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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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).

Study Type

Interventional

Enrollment (Actual)

9

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Maryland
      • Baltimore, Maryland, United States, 21205
        • Johns Hopkins Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Vismodegib
Vismodegib Treatment arm will receive Vismodegib by mouth 150 mg daily up to 1 year.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The Proportion of mCRPC Patients Treated With Vismodegib Who Achieve a Pharmacodynamic (PD) Response in Tumor Biopsies
Time Frame: Up to 1 year
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.
Up to 1 year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
GLI1 Expression
Time Frame: Up to 1 Year
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.
Up to 1 Year
Progression-free Survival (PFS)
Time Frame: Up to 1 Year
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.
Up to 1 Year
AKT1 Expression in Tumor Biopsies
Time Frame: Up to 1 Year
The tumor biopsies were evaluated for changes to Hh-regulated transcript, AKT1, between pre-treatment and post-treatment
Up to 1 Year
The Effect of Vismodegib on PSA Responses
Time Frame: Up to 1 Year
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
Up to 1 Year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Emmanuel Antonarakis, M.D., Johns Hopkins University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2014

Primary Completion (Actual)

April 1, 2016

Study Completion (Actual)

April 1, 2016

Study Registration Dates

First Submitted

April 14, 2014

First Submitted That Met QC Criteria

April 15, 2014

First Posted (Estimate)

April 16, 2014

Study Record Updates

Last Update Posted (Actual)

July 20, 2018

Last Update Submitted That Met QC Criteria

October 5, 2017

Last Verified

October 1, 2017

More Information

Terms related to this study

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Prostate Cancer

Clinical Trials on Vismodegib

3
Subscribe