Promising Early Activity With VERU-111 Provides Proof-of-Concept for Phase III Research in mCRPC

Novel α and β tubulin inhibitor, VERU-111, demonstrated preliminary anti-tumor activity in addition to a positive safety profile in male patients with metastatic castration-resistant prostate cancer (mCRPC) who are resistant to novel androgen blocking agents like abiraterone (Zytiga) or enzalutamide (Xtandi), according to results from a phase Ib/II clinical trial (NCT03752099) announced in a press release from Veru, Inc.

The results have prompted plans to meet with the FDA in the third quarter of 2020 to discuss the trial design for a phase III clinical trial of VERU-111 for this indication.

“The preliminary evidence of antitumor activity and favorable safety profile of VERU-111 observed in the dose-escalation and expansion Phase 1b study is quite encouraging. As predicted most responses occurred around the recommended Phase 2 dose and schedule,” said Mario Eisenberger, MD, R. Dale Hughes professor of Oncology and Urology at the Johns Hopkins Hospital and a Director at Veru Inc.

Thirty-nine participants were enrolled to the trial in 7 sites throughout the United States. For efficacy, the study investigator-assessed anti-tumor activity by serum prostate-specific antigen (PSA) levels, as well as local imaging with bone and CT scans. Out of 8 patients who received 4 doses of VERU-111 on a 21-day cycle at any dose level, 75% had a decrease in their PSA level (n = 6) compared with their baseline PSA levels. Of the declinations observed, 50% of patients (n = 4) had a ≥ 30%, and 25% (n = 2) had a ≥ 50% reduction in serum PSA.

Objective tumor responses were assessed per RECIST 1.1 criteria and were observed in 25% of patients (n = 2) in soft bone and tissue. Sixty-three percent of patients (n = 5) also had stable disease. These objective tumor responses lasted over 12 weeks. The co-primary end points of the study, the median duration of response (DOR), and time to cancer progression have not yet been reached. Seven of 8 patients are still receiving treatment and have an average DOR of 10 months (range, 6-14 months). Another 3 patients who are being evaluated in the study have not yet received 4 doses of VERU-111.

“All patients at the time of enrollment had evidence of disease progression with at least one novel androgen receptor targeting drug (abiraterone and enzalutamide). The initial clinical experience with VERU-111 appears favorable in the context of other FDA approved cytotoxic drugs (docetaxel and cabazitaxel) in metastatic castration-resistant prostate cancer. As for safety, the lack of neurotoxicity and the lack of significant myelosuppression observed thus far, coupled with the evidence that chronic long-term administration is feasible, strongly support the potential benefits of VERU-111 over IV cytotoxic taxanes in this setting.”

The study follows a 3x3 design with a phase I goal of determining the maximum tolerated dose (MTD) of VERU-111to be used in the phase II portion of the study. The dose was escalated from 4.5 mg to 81 mg, which was given for 7 days followed by 14 days of no drug during each 21-day cycle. Granted no dose-limiting toxicities (DLTs) were observed after 7 of dosing per cycle, the dose was then increased in the next cohort of patients. In men who completed 7 days of VERU-111 with 14 days off, the dosing schedule was expanded t 14 days of dosing with 7 days off per cycle followed by 21 days of dosing with no days off per cycle. Investigators in the study were able to measure VERU-111 blood level at a dose of 9 mg per day minimum and the levels increased with higher doses of VERU-111.

The MTD of VERU-11 was found to be 72 mg based on the observation of 3 out of 11 men experiencing grade 3 diarrhea with a higher dose, but no grade 3 diarrhea was seen in patients with received the MTD. At 63 mg and lower doses per day, patients most commonly experienced mild to moderate nausea, vomiting, diarrhea, and fatigue. No neurotoxicity or neutropenia occurred with 63 mg or lower of VERU-111. Overall, the drug was considered safe and well-tolerated.

_Reference:

_{Veru reports positive clinical results from veru-111 phase 1b/2 trial in men with metastatic castration-resistant prostate cancer, advancing to pivotal phase 3 clinical program [news release]. Miami, Florida: Veru, Inc; May 5, 2020. https://bit.ly/2WufsHZ. Accessed May 5, 2020.}