Clinical Study of SU011248 in Subjects With High Risk Prostate Cancer Who Have Elected to Undergo Radical Prostatectomy

• To evaluate the effects of SU011248 by histological examination of prostate tumors following radical prostatectomy. [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
• To determine maximum tolerable dose of SU011248 when administered with prostate cancer prior to radical prostatectomy. [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]

Prostate cancer is prevalent in the United States, with approximately 230,110 new cases and 29,900 deaths in 2004. Approximately 30% of new cases will be clinical stage T3 when they are diagnosed. This is a stage in which there is high probability that the cancer has spread beyond the prostate gland itself, making it much more difficult to treat. In these cases, when surgery is done by itself and the prostate is removed, it is still very likely that some cancer that has spread beyond the prostate remains and will get worse. Radiation applied to the prostate also does not work well on tumors that have spread beyond the prostate. Even surgery and radiation combined have not eliminated the problems caused by prostate cancer that has spread into the tissue outside the prostate itself.

New treatments are needed to deal with prostate cancer at this more serious stage. Study doctors believe that it might be possible to shrink the prostate cancer using a new drug called SUO11248 or Sunitinib. After the patients take the drug, study doctors believe the cancer will shrink back to within the prostate, and they can then surgically remove the prostate and all the cancer. Patients on this study also will be given increasing doses of Sunitinib to find out how much of the drug can be given safely.

• Drug: SU011248
  5 Subjects will receive 50.0 mg/d of the study drug for 2 weeks.
• Drug: SU011248
  5 Subjects will receive 50.0 mg/d of the study drug for 4 weeks.
• Drug: SU011248
  5 Subjects will receive 50.0 mg/d of the study drug for 1 week.
• Drug: SU011248
  5 Subjects will receive 37.5 mg/d of the study drug for 1 week.
• Drug: SU011248
  5 Subjects will receive 37.5 mg/d of the study drug for 2 weeks.

• Experimental: Group A
  5 Subjects will receive 37.5 mg/d of the study drug for 1 week.
  Intervention: Drug: SU011248
• Experimental: Group B
  5 Subjects will receive 50.0 mg/d of the study drug for 1 week.
  Intervention: Drug: SU011248
• Experimental: Group C
  5 Subjects will receive 37.5 mg/d of the study drug for 2 weeks.
  Intervention: Drug: SU011248
• Experimental: Group D
  5 Subjects will receive 50.0 mg/d of the study drug for 2 weeks.
  Intervention: Drug: SU011248
• Experimental: Group E
  5 Subjects will receive 50.0 mg/d of the study drug for 4 weeks.
  Intervention: Drug: SU011248

