Docetaxel (Taxotere) and Imatinib Mesylate (Gleevec) in Hormone Refractory Prostate Cancer

Phase I/II, Open Label Study of Sequential Taxotere® (Docetaxel) and Gleevec® (Imatinib Mesylate) in Hormone Refractory Prostate Cancer

This trial is designed to determine the proper doses of Docetaxel and Imatinib mesylate to be used to treat hormone refractory prostate cancer and to evaluate the safety and efficacy of the treatment.

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.

Inclusion Criteria:

• Patients at least 18 years of age.

• Histologically documented diagnosis of adenocarcinoma of prostate gland

• Patients must have hormone refractory prostate cancer having progressed after at least two prior hormonal manipulations with documented castrate levels of testosterone (<50 ng/dl). PSA ≥ 5 ng/ml

• Patients must have hormone-refractory prostate carcinoma as evidenced by PSA progression, with or without evidence of measurable disease, or evaluable disease by a positive bone scan. PSA progression is defined as > 25% increase in 2 consecutive tests in which the first increase in PSA should occur a minimum of 1 week from the reference value and this increase in PSA should be confirmed and ≥ 5 ng/ml

• Eligible patients will have been treated with at least two prior hormonal manipulations including androgen deprivation and may have received one prior chemotherapy regimen.

• Any chemotherapy, major surgery, or irradiation must have been completed at least 3 weeks prior to starting study drugs. Patient must have recovered from clinically significant toxicities incurred as a result of previous therapy except nail dystrophy, alopecia, grade 1 peripheral neuropathy, or radiation therapy induced affects (i.e., impotence or incontinence)

• No recent prior flutamide (Eulexin) use within the past 4 weeks, prior bicalutamide (Casodex) use within the past 6 weeks, or prior nilutamide (Nilandron) use within the past 6 weeks.

• Performance status 0,1, 2 (Eastern Cooperative Oncology Group performance status scale)

• Adequate end organ function, defined as the following:

  • total bilirubin < 1.5 x upper limit of Normal (ULN)
  • Serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) < 2.5 x ULN
  • creatinine < 1.5 x ULN
  • Absolute Neutrophil count (ANC) > 1.5 x 10^9/L
  • platelets > 100 x 10^9/L

• Written, voluntary informed consent.

• Patients must have been and continue to be on androgen deprivation therapy with a Luteinizing hormone-releasing hormone (LHRH) agonist or antagonist during study participation except for patients who had orchiectomy.

• Patients on secondary hormonal manipulation with ketoconazole and hydrocortisone who discontinued LHRH therapy must be switched to single agent LHRH analogue therapy unless they had orchiectomy.

• Patients being treated with Zometa prior to the initiation of the study will be permitted to continue with Zometa while on the study.

Exclusion Criteria:

• Patient has received any other investigational agents within 28 days of first day of study drug dosing, unless the disease is rapidly progressing.
• Patient is < 5 years free of another primary malignancy except: if the other primary malignancy is not currently clinically significant nor requiring active intervention, or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in situ. Existence of any other malignant disease is not allowed.
• Patient with Grade III/IV cardiac problems as defined by the New York Heart Association Criteria. (i.e., congestive heart failure, myocardial infarction within 6 months of study)
• Patient has a severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, chronic renal disease, or active uncontrolled infection).
• Patient with untreated brain metastasis or cord compression. However, patients with treated spinal cord compression or central nervous system (CNS) metastases that have been stable are eligible.
• Patient has known chronic liver disease (i.e., chronic active hepatitis, and cirrhosis).
• Patient has a known diagnosis of human immunodeficiency virus (HIV) infection.
• Patient received chemotherapy within 4 weeks (6 weeks for nitrosourea or mitomycin-C) prior to study entry, unless the disease is rapidly progressing.
• Patient previously received radiotherapy to at least 25 % of the bone marrow
• Patient had a major surgery within 2 weeks prior to study entry.
• Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.
• If the patient is taking steroids for prostate cancer, then the patient is ineligible for this study. If the patient is taking steroids for conditions other than prostate cancer, the patient is eligible provided that the reasons for use and dosage are documented. The investigator is urged to discuss this issue with the Study Principal Investigator for any clarification.
• No therapeutic anticoagulation with warfarin (e.g. Coumadin® or Coumadine®) will be permitted in patients participating in this study.