Phase I pharmacokinetic study of single agent trametinib in advanced cancer patients with hepatic dysfunction: An NCI Organ Dysfunction Working Group (ODWG) study.

2578 Background: Trametinib (T), an orally available MEK 1/2 inhibitor, is FDA approved for BRAFV600E/K mutant advanced melanoma, at the single agent RP2D of 2 mg QD. Its clinical development has involved a variety of refractory cancers. A phase I study was conducted to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetic (PK) profile of T in advanced solid tumor patients (pts) with varying degrees of hepatic dysfunction (HD). Methods: Advanced cancer pts with ECOG ≤2, adequate renal and bone marrow functions, were stratified (NCI ODWG Criteria) into 4 HD groups: normal (NO), mild (ML), moderate (MD), severe (SV). T was given QD on a 28-days cycle, with dose escalation occurring in sequential cohorts of pts within each HD group (starting dose: NO, ML: 2mg; MD: 1.5 mg; SV: 1mg). PK samples were collected at days 15-16 in cycle 1. Results: Between Mar '14-Nov '15, 30 (17 NO, 7 ML, 3 MD, 3SV) pts were treated. Median age 60, male 43%, ECOG≤1: 97%. Common tumor types: GI non-CRC 17%, NSCLC 17%, uveal melanoma 13%. All cohorts drug-related AEs (All Grades/Grade 3-4): skin rash 73%/7%, increased transaminases 43%/7%, fatigue 40%/7%. No DLTs so far occurred in ML, MD and SV groups. Dose delay and dose reduction occurred in 47% and 20% of all pts respectively. PK data were available in 10 NO and 6 ML HD cohort pts (Table). Of 23 pts evaluable for response, 13 (56%) had stable disease and 2 (9%) pts partial response (NSCLC; ovarian). Median duration of response was 3.6 months (range 1-13.7+). Conclusions: The RP2D for trametinib in ML group, which has completed accrual, is 2 mg QD. The PK profile in NO and ML groups is comparable. Thus far, T appeared to be tolerated within all groups. Accrual in MD and SV groups is ongoing at 1.5 mg QD and 1 mg QD respectively. Clinical trial information: NCT02070549.PK analysis for NO and ML groups. NO: 2mg QD (n=10) 90% CI ML: 2 mg QD (n=6) 90% CI AUC (ng*hr/ml) (SD) 507.5 ± 189.0 (397.9 – 617.0) 387.7 ± 201.3 (222.2 – 553.3) Cmax (ng/ml) (SD) 30.37 ± 12.15 (23.3 – 37.4) 29.53 ± 15.88 (16.5 – 42.6) Cmin (ng/ml) (SD) 16.30 ± 6.47 (12.6 – 20.1) 12.14 ± 6.95 (6.4 – 17.9) CL/F (L/hr) 4.51 ± 1.85 (3.44 – 5.57) 6.20 ± 2.82 (3.88 – 8.52) Tmax (hr) (range) median: 2 (1-4) median: 1 (0-2)

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