Abstract LB-B30: First in human, dose escalation trial of the combination of dabrafenib, trametinib, and navitoclax in patients with BRAF mutant solid tumors

Abstract

Abstract Combined BRAF and MEK inhibitor therapy is associated with responses in patients (pts) with BRAF mutant solid tumors. Preclinically, the addition of the BH3 mimetic navitoclax improves the efficacy of BRAF inhibitor therapy to BRAF mutant cell lines. CTEP study P9466 (NCT01989585) is a clinical trial designed to test the safety of the combination of dabrafenib, trametinib, and navitoclax (DTN) in patients with BRAF mutant solid tumors. The primary objective of this dose escalation trial was to determine the recommended phase 2 dose (RP2D) of DTN. From March 2014 to August 2017, 25 pts were enrolled, using a 3+3 design, at three dose levels (DL). A one week lead-in of navitoclax 150 mg QD was used to limit thrombocytopenia. Dose limiting toxicities (DLTs) occurred at every dose level and included Grade 3 (Gr) alkaline phosphatase, Gr 3 Rash, Gr 4 thrombocytopenia, and Gr 3 fever. The RP2D was determined to be D 150 mg BID, T 2 mg QD, N 225 mg QD. Severe adverse events (SAEs) occurred in 10 pts. There was one Gr 5 SAE that was possibly related to study drugs (acute kidney injury). Twenty-two of 25 pts were eligible for preliminary efficacy assessment at the time of this submission. Best response, per RECIST1.1, was complete (CR) or partial (PR) response in 6 pts, stable disease (SD) in 7 pts, and disease progression (PD) in 8 pts. Of note, PD was the best response for all 5 pts with melanoma (mel) previously treated with a BRAF inhibitor. In the 6 mel pts who had not received a prior BRAF inhibitor, 5 had a PR or CR (1). Disease control (PR or SD) was seen in most colon cancer (3 of 5) and thyroid cancer (4 of 5) pts. DTN at the RP2D was determined to be safe with preliminary efficacy in pts with BRAF mutant solid tumors. Based on this preliminary data, the randomized phase II portion of this trial of DTN compared to DT in BRAF mutant naïve patients is opening in the ETCTN in the Fall of 2017. Citation Format: Ryan J. Sullivan, Janice Mehnert, Hussain Tawbi, Donald Lawrence, Keith Flaherty, Helen Chen, Naoko Takabe, Michael Davies. First in human, dose escalation trial of the combination of dabrafenib, trametinib, and navitoclax in patients with BRAF mutant solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B30.