Study of Pre-surgery Gemcitabine + Hydroxychloroquine (GcHc) in Stage IIb or III Adenocarcinoma of the Pancreas
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.
|Study Design:||Allocation: Non-Randomized
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|
- 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.
- 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.
|Study Start Date:||October 2010|
|Estimated Study Completion Date:||June 2013|
|Estimated Primary Completion Date:||June 2012 (Final data collection date for primary outcome measure)|
Experimental: Hydroxychloroquine + Gemcitabine (HcGc)
Hydroxychloroquine orally twice daily in combination with gemcitabine for 31 days prior to surgical resection
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: PlaquenilDrug: 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
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.
|Contact: Herbert Zeh, MD||(412) firstname.lastname@example.org|
|United States, Pennsylvania|
|UPCI/UPMC Cancer Centers||Recruiting|
|Pittsburgh, Pennsylvania, United States, 15232|
|Contact: Deborah Fiehler, RN 412-623-8962 email@example.com|
|Principal Investigator:||Herbert Zeh, MD||University of Pittsburgh|