CC-115, a dual mTORC1/2 and DNA-PK inhibitor, has promising antitumour activity when combined with androgen receptor (AR) inhibition in pre-clinical models.
Phase 1b multicentre trial evaluating enzalutamide with escalating doses of CC-115 in AR inhibitor-naive mCRPC patients (n = 41). Primary endpoints were safety and RP2D. Secondary endpoints included PSA response, time-to-PSA progression, and radiographic progression.
Common adverse effects included rash (31.7% Grades 1-2 (Gr); 31.7% Gr 3), pruritis (43.9% Gr 1-2), diarrhoea (37% Gr 1-2), and hypertension (17% Gr 1-2; 9.8% Gr 3). CC-115 RP2D was 5 mg twice a day. In 40 evaluable patients, 80% achieved ≥50% reduction in PSA (PSA50), and 58% achieved ≥90% reduction in PSA (PSA90) by 12 weeks. Median time-to-PSA progression was 14.7 months and median rPFS was 22.1 months. Stratification by PI3K alterations demonstrated a non-statistically significant trend towards improved PSA50 response (PSA50 of 94% vs. 67%, p = 0.08). Exploratory pre-clinical analysis suggested CC-115 inhibited mTOR pathway strongly, but may be insufficient to inhibit DNA-PK at RP2D.
The combination of enzalutamide and CC-115 was well tolerated. A non-statistically significant trend towards improved PSA response was observed in patients harbouring PI3K pathway alterations, suggesting potential predictive biomarkers of response to a PI3K/AKT/mTOR pathway inhibitor.
ClinicalTrials.gov identifier: NCT02833883.
British journal of cancer. 2023 Nov 18 [Epub ahead of print]
Jimmy L Zhao, Emmanuel S Antonarakis, Heather H Cheng, Daniel J George, Rahul Aggarwal, Elyn Riedel, Takayuki Sumiyoshi, Joseph D Schonhoft, Amanda Anderson, Ninghui Mao, Samuel Haywood, Brooke Decker, Tracy Curley, Wassim Abida, Felix Y Feng, Karen Knudsen, Brett Carver, Mario E Lacouture, Alexander W Wyatt, Dana Rathkopf
Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA., The Sidney Kimmel Cancer Comprehensive Cancer Center at Johns Hopkins, 401 N. Broadway, Baltimore, MD, 21231, USA., University of Washington and Fred Hutch Cancer Research Center, 1144 Eastlake Avenue, Seattle, WA, 98109, USA., Duke Cancer Institute, 20 Duke Medicine Circle, Durham, NC, 27710, USA., University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, 1825 4th Street, San Francisco, CA, 94158, USA., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., Epic Sciences, 9381 Judicial Drive Suite 200, San Diego, CA, 92121, USA., Sidney Kimmel Cancer Center, Thomas Jefferson University, 914 Chestnut Street, Philadelphia, PA, 19107, USA., Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. .