LGX818 and MEK162 in Combination With a Third Agent (BKM120, LEE011, BGJ398 or INC280) in Advanced BRAF Melanoma

The LOGIC 2 Trial A Phase II, Multi-center, Open-label Study of Sequential LGX818/MEK162 Combination Followed by a Rational Combination With Targeted Agents After Progression, to Overcome Resistance in Adult Patients With Locally Advanced or Metastatic BRAF V600 Melanoma.

The primary purpose of this study is to assess the anti-tumor activity of LGX818/MEK162 in combination with targeted agents after progression on LGX818/MEK162 combination therapy, as well as the safety and tolerability of the novel triple combinations.

This study consists of two parts: in Part I/Run-In, patients naïve to selective BRAF and MEK inhibitors will be treated with the LGX818/MEK162 combination until disease progression (as defined per RECIST v1.1). Based on the genetic analysis of a tumor biopsy obtained at that time, patients will enter Part II of the study for tailored combination treatment in one of four arms of LGX818/MEK162 + either BKM120, BGJ398, INC280 or LEE011 Patients with BRAF mutant melanoma treated by LGX818/MEK162 combination in other studies can be enrolled directly in Part II of CLGX818X2109 after relapse.

Dose-escalations in the combination arms for which no MTD has been established will be based on the recommendations of a Bayesian logistic regression model guided by an escalation with overdose control criterion

INCLUSION CRITERIA:

• Age ≥ 18 years
• 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.

INCLUSION CRITERIA for triple combinations:

Progressive disease following prior treatment with LGX818/MEK162 combination. PRINCIPAL EXCLUSION CRITERIA 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.
• Patients who have developed brain metastases during Part I of the study may continue to Part II upon discussion with Novartis Medical Monitor. The brain metastasis must be either asymptomatic or treated and stable for at least 4 weeks and on a stable or tapering dose of steroids for at least 2 weeks. Patients with brain metastasis are not eligible for the combination with LEE011.
• 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-ISHguidelines) 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

Other protocol-defined inclusion/exclusion criteria may apply.