cancer patients with hydroxychloroquine in combination with gemcitabine before surgery is safe. The secondary goal is to determine if this new treatment regimen can effectively treat pancreatic cancer. This study will test the safety and efficacy of this combination in two parts, or phases.

Detailed Description: This is a phase I/II trial designed to assess the safety, tolerability and efficacy of neoadjuvant oral hydroxychloroquine (Plaquenil®) in combination with FDR gemcitabine in subjects with high risk IIb or III adenocarcinoma of the pancreas. Eligible subjects will be administered hydroxychloroquine orally once or twice daily (depending on dose) in combination with FDR gemcitabine (on days 1 and 15) for 31 days prior to surgical resection. Dose escalations of hydroxychloroquine will proceed using Storer's Up-and-Down algorithm D. Subjects will be monitored for side effects and tolerability of the drug. Pre- and post-treatment PET scans will be the primary means to assess response to therapy. Resected tumors will also be assessed for evidence of inhibition of autophagy as well as histopathologic response and margin negative resection and number of positive lymph nodes.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 35

Inclusion Criteria

Subjects with biopsy-proven adenocarcinoma of the pancreas
staged by IIb or greater by by EUS, or tumor greater than 2.6 cm on EUS or pancreatic protocol helical CT scan demonstrating venous involvement
Karnofsky performance status >/= 70.
No active second malignancy except for basal cell carcinoma of the skin
Normal renal, hepatic, and hematologic function at the time of enrollment as evidenced by:
- Serum creatinine level ≤1.5 the upper limits of normal
- Serum total bilirubin level ≤1.5 X ULN
White blood cell count >/= 3.5x109/ml per ml and platelet count ≥ 100x109 per ml
Age >18 years.
For subjects with obstructive jaundice, the biliary tract must be drained with a temporary plastic or a short permanent metallic biliary stent.
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 study entry.
Prior use of radiotherapy or investigational agents for pancreatic cancer.
Any evidence of metastasis to distant organs (liver, lung, peritoneum).
Symptomatic or endoscopic evidence of gastric outlet obstruction
Concurrent malignancies with evidence of active or measurable disease except basal cell carcinoma of the skin
Inability to adhere to study and/or follow-up procedures
History of allergic reactions or hypersensitivity to the study drugs (hydroxychloroquine, gemcitabine).
Other concurrent experimental therapy.
The effects of HCQ, and gemcitabine on the developing human fetus are unknown. For this reason 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 registration to rule out pregnancy. Should a woman become pregnant while participating in this study, she should inform her treating physician immediately. If a man impregnates a woman while participating in this study, he should inform his treating physician immediately as well.
Because patients with immune deficiency are at increased risk of lethal infections when treated with bone marrow-suppressive therapy, HIV-positive patients are excluded from the study. For patients receiving combination anti-retroviral therapy, the potential impact of pharmacokinetic interactions with HCQ and gemcitabine is unknown. Appropriate studies may be undertaken in patients with HIV and those receiving combination anti-retroviral therapy in the future.
Due to the risk of disease exacerbation, 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 EKG with 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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Hydroxychloroquine + Gemcitabine (HcGc)	Hydroxychloroquine	Hydroxychloroquine orally twice daily in combination with gemcitabine for 31 days prior to surgical resection
Hydroxychloroquine + Gemcitabine (HcGc)	Gemcitabine	Hydroxychloroquine orally twice daily in combination with gemcitabine for 31 days prior to surgical resection

Primary Outcome Measures

Name	Time	Method
Number of Participants That Experienced a Dose Limiting Toxicity (DLT)	Up to 31 days	Number of Participants at each dose level of HCQ that experienced a Dose Limiting Toxicity (DLT).

Secondary Outcome Measures

Name	Time	Method
Disease-free Survival (DFS)	Up to 30 months	Median number of months of disease-free survival for participants receiving study treatment.
Overall Survival (OS)	Up to 35 months	Median number of months of overall survival for participants receiving study treatment.
Disease-free Survival (DFS) by Response to HCQ Treatment	Up to 30 months	Median number of months of disease-free survival in participants who did and did not experience response to HCQ treatment. Patients who had \>51 % increase in their LC3-II staining were classified as having a response to HCQ.
Overall Survival (OS) by Response to HCQ Treatment	Up to 35 months	Median number of months of overall survival in participants who did and did not experience response to HCQ treatment. Patients who had \>51 % increase in their LC3-II staining were classified as having a response to HCQ.
R0 Resection Rate	Up to 30 months	Number of participants that underwent a resection with microscopically margin-negative resection in which no gross or microscopic tumor remains in the primary tumor bed (24) / number of that completed treatment (31)
Disease-free Survival (DFS) by CA 19-9 Response	Up to 30 months	Median number of months of disease-free survival for participants who experienced Ca 19-9 (surrogate biomarker) response (either an increase or decrease in Ca 19-9), or no Ca 19-9 response. Per participant increases in Ca 19-9 ranged from \>0 to 225%. Per participant decreases in Ca 19-9 ranged from \>0 to 100%.
Overall Survival (OS) by CA 19-9 Response	Up to 35 months	Median number of months of overall survival for participants who experienced Ca 19-9 (surrogate biomarker) response (either an increase or decrease in Ca 19-9), or, no Ca 19-9 response. Per participant increases in Ca 19-9 ranged from \>0 to 225%. Per participant decreases in Ca 19-9 ranged from \>0 to 100%.
Disease-free Survival by p53 Genetic Status	Up to 35 months
Overall Survival (OS) by p53 Mutant Status	Up to 35 months