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

Phase 2

Completed

Conditions: Pancreatic Cancer

Interventions: Drug: gemcitabine
Drug: abraxane
Drug: hydroxychloroquine

Registration Number: NCT01978184

Lead Sponsor: Nathan Bahary, MD

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 104

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
gemcitabine and abraxane	abraxane	Gemcitabine and Abraxane will be administered on an outpatient basis on Days 3, 10, 17, 31, 38, and 45 as an intravenous infusion. The dose on Day 3 will be 1000 mg/m of gemcitabine followed by a 125 mg/m2 of abraxane and the infusion will take 1 hour. The second dose and infusion time may be decreased. Prior to each gemcitabine infusion, subjects will be pre-medicated with an FDA-approved anti-emetic (anti-nausea medication) in an effort to prevent nausea, at the discretion of the study physician.
gemcitabine, abraxane and hydroxychloroquine	abraxane	Gemcitabine and Abraxane will be administered on an outpatient basis on Days 3, 10, 17, 31, 38, and 45 as an intravenous infusion. The dose on Day 3 will be 1000 mg/m of gemcitabine followed by a 125 mg/m2 of abraxane and the infusion will take 1 hour. The second dose and infusion time may be decreased. Prior to each gemcitabine infusion, subjects will be pre-medicated with an FDA-approved anti-emetic (anti-nausea medication) in an effort to prevent nausea, at the discretion of the study physician. Hydroxychloroquine is an oral drug (capsule) that subjects will take once or twice a day at home. The dose of hydroxychlorquien will be 1200mg. This is an experimental drug. Subjects will take their first dose of hydroxychloroquine on Day 1 (48 hours before the first infusion of gemcitabine/abraxane), and will continue to take it every day until the day before surgery.
gemcitabine and abraxane	gemcitabine	Gemcitabine and Abraxane will be administered on an outpatient basis on Days 3, 10, 17, 31, 38, and 45 as an intravenous infusion. The dose on Day 3 will be 1000 mg/m of gemcitabine followed by a 125 mg/m2 of abraxane and the infusion will take 1 hour. The second dose and infusion time may be decreased. Prior to each gemcitabine infusion, subjects will be pre-medicated with an FDA-approved anti-emetic (anti-nausea medication) in an effort to prevent nausea, at the discretion of the study physician.
gemcitabine, abraxane and hydroxychloroquine	gemcitabine	Gemcitabine and Abraxane will be administered on an outpatient basis on Days 3, 10, 17, 31, 38, and 45 as an intravenous infusion. The dose on Day 3 will be 1000 mg/m of gemcitabine followed by a 125 mg/m2 of abraxane and the infusion will take 1 hour. The second dose and infusion time may be decreased. Prior to each gemcitabine infusion, subjects will be pre-medicated with an FDA-approved anti-emetic (anti-nausea medication) in an effort to prevent nausea, at the discretion of the study physician. Hydroxychloroquine is an oral drug (capsule) that subjects will take once or twice a day at home. The dose of hydroxychlorquien will be 1200mg. This is an experimental drug. Subjects will take their first dose of hydroxychloroquine on Day 1 (48 hours before the first infusion of gemcitabine/abraxane), and will continue to take it every day until the day before surgery.
gemcitabine, abraxane and hydroxychloroquine	hydroxychloroquine	Gemcitabine and Abraxane will be administered on an outpatient basis on Days 3, 10, 17, 31, 38, and 45 as an intravenous infusion. The dose on Day 3 will be 1000 mg/m of gemcitabine followed by a 125 mg/m2 of abraxane and the infusion will take 1 hour. The second dose and infusion time may be decreased. Prior to each gemcitabine infusion, subjects will be pre-medicated with an FDA-approved anti-emetic (anti-nausea medication) in an effort to prevent nausea, at the discretion of the study physician. Hydroxychloroquine is an oral drug (capsule) that subjects will take once or twice a day at home. The dose of hydroxychlorquien will be 1200mg. This is an experimental drug. Subjects will take their first dose of hydroxychloroquine on Day 1 (48 hours before the first infusion of gemcitabine/abraxane), and will continue to take it every day until the day before surgery.

