GX818 in Combination With Agents (MEK162; BKM120; LEE011; BGJ398; INC280) in Advanced BRAF Melanoma

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 100

Inclusion Criteria

•locally advanced or metastatic melanoma
•confirmed BRAF V600 mutation
•patients naïve to a selective BRAF inhibitor
•fresh tumor biopsy at baseline, and patient agrees for a mandatory biopsy at the time of relapse
•life expectancy = 3 months
•World Health Organization (WHO) Performance Status = 2.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 75
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 25

Exclusion Criteria

•Previous treatment with RAF-inhibitor
•Symptomatic or untreated leptomeningeal disease
•Symptomatic brain metastases.
•Known acute or chronic pancreatitis
•Clinically significant cardiac disease
•AST/SGOT and ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver metastases are present
•Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral interventional drug
•Previous or concurrent malignancy.
•Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation

Specific exclusion criteria for each treatment arm:

LGX818/MEK162:

History or current evidence of retinal disease History of Gilbert's syndrome.

LGX818/BKM120:

Patients with diabetes mellitus requiring insulin treatment
Patient has mood disorders

LGX818/BGJ398:

History and/or current evidence of ectopic mineralization/ calcification Current evidence of corneal disorder/ keratopathy Patients with current evidence of endocrine alteration of calcium/phosphate homeostasis.

History of congenital long QT- syndrome and/or hypokalaemia CTCAE Grade = 3 and/or magnesium levels below the clinically relevant lower limits before study entry
Ionized (i) calcium (Ca) > ULN Serum inorganic phosphorus (Pi) > ULN

LGX818/LEE011:

History of congenital long QT- syndrome and/or hypokalaemia CTCAE Grade = 3 and/or magnesium levels below the clinically relevant lower limits before study entry

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To assess the anti-tumor activity of LGX818 in combination with targeted agents after progression on LGX818 single agent therapy;Secondary Objective: - To characterize the safety and tolerability of LGX818 alone, and in combination with targeted agents<br>- To identify MTD/RP2D for the BKM120, LEE011, INC280, BGJ398 combinations in patients pre-treated with LGX818.<br>- To determine the PK profile of LGX818 and the combination partners<br>- To assess anti-tumor activity of LGX818 alone, and of LGX818 in combination with targeted agents after progression on single agent LGX818<br>- To assess gene alterations/expression relevant to the RAF/MEK/ERK and PI3K/AKT pathways in tumor tissue at baseline and at progression following LGX818 single agent therapy;Primary end point(s): Overall response rate ;Timepoint(s) of evaluation of this end point: 3 years

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): - Incidence and severity of adverse events <br>- Incidence rate of Dose Limiting Toxicities (DLTs) in Cycle 1 of Combination Part (Part II) <br>- Plasma concentration and derived PK parameters of LGX818 and combination partners<br>- Overall Response Rate (ORR) (Part I), Progression Free Survival (PFS)(Part I and II), Duration Of Response (DOR) (Part II), Overall Survival (OS) (Part II)<br>- Molecular status (mutation/amplification/expression) of markers relevant to the RAF/MEK/ERK and PI3K/AKT pathways ;Timepoint(s) of evaluation of this end point: - 3 years <br>- 3 years <br>- 3 years <br>- 3 years <br>- baseline, at progression with LGX818 single agent treatment up to 3 years

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