Date: 2016-07-26
Type of information: Halting of the trial
phase: 3
Announcement: halting of the trial
Company: Tokai Pharmaceuticals (USA - MA)
Product: galeterone
Action
mechanism: antiandrogen. Galeterone is an oral small molecule that utilizes the mechanistic pathways of current second-generation hormonal therapies, including abiraterone and enzalutamide, while also introducing a unique third mechanism – androgen receptor degradation – that impairs the function of androgen receptors, decreasing their sensitivity to androgen activity and reducing tumor growth. Galeterone has been studied in over 250 subjects in Phase 1 and Phase 2 clinical trials, including in CRPC patients with and without the AR-V7 splice variant. In these trials, galeterone demonstrated good tolerability and showed clinically meaningful reductions in levels of prostate specific antigen, or PSA, a biochemical marker used to evaluate prostate cancer patients for signs of response to therapy.
Disease: prostate cancer
Therapeutic area: Cancer - Oncology
Country: Australia, Belgium, Canada, France, Italy, Spain, Uk, USA
Trial
details: ARMOR3-SV is a pivotal Phase 3 clinical trial of galeterone in men with metastatic castration-resistant prostate cancer (mCRPC) whose tumor cells express the AR-V7 splice variant, a truncated form of the androgen receptor that has been associated with non-responsiveness to commonly-used oral therapies for mCRPC. ARMOR3-SV is designed to evaluate whether administration of galeterone results in a statistically significant increase in radiographic progression free survival as compared to Xtandi® (enzalutamide) in 148 treatment-naive mCRPC patients whose prostate tumor cells express the AR-V7 splice variant. ARMOR3-SV is the first pivotal trial in prostate cancer to employ a precision medicine approach for patient selection. Top-line results from ARMOR3-SV are anticipated by mid-2017. (NCT02438007)
Latest
news: * On July 26, 2016, Tokai Pharmaceuticals announced that it plans to discontinue the ARMOR3-SV clinical trial, the company’s pivotal Phase 3 study comparing galeterone to enzalutamide in treatment-naïve metastatic castration-resistant prostate cancer (mCRPC) patients whose prostate tumors express AR-V7, following the recommendation made by the trial’s independent Data Monitoring Committee (DMC). Based on a review of all safety and efficacy data, the DMC determined that the ARMOR3-SV trial will likely not succeed in meeting its primary endpoint of demonstrating an improvement in radiographic progression-free survival (rPFS) for galeterone versus enzalutamide in AR-V7 positive mCRPC. In making its recommendation, the DMC did not cite any safety concerns with galeterone in the trial. The company plans to present data from the trial in a scientific forum once fully available and analyzed. The company intends to evaluate its ongoing ARMOR2 expansion in mCRPC patients with acquired resistance to enzalutamide, and the planned study in patients who rapidly progress on either enzalutamide or abiraterone acetate. Tokai plans to allow all patients currently enrolled in the ARMOR2 and ARMOR3-SV trials to continue on therapy following consultation with their physicians and study investigators. The appropriate health authorities and clinical study investigators are being notified that ARMOR3-SV is being discontinued. As of June 30, 2016, Tokai had approximately $43.9M in cash and cash equivalents. * On January 7, 2016, Tokai Pharmaceuticals provided an update on its ARMOR3-SV study.The company now expects to complete enrollment in this trial during the second half of 2016 and to have top-line data available by mid-2017. This change in guidance reflects the timing for implementation of the AR-V7 clinical trial assay as well as a delay in initiating clinical sites in Western Europe and Australia during the fourth quarter of 2015. The AR-V7 assay has now been implemented in all regions. Patients are being screened at more than 85 clinical sites globally, and the number of clinical sites is expected to exceed 100 by the end of the first quarter. Notably, AR-V7 prevalence observed in ARMOR3-SV to date has been consistent with the company’s expectations and is in line with the published literature. The second study is an expansion of an arm of the ongoing Phase 2 clinical trial of galeterone (ARMOR2) in mCRPC patients who have progressed following an initial response to enzalutamide. The expansion of the cohort from nine to 30 patients follows a compelling response seen in a post-enzalutamide patient. This patient did not initially show a PSA response until after seven months of galeterone treatment, at which time the patient’s PSA level rapidly dropped by over 90 percent and has remained at less than 0.1µg/L for over a year. This expanded post-enzalutamide cohort will assess reduction in PSA levels and safety. * On June 24, 2015, Tokai Pharmaceuticals announced the initiation of ARMOR3-SV, Tokai’s pivotal Phase 3 clinical trial of galeterone in men with metastatic castration-resistant prostate cancer (mCRPC) whose tumors express the AR-V7 splice variant, which is a truncated form of the androgen receptor (AR) that has been associated with non-responsiveness to commonly-used oral therapies for mCRPC. Tokai also announced that the components of the AR-V7 clinical trial assay have been finalized by its collaborator, Qiagen and that global deployment of the assay is now underway. ARMOR3-SV will compare galeterone to Xtandi® (enzalutamide) in 148 mCRPC treatment-naïve patients whose prostate tumors express the AR-V7 splice variant. These truncated ARs are missing the C-terminal end of the AR that contains the ligand-binding domain, which is known as C-terminal loss. AR-V7 is the most common form of C-terminal loss. The pivotal trial will employ a precision medicine approach for selection of patients with the AR-V7 splice variant by using an AR-V7 clinical trial assay successfully optimized for global use by Qiagen. The primary endpoint of ARMOR3-SV is radiographic progression-free survival assessed by blinded independent central review. The design of ARMOR3-SV is aligned with feedback obtained from the U.S. Food and Drug Administration and the European Medicines Agency. ARMOR3-SV has been initiated at more than 15 sites in the United States, with site initiations in Canada and the United Kingdom anticipated later in June. Additional study centers throughout North America, Western Europe and Australia are expected to join the study in the coming months. In addition, with recent finalization of the components of the AR-V7 clinical trial assay, technology transfer activities and training of the global central laboratories are underway, and screening of eligible patients for the splice variant is expected to begin in July. The company expects topline data from ARMOR3-SV to be available by the end of 2016.
With the ARMOR3-SV trial building momentum, Tokai now plans to expand galeterone development into broader mCRPC populations, including the initiation of two additional studies during the first half of 2016 in patients who have shown resistance following treatment with either abiraterone or enzalutamide. The first of these studies is an open-label, two-part Phase 2 clinical trial designed to evaluate galeterone in men whose mCRPC rapidly progressed following treatment with either abiraterone or enzalutamide. The first part of the study will evaluate the rates of prostate-specific antigen (PSA) decline in approximately 36 patients. Following completion of the first part of the study, Tokai may then expand the study to a second, randomized phase that will compare galeterone to the next alternate androgen signaling inhibitor, with efficacy endpoints to include time to PSA progression and rPFS. Tokai plans to evaluate all patients enrolled in this open-label study for the presence of AR-V7, but AR-V7+ status is not a criterion for inclusion in the trial.
