Efficacy, safety, and pharmacokinetics (PK) of the BRAF inhibitor dabrafenib (D) hydroxypropyl methylcellulose (HPMC) capsule formulation in combination with the MEK1/2 inhibitor trametinib (T) in patients (pts) with BRAF mutation-positive metastatic melanoma (MM)

Background: Preclinical studies ofD + T show enhanced activity in BRAF mutant MM vs either drug alone. D + T safety and efficacy were evaluated in a 4-part (A–D) phase I/II study. Part D assessed the impact on efficacy, safety and PK of a more stable HPMC capsule formulation of D alone, and in combination with T, instead of the gelatin capsule used in Parts A–C. Methods: 110BRAFV600E/KMM pts with RECIST measurable disease were randomized to 4 cohorts. Dose-limiting toxicities (DLTs) were evaluated for the first 3 weeks of treatment. PK sampling was done on Days 1 and 21. Primary endpoints were PK and safety; secondary endpoints were response rate (RR) and overall survival (OS). Results: Median age was 54 years, 58% male, 65% ECOG PS 0, 88% V600E, 68% M1c stage, 97% no prior brain metastases, and 45% LDH > ULN. Treatment (tx) with D HPMC + T had little impact on ratio of D Cmax (1.16) and D AUC (1.23) vs D tx alone; but led to higher ratio of D Cmax(1.51) but similar D AUC (1.10) vs D gelatin + T seen in Part B. Median progression-free survival (PFS) and RR are in Table. Median PFS not reached in D4. No DLTs occurred in the first 15 subjects enrolled in D4. Most common AEs (≥40%) for all cohorts were pyrexia, nausea, chills, vomiting, arthralgia, and fatigue. Most common grade >3 AEs (all 5%) were hypertension, pyrexia, increased GGT, and hyponatremia. 11% of pts discontinued treatment due to an AE. There were no major differences in toxicities between cohorts and Parts A–C. Conclusions: The D + T combination had an acceptable safety profile with clinically manageable side effects. D HPMC + T had little impact on D Cmax and D AUC vs D alone. D HPMC led to higher D Cmaxbut similar D AUC vs gelatin + T. Meaningful clinical activity was seen in all dose combinations with D HPMC +T; PFS, RR, and duration of response were consistent with other study parts. Phase 3 studies with D HPMC + T are ongoing. Clinical trial information: NCT01072175.