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

Phase 1/Phase 2
18 Years
Not Enrolling
Prostate Cancer, Prostatic Neoplasms

Thank you

Trial Information

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.

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

- 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

- 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.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Percentage of Participants With Prostate Specific Antigen (PSA) Response

Outcome Description:

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.

Outcome Time Frame:

up to 9 months

Safety Issue:


Principal Investigator

Anna Ferrari, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

New York University Cancer Institute


United States: Institutional Review Board

Study ID:

NYU 04-47 (H12554)



Start Date:

May 2005

Completion Date:

May 2010

Related Keywords:

  • Prostate Cancer
  • Prostatic Neoplasms
  • hormone refractory prostate cancer
  • tyrosine kinase inhibitor
  • Gleevec
  • PSA
  • prostate specific antigen
  • growth factor receptor inhibitor
  • androgen independent
  • Neoplasms
  • Prostatic Neoplasms



NYU Clinical Cancer CenterNew York, New York  10016
Bellevue HospitalNew York, New York  10016
NYU Tisch HospitalNew York, New York  10016