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