Primary Outcome Measures

Name	Time	Method
CT Tumor Size	Baseline - At the time of diagnosis, prior to treatment	Tumor size as measured via computerized tomography (CT) scan (as a variable in the proportional odds logistic regression, secondary analysis of Evans Grade).
Age at Diagnosis	Baseline - At the time of diagnosis, prior to treatment	The mean age of patients at the time of diagnosis of disease (as a variable in the proportional odds logistic regression, secondary analysis of Evans Grade).
Age-Adjusted Charlson Comorbidity Index	Prior to treatment	The Charlson Comorbidity Index is a method of categorizing comorbidities of patients based on the International Classification of Diseases (ICD) diagnosis codes found in administrative data, such as hospital abstracts data. Each comorbidity category has an associated weight (from 1 to 6), based on the adjusted risk of mortality or resource use, and the sum of all the weights results in a single comorbidity score for a patient. A score of zero indicates that no comorbidities were found. The higher the score, the more likely the predicted outcome will result in mortality or higher resource use. Up to 12 comorbidities with various weightings can result in a maximum score of 24. The minimum score is zero.
Evans Grade Histopathologic Response	Up to 4 years	The number of patients who exhibited an Evans grade Histologic response (I, IIA, IIB, or III) to pre-operative gemcitabine / nab-paclitaxel. Histological response validated scoring system by Evans is as follows: Grade I: 1-9% tumor destruction, Grade II: 10 - 90%, Grade III: \>90% tumor destruction (Grade IIA = 10-50% of tumor cells destroyed; Grade IIB = 50-90% of tumor cells destroyed), Grade IV: Absence of viable tumor cells.
Type of Surgical Procedure (Operation)	At the time of surgery (≥2 weeks and ≤6 weeks post chemotherapy)	The number of participants in having each type of surgical resection procedure: Celiac Axis Resection With Distal Pancreatectomy (DPCAR) (Modified Appleby), Distal Pancreatectomy, Total Pancreatectomy, or Whipple. (Operation variable used in the proportional odds logistic regression, secondary analysis of Evans Grade).
Robotic Resection Surgery	At the time of surgery (≥2 weeks and ≤6 weeks post chemotherapy)	The number of participants who had robotic resection surgery. (Robotic surgery variable used in the proportional odds logistic regression, secondary analysis of Evans Grade).
Cancer Diagnosis Stage	Baseline - At the time of diagnosis, prior to treatment	The number of participants in cancer diagnosis stage groups. Stage 0: cancer hasn't spread to nearby tissues/located in the same of origin.Stage I: cancers hasn't grown deeply into nearby tissues or spread to lymph nodes or other parts of the body. Stage II and III: cancers have grown more deeply into nearby tissues (may have metastasized to lymph nodes but not other parts of the body). Stage IV: most advanced stage (metastatic cancer) ; cancer has spread to other parts of the body. Stages subdivided further into the categories "A" (less agressive disease) and "B" (more advanced cancer). Example: stage IIA is less aggressive than stage IIB, but stage IIIA is more aggressive than stage IIB. (Stage variable used in the proportional odds logistic regression, secondary analysis of Evans Grade).

Secondary Outcome Measures

Name	Time	Method
Positive Lymph Node Involvement	At the time of surgery (≥2 weeks and ≤6 weeks post chemotherapy)	The proportion of participants with positive (disease) lymph nodes involvement.
Carbohydrate Antigen 19-9 (CA19-9) Response	After treatment (50-67 days post treatment/surgery)	Levels of Carbohydrate antigen 19-9 (CA19-9) response to pre-operative gemcitabine/ nab-paclitaxel measured in the serum (original scale).
Rate of R0 Resection	At the time of surgery (≥2 weeks and ≤6 weeks post chemotherapy)	The proportion of participants having resection for cure or complete remission, in which the surgical margins are negative for tumor cells. R0 resection indicates a microscopically margin-negative resection, in which no gross or microscopic tumor remains in the primary tumor bed.