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

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ClinicalTrials.gov Identifier: NCT01978184
Recruitment Status : Completed
First Posted : November 7, 2013
Results First Posted : March 27, 2019
Last Update Posted : March 27, 2019
Sponsor:
Information provided by (Responsible Party):
Nathan Bahary, MD, University of Pittsburgh

Tracking Information
First Submitted Date  ICMJE October 30, 2013
First Posted Date  ICMJE November 7, 2013
Results First Submitted Date  ICMJE March 3, 2019
Results First Posted Date  ICMJE March 27, 2019
Last Update Posted Date March 27, 2019
Study Start Date  ICMJE November 2013
Actual Primary Completion Date February 6, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 25, 2019)
  • Evans Grade Histopathologic Response [ Time Frame: 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.
  • Age at Diagnosis [ Time Frame: 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).
  • CT Tumor Size [ Time Frame: 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).
  • Cancer Diagnosis Stage [ Time Frame: 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).
  • Type of Surgical Procedure (Operation) [ Time Frame: 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 [ Time Frame: 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).
  • Age-Adjusted Charlson Comorbidity Index [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 6, 2013)
Histologic response to pre-operative gemcitabine/ nab-paclitaxel [ Time Frame: up to 3 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 25, 2019)
  • Carbohydrate Antigen 19-9 (CA19-9) Response [ Time Frame: Prior to treatment (average 73.3 +/- 9.9 days prior to surgery) ]
    Levels of Carbohydrate antigen 19-9 (CA19-9) response to pre-operative gemcitabine/ nab-paclitaxel measured in the serum (original scale)
  • Carbohydrate Antigen 19-9 (CA19-9) Response [ Time Frame: 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).
  • Positive Lymph Node Involvement [ Time Frame: At the time of surgery (≥2 weeks and ≤6 weeks post chemotherapy) ]
    The proportion of participants with positive (disease) lymph nodes involvement.
  • Rate of R0 Resection [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 6, 2013)
  • Carbohydrate antigen 19-9 (CA19-9) response to pre-operative gemcitabine/ nab-paclitaxel [ Time Frame: Up to 3 years ]
  • Rate of R0 resection and positive lymph node ratio [ Time Frame: Up to 3 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Randomized Phase II Trial of Pre-Operative Gemcitabine and Nab Paclitacel With or With Out Hydroxychloroquine
Official Title  ICMJE Randomized Phase II Trial of Pre-Operative Gemcitabine and Nab Paclitacel With or With Out Hydroxychloroquine
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 Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Pancreatic Cancer
Intervention  ICMJE
  • Drug: gemcitabine
    Other Name: Gemzar
  • Drug: abraxane
    Other Name: nab-Paclitacel
  • Drug: hydroxychloroquine
    Other Name: Plaquenil
Study Arms  ICMJE
  • Experimental: gemcitabine and 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.
    Interventions:
    • Drug: gemcitabine
    • Drug: abraxane
  • Experimental: gemcitabine, abraxane and 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.

    Interventions:
    • Drug: gemcitabine
    • Drug: abraxane
    • Drug: hydroxychloroquine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 25, 2019)
104
Original Estimated Enrollment  ICMJE
 (submitted: November 6, 2013)
60
Actual Study Completion Date  ICMJE February 28, 2018
Actual Primary Completion Date February 6, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01978184
Other Study ID Numbers  ICMJE UPCI# 13-074
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Nathan Bahary, MD, University of Pittsburgh
Study Sponsor  ICMJE Nathan Bahary, MD
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Herbert Zeh, MD University of Pittsburgh CancerCenters
PRS Account University of Pittsburgh
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP