A phase 1, multicenter, open-label study of a new BRAF inhibitor ABM-1310 in adult patients (pts) with BRAFv600-mutated solid tumors.

3098 Background: ABM-1310 is a novel small-molecule BRAF inhibitor with high water solubility, cell permeability, and blood-brain barrier penetration as demonstrated in preclinical studies. Here we report preliminary findings from a first-in-patient phase 1 study of ABM-1310. Methods: This US multicenter, open-label, dose-escalation with cohort expansion trial includes adult pts with advanced BRAFv600-mutated solid tumors, including those with active brain metastasis from solid tumors or primary malignant brain tumors. Previous BRAF/MEK inhibitor treatment is permitted. In dose escalation Part A, ABM-1310 monotherapy is given orally twice a day (25–250 mg bid). In dose escalation Part B, ABM-1310 (100 and 200 mg bid) is given in combination with the MEK inhibitor cobimetinib (60 mg QD d1–21 q4w). Primary objectives: determine maximum tolerated dose and recommended phase 2 dose of ABM-1310 ± cobimetinib. Secondary objectives: safety/tolerability; pharmacokinetics; preliminary efficacy. Dose-limiting toxicities (DLTs) are assessed during cycle 1 by a 3+3 design. Results: As of November 28, 2022, 20 pts (65% male; median age 57.5 years) have been treated with ABM-1310 monotherapy across six dose levels in Part A: 25 mg bid (n=3); 50 mg bid (n=3); 100 mg bid (n=4); 150 mg bid (n=4); 200 mg bid (n=4); 250 mg bid (n=2). All pts experienced adverse events (AEs), most frequently skin rash (40%) and QT prolongation (20%). Three pts had drug-related grade ≥3 AEs (nausea/vomiting, QT prolongation and rash) and two had drug-related serious AEs (SAEs) (nausea/vomiting and creatinine increase). Among 16 efficacy evaluable pts, two (pleomorphic xanthoastrocytoma and glioblastoma) had a partial response (PR) and eight had stable disease (SD) as their best response (per RECIST or RANO). In Part B, two ABM-1310 dose levels were assessed in combination with cobimetinib: 100 mg bid (n=3) and 200 mg bid (n=3). Four pts had AEs and drug-related AEs (rash and QT prolongation). There were no SAEs. Among three evaluable pts, one (melanoma) had a PR and one had SD as their best response. There were no confirmed DLTs in either dose-escalation Part A or B, although a few pts had ABM-1310 treatment interruption and subsequent dose reduction. No pts discontinued prematurely for any safety or tolerability reason and there were no drug-related deaths. Preliminary assessment of ABM-1310 drug exposure vs dosage showed a linear dose-proportional relationship. This trial is ongoing. Conclusions: ABM-1310 at the currently tested doses up to 200 mg bid, either alone or in combination with cobimetinib, was generally well tolerated, with no new safety signals. Preliminary efficacy data demonstrate favorable activity of ABM-1310 in pts with BRAFv600-mutated solid tumors, including primary CNS tumors, and pts previously refractory to other BRAF/MEK inhibitors and I/O therapies. Clinical trial information: NCT04190628 .