Study of Bevacizumab and Erlotinib for Patients With Hormone Refractory Prostate Cancer

In this Phase I/Phase II study, the primary objectives are to establish the maximum tolerated
dose of docetaxel, erlotinib, bevacizumab, and prednisone in patients with metastatic hormone
refractory prostate cancer and to determine the efficacy of this regimen for treatment of
metastatic HRPC. In the phase I portion of the study, eligible patients will be enrolled and
treated using a "3+3" design. Docetaxel will be started at 55 mg/m2 every cycle (21 days) and
dose escalated by 10 mg/m2 at each cohort level. The dose of bevacizumab will be held
constant at 15 mg/kg every 3 weeks and erlotinib will be provided at 200 mg PO daily from
days 216 as described in previous safety studies. All patients will receive prednisone 5 mg
PO bid. Eighteen patients will be treated in the phase I portion. The phase II dose for this
combined treatment will be defined as either the highest dosage cohort in which 6 patients
are treated and there are less than 3 dose limiting toxicities (DLTs); or the combination of
docetaxel, erlotinib, and bevacizumab at the cohort 3 dose level, whichever is the lower
dose. Another 37 patients will be enrolled for the phase II study. All patients will receive
the phase II recommended dose as determined by the phase I portion of the study.

Inclusion Criteria:

- Histologically documented diagnosis of prostate adenocarcinoma (PCa) not amenable to
curative therapy.

- Evidence of progressive metastatic disease.

- Surgically or medically castrated. Patients must continue on medical castration (LHRH
agonists) throughout protocol participation. Patients who have discontinued LHRH
agonists should be restarted on therapy. Testosterone levels should be obtained prior
to protocol initiation and should be less than 50 ng/mL.

- Previous antiandrogen and hormonal therapies must have been discontinued prior to
protocol initiation.

- Receiving bisphosphonate therapies should have had this therapy started at least 4
weeks prior to treatment initiation and should be on a stable dose. Although being on
bisphosphonate therapy is not an exclusion to the study, bisphosphonate therapy should
not be started during the study.

- Fully recovered and greater than 4 weeks from any major surgery or radiation therapy.
There must be greater than 8 weeks from last dose of radionucleotide administration.
There must be greater than 7 days from minor surgical procedures (eg portacath
insertion, fine needle aspirations or core biopsies).

- No previous cytotoxic therapy including estramustine or suramin. No previous therapies
with anti-angiogenic agents including thalidomide or bevacizumab.

- No history of brain metastases.

- No current congestive heart failure (defined as New York Heart Association Class II,
III, or IV).

- Well-controlled blood pressure. Those with a history of hypertension should be
well-controlled on a regimen of anti-hypertensive medication (exclude if BP>150/100).

- No history of significant bleeding (e.g. upper or lower gastrointestinal bleeding or
hemoptysis) within 6 months of protocol enrollment.

- No history of gastrointestinal perforation, intraabdominal fistula, or intraabdominal
abscess within 6 months of protocol enrollment.

- No history of arterial thrombotic events within 6 months of protocol enrollment.

- No active serious non-healing wound, ulcer, or bone fracture.

- Eastern Cooperative Oncology Group (ECOG) performance status between 0 and 1.

- > 18 years old.

- Adequate hematopoietic and organ function.

- Able to swallow capsules.

- Willing to use effective means of contraception for study duration and for at least 3
months after the completion of protocol therapy.

- Able to provide informed consent.

Exclusion Criteria:

- Active second malignancy other than basal or squamous skin cancer. Patients who have
completed all necessary therapy and are considered to have less than a 30% risk of
relapse by their physician are not thought to have an active second malignancy.

- Serious concurrent uncontrolled medical disorder.

- Disease for whom corticosteroids are contraindicated such as an active peptic ulcer or
uncontrolled diabetes. Patients with controlled diabetes may be considered but must be
made aware that their diabetic medications may require adjustment.

- Received prior treatment with a tyrosine kinase inhibitor, estimated glomerular
filtration rate inhibitor (EGFR), or vascular endothelial growth factor (VEGF)
inhibitor. For the phase II trial, patients who have had previous cytotoxic therapy
will not be eligible.

- Currently or have recently participated in a clinical trial (within 4 weeks from the
first day of treatment) or are receiving investigational therapies.

- Unable to comply with study or follow-up procedures.