Multimodality Phase II Study in Prostate Cancer

In many common malignancies such as breast cancer, trimodality therapy represents the
standard-of-care approach, including initial surgical resection followed by systemic
chemotherapy followed by radiotherapy for optimal local control, and targeted hormonal or
biologic therapy for a period of time to reduce the ongoing risk of systemic disease
recurrence. These approaches have reduced recurrence rates and improved overall survival in
the adjuvant setting in breast cancer; however, the treatment of men with PSA recurrence
following radical prostatectomy has generally been unsatisfying, given the high rates of
persistent or recurrent disease despite salvage radiotherapy.

The primary purpose of the study is to determine the rate of biochemical (PSA) progression
free survival (bPFS) in men with PSA recurrent non-metastatic prostate cancer following
radical prostatectomy, who receive multimodality therapy consisting of local salvage
external beam radiotherapy and systemic docetaxel-based chemotherapy plus the targeted
anti-VEGF biologic therapy sunitinib. Biochemical PFS will be defined as the proportion of
subjects at 24 months, post-registration, with one of the following: 1) a serum PSA value of
0.2 ng/ml or more above the post-radiotherapy PSA nadir and confirmed 4 weeks later by a
second PSA measurement that was higher than the first by any amount, 2) a continued rise in
the PSA level following study treatment if no nadir is experienced, defined as 2 rising
values greater than the baseline PSA and separated by at least 4 weeks, 3) evidence of
clinical progression or initiation of systemic therapy for progressive disease, or 4) death.
Secondary objectives include finding the rate of biochemical (PSA) disease free survival
over time, Two-, three-, five-, and six- year risk of local recurrence (proportion), two-,
three-, five-, and six-year risk of metastases and metastasis-free survival, two-, three-,
five-, and six-year risk of metastases and metastasis-free survival, Safety, feasibility,
and tolerability as assessed by NCI Common Toxicity Scales (v3.0), quality of life
questionnaire (EPIC-short form surveys), achievement of accrual goals. Finally, a comparison
of RNA expression profiles from original prostate radical prostatectomy specimen among those
with PSA relapse at 2 and 5 years as compared to those without PSA relapse at the primary
endpoint.

Inclusion Criteria:

1. Prostate adenocarcinoma with evidence of recurrent disease as measured only by rising
PSA, without evidence of metastatic disease by bone scan or CT scan within 4 weeks of
entry

2. PSA ≤ 3.0 ng/ml and ≥ 0.1 ng/ml within 2 weeks of registration

3. Radical prostatectomy within 4 years of registration.

4. Rising PSA as defined by 1 or more PSA values greater than the nadir value after
radical prostatectomy, separated by at least 4 weeks.

5. Gleason sum at radical prostatectomy of 7-10 (4+3 or 3+4 allowed)

6. Informed consent

7. Age > 18 years.

8. Adequate laboratory parameters:

- leukocytes ≥ 3,000/uL

- absolute neutrophil count ≥ 1,500/uL

- platelets ≥ 75,000/uL

- hemoglobin > 9.0 g/dl

- total bilirubin within normal institutional limit

- AST(SGOT)/ALT(SGPT) < 2.5x institutional upper limit

- creatinine < 2.0x institutional upper limit

9. Karnofsky Performance Status ≥ 80 (Attachment 2).

10. Written, signed, dated, and witnessed IRB approved informed consent form (ICF) before
any screening procedures are performed.

11. Peripheral neuropathy ≤ grade 1

Exclusion Criteria:

1. Evidence of metastatic disease by CT scan, physical exam, or bone scan within 4 weeks
of registration

2. History of bleeding disorders or medical comorbidities that in the opinion of the
investigator would preclude the use of systemic chemotherapy

3. Prior systemic or biologic therapy, including pre-operative therapies or adjuvant
chemotherapy, biologic therapy, or hormonal therapy

4. Life expectancy of less than 5 years from medical co-morbidities by physician
judgment

5. Non-adenocarcinoma prostate cancer pathology at radical prostatectomy

6. Prior radiotherapy to the abdomen or pelvis

7. Less than or equal to 6 weeks from prior major surgery, including radical
prostatectomy, open biopsy, or traumatic injury.

8. Recent cardiovascular event (within 12 months) including unstable angina, myocardial
infarction, severe or at rest claudication, or stroke/CVA.

9. Subjects receiving known strong CYP3A4 isoenzyme inhibitors and/or inducers. Subjects
on acceptable CYP3A4 isoenzyme inhibitors and/or inducers are eligible, provided they
have been taking a stable regimen for at least 4 weeks prior to screening.

10. Presence of a non-healing wound or ulcer.

11. Grade >= 3 hemorrhage within the past month.

12. Hypertension with systolic blood pressure of >140 mm Hg and/or diastolic pressure >90
mm Hg at the time of screening. Anti-hypertensive medications are permitted.

13. Subjects with American Heart Association (AHA) Class 2-4 heart disease or any history
of congestive heart failure with an ejection fraction <50%.

14. Subjects with inability to tolerate or absorb oral medications.

15. QTc interval >480 msec on baseline EKG. Subjects may not be taking a medication known
to significantly prolong the QTc interval.

16. Subjects who have not recovered from prior biopsy, surgery, traumatic injury, and/or
radiation therapy.

17. Anticoagulation with warfarin (therapeutic doses of warfarin for catheter patency are
permitted). Low molecular weight heparin is permitted.

18. Active infection(s), active antimicrobial therapy or serious intercurrent illness.

19. Any other major medical or psychiatric illness that, in the investigator's judgment,
will substantially increase the risk associated with the subject's participation in
this study, including inability to absorb oral medications.

20. Any history of hemoptysis within the past 12 months