Phase 1/2 study of orteronel (TAK-700), an investigational 17,20-lyase inhibitor, with docetaxel-prednisone in metastatic castration-resistant prostate cancer
Investigational New Drugs
Docetaxel; Genitourinary cancers; Orteronel; Phase 1/2 clinical trial; Prednisone; Prostate cancer
© 2015 Springer Science+Business Media New York. Background: Docetaxel-prednisone (DP) is an approved therapy for metastatic castration-resistant prostate cancer (mCRPC). Orteronel (TAK-700) is an investigational, selective, non-steroidal inhibitor of 17,20-lyase, a key enzyme in androgenic hormone production. This phase 1/2 study evaluated orteronel plus DP in mCRPC patients. Methods: Adult men with chemotherapy-naïve mCRPC, serum prostate-specific antigen (PSA) ≤5 ng/mL, and serum testosterone <50 ng/dL received oral orteronel 200 or 400 mg twice-daily (BID) in phase 1 to determine the recommended dose for phase 2, plus intravenous docetaxel 75 mg/m2 every 3 weeks, and oral prednisone 5 mg BID. Phase 2 objectives included safety, pharmacokinetics, and efficacy. Results: In phase 1 (n∈=∈6, orteronel 200 mg; n∈=∈8, orteronel 400 mg), there was one dose-limiting toxicity of grade 3 febrile neutropenia at 400 mg BID. This dose was evaluated further in phase 2 (n∈=∈23). After 4 cycles, 68, 59, and 23 % of patients achieved ≤30, ≤50, and ≤90 % PSA reductions, respectively; median best PSA response was -77 %. Seven of 10 (70 %) RECIST-evaluable patients achieved objective partial responses. Median time to PSA progression and radiographic disease progression was 6.7 and 12.9 months, respectively. Dehydroepiandrosterone-sulfate (DHEA-S) and testosterone levels were rapidly and durably reduced. Common adverse events were fatigue (78 %), alopecia (61 %), diarrhea (48 %), nausea (43 %), dysgeusia (39 %), and neutropenia (39 %). Orteronel and docetaxel pharmacokinetics were similar alone and in combination. Conclusions: Orteronel plus DP was tolerable, with substantial reductions in PSA, DHEA-S, and testosterone levels, and evidence for measurable disease responses.
Petrylak, D., Gandhi, J., Clark, W., Heath, E., Lin, J., Oh, W., Agus, D., Carthon, B., Moran, S., Kong, N., Suri, A., Bargfrede, M., & Liu, G. (2015). Phase 1/2 study of orteronel (TAK-700), an investigational 17,20-lyase inhibitor, with docetaxel-prednisone in metastatic castration-resistant prostate cancer. Investigational New Drugs, 33 (2). http://dx.doi.org/10.1007/s10637-014-0199-x