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

Study Overview
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Brief Summary
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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.

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

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: gemcitabine
* Drug: abraxane
* Drug: hydroxychloroquine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: gemcitabine and abraxane<br>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. | Drug: gemcitabine<br> <br> * Other names: Gemzar;Drug: abraxane<br> <br> * Other names: nab-Paclitacel;|
| Experimental: gemcitabine, abraxane and hydroxychloroquine<br>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. | Drug: gemcitabine<br> <br> * Other names: Gemzar;Drug: abraxane<br> <br> * Other names: nab-Paclitacel;Drug: hydroxychloroquine<br> <br> * Other names: Plaquenil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evans Grade Histopathologic Response | 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. | Up to 4 years | 
| Age at Diagnosis | 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). | Baseline - At the time of diagnosis, prior to treatment | 
| CT Tumor Size | Tumor size as measured via computerized tomography (CT) scan (as a variable in the proportional odds logistic regression, secondary analysis of Evans Grade). | Baseline - At the time of diagnosis, prior to treatment | 
| Cancer Diagnosis Stage | 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). | Baseline - At the time of diagnosis, prior to treatment | 
| Type of Surgical Procedure (Operation) | 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). | At the time of surgery (≥2 weeks and ≤6 weeks post chemotherapy) | 
| Robotic Resection Surgery | The number of participants who had robotic resection surgery. (Robotic surgery variable used in the proportional odds logistic regression, secondary analysis of Evans Grade). | At the time of surgery (≥2 weeks and ≤6 weeks post chemotherapy) | 
| Age-Adjusted Charlson Comorbidity Index | 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. | Prior to treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Carbohydrate Antigen 19-9 (CA19-9) Response | Levels of Carbohydrate antigen 19-9 (CA19-9) response to pre-operative gemcitabine/ nab-paclitaxel measured in the serum (original scale) | Prior to treatment (average 73.3 +/- 9.9 days prior to surgery) | 
| Carbohydrate Antigen 19-9 (CA19-9) Response | Levels of Carbohydrate antigen 19-9 (CA19-9) response to pre-operative gemcitabine/ nab-paclitaxel measured in the serum (original scale). | After treatment (50-67 days post treatment/surgery) | 
| Positive Lymph Node Involvement | The proportion of participants with positive (disease) lymph nodes involvement. | At the time of surgery (≥2 weeks and ≤6 weeks post chemotherapy) | 
| Rate of R0 Resection | 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. | At the time of surgery (≥2 weeks and ≤6 weeks post chemotherapy) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatic Cancer, resectable adenocarcinoma of the pancreas