Clinical Trials of Note

Table 1. Phase III Melanoma Trials (Currently Recruiting)

The NRAS Melanoma and MEK Inhibitor (NEMO) trial1 is a randomized, phase III, open-label, multicenter, dual-arm study to compare the efficacy of MEK162 45 mg twice daily versus dacarbazine 1000 mg/m2 IV every 3 weeks in patients with advanced unresectable (stage IIIc) or metastatic (stage IV) NRAS mutation—positive melanoma. This study, funded by Novartis, is enrolling approximately 393 patients who will be randomized in a 2:1 ratio to receive either MEK162 or dacarbazine. Patients will be stratified according to criteria from: the American Joint Committee on Cancer stage (IIIC, IVM1a, and IVM1b vs IVM1c), the Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1), and prior first-line therapy (ipilimumab vs none).

The primary end point of the study is progressionfree survival (PFS) and a key secondary end point is overall survival (OS). Other secondary end points include overall response rate; time to objective response; duration of response; disease control rate (defined as the proportion of patients with a best overall response rate of complete response, partial response, or stable disease); number of patients with adverse events (AEs) and with serious AEs; time to definitive 10% deterioration in the global health status score (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 [EORTC QLQ-C30]); and change from baseline in the EuroQol Group standardized instrument for use as a measure of health outcome (EQ-5D-5L).

The study began in July 2013 and will be completed in May 2016. The final data collection date for the primary outcome measure will occur in December 2014.

A second Novartis-sponsored phase III trial2 (COLUMBUS) began in September 2013 and is scheduled to end in June 2017. This study compares the combination of LGX818 (a highly potent RAF inhibitor) plus MEK162 and LGX818 monotherapy versus vemurafenib in BRAF-mutant melanoma. This prospective, randomized, open-label, multicenter, parallel group, 3-arm study aims to enroll approximately 900 patients with locally advanced unresectable or metastatic melanoma with BRAF V600 mutation. Patients will be randomized 1:1:1 to one of 3 treatment arms: (1) LGX818 plus MEK162 (combination arm), (2) LGX818 monotherapy (LGX818 arm), or (3) vemurafenib.

The primary outcome measure is PFS. Secondary outcome measures include OS; objective response rate; time to response; disease control rate; duration of objective response; number of patients with AEs and serious AEs; ECOG Performance status; time to definitive 10-point deterioration in ECOG performance status; pharmacokinetics of LGX818 and MEK162; time to definitive 10% deterioration in global health status (EORTC QLQ-C-30); time to definitive 10% deterioration in the FACT-M melanoma subscale; and global health status (EQ-5D).

The doses of the experimental treatments are as follows: arm 1, LGX818 300 mg orally once daily in a fasting state; arm 2, LGX818 450 mg orally once daily in a fasting state and MEK162 45 mg orally twice daily in a fasting state; and arm 3, vemurafenib 960 mg orally twice daily.

Other phase III trials now enrolling subjects are listed in Table 1. Trial protocols under development include targeted therapies and combinations of therapies, including CDK 4/6 inhibitors, BRAF or MEK inhibitors combined with murine double minute 2 (MDM2) inhibitors, and BRAF plus MEK inhibitors plus PD-1 antibodies.

References

1. ClinicalTrials.gov. Study comparing the efficacy of MEK162 versus dacarbazine in unresectable or metastatic NRAS mutation- positive melanoma. http://clinicaltrials.gov/ct2/show/ study/NCT01763164. Accessed March 2, 2014.
2. ClinicalTrials.gov. Study comparing combination of LGX818 plus MEK162 and LGX818 monotherapy versus vemurafenib in BRAF mutant melanoma (COLUMBUS). http://clinicaltrials .gov/ct2/show/study/NCT01909453. Accessed March 2, 2014.