A 2 Part, Phase III randomized, open label, multicenter study of LGX818 plus MEK162 versus vemurafenib and LGX818 monotherapy in patients with unresectable or metastatic BRAF V600 mutant melanoma
- Zale Lipshy University Hospital
This is a 2-part, randomized, open label, multi-center, parallel group, phase iii study comparing the efficacy and safety of both, LGX818 plus MeK162 versus vemurafenib and LGX818 monotherapy in patients with locally advanced unresectable or metastatic melanoma with BRaF V600 mutation.
Part 1: Patients will be randomized in a 1:1:1 ratio to one of the 3 treatment arms: 1) LGX818 450 mg QD plus MeK162 45mg BiD (denoted as Combo 450) 2) LGX818 300mg QD monotherapy (denoted as LGX818 arm) or 3) vemurafenib 960 mg BiD. approximately 576 patients will be enrolled in part 1 of the study.
Part 2: Patients will be randomized in a 3:1 ratio to one of the 2 treatment arms: 1) LGX818 300mg QD plus MeK162 45mg BiD (denoted as Combo 300) or 2) LGX818 300mg QD monotherapy (denoted as LGX818 arm). approximately 320 patients will be enrolled in part 2 of the study.
a notification will be sent to the study participating sites to inform them of screening
closure in part 1 and enrollment opening in part 2.
Phase iii, randomized, the investigational drugs are LGX818 and MeK162. The
control drug is vemurafenib.
The following treatment arms are considered:
* Combo 450: LGX818 450mg QD plus MeK162 45mg BiD or
* LGX818: LGX818 300mg QD monotherapy or
* vemurafenib 960mg BiD
* Combo 300: LGX818 300mg QD plus MeK162 45mg BiD or
* LGX818: LGX818 300mg QD monotherapy
The 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). Combo 450 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 Combo 450 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. a MeK162 single agent arm will not be included as MeK162 monotherapy has shown limited efficacy in BRaF mutant metastatic melanoma.
in addition, as part of protocol amendment 3, the contribution of MeK162 to the Combination
will be evaluated further using Combo 300. This will further support the determination of the
degree of the MeK162 contribution and whether the contribution is by its own anti-tumor
effect and/or by allowing delivery of a higher dose of the more active drug LGX818.
The study is open label study. in part 1. patients will be randomized in a 1:1:1 ratio to Combo 450, LGX818 monotherapy, or vemurafenib. in part 2, patients will be randomized in a 3:1 ratio to Combo 300 or LGX818 monotherapy. Randomization will be 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) Prior first-line immunotherapy.
Patients eligible for inclusion in this study have to meet all of the following key
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 or unknown primary melanoma AJCC Stage IIIB, IIIC or IV;
4. Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as
determined by a Novartis designated central laboratory(ies);
5. Naive untreated patients or patients who have progressed on or after prior first
-line immunotherapy for unresectable locally advanced or metastatic
Note: Prior adjuvant therapy is permitted (e.g. IFN, IL-2 therapy, any other
immunotherapy or radiotherapy),except the administration of BRAF or MEK inhibitors.
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 within 72 hours prior to first dose.