• Weir HK, Thun MJ, Hankey BF, Ries LA, Howe HL, Wingo PA, Jemal A, Ward E, Anderson RN, Edwards BK. Annual report to the nation on the status of cancer, 1975-2000, featuring the uses of surveillance data for cancer prevention and control. J Natl Cancer Inst. 2003 Sep 3;95(17):1276-99. Review. Erratum in: J Natl Cancer Inst. 2003 Nov 5;95(21):1641.
• Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999 May 5;281(17):1591-7.
• Roehl KA, Han M, Ramos CG, Antenor JA, Catalona WJ. Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results. J Urol. 2004 Sep;172(3):910-4.
• Kasamon KM, Dawson NA. Update on hormone-refractory prostate cancer. Curr Opin Urol. 2004 May;14(3):185-93. Review.
• Zagars GK. Prostate-specific antigen as a prognostic factor for prostate cancer treated by external beam radiotherapy. Int J Radiat Oncol Biol Phys. 1992;23(1):47-53.
• Stamey TA, Kabalin JN, Ferrari M. Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. III. Radiation treated patients. J Urol. 1989 May;141(5):1084-7.
• Kabalin JN, Hodge KK, McNeal JE, Freiha FS, Stamey TA. Identification of residual cancer in the prostate following radiation therapy: role of transrectal ultrasound guided biopsy and prostate specific antigen. J Urol. 1989 Aug;142(2 Pt 1):326-31.
• Zagars GK, von Eschenbach AC, Johnson DE, Oswald MJ. Stage C adenocarcinoma of the prostate. An analysis of 551 patients treated with external beam radiation. Cancer. 1987 Oct 1;60(7):1489-99.
• Bagshaw MA, Cox RS, Ramback JE. Radiation therapy for localized prostate cancer. Justification by long-term follow-up. Urol Clin North Am. 1990 Nov;17(4):787-802.
• Wheeler JA, Zagars GK, Ayala AG. Dedifferentiation of locally recurrent prostate cancer after radiation therapy. Evidence for tumor progression. Cancer. 1993 Jun 1;71(11):3783-7.
• Cumming JA, Ritchie AW, Goodman CM, McIntyre MA, Chisholm GD. De-differentiation with time in prostate cancer and the influence of treatment on the course of the disease. Br J Urol. 1990 Mar;65(3):271-4.
• Stamey TA and McNeal JE: Adenocarcinoma of the prostate. In Campbell's Urology 6th edition (Walsh PC, Retik AB, Stamey MA and Vaughan ED, eds), W.B. Saunders Co., pp 1159-1221, 1992.
• Stamey TA, Villers AA, McNeal JE, Link PC, Freiha FS. Positive surgical margins at radical prostatectomy: importance of the apical dissection. J Urol. 1990 Jun;143(6):1166-72; discussion 1172-3.
• Rosen MA, Goldstone L, Lapin S, Wheeler T, Scardino PT. Frequency and location of extracapsular extension and positive surgical margins in radical prostatectomy specimens. J Urol. 1992 Aug;148(2 Pt 1):331-7.
• Catalona WJ, Bigg SW. Nerve-sparing radical prostatectomy: evaluation of results after 250 patients. J Urol. 1990 Mar;143(3):538-43; discussion 544.
• Stein A, deKernion JB, Dorey F. Prostatic specific antigen related to clinical status 1 to 14 years after radical retropubic prostatectomy. Br J Urol. 1991 Jun;67(6):626-31.
• Frazier HA, Robertson JE, Humphrey PA, Paulson DF. Is prostate specific antigen of clinical importance in evaluating outcome after radical prostatectomy. J Urol. 1993 Mar;149(3):516-8.

Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the prostate glad.
• Informed of, willing, and able to comply with, the requirements of the investigational study and have signed a written informed consent in accordance with institutional regulatory guidelines.
• Subjects defined as being at high risk for disease relapse based on the following criteria: PSA > 10 ng/ml, and any one of the following: Gleason > 7 or T stage > T2b.
• Patients must have elected to and are a candidate to undergo a radical prostatectomy.
• Males greater than 18 years of age and less than or equal to 75 years of age (physiologic) any racial/ethnic group.
• Free of significant abnormal findings as determined by screening history, physical exam, vital signs (blood pressure, heart rate, respiration rate, and temperature), and urinalysis.
• Performance status: ECOG < 2.
• Life expectancy of at least 5 years.
• Absolute granulocyte count > 1,500/mm3.
• Platelet count > 100,000.
• Hemoglobin > 9.0 g/dL.
• Serum calcium < 12.0 mg/dL Adequate hepatic function as evidenced by ALT and AST values within normal range. Adequate organ function as defined by the following criteria: Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) < 2.5 x local laboratory upper limit of normal (ULN), or AST and ALT < 5 x ULN if liver function abnormalities are due to underlying malignancy.
• Creatinine < 1.5 ULN.

Exclusion Criteria:

• Patients who have stage T2a or less prostate cancer, Gleason < 6, PSA <10-ng/mL.
• Prior hormonal, surgical, radiopharmaceutical or radiation therapy, cryotherapy, biological response modifiers, or systematic chemotherapy to treat prostatic carcinoma.
• Surgery within four weeks of study entry.
• Evidence of regional and/or distant metastases.
• Use of an investigational drug within 30 days prior to study entry.
• NCI CTCAE Version 3.0 grade 3 hemorrhage within 4 weeks of starting the study treatment.
• Any of the following thing the 12 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism.
• Ongoing cardiac dysrhythmias of NCI CTCAE Version 3.0 grade > 2.
• Prolonged QTc interval on baseline EKG.
• Uncontrolled Hypertension (>150/100 mm Hg despite optimal medical therapy).
• Patients receiving CYP3A4 inducers or inhibitors; patients should not take grapefruit juice or St. John's Wort while on the study
• Known active infection.