Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Vismodegib Treatment arm will receive Vismodegib by mouth 150 mg daily up to 1 year.

Vismodegib

Emmanuel Antonarakis, M.D.

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).

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

A Pharmacodynamic Study of Vismodegib in Men With Metastatic Castration-resistant Prostate Cancer (mCRPC) With Accessible Metastatic Lesions for Tumor Biopsy

The primary endpoint is the proportion of mCRPC patients treated with vismodegib who achieve a pharmacodynamic (PD) response in tumor biopsies, defined as both a decrease in GLI1 mRNA greater than 1.2 times the standard deviation (SD) of the baseline values and a ≥50% (≥2-fold) reduction in GLI1 messenger ribonucleic acid (mRNA) expression in metastatic tumor biopsies after 4 weeks of treatment when comparing post-treatment biopsy to pre-treatment biopsy in the same patient.

Suppression by vismodegib in tumor tissue of Hh-regulated transcripts and proteins was defined as the change from baseline in expression levels of GLI1 in situ tissue expression by mRNA in situ hybridization.

Progression-free survival (PFS) is defined by the Prostate Cancer Working Group 2 (PCWG2) criteria using RECIST 1.1 criteria for each patient. PFS is defined as the time of first dose (a) until prostate specific antigen (PSA) progression (by 25% increase in PSA from nadir) or death and (b) until any evidence of progression (by 25% increase in PSA from nadir, a new lesion on bone or CT scan, or physical examination) or death. PFS will be assigned to the earliest observed time.

The tumor biopsies were evaluated for changes to Hh-regulated transcript, AKT1, between pre-treatment and post-treatment

The effect of vismodegib on PSA responses will be assessed as the number of patients with participants with ≥50% PSA reductions at any time point during study

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Vismodegib Treatment arm will receive Vismodegib by mouth 150 mg daily up to 1 year.

Vismodegib

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

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.

Emmanuel Antonarakis, MD

The design had 90% power to detect a true 65% PD response rate across patients, with a false-positive rate of 3.3% under the null hypothesis that vismodegib has no effect in downregulating Gli1 expression.

The Proportion of mCRPC Patients Treated With Vismodegib Who Achieve a Pharmacodynamic (PD) Response in Tumor Biopsies

One patient did not receive a post-treatment biopsy, and another patient had insufficient tissue for evaluation from the repeat biopsy

GLI1 Expression

Progression-free Survival (PFS)

AKT1 Expression in Tumor Biopsies

Seven patients were evaluable for PSA response. One participant had no measurable PSA production at enrollment, and PSA remained \<0.01 throughout the study. A second patient had disease progression prior to the first on-study PSA evaluation.

Spots Global Cancer Trial Database for accessible metastatic lesions for tumor biopsy