1131TiP - Phase 1 study evaluating safety and tolerability of MEDI4736, an anti-programmed cell death ligand-1 (PD-L1) antibody, in combination with dabrafen...

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Cancer Immunology and Immunotherapy
Melanoma and other Skin Tumours
Presenter Michael Gordon
Citation Annals of Oncology (2014) 25 (suppl_4): iv374-iv393. 10.1093/annonc/mdu344
Authors M.S. Gordon1, J. Lutzky2, D. Lawrence3, M. Butler4, P.A. Ascierto5, B. Hug6, A. Blake-Haskins7, A. Di Pietro8, X. Li7, P.B. Robbins9, A. Ribas10
  • 1Pinnacle Oncology Hematology, Pinnacle Oncology Hematology, 85258 - Scottsdale/US
  • 2Medical Oncology, Mount Sinai Comprehensive Cancer Center, Miami Beach/US
  • 3Cancer Centre, Massachusetts General Hospital Cancer Center, Boston/US
  • 4Princess Margaret Hospital, Princess Margaret Hospital, M5T 2M9 - Toronto/CA
  • 5Unit Of Medical Oncoloty And Innovative Therapy, Istituto Nazionale Tumori Fondazione G. Pascale, Napoli/IT
  • 6Glaxosmithkline, GlaxoSmithKline, Philadelphia/US
  • 7Oncology, MedImmune, LLC, Gaithersburg/US
  • 8Immuno-oncology, MedImmune, Gaithersburg/US
  • 9Oncology, MedImmune, 20878 - Gaithersburg/US
  • 10Oncology, UCLA Jonsson Comprehensive Cancer Center, Los Angeles/US

Abstract

Background

Targeted treatments have significantly improved outcomes in patients (pts) with metastatic melanoma (MM). The combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, provides high response rates in BRAF mutation-positive melanoma (BRAF V600E/K melanoma). Trametinib has also shown clinical activity in BRAF wild-type (WT) melanoma. The addition of an immunomodulator may further improve clinical outcomes in metastatic melanoma pts. MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD-80 and is associated with a low frequency of anti-drug antibodies, showed durable clinical activity in a Phase 1 study of pts with solid tumors including melanoma. MEDI4736 is being evaluated in combination with dabrafenib/trametinib or trametinib alone in BRAF mutation-positive or BRAF mutation-negative melanoma.

Trial design

This global multicenter, open-label Phase 1b study (NCT02027961) is enrolling adults with unresectable or MM and ECOG performance status 0–1 into 3 cohorts. In cohort A, BRAF-V600E/K melanoma pts receive dabrafenib orally (PO) twice daily, trametinib PO once daily (QD) and MEDI4736 intravenously (IV) every 2 wks (q2w), given concomitantly followed by continued dabrafenib/trametinib until progressive disease (PD). In cohorts B and C, BRAF mutation-negative (BRAF-WT) pts receive trametinib PO QD and MEDI4736 IV q2w according to 2 different treatment schedules,until PD. Primary objectives are determination of maximum tolerated dose (dose-limiting toxicity) and safety profile (adverse events, laboratory evaluations, physical exams, echocardiograms/electrocardiograms) of MEDI4736 in combination with dabrafenib/trametinib or trametinib alone. Secondary objectives include antitumor activity (objective response based on RECIST, duration of response, PFS, and overall survival), pharmacokinetic profile, and immunogenicity of the combination. Exploratory objectives include biomarkers, patient-reported outcomes, and tumor growth parameters. Recruitment is ongoing (target: 69 pts). This abstract was accepted and previously presented at the 2014 ASCO Annual Meeting Chicago, June 2014 (TPS9108).

Disclosure

M.S. Gordon and D. Lawrence: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; J. Lutzky: Medimmune/Astra-Zeneca: clinical trial support. Genentech, BMS, Prometheus: both clinical trial support and speaker bureau. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; M. Butler: Financial support from MedImmune to cover the costs of conducting sponsored clinical studies of Medi4736. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; P.A. Ascierto: Consultancy/research funding/honoraria: BMS, Roche-Genentech, Merck Sharp & Dohme, GSK, Ventana, and Novartis. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; B. Hug: Employee of GlaxoSmithKline. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; A. Blake-Haskins, A. Di Pietro, X. Li and P.B. Robbins: Employee of MedImmune and owns stock/stock options in AstraZeneca; A. Ribas: Consultant/funding/stock options Amgen Daiichi-Sankyo GSK Genentech-Roche Merck Novartis Pierre-Favre Kite Pharma Flexus. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.