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Phase 1b study of enzalutamide plus CC-115, a dual mTORC1/2 and DNA-PK inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC).
Zhao, Jimmy L; Antonarakis, Emmanuel S; Cheng, Heather H; George, Daniel J; Aggarwal, Rahul; Riedel, Elyn; Sumiyoshi, Takayuki; Schonhoft, Joseph D; Anderson, Amanda; Mao, Ninghui; Haywood, Samuel; Decker, Brooke; Curley, Tracy; Abida, Wassim; Feng, Felix Y; Knudsen, Karen; Carver, Brett; Lacouture, Mario E; Wyatt, Alexander W; Rathkopf, Dana.
Afiliación
  • Zhao JL; Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
  • Antonarakis ES; University of Minnesota Masonic Cancer Center, Minneapolis, MN, 55455, USA.
  • Cheng HH; The Sidney Kimmel Cancer Comprehensive Cancer Center at Johns Hopkins, 401 N. Broadway, Baltimore, MD, 21231, USA.
  • George DJ; R&D in Oncology, AstraZeneca, New York, NY, 10016, USA.
  • Aggarwal R; University of Washington and Fred Hutch Cancer Research Center, 1144 Eastlake Avenue, Seattle, WA, 98109, USA.
  • Riedel E; Duke Cancer Institute, 20 Duke Medicine Circle, Durham, NC, 27710, USA.
  • Sumiyoshi T; University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, 1825 4th Street, San Francisco, CA, 94158, USA.
  • Schonhoft JD; Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
  • Anderson A; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
  • Mao N; Epic Sciences, 9381 Judicial Drive Suite 200, San Diego, CA, 92121, USA.
  • Haywood S; Epic Sciences, 9381 Judicial Drive Suite 200, San Diego, CA, 92121, USA.
  • Decker B; Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
  • Curley T; Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
  • Abida W; Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
  • Feng FY; Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
  • Knudsen K; Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
  • Carver B; University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, 1825 4th Street, San Francisco, CA, 94158, USA.
  • Lacouture ME; Sidney Kimmel Cancer Center, Thomas Jefferson University, 914 Chestnut Street, Philadelphia, PA, 19107, USA.
  • Wyatt AW; Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
  • Rathkopf D; Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
Br J Cancer ; 130(1): 53-62, 2024 01.
Article en En | MEDLINE | ID: mdl-37980367
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02833883.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Feniltiohidantoína / Pirazinas / Triazoles / Benzamidas / Neoplasias de la Próstata Resistentes a la Castración Límite: Humans / Male Idioma: En Revista: Br J Cancer Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Feniltiohidantoína / Pirazinas / Triazoles / Benzamidas / Neoplasias de la Próstata Resistentes a la Castración Límite: Humans / Male Idioma: En Revista: Br J Cancer Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido