This is a single-arm pharmacodynamic study with mandatory metastatic tumor biopsies in men with castration-resistant prostate cancer.

The trial will evaluate the effect of vismodegib on tumor tissue in men with metastatic CRPC by obtaining tumor biopsies at baseline and after 4 weeks of treatment with vismodegib.

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

All patients were required to have biopsies of the tumor and skin (a surrogate tissue) at baseline and after 4 weeks of therapy. 9 patients were enrolled. A nuclear medicine bone scan and CT scan of the C/A/P were performed to establish a baseline of the metastatic disease burden.