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RATIONALE: Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. GDC-0449 may slow the growth of tumor cells. It is not yet known whether giving gemcitabine hydrochloride together with GDC-0449 is more effective than gemcitabine hydrochloride alone in treating patients with pancreatic cancer.
PURPOSE: This randomized phase II trial is studying gemcitabine hydrochloride and GDC-0449 to see how well they work compared with gemcitabine hydrochloride alone in treating patients with recurrent or metastatic pancreatic cancer.
- To compare the progression-free survival (PFS) of patients with recurrent or metastatic pancreatic cancer treated with gemcitabine hydrochloride with vs without hedgehog antagonist GDC-0449.
- To compare the overall survival of these patients.
- To compare the objective response rate in these patients.
- To determine the toxicity of these regimens in these patients.
- To determine the activity, in an exploratory analysis, of gemcitabine hydrochloride and hedgehog antagonist GDC-0449 in patients who progress on gemcitabine hydrochloride alone.
- To determine if tumor immunohistochemical expression patterns of proteins in the hedgehog (Hh) pathway (including Sonic Hh [Shh], Indian Hh, patched [PTCH], Smoothened [SMO], and glioma-associated [GLI]1 and 2) within pancreatic tissue obtained at the time of curative-intent surgery predict response and prognosticate outcome of patients treated with or without hedgehog antagonist GDC-0449 at the time of relapse.
- To determine the prognostic ability (relapse-free survival) of these biologic markers in an archival cohort of patients undergoing resection.
- To determine the expression pattern of pancreatic cancer stem cell (CSC) markers (including CD44, CD24, CD133, ALDH, and ESA) by IHC on these archival tissues in relation to Hh pathway markers and to correlate these with clinical outcomes.
- To determine whether high baseline serum Shh, as well as changes in serum Shh during treatment, predict treatment efficacy and/or prognosticate clinical outcome.
- To determine the frequency of mutation of Hh pathway genes (PTCH, SMO, SuFU) and if the presence or absence of mutations are correlated with clinical outcome.
- To determine the frequency of amplification of Hh pathway genes and gene copy number by quantitative PCR of GLI1 and SMO in those tumors that have high protein expression as seen by IHC and to correlate gene amplification with clinical outcome.
- To determine if there is a correlation of K-ras mutation and MET and RON expression, amplification, or mutation status with Hh pathway abnormalities, CSC markers, and clinical outcomes.
- To determine if baseline contrast perfusion imaging volume transfer constant (Ktrans) within primary and liver metastatic lesions, as measured on a 256-detector CT scanner, predicts objective response rates and other endpoints, including PFS of patients treated with gemctibine with versus without GDC-0449.
- To determine if treatment with gemcitabine and GDC-0449 improves tumor perfusion, as measured by Ktrans over the course of treatment by serial CT scans every 2 courses compared to tumors treated with gemcitabine alone.
- To determine if improved tumor perfusion with GDC-0449 treatment (if observed) improves objective response rates and other clinical endpoints including PFS.
OUTLINE: This is a multicenter, safety lead-in study (part I) followed by a randomized study (part II). An initial 6 patients are enrolled in the part I portion of the study. If no dose-limiting toxicities occur in these patients, subsequent patients are enrolled in the part II portion of the study.
- Part I (safety lead-in study): Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and oral hedgehog antagonist GDC-0449 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
- Part II (randomized study): Patients are stratified according to disease status (recurrent after surgery vs metastatic) and ECOG performance status (0 vs 1). Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and oral placebo once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. At the time of disease progression, patients are unblinded and may crossover to arm II.
- Arm II: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and oral hedgehog antagonist GDC-0449 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Tumor tissue, blood, serum, and plasma samples are collected periodically for biomarker and other analyses.
After completion of study treatment, patients are followed periodically.
PROJECTED ACCRUAL: A total of 118 patients (6-12 part I plus 106 part II) will be accrued for this study.
Allocation: Randomized, Control: Placebo Control, Masking: Open Label, Primary Purpose: Treatment
Hedgehog antagonist GDC-0449, gemcitabine hydrochloride, placebo
University of Chicago Cancer Research Center
National Cancer Institute (NCI)
Published on BioPortfolio: 2014-07-24T14:10:03-0400
RATIONALE: GDC-0449 may slow the growth of tumor cells. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by k...
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