Satraplatin and Prednisone to Treat Prostate Cancer

Background:

- Satraplatin is an oral, third-generation platinum analog that has recently been shown to
increase prostatic specific antigen (PSA) decline rates and progression-free survival in
hormone-resistant prostate cancer.

- Satraplatin acts by binding to deoxyribonucleic acid (DNA) forming intra- and
interstrand cross links (DNA adducts), resulting in cell-cycle arrest in G2 phase and
eventual apoptosis. One of the mechanisms that bring about resistance to platinum-based
chemotherapy is removal of the platinum-DNA adducts by DNA repair pathways, called
nucleotide excision repair (NER) and base excision repair (BER) pathways.

- Polymorphisms in the DNA repair genes causing impaired NER and BER capability has
recently been shown in some cancers, including head and neck squamous cell carcinoma,
non-small cell lung carcinoma, and ovarian carcinoma to predict better treatment outcome
and response to platinum treatment.

Objectives:

- Primary objective of this single arm study is to determine if the presence of ERCC1
variant gene polymorphism which is involved with DNA damage repair may be associated
with an impact on the progression-free survival of patients with metastatic prostate
cancer.

- Secondary objectives of this study includes demonstration of biologic effect by the drug
satraplatin in the patient and in the tumor whenever possible, by obtaining tissue
biopsy and white blood cell collections, to determine correlation of biologic or
clinical effects with PSA progression, evaluate correlations between genotype
expression, repair pathways and clinical events, and obtain laboratory correlates which
will include pharmacogenetic analysis of prostate cancer patients with genotyping using
Polymerase chain reaction (PCR) followed by either restriction fragment length
polymorphism or direct sequencing to genotype single nucleotide polymorphisms of ERCC1,
x-ray repair cross-complementing protein 1 (XRCC1), and poly (ADP-ribose) polymerase 1
(PARP1).

Eligibility:

- Patients with metastatic androgen-independent prostate cancer.

- Had docetaxel-based chemotherapy, but no more than 1 previous cytotoxic chemotherapy
line.

- Good organ function.

Design:

- Phase II trial with single stage design and a planned accrual of 66 patients.

- Progression-free survival will be determined using a Fisher's exact test.

- Will treat all enrolled patients with oral satraplatin 80 mg/m^2 dose on days 1-5 of
every 35-days cycle plus Prednisone 5 mg twice daily every 35 days.

- Genotyping will be performed after the first 20 patients to determine if the proportion
for wild-type ERCC1 and variants follow a 20:80 split.

- INCLUSION CRITERIA:

A. Patients must have histopathological confirmation of prostate cancer by the Laboratory
of Pathology of the National Cancer Institute (NCI) or Pathology Department of the National
Naval Medical Center or Walter Reed Army Medical Center prior to entering this study.
Patients whose pathology specimens are not available may be enrolled in the trial if the
patient has a clinical course consistent with prostate cancer and available documentation
from an outside pathology laboratory of the diagnosis. In cases where original tissue
blocks or archival biopsy material is available, all efforts should be made to have the
material forwarded to the research team for use in correlative studies.

B. Patients must have metastatic progressive androgen-independent prostate cancer. There
must be radiographic evidence of disease (by computed tomography (CT) scan or bone scan)
after primary treatment that has continued to progress despite hormonal agents. Progression
requires that a measurable lesion is expanding, new lesions have appeared, and/or that
prostatic specific antigen (PSA) is continuing to rise on successive measurements. Patients
must have progressive disease after receiving 1 prior docetaxel-based cytotoxic
chemotherapy. Patients on flutamide for the prior 6 months must have disease progression at
least 4 weeks after withdrawal. Patients on bicalutamide or nilutamide must have
progression at least 6 weeks after withdrawal.

C. Patients may only have received 1 prior cytotoxic chemotherapy. For the purpose of this
study, multiple courses of a taxane-based regimen may count as a single regimen. Multiple
courses of a non-taxane agent or a combination chemotherapy regimen, administered in a
similar fashion may count as a single regimen.

