Trial Information

A Phase II Study of SU011248 in Men With Advanced Prostate Cancer

Background: There are nearly 30,000 deaths per year in the United States from prostate
cancer, making this a large and important target patient population for new therapeutics.
The mainstay of therapy for advanced prostate cancer is androgen deprivation therapy (ADT).
Although ADT is effective in the large majority of men with advanced prostate cancer, the
favorable response to ADT is only transient. In hormone-refractory, metastatic prostate
cancer the only effective systemic treatment is cytotoxic chemotherapy. The median duration
of response to standard, taxane-based chemotherapy is approximately six months, and median
survival in contemporary studies is only 16-18 months. Thus, there is an urgent need for
new therapeutic agents to treat advanced prostate cancer.

SU011248 is an orally administered inhibitor of the vascular endothelial growth factor
(VEGF) receptors, platelet-derived growth factor (PDGF) receptor, FLT-3 and c-KIT. SU011248
has demonstrated significant clinical activity in other malignancies, but its activity in
prostate cancer has not been studied to date. Clinical trials have demonstrated that
SU011248 is generally well tolerated, with mild fatigue and diarrhea the most common adverse
effects. Preclinical studies have demonstrated that levels of VEGF and PDGF are elevated in
prostate cancer and may correlate with worse outcome. The inhibition of several pathways
implicated in prostate cancer progression by SU011248 suggests that it might have
significant anti-tumor activity in men with AIPC.

Many of the new, targeted agents are efficacious in only a subset of patients with a
particular malignancy, and these subsets may be definable on the basis of specific tumor
mutations or patterns of gene expression. Identification of reliable predictive methods is
crucial in moving forward with targeted therapies, and we believe that exploratory clinical
trials such as this one should incorporate assays designed to address this issue.

Objective/Hypothesis: The objective of this proposal is to determine whether SU011248 is an
effective treatment in two cohorts of men with advanced prostate cancer: men with
androgen-independent prostate cancer (AIPC) who have not been treated with chemotherapy
(Group A), and men with taxane-refractory, metastatic disease (Group B). We hypothesize
that specific serum biomarkers and tumor mutations may predict response and may allow
optimal subject selection in the future.

Specific Aims: (1) To evaluate the efficacy and safety of SU011248 in men with chemo-naïve
AIPC, (2) to evaluate the efficacy and safety of SU011248 in men with metastatic,
taxane-resistant AIPC, (3) to measure serum biomarkers in men with AIPC prior to and
following treatment with SU011248 and correlate these markers with clinical response, and
(4) to mutational analysis from tumor specimens of men with metastatic prostate cancer
treated with SU011248 and correlate with clinical response.

Study Design: We will conduct a phase II clinical trial in two groups of subjects: men with
AIPC who have not yet developed overt metastases (Group A), and men with taxane-refractory,
metastatic disease (Group B). Men in both groups will receive single-agent SU011248 on a
six-week repeating schedule, with four weeks of daily treatment followed by a two-week rest.
The primary endpoint will be PSA response rate. Secondary endpoints will include time to
disease progression, objective response rate, and safety parameters. Eligibility for this
study will require signed informed consent, adenocarcinoma of the prostate, documented PSA
progression despite ADT, reasonable functional status, resolution of toxic effects from
prior treatments, and acceptable bone marrow, hepatic, renal and cardiac function. A
Simon's two-stage design will be employed to allow early termination for lack of efficacy.
Ultimately, 30 patients will be enrolled in each group, for a total of 60 patients. A
defined program of history and physical examinations, radiographic studies, and laboratory
tests including PSA will be carried out to determine the efficacy and safety of SU011248 in
this patient population.

All subjects will have blood and urine collected for research purposes, and men in Group B
will have tumor biopsy prior to enrollment. Translational studies aimed at identifying
specific biomarkers in the blood will include analysis of serum cytokine levels including
VEGF and others, circulating endothelial cells and endothelial precursors, white blood cell
differential, and bone turnover markers. Tumor samples will be analyzed for the presence of
predictive tumor mutations.

Relevance: Our ultimate goals are to determine whether SU011248 is an important therapeutic
agent in men with advanced prostate cancer, and to identify predictive markers of
anti-cancer activity within individual subjects that would allow selective treatment of
appropriate subjects in the future. The data obtained should also contribute to our general
understanding of serum biomarkers and genetic changes in advanced prostate cancer. Positive
results of our trial would lead to expanded, multi-center trials of SU011248 in men with
advanced prostate cancer.