a study of vismodegib in men with metastatic crpc with accessible metastatic lesions for tumor biopsy

Conditions: Prostate Cancer

Summary: 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).

Eligibility criteria:
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

Keywords: vismodegib metastatic castration-resistant prostate cancer accessible metastatic lesions for tumor biopsy