Abstract OT2-07-06: Phase Ib study to assess the safety, tolerability, and clinical activity of gedatolisib in combination with palbociclib and either letrozole or fulvestrant in women with metastatic or locally advanced/recurrent breast cancer (B2151009)
Authors: Forero A , Han HS , Dees EC , Wesolowski R , Bardia A , Kabos P , Kern KA , Perea R , Pierce KJ , Houk B , Rugo HS 
Published: February 2018

Abstract
Background:Hormone receptor positive (HR+) disease is the most common subset of advanced breast cancer (BC). The majority of women with HR+ metastatic BC (MBC) develop resistance to endocrine therapy (ET), with a median survival of 2-3 years. A new strategy to treat HR+ MBC involves the combination of ET and a cyclin-dependent kinase 4/6 inhibitor (CDKi 4/6), which has demonstrated improved progression-free survival (PFS) in both first-and later-line MBC. Preclinical evidence in PI3K-mutant cell-line xenografts demonstrated that combinations of PI3K and CDK4/6i reduced intrinsic and adaptive resistance to ET, leading to tumor regression (Vara, 2004; Pfizer data). Inhibition of the PI3K/mTOR pathway by gedatolisib (G) may provide a new therapy to overcome ET resistance. These findings support developing the triplet combination of G with the CDKi 4/6 palbociclib (P)+letrozole (L) or fulvestrant (F) for the treatment of patients (pts) with ER+/HER2- BC.
Methods: This ongoing study in women with ER+/HER2- MBC, in first- and later-line settings, includes a dose-escalation (DE) to evaluate dose-limiting toxicities (DLTs, primary endpoint [pEP]) and determine the maximum tolerated dose and recommended phase 2 dose (RP2D) for a triplet regimen of G+P+L or G+P+F. The escalation rules follow the modified toxicity probability interval method (G doses: 180 and 215 mg IV weekly). Treatment assignment to the triplet is based on investigator decision and bone-only disease is permitted. After RP2D determination for each triplet, a 3-arm expansion for early signs of efficacy (ESOE) will investigate objective response rate (ORR) compared to historical controls [pEP] of Arm A) G+P+L in first-line, B) G+P+F in pts with no prior CDKi 4/6 in second-line and C) G+P+F in pts who have received prior CDKi 4/6. Pts receive G+P (125 mg oral daily for 21 days [D] on and 7 D off) + L (2.5 mg oral daily) or F (500 mg IM on D1, 15 of cycle [C] 1; D1 of C2 and then 500 mg IM on D1 of all 28-D cycles). Secondary endpoints include safety, tumor response (DE), PFS (ESOE), pharmacokinetics (PK), and biomarker correlations associated with the PI3K/mTOR pathway.
Results: 27 pts received G (180 mg/week) in combination with P+L (L cohort, n=12) or P+F (F cohort, n=15). Median prior therapies were: L cohort: 1 (range: 0-4); F cohort: 2 (range 1-5). The 3 most common, drug-related adverse events (%) were in L cohort: nausea (75), neutropenia (67), and stomatitis (67); F cohort: stomatitis (67), nausea (60), and neutropenia (53). C1 DLTs were: L cohort: grade (gr) 3 neutropenia (n=1); F cohort: gr 3 stomatitis (n=1). Preliminary rates of stable disease/partial response were: L cohort: 33%/16%; F cohort: 40%/13%. PK parameters and next-generation sequencing of PI3K-related mutations are pending.
Conclusions: G can be combined with P+L or P+F with manageable toxicity and promising preliminary antitumor activity, even in heavily pretreated pts. Dose escalation, followed by expansion for ESOE, is ongoing.
This study is sponsored by Pfizer. Editorial support was provided by Engage Scientific Solutions and was funded by Pfizer.
Citation Format: Forero A, Han HS, Dees EC, Wesolowski R, Bardia A, Kabos P, Kern KA, Perea R, Pierce KJ, Houk B, Rugo HS. Phase Ib study to assess the safety, tolerability, and clinical activity of gedatolisib in combination with palbociclib and either letrozole or fulvestrant in women with metastatic or locally advanced/recurrent breast cancer (B2151009) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-06.