Trial Outcomes & Findings for A Study of Vismodegib in Men With Metastatic CRPC With Accessible Metastatic Lesions for Tumor Biopsy (NCT NCT02115828)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

EARLY_PHASE1

Target enrollment

9 participants

Primary outcome timeframe

Up to 1 year

Results posted on

2018-07-20

Participant Flow

A total of 9 patients were enrolled on the study

Participant milestones

Participant milestones
Measure	Vismodegib Vismodegib Treatment arm will receive Vismodegib by mouth 150 mg daily up to 1 year. Vismodegib
Overall Study STARTED	9
Overall Study COMPLETED	9
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Vismodegib n=9 Participants Vismodegib Treatment arm will receive Vismodegib by mouth 150 mg daily up to 1 year. Vismodegib
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	9 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	65 years n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants
Sex: Female, Male Male	9 Participants n=5 Participants
Region of Enrollment United States	9 participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 1 year

Population: 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 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.

Outcome measures

Outcome measures
Measure	Vismodegib n=9 Participants Vismodegib Treatment arm will receive Vismodegib by mouth 150 mg daily up to 1 year. Vismodegib
The Proportion of mCRPC Patients Treated With Vismodegib Who Achieve a Pharmacodynamic (PD) Response in Tumor Biopsies	7 Participants

SECONDARY outcome

Timeframe: Up to 1 Year

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

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.

Outcome measures

Outcome measures
Measure	Vismodegib n=7 Participants Vismodegib Treatment arm will receive Vismodegib by mouth 150 mg daily up to 1 year. Vismodegib
GLI1 Expression	-9.8 expression fold change Interval -8841.0 to 122.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Vismodegib n=9 Participants Vismodegib Treatment arm will receive Vismodegib by mouth 150 mg daily up to 1 year. Vismodegib
Progression-free Survival (PFS)	1.9 months Interval 1.3 to 1.9

SECONDARY outcome

Timeframe: Up to 1 Year

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

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

Outcome measures

Outcome measures
Measure	Vismodegib n=7 Participants Vismodegib Treatment arm will receive Vismodegib by mouth 150 mg daily up to 1 year. Vismodegib
AKT1 Expression in Tumor Biopsies	-1.15 expression fold change Interval -5.28 to 2.93

SECONDARY outcome

Timeframe: Up to 1 Year

Population: 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.

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

Outcome measures

Outcome measures
Measure	Vismodegib n=7 Participants Vismodegib Treatment arm will receive Vismodegib by mouth 150 mg daily up to 1 year. Vismodegib
The Effect of Vismodegib on PSA Responses	1 participants

Adverse Events

Vismodegib

Serious events: 5 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Vismodegib n=9 participants at risk Vismodegib Treatment arm will receive Vismodegib by mouth 150 mg daily up to 1 year. Vismodegib
Cardiac disorders chest pain and shortness of breath	11.1% 1/9 • Number of events 1
Hepatobiliary disorders observation post-TACE	11.1% 1/9 • Number of events 1
General disorders Pain grade 3	11.1% 1/9 • Number of events 1
Respiratory, thoracic and mediastinal disorders Pneumonia	11.1% 1/9 • Number of events 1
Gastrointestinal disorders Nausea	11.1% 1/9 • Number of events 1
Gastrointestinal disorders vomiting	11.1% 1/9 • Number of events 1
Metabolism and nutrition disorders Dehydration	11.1% 1/9 • Number of events 1

Other adverse events

Other adverse events
Measure	Vismodegib n=9 participants at risk Vismodegib Treatment arm will receive Vismodegib by mouth 150 mg daily up to 1 year. Vismodegib
Nervous system disorders dysgeusia	33.3% 3/9 • Number of events 4
Metabolism and nutrition disorders anorexia	33.3% 3/9 • Number of events 5
General disorders fatigue	66.7% 6/9 • Number of events 9
Gastrointestinal disorders nausea	66.7% 6/9 • Number of events 6
Gastrointestinal disorders vomiting	44.4% 4/9 • Number of events 4
Musculoskeletal and connective tissue disorders musculoskeletal pain	66.7% 6/9 • Number of events 12

Additional Information

Emmanuel Antonarakis, MD

Johns Hopkins University

Phone: 410-502-7528

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place