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)

Lynn Mara Schuchter, Ragini Reiney Kudchadkar, Rene Gonzalez, Donald P. Lawrence, Jeffrey Alan Sosman, Jeffrey R. Infante, Adil Daud, Richard Kefford, Jonathan S. Cebon, William Howard Sharfman, Ravi K. Amaravadi, Peter D. Boasberg, Karl D. Lewis, Keith Flaherty, Danielle Ouellet, Shonda M. Little, Jennifer Clark, Geoffrey Thomas Gibney, Kiran Patel, Omid Hamid

Research output: Contribution to journalMeeting abstractpeer-review


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.
Original languageEnglish
Pages (from-to)9066-9066
Number of pages1
JournalJournal of Clinical Oncology
Issue numberSupplement 15
Publication statusPublished - 20 May 2013
Externally publishedYes
EventAnnual Meeting of the American Society of Clinical Oncology (ASCO) - Chicago, United States
Duration: 31 May 20134 Jun 2013

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