Abstract 338TiP
Background
Current standard of care for HR+ advanced breast cancer (ABC) uses endocrine therapy (ET) to arrest tumor growth. Unfortunately, most patients eventually develop ET resistance. Activation of the PI3K/AKT/mTOR and CDK4/6 signalling pathways has been linked to ET resistance, leading to combination therapies coupling ET with inhibitors of these signalling pathways. In the phase 3 PALOMA-3 study (NCT01942135), adding the CDK4/6 inhibitor palbociclib to ET with fulvestrant significantly prolonged progression-free survival (PFS). Improved PFS was also observed in the phase 2 FAKTION study (NCT01992952), in which fulvestrant was combined with the potent, selective inhibitor of AKT1, -2 and -3, capivasertib (AZD5363) in aromatase inhibitor-resistant HR+/HER2–ABC patients. Concomitant inhibition of the PI3K/AKT/mTOR and CDK4/6 signalling pathways with ET may further improve clinical benefit and increase the barrier to ET resistance.
Trial design
CAPItello-292 is a phase 1b/3 study to evaluate the safety and efficacy of capivasertib, palbociclib and fulvestrant compared with placebo, palbociclib and fulvestrant in patients with ET-resistant, HR+/HER2– ABC. In phase 1b, up to 72 patients with ABC will be enrolled to identify the recommended phase 3 dose (RP3D) for capivasertib and palbociclib. Cohort 1 will receive capivasertib (320 mg PO BD 4 days on/3 days off for 4 weeks), palbociclib (125 mg PO OD, 3/4 weeks) and fulvestrant (500 mg IM monthly, plus a loading dose in cycle 1 day 15); the primary endpoints are safety and tolerability. In phase 3, up to 628 patients with HR+/HER2− locally advanced (inoperable) or metastatic ABC following recurrence or progression on or after ET will be randomized 1:1 to receive either the RP3D of capivasertib or placebo, plus palbociclib and fulvestrant until disease progression, unacceptable toxicity or withdrawal of consent. The phase 3 primary endpoint is PFS; secondary endpoints include safety, tolerability and overall survival in all patients and PFS in the PIK3CA/AKT1/PTEN-altered subgroup. Enrolment in phase 1b started in April 2021 (NCT04862663).
Clinical trial identification
NCT04862663.
Editorial acknowledgement
We thank Julia SP Mawer, PhD, of Oxford PharmaGenesis, Oxford, UK, who provided medical writing assistance.
Legal entity responsible for the study
AstraZeneca.
Funding
CAPItello-292 is funded and overseen by AstraZeneca.
Disclosure
E. Hamilton: Financial Interests, Institutional, Advisory Role: Pfizer, Genentech/Roche, Flatiron Health, Lilly, Puma Biotechnology, Daiichi Sankyo, Mersana, Boehringer Ingelheim, Cascadian Therapeutics, Elsai; Financial Interests, Institutional, Research Grant: AstraZeneca, Hutchinson MediPharma, OncoMed, MedImmune, StemCentRx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Mersana, Millenium, TapImmune, Cascadian Therapeutics, Lilly, BerGenBio, Medivation, Pfizer, Tesaro, Kadmon,. G. Schiavon, L.M. Grinsted, E.C. De Bruin, M.T. Catanese: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. H.S. Rugo: Financial Interests, Institutional, Research Grant: Pfizer, Merck, Novartis, Lilly, Genentech, OBI, Odonate, Daiichi Sankyo, Seattle Genetics, Eisai, Macrogenics, Sermonix, Immunomedics, and AstraZeneca; Financial Interests, Personal, Other, Honoraria: Samsung, Mylan and Puma.