ARMOR (Androgen Receptor Modulation Optimized for Response) is Tokai’s clinical development program for the evaluation of galeterone in patients with prostate cancer. Galeterone has been administered to over 200 prostate cancer patients and healthy volunteers in Phase 1 and Phase 2 clinical trials. ARMOR1 was an open label, dose escalation Phase 1 clinical trial of galeterone in patients with castration resistant prostate cancer, or CRPC. ARMOR2 is an open label Phase 2 clinical trial in CRPC patients which is ongoing.
ARMOR (Androgen Receptor Modulation Optimized for Response) is Tokai’s clinical program for the evaluation of TOK-001. The first clinical trial in that program, ARMOR1, is a Phase 1/2 open-label trial that will assess both safety and efficacy of once-daily treatment with TOK-001 in patients with castration resistant prostate cancer (CRPC). The Phase 1 component of the trial is a multiple-dose safety study to evaluate escalating dose levels of TOK-001 and is expected to enroll 10 patients. The Phase 2 portion of the trial is expected to enroll 40 patients, who will receive one of two target dosing regimens as identified by the Phase 1 results. The primary endpoints of the Phase 1/2 trial are safety and reduction in prostate-specific antigen (PSA) levels from baseline levels measured at first visit. Patients who respond to therapy will have the opportunity to continue treatment with TOK-001 in an extension arm of the trial. Read more about ARMOR1 clinical trial initiation.
The Phase 1/2 trial is being conducted at leading prostate cancer treatment centers in the Unites States, including the Cancer Centers of the Carolinas/Greenville Hospital System University Medical Center, Comprehensive Cancer Centers of Nevada, Dana-Farber Cancer Institute, Fred Hutchinson/University of Washington Cancer Consortium, Roswell Park Cancer Institute, San Bernardino Urological Associates, Sidney Kimmel Comprehensive Cancer Center and University of California, Los Angeles. Please visit www.clinicaltrials.gov for clinical trial details and enrollment information.
Galeterone was reformulated prior to the initiation of the ARMOR2 clinical trial in order to increase the drug exposure and mitigate the effect of food on oral bioavailability. The new formulation has been shown to be unaffected by diet. The optimized formulation is being administered in ARMOR2 and will be used in all future clinical trials.
ARMOR1 was a 49 patient, multi-center, open-label, dose-escalation study of galeterone for the treatment of chemotherapy naïve non-metastatic and metastatic CRPC. ARMOR1 provided proof-of-concept for galeterone for the treatment of CRPC and results showed prostate-specific antigen (PSA) and tumor responses and a favorable safety profile.
The study evaluated safety and reduction in PSA levels from baseline measured at first visit. PSA reductions were seen within all doses tested and tumor shrinkage by CT scan was observed at the high dose. No cases of mineralocorticoid excess (ME), a clinical syndrome that is commonly associated with other CYP17 lyase inhibitors, were observed and no concomitant prednisone therapy was required in patients in ARMOR1. Patients who responded to therapy continued treatment with galeterone in an extension arm of the trial. Data from ARMOR1 were presented at the 2012 American Association for Cancer Research Annual Meeting and the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting.
ARMOR2 is a two-part Phase 2 open label clinical trial of galeterone for the treatment of CRPC. Part 1 of the trial was a dose escalation phase designed to confirm the dose of galeterone to be evaluated in Part 2 of the trial. Tokai is currently evaluating the 2550 mg/day dose for safety and efficacy in Part 2 of the trial in a total of up to 108 patients, in four distinct CRPC patient populations.
Tokai announced interim data from the ARMOR2 trial at the ASCO 2014 Annual Meeting. The interim data included patients who had not previously undergone chemotherapy and had not received treatment with Zytiga or Xtandi (referred to as CRPC treatment-naïve patients), and patients whose disease progressed during treatment with Zytiga (referred to as Zytiga-refractory patients). Tokai reported that in 51 evaluable CRPC treatment-naïve patients, galeterone showed clinically meaningful reductions in levels of PSA. Specifically, data showed the following:
- Non-metastatic and metastatic CRPC treatment-naïve patients at the selected Phase 2 dose of 2550 mg/day: During the first 12 weeks of dosing, 82% of patients showed maximal reduction in PSA levels of at least 30%, and 75% of patients showed maximal reduction in PSA levels of at least 50%.
- Metastatic CRPC treatment-naïve patients at the selected Phase 2 dose of 2550 mg/day: During the first 12 weeks of dosing, 85% of patients showed maximal reduction in PSA levels of at least 30%, and 77% of patients showed maximal reduction in PSA levels of at least 50%.
Tokai also presented data from a retrospective subset analysis in which four treatment-naïve CRPC patients in ARMOR2 were identified as having truncated androgen receptors with C-terminal loss. All four of these patients had maximal reductions in PSA levels of at least 50%. These data are consistent with galeterone’s mechanism of action of androgen receptor degradation, which does not require a functional ligand binding domain.
Galeterone was well tolerated. Approximately 90% of all treatment-emergent adverse events reported were grade 1 or 2 in severity and were generally manageable and reversible. The majority of these events were assessed as not related or unlikely related to galeterone. In addition, there were no reported cases of seizure or mineralocorticoid excess.
Future Clinical Development
Tokai believes galeterone may be well suited to treat different prostate cancer patient populations, from early-stage prostate cancer to end-stage salvage metastatic CRPC patients, because of its efficacy, safety and tolerability. Initial development of galeterone is focused on the treatment of patients with castration resistant prostate cancer, or CRPC, whose prostate tumor cells express an altered androgen receptor that is truncated. Tokai intends to conduct a pivotal clinical trial in these patients who may not be effectively treated by currently approved therapies. Although the initial development focus for galeterone is for the treatment of these patients, Tokai is conducting the Phase 2 ARMOR2 trial of galeterone in multiple CRPC patient populations.