Phase I/II, Open Label Study of Sequential Taxotere® (Docetaxel) and Gleevec® (Imatinib Mesylate) in Hormone Refractory Prostate Cancer
Androgen-independent prostate cancer is the second most common cause of cancer death in men.
These patients have limited treatment options. Docetaxel(Taxotere) is the single most
active agent for the treatment of hormone refractory prostate cancer. Phase II clinical
trials including docetaxel combinations with other microtubule inhibitors have shown 60-70%
prostate specific antigen (PSA) declines greater than 50% and 30-40% measurable disease
responses. However, the duration of response is limited to roughly 22 weeks. Combinations
with new agents are needed to increase the rate and duration of response over existing
docetaxel containing combinations.
The platelet derived growth factor receptor(PDGFR)and platelet derived growth factor (PDGF)
A are frequently expressed (80%) in primary and bone marrow metastasis of human prostate
cancer (PC). Recent experimental evidence suggests that activation of PDGFR/PDGF can be
oncogenic in the development and/or progression of PC. There is also evidence that PC cells
that express PDGF promote PDGFR expression in endothelial cells and neo- angiogenesis.
Together, these experimental evidence supports that inhibition of PDGFR may be of
therapeutic benefit to advanced prostate cancer patients.
Gleevec (Imatinib mesylate ) is a potent inhibitor of PDGFR. Consistent with these
observations, treatment with Gleevec in an experimental prostate cancer mouse model was
better than paclitaxel alone in reducing bone metastasis but the antitumor effect was
strongest with the combination of both. In a phase I study of heavily pretreated hormone
refractory PC patients, Gleevec 600 mg/daily lead-in for 30 days followed by Gleevec 600
mg/daily with Paclitaxel 30mg/m2 weekly x4 weeks every 6 weeks induced a >50% PSA decline in
7% and 38% of patients respectively with acceptable toxicity. These observations suggested
that this combination merits further investigation.
With high-dose docetaxel (70mg/m^2) being the single most active agent in hormone refractory
prostate cancer and no data existing in the use of high-docetaxel with Gleevec, a phase
I/II study to determine the maximum tolerated dose (MTD) of the combination and optimum dose
for a phase II trial is warranted.
Gleevec is expected to affect the activation status of sensitive receptor tyrosine kinase
targets and associated signaling effectors in the tumor cells and the neovasculature.
However, it is not fully established to what extent alterations of the target and /or other
molecules in the signaling pathway are essential for Gleevec's antitumor activity in
prostate cancer patients. It is also unknown whether preexisting molecular changes in the
prostate tumors of individual patients could affect Gleevec's activity even in the presence
of the targets. Therefore, an assessment of the expression levels and/or presence of
mutations of selected molecules in specimens of patients in clinical trials may contribute
in various ways: 1. to understand the requirements to elicit or inhibit a response to the
combination, 2. whether adding other targeted agents may improve response and/or 3. whether
selection of patients that might benefit should be based on the tumor profile. Thus,
whenever possible specimens form the primary and/or metastatic sites should be retrieved
and/or obtained to perform these analyses.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Percentage of Participants With Prostate Specific Antigen (PSA) Response
PSA response is defined as a greater than or equal to a 50% decrease in PSA from the baseline without clinical or radiologic evidence of progression according to the Response Evaluation Criteria in Solid Tumors (RECIST). PSA concentration was measured at baseline on day 1/cycle 1 before treatment, then day 1 of every cycle afterwards during therapy.
up to 9 months
Anna Ferrari, MD
New York University Cancer Institute
United States: Institutional Review Board
NYU 04-47 (H12554)
|NYU Clinical Cancer Center||New York, New York 10016|
|Bellevue Hospital||New York, New York 10016|
|NYU Tisch Hospital||New York, New York 10016|