D. Patients must have a life expectancy of more than 3 months.

E. Patients must have a performance status of 0 to 2 according to the Eastern Cooperative
Oncology Group (ECOG) criteria.

F. Patients must have adequate organ function as defined below:

Leukocytes greater than or equal to 3,000/microl.

Absolute Neutrophil Count greater than or equal to 1,500/microl.

Platelets greater than or equal to 100,000/microl.

Total bilirubin less than or equal to 1.5 times institutional upper limits of normal
(Except patients with Gilbert's disease who may proceed despite elevated total bilirubin).

Aspartate aminotransferase (AST)serum glutamic oxaloacetic transaminase(SGOT) and alanine
aminotransferase (ALT)serum glutamic pyruvic transaminase (SGPT) less than or equal to 2.5
times institutional upper limit of normal

Creatinine less than or equal to 1.5 times institutional upper limits of normal.

OR

Creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for patients with
creatinine levels above institutional normal.

G. Patients must have recovered from any acute toxicity related to prior therapy, including
surgery. Toxicity should be <= grade 1 or returned to baseline.

H. Hormonal profile: all patients who have not undergone bilateral surgical castration must
continue suppression of testosterone production by appropriate usage of gonadotropin
releasing hormone (GnRH) agonists.

I. Patients must not have any ongoing malignancies requiring active therapy.

J. Patients must be able to understand and sign an informed consent form.

K. Concurrent use of bisphosphonates will be allowed if patients have previously been on
it; if patients are not on bisphosphonates at the time of study enrollment, bisphosphonates
may be started at cycle 2.

L. Patients who require hematopoietic growth factor support (e.g. epogen, darbepoetin), but
not myeloid growth factors (except after cycle 1 day 1 if clinically indicated),
non-steroidal anti-inflammatory drug (NSAIDs), and other maintenance medications prior to
study entry will be allowed to continue their supportive therapies.

M. Results from embryo-fetal development indicated that satraplatin should be considered a
teratogen in women of childbearing potential and hazardous in respect to spermatogenesis
for men. For this reason, men must agree to use adequate contraception (abstinence;
hormonal or barrier method of birth control) prior to study entry and for the duration of
study participation.

N. Patients must be able to swallow capsules.

O. Patients on chronic stable steroids (equivalent to no more than 10 mg of prednisone
daily dose) used for non-cancer treatment may be allowed on study.

EXCLUSION CRITERIA:

A. Patients who have had prior treatment with satraplatin or other platinum containing
compounds will be excluded.

B. Patients may not be receiving any other investigational agents.

C. Patients with known active brain metastases are excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

D. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to satraplatin or prednisone.

E. Uncontrolled intercurrent illness including, but not limited to ongoing or active
serious infection, symptomatic congestive heart failure, unstable angina pectoris, or
psychiatric illness/social situations that would limit patient compliance with study
requirements.

F. Prior radiation therapy to greater than 30 percent of the bone marrow, or who have
received strontium-89, rhenium-186, or rhenium-188 will be excluded from this trial.
Patients who have received prior radiotherapy must have recovered from acute toxicity due
to radiation. Patients who have received samarium-153 are eligible for the study because
samarium has a significantly reduced half-life compared to aforementioned isotopes.

G. Patients with immune deficiency are at increased risk of lethal infections when treated
with marrow-suppressive therapy. Therefore, human immunodeficiency virus (HIV)-positive
patients are excluded from the study.

H. Patients with a history of major gastrointestinal surgery or pathology likely to
influence absorption of oral medications, like bypass surgeries, Whipple's procedure, or
any surgery that would impair reliable absorption of oral drugs.

I. Patients with a disease where corticosteroids are contraindicated, e.g. active gastric
or duodenal ulcer, or poorly controlled insulin dependent diabetes. Patients with
well-controlled insulin-dependent diabetes mellitus may be considered, providing they
understand their glucose levels will increase, and their insulin dose will require
adjusting.

J. Because no dosing or adverse event data are currently available on the use of
satraplatin in patients less than 18 years of age, children are excluded from this study.