This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all ICH GCP Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial participants.

Males or females age were eligible for enrollment if they were ≥ 18 years of age, had histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma American Joint Committee on Cancer Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors, with evidence of measurable or non-measurable lesions as detected by radiological or photographic methods according to guidelines based on Response Evaluation Criteria in Solid Tumors v1.1, had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and adequate bone marrow, hepatic and renal function.

Key exclusion criteria included participants with symptomatic brain metastasis, history of reaction to any of the study medications, symptomatic or untreated leptomeningeal disease, history or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes), clinically significant cardiac disease, impaired hepatic function as defined by Child-Pugh class B or C, impaired gastrointestinal function or disease which might have significantly altered the absorption of study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection), known hyper-coagulability risks other than malignancy (e.g., Factor V Leiden syndrome), thromboembolic event except catheter-related venous thrombosis ≤ 12 weeks prior to starting study treatment, discontinuation of prior BRAF and/or MEK inhibitor treatment due to left ventricular dysfunction, pneumonitis/interstitial lung disease, or RVO.

Participants were also excluded if they had use within 2 weeks prior to the start of encorafenib/binimetinib treatment on Day 1 and through DDI phase (Day 28), of any herbal medications/supplements or any medications or foods that are substrates, inhibitors or inducers of CYP3A4/5, consumption of grapefruit, pomegranates, star fruits, Seville oranges or products containing the juice. Due to the use of modafinil in this study, participants were also excluded if they had a history of psychosis, depression, mania, angioedema, mitral valve prolapse, or left ventricular hypertrophy.

A schematic for the study design is presented in Fig. 1. Encorafenib 450 mg QD and binimetinib 45 mg BID were administered starting on Day 1. Patients then received continuous treatment of 400 mg QD modafinil on Day 15 through Day 21. Blood samples for measurement of plasma concentrations of encorafenib (and its metabolite, LHY746) and binimetinib (and its active metabolite, AR00426032), were collected at 0, 1, 2, 3, 4, 6 and 8 h post dose on Day 14 and Day 21.

Study design

Abbreviations: PK = pharmacokinetics

Modafinil was administered at 400 mg for 7 days to ensure sufficient time for CYP3A4 induction, while minimizing the time for which patients may have reduced exposures to encorafenib [9, 10].​ While modafinil is considered a weak inducer at 200 mg/day, at a higher dosage (400 mg/day) modafinil is considered a moderate inducer of CYP3A [11]. Furthermore, the effect of modafinil (200 mg for 7 days followed by 400 mg for 21 days) on CYP3A4 substrate triazolam PK was moderate, with a 59% decrease on mean AUCinf [10]. Lastly, modafinil has been shown to be well tolerated with headache as the only observed AE in > 15% of patients [12].

Human PK plasma samples were analyzed for quantitation of all PK analytes at PPD (Middleton, Wisconsin, US) using validated, sensitive, and specific HPLC/MS/MS methods in compliance with laboratory SOPs.

PK parameters including, but not limited to, Cmax and AUClast were calculated for each participant using noncompartmental analysis (NCA) methods using the WinNonlin software package (Phoenix WinNonlin Professional, version 8.0 Pharsight Corporation, Mountain View, California) for PK analytes including encorafenib and its metabolite LHY746, and binimetinib and its metabolite AR00426032.

Safety was assessed during the DDI phase (Day − 7, Day 1, Day 14, Day 15, Day 21, and Day 28) and in the post DDI phase every 3 to 4 weeks until discontinuation of study drug. Safety monitoring included SAEs, laboratory profiles (hematology, biochemistry, coagulation, cardiac/muscle enzymes, urinalysis), physical examination (including vital signs, ophthalmic and dermatological examinations), ECOG PS assessment, and cardiac profiles (ECG and MUGA or ECHO), concomitant medications and/or therapies. AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA, http://www.meddra.org) classification system version 22.1 and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

The PK data was analyzed after the first 6 patients were enrolled to look for an indication that the moderate inducer was having a significant effect on encorafenib PK. Since there was a ≥ 20% change in mean encorafenib AUC, an additional 6 patients were to be enrolled to more fully characterize the effect. Assuming an intrasubject variation of 36.4% for encorafenib AUCtau, there was an 80% probability with fixed sample sizes of 6 and 12 subjects that a treatment difference would be detected if the true effect size is 74% and 46%, respectively [13].

All patients who received at least one dose of any study drug were included in the Safety Set population. The Evaluable PK Set included all patients with sufficient concentration data to calculate at least one PK parameter for encorafenib and binimetinib on Days 14 and 21. Patients who discontinued, missed 3 or more consecutive doses of encorafenib prior to completion of the last PK sampling on Day 14, or required a dose reduction of encorafenib prior to completion of the last PK sampling on Day 14 were excluded from the Evaluable PK set. In addition, patients who missed any dose of study drugs on any of the PK days, or who vomited within 4 h after dosing on any of the PK days were excluded from Evaluable PK set.

An analysis of variance (ANOVA) was performed on the natural log (ln)-transformed Cmax and AUClast of encorafenib, LHY746, binimetinib, and AR00426032. The least squares means (LSM) geometric mean ratio (GMR) and associated 90% confidence interval (CI) for each PK parameter were calculated using the exponentiation of the difference between treatment LSM from the analyses on the ln-transformed parameters and expressed as a percentage of Day 21 relative to Day 14.