A Phase Ib/II Study of LEE011 in Combination With MEK162 in Patients With NRAS Mutant Melanoma

A Phase Ib/II, Multicenter, Open Label, Study of LEE011 in Combination With MEK162 in Adult Patients With NRAS Mutant Melanoma

In the phase Ib, the primary purpose is to establish the maximum tolerated dose (MTD)(s)/recommended phase ll dose (RP2D) and schedule of LEE011 and MEK162 orally administered combination. Once the MTD(s)/RP2D have been determined for each tested schedule, additional patients will be enrolled in the phase II portion of the study at the RP2D on the chosen schedule in order to assess the anti-tumor activity of the combination in addition to continued evaluation of safety.

Inclusion Criteria:

• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1.

• Patients enrolled into phase Ib may be enrolled with evaluable disease only. Patients enrolled into the phase II expansion must have at least one measurable lesion as defined by RECIST 1.1 criteria for solid tumors.

• Patients must have adequate organ function, as defined by the following parameter

  1. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L.
  2. Hemoglobin (Hgb) ≥ 9 g/dL.
  3. Platelets ≥ 75 x 109/L without transfusions within 21 days before 1st treatment.
  4. PT/INR and aPTT ≤ 1.5 ULN.
  5. Serum creatinine ≤1.5 ULN.
  6. Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN).
  7. AST and ALT ≤ 3 x ULN, except in patients with tumor involvement of the liver who must have AST and ALT ≤ 5 x ULN.

Exclusion Criteria:

• Presence of any brain metastases detected by MRI or CT with i.v. contrast of the brain at screening.

• Uncontrolled arterial hypertension despite medical treatment

• Impaired cardiac function or clinically significant cardiac diseases, including any of the following:

  1. Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO).
  2. Congenital long QT syndrome or family history of unexpected sudden cardiac death.
  3. QTcF corrected with Frederica's or Bazett's formula QTcB >450 ms for males and >470 ms for females on screening ECG.
  4. Angina pectoris ≤ 3 months prior to starting study drug
  5. Acute myocardial infarction ≤ 3 months prior to starting study drug
  6. Clinically significant resting bradycardia
  7. History or presence of ventricular tachyarrhythmia
  8. Unstable atrial fibrillation (ventricular response >100 bpm)
  9. Complete left bundle branch block
  10. Right bundle branch block and left anterior hemi block (bifascicular block)
  11. Obligate use of a cardiac pacemaker or implantable cardioverter defibrillator
  12. Any other clinically significant heart disease

• Patients who are currently receiving treatment with agents that are known to cause QTc prolongation in humans.

• Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) or elevated baseline CK levels (≥ Grade 2)

• Patients who are currently receiving treatment with agents that are metabolized predominantly through CYP3A4 and that have a narrow therapeutic window.

• Patients with concurrent severe and/or uncontrolled concurrent medical conditions that could compromise participation in the study (i.e. uncontrolled diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection).

• 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).

Other protocol related inclusion/exclusion criteria may apply.