Patient case: 61-year-old male with melanoma; genetic feature: BRAF amplification

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

Summary: 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.

Detailed description: 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

Eligibility: 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.

Relevance to patient case: possibly relevant