Abstract B31: A Phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors
Authors: Yamada Yasuhide , Ishikawa Norifumi , Kakizume Tomoyuki , Tajima Takeshi , Hewes Becker , Doi Toshihiko 
Published: May 2016

Abstract
Background: Ribociclib (LEE011), an orally bioavailable, highly specific cyclin-dependent kinase (CDK) 4/6 inhibitor, causes cell cycle arrest and tumor growth inhibition in multiple preclinical models with intact retinoblastoma protein (pRb+). During a Phase I dose escalation study in the US and Europe, preliminary signs of clinical activity were observed when patients with pRb+ advanced solid tumors and lymphomas were treated with single-agent ribociclib (NCT01237236). Here we report on a Phase I dose escalation study in Japanese patients with advanced solid tumors (NCT01898845).
Methods: Patients with pRb+ advanced solid tumors were treated with escalating doses of ribociclib on a 21-of-28-day schedule. Dose escalation decisions were based on the synthesis of relevant data, guided by a Bayesian Logistic Regression Model and escalation with overdose control principle. The primary objective was to establish the maximum tolerated dose and/or recommended dose for expansion (RDE) of ribociclib. Secondary objectives included assessment of the safety, pharmacokinetics, and preliminary antitumor activity of ribociclib.
Results: As of January 28, 2015, 17 patients (median age 57 years [range 33-73]) were treated with 400 mg (n = 4) and 600 mg (n = 13) ribociclib. Primary sites of cancer were breast (n = 4), esophagus (n = 9), peritoneum (n = 3), and soft tissue (n = 1). Patients were heavily pretreated: 71% (n = 12) received ≥3 prior antineoplastic regimens. Median durations of treatment were 54.5 days (400 mg) and 59.0 days (600 mg). The mean relative dose intensities were 100% (400 mg) and 98% (600 mg). Six dose-limiting toxicities were reported: one at 400 mg (Grade [G]3 febrile neutropenia) and five at 600 mg (G3 febrile neutropenia [n = 1]; G4 neutropenia [n = 1]; G4 thrombocytopenia [n = 1]; G3 QTc prolongation [n = 2]). The RDE was declared as 600 mg/day on a 21-of-28-day schedule. Ribociclib was absorbed rapidly (the median Tmax on Cycle 1 Day 1 was 3.12 h [range 1.97-6.00] at 400 mg and 2.97 h [range 1.92-5.87] at 600 mg), and dose-dependent increases in exposure (AUC) were observed. The geometric mean effective half-life on Cycle 1 Day 21 was 63.6 h at 400 mg, and 53.6 h at 600 mg. The most frequent study drug-related adverse events (all-grade, &gt;35% of patients) were (all-grade; G3/4): leukopenia (100%; 82%), neutropenia (94%; 77%), lymphopenia (82%; 53%), thrombocytopenia (71%; 24%), QTc prolongation (41%; 12%), increased creatinine (41%; 0%), nausea (41%; 0%), vomiting (41%; 0%), and anemia (35%; 6%). Four patients had stable disease as best overall response.
Conclusions: Single-agent ribociclib demonstrated an acceptable safety and tolerability profile in Japanese patients with advanced solid tumors. The RDE was declared as 600 mg/day on a 21-of-28-day schedule. Ribociclib was absorbed rapidly and showed a dose-dependent plasma exposure. Ribociclib is currently being studied at lower doses in combination with other agents in Japanese patients, including in patients with breast cancer.
Citation Format: Yasuhide Yamada, Norifumi Ishikawa, Tomoyuki Kakizume, Takeshi Tajima, Becker Hewes, Toshihiko Doi. A Phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B31.