1. Phase I trial of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib and AKT inhibitor capivasertib in patients with BRCA1/2 and non-BRCA1/2 mutant cancers
- Author
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Yap T, Kristeleit R, Michalarea V, Pettitt S, Lim J, Carreira S, Roda D, Miller R, Riisnaes R, Miranda S, Figueiredo I, Nava Rodrigues D, Ward S, Matthews R, Parmar M, Turner A, Tunariu N, Chopra N, Gevensleben H, Turner N, Ruddle R, Raynaud F, Decordova S, Swales K, Finneran L, Hall E, Rugman P, Lindemann J, Foxley A, Lord C, Banerji U, Plummer R, Basu B, Lopez J, Drew Y, and de Bono J
- Abstract
Preclinical studies have demonstrated synergy between poly(ADP-ribose) polymerase (PARP) and phosphatidylinositol-3-kinase (PI3K)/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)-deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose-escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2-wildtype cancers harboring somatic DNA damage response (DDR) or PI3K/AKT pathway alterations. The combination was well-tolerated. Recommended phase 2 doses for the two schedules were: olaparib 300mg BID with either capivasertib 400mg BID 4-days-on, 3-days-off, or capivasertib 640mg BID 2-days-on, 5-days-off. Pharmacokinetics were dose-proportional. Pharmacodynamic studies confirmed pGSK3beta suppression, increased pERK and decreased BRCA1 expression. 25 (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST CR/PR or stable disease =4 months), including patients with tumors harboring germline BRCA1/2-mutations and BRCA1/2-wildtype cancers with or without DDR and PI3K/AKT pathway alterations. Copyright ©2020, American Association for Cancer Research.
- Published
- 2020