Trial of GM-CSF Given in Combination With Ketoconazole and Mitoxantrone in Patients With Progressive Prostate Cancer

Prostate cancer is the second leading cause of cancer death in American men. Hormonal
ablation, in the form of medical or surgical castration is the cornerstone of management for
metastatic prostate cancer however, treatment options for a patient in whom androgen
ablation fails are limited. Second-line hormonal agents are generally associated with low
response rates and no documented survival benefit.

A variety of taxane-based regimens have been tested in hormone refractory prostate cancer,
yielding response rates between 38% - 69%. As responses to taxane-based regimens have
appeared to exceed those typically associated with mitoxantrone plus prednisone,
taxane-based therapy has been widely used in the community, typically as first line therapy.
Second line therapy, which are non-taxane based and have comparable activities do not exist.

This study builds on experience in drug development for advanced prostate cancer
demonstrating the following:

1. Ketoconazole produces serologic and objective clinical responses in over 50% of
patients with disease progression on oral antiandrogen.

2. GM-CSF, as a potent stimulator of dendritic cells, has demonstrated clinical activity
in prostate cancer.

3. GM-CSF is well tolerated in patients with prostate cancer. The addition of GM-CSF to
antitumor therapy may augment the T cell response to apoptotic tumor cells and
therefore may improve the clinical benefit produced by such agents.

4. The addition of mitoxantrone with ketoconazole demonstrated improved clinical benefit
relative to the published data with each single agent.

The importance of this trial in the broader context of clinical research for prostate cancer
is twofold: One, it represents an attempt to offer second line immunotherapy plus
chemotherapy to patients who have failed prior frontline taxane based therapy. Two, this is
the first trial to assess the combination of GM-CSF plus ketoconazole and mitoxantrone.

- Histologically confirmed adenocarcinoma of the prostate

- Testosterone < 50 ng/dL. Patients must continue primary androgen deprivation with an
LHRH analogue if they have not undergone orchiectomy.

- Progressive disease after androgen deprivation.

- Patients who are receiving an antiandrogen as part of primary androgen ablation must
demonstrate disease progression following discontinuation of antiandrogen.

- Karnofsky Performance Status ≥ 60%.

- One prior taxane based chemotherapy for prostate cancer. No more than two prior
systemic therapies. At least four weeks have lapsed since prior therapy.

- Patients may have had prior ketoconazole, aminoglutethimide or corticosteroids for
treatment of progressive prostate cancer.

- Patients receiving any other hormonal therapy, including any dose of megestrol
acetate (Megace), Proscar (finasteride), any herbal product known to decrease PSA
levels (e.g., Saw Palmetto and PC-SPES), or any systemic corticosteroid must
discontinue the agent for at least 4 weeks prior to enrollment. Progressive disease
must be documented after discontinuation of the hormonal therapy.

- Patients on stable doses of bisphosphonates that show subsequent tumor progression
may continue on this medication; however, patients are not allowed to initiate
bisphosphonate therapy within one month prior to starting therapy or throughout the
study.

- Liver function tests (ALT, AST) less than 1.5 x upper limit of normal (ULN). The
bilirubin must be within normal limits.

- ANC >1500/µl, Platelet count > 100,00/µl, Creatinine <1.5 x ULN, Hemoglobin > 8 mg/dl

- Ejection fraction ≥45%.