Abstract CT110: Ribociclib in combination with everolimus and exemestane in men and postmenopausal women with HR+/HER2− advanced breast cancer following progression on a CDK4/6 inhibitor: Safety, tolerability, and pharmacokinetic results from Phase 1 of TRINITI-1 study
Authors: Hurvitz Sara , Yardley Denise , Zelnak Amelia , DeMichele Angela , Tan-Chiu Elizabeth , Ma Cynthia , Small Tania , Tucci Chris , Samant Tanay , Purkayastha Das , Moulder Stacy , Bardia Aditya 
Published: July 2017

Introduction: Preclinical data of improved antitumor activity upon addition of ribociclib to everolimus (EVE) and the interplay of CDK4/6 and the PI3K/mTOR pathway suggest a potential use for combination therapy to restore sensitivity to both CDK4/6 inhibition and endocrine therapy in patients whose disease progresses with CDK4/6 inhibitors. We present Phase 1 data of ribociclib (dosed continuously) + EVE + exemestane (EXE) in patients with endocrine-resistant ABC. Methods: TRINITI-1 is a Phase 1/2, open-label study of ribociclib (250 mg/d or 300 mg/d) + EVE 2.5 mg/d + EXE 25 mg/d in men and postmenopausal women with hormone receptor-positive, HER2− ABC who had progressed on 1 to 3 lines of systemic endocrine therapy, had measurable disease and/or lytic/mixed bone lesions, and had an Eastern Cooperative Oncology Group performance status score of ≤1 (NCT02732119). Progression on a CDK4/6 inhibitor was required only for patients in Phase 2. Patients with visceral crisis, unstable CNS metastases, progression after treatment with &gt;1 CDK4/6 inhibitor, or clinically significant heart disease were excluded. The primary objective of Phase 1 was identification of the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of ribociclib + EVE + EXE. Secondary objectives included safety, tolerability, and pharmacokinetic analyses. Results: Among the 17 patients evaluated, 0 and 1 (11%) DLTs were noted in the ribociclib 250 mg/d and 300 mg/d cohorts, respectively (Grade 3 febrile neutropenia and Grade 4 neutropenia). Thus, MTD was not reached, and ribociclib 300 mg/d + EVE 2.5 mg/d + EXE 25 mg/d was declared the RP2D. Grade 3/4 drug-related AEs occurred in 75% of patients in each cohort; Grade 3/4 AEs (in &gt;20% of patients) included neutropenia (25% and 50% in 250 mg and 300 mg cohorts, respectively) and decreased neutrophil count (38% and 0%). No increases in liver function tests or QTcF occurred. Median steady-state trough concentrations (Ctrough) of ribociclib at cycle 1, day 15, were 160 ng/mL and 210 ng/mL in the 250 mg/d and 300 mg/d cohorts, respectively, consistent with single-agent ribociclib 280 mg (164 ng/mL). However, median steady-state EVE Ctrough levels when combined with 250 mg and 300 mg ribociclib were within the therapeutic target of 5-15 ng/mL (7.8 ng/mL and 9.4 ng/mL, respectively) and were 2- to 3-fold greater than expected based on single-agent data.Conclusions: Ribociclib at 250 mg/d or 300 mg/d + EVE 2.5 mg/d + EXE 25 mg/d dosed continuously was safe in patients with HER2-, HR+ ABC. Ribociclib 300 mg/d was chosen for the RP2D and is being studied in Phase 2. Ribociclib Ctrough was similar to expected values, whereas EVE Ctrough was 2- to 3-fold greater than expected, resulting in EVE exposure within the therapeutic range despite the low EVE dose.

Citation Format: Sara Hurvitz, Denise Yardley, Amelia Zelnak, Angela DeMichele, Elizabeth Tan-Chiu, Cynthia Ma, Tania Small, Chris Tucci, Tanay Samant, Das Purkayastha, Stacy Moulder, Aditya Bardia. Ribociclib in combination with everolimus and exemestane in men and postmenopausal women with HR+/HER2− advanced breast cancer following progression on a CDK4/6 inhibitor: Safety, tolerability, and pharmacokinetic results from Phase 1 of TRINITI-1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT110. doi:10.1158/1538-7445.AM2017-CT110