2093 - A randomised phase II feasibility study of intermittent versus continuous dosing of targeted therapy in patients with BRAFV600 mutant advanced melanoma (INTERIM)

Background

BRAF and MEK inhibitor (BRAF+MEKi) combination therapy has helped extend median life expectancy of BRAF mutant advanced melanoma patients to over 2 years. Acquired resistance limits duration of benefit and treatment-related toxicity can be a problem. Clinical reports suggest that intermittent dosing to manage side-effects does not compromise efficacy and can help patients to remain on treatment longer. In a mouse model, tumour cells resistant to the BRAF inhibitor vemurafenib appear to suffer a fitness deficit in the absence of drug, so that intermittent dosing could delay or prevent the emergence of resistant tumours. We hypothesise that intermittent dosing with BRAF+MEKi will sustain patients on treatment for longer, delay disease progression and improve quality of life (QoL). However, patient and investigator acceptance of randomisation and compliance with less treatment is uncertain.

Trial design

INTERIM is a UK national portfolio multi-centre feasibility trial developed by the NCRI Skin Cancer Clinical Studies Group. Patients with BRAF^V600 mutant stage 3 unresectable or metastatic melanoma with ECOG performance status (PS) 0-2 due to start BRAF+MEKi are randomised to receive dabrafenib (150mg bid) and trametinib (2mg od) either continuously or intermittently (dabrafenib days 1-21 and trametinib days 1 – 14) on a 28 day cycle. Concomitant immunotherapy is not allowed. Randomisation is stratified for brain metastases, PS, stage and lactate dehydrogenase level. We will recruit 150 patients (75 patients per arm) in 18 months at 20 UK sites to provide reliable information on recruitment, treatment compliance, progression-free survival and overall QoL (composite primary endpoint). Secondary endpoints include safety, health-economic evaluation, patient reported outcomes focusing on skin toxicity and patient experience. In addition we will explore ctDNA as a predictive biomarker and in tracking evolution of patients’ tumours. Pharmacokinetic sampling will be performed in a subset of patients to help refine the intermittent schedule. From November 2017 until April 2018, 11 patients have been randomised at 9 sites.

Clinical trial identification

EudraCT: 2016-005228-27.

Legal entity responsible for the study

Cambridge University Hospital NHS Foundation Trust.

Funding

National Institute for Health Research (NIHR) Research for Patient Benefit Grant.

Editorial Acknowledgement

Disclosure

P.G. Corrie: Honoraria: Merck Sharp & Dohme (MSD), Novartis, Bristol Myers Squibb (BMS); Consultancy/ advisory role: Celgene, Incyte, BMS, Novartis, MSD, Pierre Fabre; Speakers’ bureau: Novartis, MSD; Travel, accommodation, expenses: MSD, BMS; Research funding (institution): Celgene. R.N. Matin: Consultancy/advisory role: Simon-Kucher and Partners, Healthcare Partners Institution; Research funding: Barco NV, Skin MD Now, Inc. A. Gupta: Travel, accommodation, expenses: Bristol-Myers Squibb. C. Mather: Immediate family member employed: Aegerion and Cardiome in last 2 years; Immediate family member holds stock: Aegerion and Cardiome. M.R. Middleton: Honoraria: Amgen, Roche; Consultancy: Merck, CytomX, Therapeutics, RigonTEC, BMS, Newlink Genetics, Novartis; Expenses: Merck; Institution funding: Immunocore, Novartis, AstraZeneca, Roche, Amgen, Millennium, BMS, Vertex, Merck, Pfizer, RogonTEC, Replimune, Array BioPharma, TC Biopharma, Regneron. All other authors have declared no conflicts of interest.