A Study of Vismodegib in Men With Metastatic CRPC With Accessible Metastatic Lesions for Tumor Biopsy

The study will enroll 10 evaluable patients. Patients will receive a 30-day supply of 150 mg
of vismodegib on day one of each cycle daily by mouth, beginning on Day 1, and continuously
until one of the following occurs: Disease progression, intolerable toxicity most probably
attributable to vismodegib or withdrawal from the study.

Tumor biopsies (nodal or visceral), skin biopsies, and CTCs will be obtained at baseline and
after 4 weeks of treatment. PSA evaluations will be conducted every 4 weeks, imaging
assessments (CT and Bone scan) will be conducted every 12 weeks and routine labs (blood
counts and chemistry panel) will be conducted every 4 weeks.

The investigator's intent is to examine the fold change in GLI1 expression in each man
following exposure to drug (comparing pre-treatment and on-treatment core biopsy samples). As
secondary endpoints, the investigator will also explore clinical response (PSA responses,
progression-free survival [PFS], radiographic responses), safety, and will examine changes
from baseline in Gli2, PTCH1, and AKT1 mRNA levels by qRT-PCR, in situ GLI1 expression in
tissue sections by mRNA in situ hybridization, and GLI1 expression in isolated circulating
tumor cells (CTCs).

Inclusion Criteria:

- Men with metastatic castration-resistant prostate cancer (mCRPC), with accessible
metastatic soft-tissue lesions for tumor biopsy

- Greater than 18 years of age

- Evidence of disease progression (PSA progression, or radiographic/clinical progression
[PCWG2])

- PSA progression is defined as at least two consecutive rises in serum PSA,
obtained at a minimum of 1-week intervals, and each value ≥ 2.0 ng/mL.

- Radiographic progression is defined for soft tissue lesions using RECIST
criteria, i.e. an increase greater than 20% in the sum of the longest diameter of
all target lesions based on the smallest sum longest diameter since treatment
started or the appearance of one of more new lesions with a confirmatory scan 6
or more weeks later. Radiographic progression will be defined for bone lesions as
the appearance of two new lesions with a confirmatory scan performed 6 or more
weeks later that shows at least 2 or more additional new lesions.

- Presence of ≥1 metastatic site (nodal, visceral) that is amenable to core biopsy

- Castrate serum testosterone (<50 ng/dL)

- Prior anti-androgens are permitted but not required (2 week washout from
anti-androgens)

- Prior abiraterone and enzalutamide are permitted (2 week washout for both agents)

- Prior immunotherapy (e.g. sipuleucel-T), and chemotherapy are permitted (4 week
washout period from chemotherapy)

- Bisphosphonates and denosumab are permitted, if on a stable dose for ≥4 weeks

- Life expectancy ≥12 months

- Adequate renal, liver, and bone marrow function with the following acceptable initial
laboratory values:

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be ≤ 2.5
x the upper limit of normal (ULN).

- Total bilirubin must be ≤ 1.5 x ULN.

- Estimated creatinine clearance using the Cockcroft-Gault formula must be > 40
mL/minute (See section 12.2 for formula)

- Absolute neutrophil count (ANC) must be ≥ 1500/μL

- Platelet count must be ≥ 100,000/μL

- Willing and able to provide written informed consent and HIPAA authorization for the
release of personal health information.

NOTE: HIPAA authorization may be either included in the informed consent or obtained
separately.

- Karnofsky Performance status/ECOG Performance Status ≥70/2 (Appendix A: Performance
Status Criteria)

- Male patients must use condoms at all times, even after a vasectomy, during sexual
intercourse with female partners of reproductive potential during treatment with
vismodegib and for 2 months after the last dose to avoid exposing a pregnant partner
and unborn fetus to vismodegib.

Exclusion Criteria:

- Current use of systemic corticosteroids (>5 mg prednisone)

- Known brain metastases, or untreated meningeal/dural disease

- Receiving any other investigational agents or receipt of another investigational agent
within 4 weeks of study entry

- Patients taking anticoagulants or with a history of a bleeding diathesis (due to need
for visceral biopsy)

- Use of any prohibited concomitant medications (washout period of 1 week)

- Insufficient time from last prior regimen or radiation exposure (washout period of 4
weeks)

- Grade > 2 treatment-related toxicity from prior therapy

- Any other condition which, in the opinion of the Investigator, would preclude
participation in this trial