A Phase III randomized, 3-arm, open label, multicenter study of LGX818 plus MEK162 and LGX818 monotherapy compared with vemurafenib in patients with unresectable or metastatic BRAF V600 mutant melanoma

Summary

This is a prospective, randomized, open label, multi-center, parallel group, 3-arm phase iii study comparing the efficacy and safety of both, LGX818 plus MeK162 and LGX818 monotherapy, as compared to vemurafenib in patients with locally advanced unresectable or metastatic melanoma with BRaF V600 mutation.

The study consists of 3 treatment arms: 1) LGX818 plus MeK162 (denoted as Combination arm) 2) LGX818 monotherapy (denoted as LGX818 arm) 3) vemurafenib.

The current study design is aligned with the key concepts outlined in the FDa and eMa guidance for the clinical co-development of two investigational drugs for use in combination (FDa 2010; CHMP 2012). Both the Combination and LGX818 will be compared to vemurafenib as it is the current standard of care for the treatment of patients with locally
advanced unresectable or metastatic melanoma with BRaF V600 mutation. The Combination will also be compared with its more active single agent component, LGX818, in order to evaluate the contribution (efficacy and safety) of MeK162 to the Combination (see Section 10.5.2 for details). a MeK162 single agent arm will not be included as MeK162 monotherapy has shown limited efficacy in BRaF mutant metastatic melanoma
[CMeK162X2201].

The study will be an open label study. Patients will be randomized in a 1:1:1 ratio and
stratified based on the following factors:
i) american Joint Committee on cancer stage (iiiB + iiiC + iVM1a + iVM1b vs. iVM1c);
ii) eCoG performance status (0 vs. 1);
iii) BRaF mutation status (V600e vs. V600K) .

Participant Eligibility

Patients eligible for inclusion in this study have to meet all of the following key
criteria.
1. Signed written informed consent;
2. Male or female patient, age >= 18 years;
3. Histologically confirmed diagnosis of locally advanced, unresectable or metastatic
cutaneous melanoma AJCC Stage IIIB, IIIC or IV;
4. Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrollment, as
determined by a Novartis designated central laboratory(ies);
5. Naive untreated patient for unresectable locally advanced or metastatic melanoma;
Note: Prior adjuvant therapy is permitted (e.g. IFN, IL-2 therapy, any other
immunotherapy or radiotherapy).
6. Evidence of at least one measurable lesion as detected by radiological or photographic
methods according to Novartis guideline version 3.1 based on RECIST version 1.1;
Note: A previously irradiated lesion is eligible to be considered as a measurable lesion
provided that there is objective evidence of progression of the lesion since discontinuation
of therapy and prior to starting study drug.
7. ECOG performance status of 0 or 1;
8. Adequate bone marrow, organ function and laboratory parameters:

* Absolute neutrophil count (ANC) >= 1.5 x 109/L,

* Hemoglobin (Hgb) >= 10 g/dL without transfusions,

* Platelets (PLT) >= 100 x 109/L without transfusions,

* AST and/or ALT <= 2.5 x upper limit of normal (ULN); patient with liver metastases
<= 5 xULN,

* Total bilirubin <= 2 x ULN,

* Creatinine <= 1.5 mg/dL, or calculated creatinine clearance (determined as per
Cockcroft-Gault) >= 50mL/min;
9. Adequate cardiac function:

* left ventricular ejection fraction (LVEF) >= 50% as determined by a multigated
acquisition (MUGA) scan or echocardiogram,

* QTc interval <= 480 ms;
10. Able to take oral medications;
11. Patient is deemed by the Investigator to have the initiative and means to be compliant with
the protocol (treatment and follow-up);
12. Negative serum β-HCG test (female patient of childbearing potential only) performed
centrally within 72 hours prior to first dose.