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

Phase 1

Conditions: ocally Advanced or Metastatic BRAF V600 Melanoma
MedDRA version: 17.0Level: LLTClassification code 10027481Term: Metastatic melanomaSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2013-004552-38-IT

Lead Sponsor: OVARTIS FARMA S.p.A.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 140

Inclusion Criteria

•Age = 18 years at the start of dosing
•Histologically confirmed diagnosis of unresectable stage III or metastatic melanoma (stage IIIC to IV per American Joint Committee on Cancer [AJCC])
•Documented evidence of BRAF V600 mutation.
•Newly obtained tumor biopsy at baseline, and patient agrees to a mandatory biopsy at the time of progression, if not medically contraindicated.
•Evidence of measurable disease, as determined by RECIST v1.1.
•Life expectancy = 3 months.

Inclusion criteria for triple combinations:
Progressive disease following prior treatment with LGX818/MEK162 combination.
A pre-LGX818/MEK162 combination archival tumor sample must be available

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 112
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 28

Exclusion Criteria

•Symptomatic or untreated leptomeningeal disease
Symptomatic or untreated leptomeningeal disease.
•Symptomatic brain metastases. Patients previously treated or untreated for brain metastases that are asymptomatic in the absence of corticosteroid therapy or on a stable dose of steroids for four weeks are allowed to enroll. Brain metastases must be stable at least 4 weeks with verification by imaging (e.g. brain MRI completed at screening demonstrating no current evidence of progressive brain metastases). Patients are not permitted to receive enzyme inducing anti-epileptic drugs.
•Known acute or chronic pancreatitis.
•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 including any of the following:
•CHF requiring treatment (NYH grade = 2),
•LVEF < 50% as determined by MUGA scan or ECHO
•History or presence of clinically significant ventricular arrhythmias or atrial fibrillation
•Clinically significant resting bradycardia
•Unstable angina pectoris = 3 months prior to starting study drug
•Acute Myocardial Infarction (AMI) = 3 months prior to starting study drug,
•QTcF > 480 msec.
Patients with any of the following laboratory values at Screening/baseline:
•Absolute neutrophil count (ANC) <1,500/mm3 [1.5 x 109/L]
•Platelets < 100,000/mm3 [100 x 109/L]
•Hemoglobin < 9.0 g/dL
•Serum creatinine >1.5 x ULN or calculated or directly measured CrCl < 50% LLN (lower limit of normal)
•Serum total bilirubin >1.5 x ULN
•AST/SGOT or ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver metastases are present

Additional exclusion criteria for the triple combinations:

LGX818/MEK162/BKM120:
•Patients with fasting glucose > 120 mg/dL or 6.7 mmol/L, and HbA1c > 8 %.
•Patient has any of the following mood disorders as judged by the Investigator or a Psychiatrist:
•Patient has a score = 12 on the PHQ-9 questionnaire
•Patient has = CTCAE grade 3 anxiety
LGX818/MEK162/BGJ398:
•History and/or current evidence of significant ectopic mineralization/ calcification with the exception of calcified lymph nodes and asymptomatic vascular calcification.
•Current evidence of corneal disorder/ keratopathy incl. but not limited to bullous/ band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivits etc., confirmed by ophthalmologic examination
LGX818/MEK162/LEE011:
•Patients with uncontrolled hypertension (please refer to WHO-ISH guidelines) are excluded from study.
•QTcF >450 ms for males and >470 ms for females Congenital long QT syndrome or family history of unexpected sudden cardiac death and/or hypokalemia CTCAE Grade = 3 and magnesium levels below the clinically relevant lower limits at study entry
•Current evidence of brain metastasis or brain metastasis detected by mandatory CT/MRI at screening
•PT/INR or aPTT > 1.5xULN

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/MEK162 in combination with targeted agents after progression on LGX818/MEK162 combination therapy;Secondary Objective: - To characterize the safety and tolerability of LGX818/MEK162 in combination with targeted agents<br>- To estimate the MTD/RP2D of triple combinations after progression on LGX818/MEK162 therapy<br>- To further assess anti-tumor activity of LGX818/MEK162 combination, and in combination with targeted agents after progression on LGX818/MEK162 combination<br>- To characterize genomic alterations in tumor tissue at baseline and at tumor progression<br>- To determine the PK profiles of LGX818, MEK162 and the third agents when given in combination and to assess drug-drug interaction<br>;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>- PFS, DOR, TTR, DCR and OS (Part II only)<br>- Genomic alteration status(mutation/amplification/expression) of pre-defined markers <br>- Plasma concentration and derived PK parameters of LGX818/MEK162 and targeted agents;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/MEK162 up to 3 years

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