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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Pittsburgh
ClinicalTrials.gov Identifier:
NCT01128296
First received: May 20, 2010
Last updated: December 9, 2013
Last verified: December 2013
  Purpose

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.


Condition Intervention Phase
Pancreatic Cancer
Drug: Hydroxychloroquine
Drug: Gemcitabine
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Study of Preoperative Gemcitabine in Combination With Oral Hydroxychloroquine (GcHc) in Subjects With High Risk Stage IIb or III Adenocarcinoma of the Pancreas

Resource links provided by NLM:


Further study details as provided by University of Pittsburgh:

Primary Outcome Measures:
  • To establish the safety and tolerability of a novel regimen of pre-operative oral hydroxychloroquine in combination with gemcitabine (GCHC) in patients with high risk stage IIb or III adenocarcinoma of the pancreas [ Time Frame: During 31 days of study drug regimen ] [ Designated as safety issue: Yes ]
    The proportion of patients experiencing DLT will be calculated for each dose level, with 90% exact binomial confidence intervals. The dose-toxicity function will be estimated by means of logistic regression, with dose considered as a continuous variable, along with 90% confidence intervals. The dose with estimated probability of toxicity closest to 1/6 will be reported as the recommended Phase II dose.


Secondary Outcome Measures:
  • To establish the potential biologic activity and suitability for phase II study of GCHC, as determined by the rate of grade III or better histopathologic response. [ Time Frame: Surgical resection after 31 days of study drug regimen ] [ Designated as safety issue: No ]
    The histopathologic response of patients will be tabulated by dose. The proportion of patients experiencing of grade III or better histopathologic response will be calculated for each dose level, with 90% exact binomial confidence intervals. The dose-response function will be estimated by means of logistic regression, dose considered as a continuous variable, along with 90% confidence intervals

  • To establish the potential biological activity and suitability for phase II study of GCHC by radiographic tumor response, as assessed by [18F]- FDG PET. [ Time Frame: Prior to and after 31 days of study drug regimen (pre-surgical resection) ] [ Designated as safety issue: No ]
    Radiographic response will be assessed by category as described in the protocol and also by percent change in SUV from baseline. The proportions of CRs, SDs and PDs at each dose level will be calculated with 90% confidence intervals. The dose-response function will be estimated by means of a cumulative logit model (for ordered outcomes), with 90% confidence intervals. The dose-response model of percent change from baseline in SUV will be determined by linear regression, or, possibly, a generalized linear model.

  • Determine the effects of hydroxychloroquine on the plasma pharmacokinetics and metabolism of gemcitabine [ Time Frame: Days 1, 2, 3, 16, and 17 ] [ Designated as safety issue: No ]
    The following PK parameters will be determined: peak concentration (Cmax), the time to maximum concentration (Tmax), the area under the plasma concentration versus time curve (AUC), volume of distribution Vz, Vz/Fm), clearance terms (CL, CL/Fm), elimination rate constants, and elimination half-lives (t1/2). The values for these parameters obtained in the presence of hydroxychloroquine therapy will be compared with historically reported values of gemcitabine pharmacokinetic parameters.

  • Biomarker response (Ca 19-9), antibodies to cardiolipin, sMICA levels [ Time Frame: Prior to and after 31 days of study drug regimen (pre-surgical resection), post-surgical resection, every 3 months until disease progression ] [ Designated as safety issue: No ]
    The relationship of change in Ca 19-9 to dose will be characterized by a linear, or, if necessary, generalized linear or nonlinear regression model, with appropriate confidence intervals.

  • Correlate the level of autophagy in resected pancreatic adenocarcinomas with measures of clinical outcome, histopathologic response and [18F]- FDG PET. [ Time Frame: Surgical resection after 31 days of study drug regimen ] [ Designated as safety issue: No ]
    Autophagy (LC3) in resected tissue will be a predictor in generalized linear models of these endpoints, with link and variance functions chosen according to the type of endpoint. Cumulative logit models will be appropriate for clinical outcome and histopathologic response, while a continuous GLM will be chosen for SUV, where the link and variance functions will be determined from exploratory graphical analyses.

  • Correlate the levels of autophagic markers in peripheral blood mononuclear cells with histopathologic response and changes in the [18F]- FDG PET activity. [ Time Frame: Prior to and after 31 days of study drug regimen (pre-surgical resection), post-surgical resection, every 3 months until disease progression ] [ Designated as safety issue: No ]
    Changes across treatment in autophagic markers in peripheral blood mononuclear cells cells (e.g., HMGB1) will be a predictors in generalized linear models of histopathologic response and FDG-PET activity, with link and variance functions chosen according to the type of endpoint, as above. Similarly, the effect of hydroxychloroquine dose on changes in serum antibodies to cardiolipin and serum soluble MICA will be modeled by initial graphical and descriptive display, followed by an appropriate linear or nonlinear regression model.

  • Assess coagulation parameters during the protocol treatment. [ Time Frame: Prior to and after 31 days of study drug regimen (pre-surgical resection), post-surgical resection ] [ Designated as safety issue: Yes ]
    Coagulation parameter will provide the basis for future studies in Phase II and III.


Estimated Enrollment: 40
Study Start Date: October 2010
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Hydroxychloroquine + Gemcitabine (HcGc)
Hydroxychloroquine orally twice daily in combination with gemcitabine for 31 days prior to surgical resection
Drug: Hydroxychloroquine
Oral dosing daily starting at 48 hours before first dose of gemcitabine (starting on Day -2) and for a total of 31 days (ending on Day 29), prior to surgical resection. Capsules are available in 200 mg strengths. Daily doses are 200, 400, 600, 800, 1000, or 1200 mg, and will be administered BID for doses above 200 mg.
Other Name: Plaquenil
Drug: Gemcitabine
Intravenous administration on Days 1 and 15, with the infusion given at the fixed dose rate of 10mg/m2/min (e.g. 150 min for a 1500 mg/m2 dose).
Other Name: Gemzar

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.

  Eligibility

Ages Eligible for Study:   19 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01128296

Locations
United States, Pennsylvania
UPCI/UPMC Cancer Centers
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
University of Pittsburgh
Investigators
Principal Investigator: Herbert Zeh, MD University of Pittsburgh
  More Information

No publications provided

Responsible Party: University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01128296     History of Changes
Other Study ID Numbers: UPCI 09-122, PO1101944
Study First Received: May 20, 2010
Last Updated: December 9, 2013
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by University of Pittsburgh:
high risk stage IIb or III adenocarcinoma of the pancreas

Additional relevant MeSH terms:
Adenocarcinoma
Pancreatic Neoplasms
Carcinoma
Digestive System Diseases
Digestive System Neoplasms
Endocrine Gland Neoplasms
Endocrine System Diseases
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Pancreatic Diseases
Gemcitabine
Hydroxychloroquine
Anti-Infective Agents
Antimalarials
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antiparasitic Agents
Antiprotozoal Agents
Antirheumatic Agents
Antiviral Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Radiation-Sensitizing Agents

ClinicalTrials.gov processed this record on November 20, 2014