A phase Ib/II study of LEE011 in combination with MEK162 in patients with NRAS mutant melanoma
- Conditions
- locally advanced or metastatic NRAS mutant melanomaTherapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2012-004104-35-NO
- Lead Sponsor
- ovartis Pharma Services AG
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 102
- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2
- 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.
- Patients must have adequate organ function, as defined by the following parameters:
a. Bone marrow:
• Absolute Neutrophil Count (ANC) = 1.5 x 109/L
• Hemoglobin (Hgb) = 9 g/dL
• Platelets = 75 x 109/L without transfusions within 21 days before 1st treatment
b. Serum creatinine =1.5 ULN
c. Serum total bilirubin = 1.5 x upper limit of normal (ULN)
d. Aspartate Aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and ALT (SGPT) = 3 x ULN, except in patients with tumor involvement of the liver who must have AST and ALT = 5 x ULN
Other, protocol related inclusion criteria may apply.
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 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 8
- Symptomatic brain metastases. Patients previously treated or untreated for brain metastases that are asymptomatic in the absence of corticosteroid therapy are allowed to enroll. Brain metastases must be stable for at least 2 weeks after
completion of the definitive therapy with verification by imaging (e.g. brain MRI completed at screening
demonstrating no current evidence of progressive brain metastases).
- Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
a. Left ventricular ejection fraction (LVEF) < 50% as
determined by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO)
b. Congenital long QT syndrome or family history of unexpected sudden cardiac death
c. QTc corrected with Frederica’s or Bazett’s formula (QTcF) >450 ms for males and >470 ms for females on screening ECG
d. Any other clinically significant heart disease such as angina pectoris, resting bradycardia, left bundle branch block, ventricular tachyarrhythmia, unstable atrial fibrillation, branch block or hemi block, acute myocardial infarction or any heart disease that requires the use of a cardiac pacemaker or implantable cardioverter defibrillator
- Patients who are currently receiving treatment with agents that are known to cause QTc prolongation in humans.
- 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 (e.g.,
uncontrolled hypertension and/or diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection)
- Current evidence of retinal disease; history of CSR, RVO or ophthalmology as assessed by ophthalmologic examination at baseline that would be considered a risk factor for CSR/RVO (e.g., optic disc cupping, visual field defects, IOP > 21 mm Hg)
Other, protocol related exclusion criteria may apply.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: In the phase Ib, the primary purpose is to establish the maximum tolerated dose (MTD (s)/recommended phase ll dose (RP2D) of the LEE011 and MEK162 orally administered combination. Once the MTD(s)/RP2D have been determined, the PhII part will begin in order to assess antitumor activity of LEE011and MEK162 orally administered combination.;Secondary Objective: This study will also assess the safety, tolerability, PK and preliminary evidence of antitumor activity of the LEE011-MEK162 combination in NRAS mutated melanoma patients;Primary end point(s): 1. incident of dose limiting toxicities (Phase Ib)<br>2. objective response rate (Phase II);Timepoint(s) of evaluation of this end point: 1. cycle 1 = 28 days (from the time of first dose)<br>2. baseline, every 2-4 months
- Secondary Outcome Measures
Name Time Method Secondary end point(s): 1. plasma concentration-time profiles of LEE011 and MEK162 (phase Ib)<br>2. Pharmacokinetics (PK) parameters including but not limited to AUCtau, Cmax, Tmax, CL/F, accumulation ration (Racc) and T1/2, acc2. incidence of adverse drug reactions<br>3. duration of response (phase II)<br>4. time to progression (phase II)<br>5. progression free survival (phase II)<br>6. overall survival (phase II)<br>7. best overall response (phase II);Timepoint(s) of evaluation of this end point: 1-2. up to 24 weeks<br>3-7. approx. 12 months