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) Journal Article

   

Authors:	Zhao, J. L.; Antonarakis, E. S.; Cheng, H. H.; George, D. J.; Aggarwal, R.; Riedel, E.; Sumiyoshi, T.; Schonhoft, J. D.; Anderson, A.; Mao, N.; Haywood, S.; Decker, B.; Curley, T.; Abida, W.; Feng, F. Y.; Knudsen, K.; Carver, B.; Lacouture, M. E.; Wyatt, A. W.; Rathkopf, D.
Article Title:	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)
Abstract:	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. © 2023, The Author(s), under exclusive licence to Springer Nature Limited.
Keywords:	signal transduction; adult; cancer chemotherapy; cancer survival; clinical article; controlled study; human tissue; treatment response; aged; unclassified drug; gene mutation; human cell; gene deletion; clinical trial; constipation; drug tolerability; fatigue; cancer growth; diarrhea; drug dose comparison; drug dose reduction; drug efficacy; drug safety; drug withdrawal; hypertension; side effect; cancer patient; antineoplastic agent; anorexia; prostate specific antigen; protein analysis; progression free survival; controlled clinical trial; multiple cycle treatment; pyrazines; nausea; cohort analysis; steroid; tumor biopsy; antineoplastic activity; in vitro study; pathology; phosphatidylinositol 3 kinase; protein p53; tumor marker; docetaxel; cancer hormone therapy; coughing; drug dose escalation; dyspnea; hyperglycemia; pruritus; gleason score; prostate-specific antigen; cancer inhibition; maculopapular rash; disease severity; dna; multicenter study; western blotting; prostate biopsy; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; peripheral edema; brachytherapy; single drug dose; open study; dermatitis; time to maximum plasma concentration; drug blood level; phase 1 clinical trial; mammalian target of rapamycin inhibitor; triacylglycerol lipase blood level; dry skin; loss of function mutation; mtor signaling; pyrazine derivative; dna determination; triazoles; nitriles; nitrile; triazole derivative; dysgeusia; triacylglycerol lipase; circulating tumor cell; castration resistant prostate cancer; phenylthiohydantoin; reaction time; protein serine threonine kinase inhibitor; benzamide derivative; benzamides; dna dependent protein kinase; eosinophil; mammalian target of rapamycin complex 1; exploratory research; demographics; phosphatidylinositol 3-kinases; mammalian target of rapamycin complex 2; akt signaling; pi3k/akt signaling; body weight loss; high throughput sequencing; enzalutamide; antiandrogen therapy; dna sequencing; humans; human; male; article; circulating tumor dna; prostatic neoplasms, castration-resistant; cell counting; dna screening; metastatic castration resistant prostate cancer; patient history of radiotherapy; patient history of chemotherapy; liquid biopsy; nu 7441; maximum concentration; genetic profile; cc 115; accumulation ratio; sapanisertib; mechanistic target of rapamycin complex 1; 1-ethyl-7-(2-methyl-6-(1h-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino(2,3-b)pyrazin-2(1h)-one; cwr22 cell line; patient history of prostatectomy; peak-trough fluctuation
Journal Title:	British Journal of Cancer
Volume:	130
Issue:	1
ISSN:	0007-0920
Publisher:	Nature Publishing Group
Date Published:	2024-01-31
Start Page:	53
End Page:	62
Language:	English
DOI:	10.1038/s41416-023-02487-5
PUBMED:	37980367
PROVIDER:	scopus
PMCID:	PMC10781677
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85176799340&doi=10.1038%2fs41416-023-02487-5&partnerID=40&md5=364b383670bf34ff9851235c65e40108
Notes:	Article -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/213259