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

Study Overview
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Brief Summary
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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.

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

Conditions
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Locally Advanced or Metastatic NRAS Mutant Melanoma

Intervention / Treatment
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* Drug: LEE011
* Drug: MEK162


Participation Criteria
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Eligibility Criteria
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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 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. PT/INR and aPTT ≤ 1.5 ULN. Serum creatinine ≤1.5 ULN. Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN). 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: Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO). Congenital long QT syndrome or family history of unexpected sudden cardiac death. QTcF corrected with Frederica's or Bazett's formula QTcB >450 ms for males and >470 ms for females on screening ECG. Angina pectoris ≤ 3 months prior to starting study drug Acute myocardial infarction ≤ 3 months prior to starting study drug Clinically significant resting bradycardia History or presence of ventricular tachyarrhythmia Unstable atrial fibrillation (ventricular response >100 bpm) Complete left bundle branch block Right bundle branch block and left anterior hemi block (bifascicular block) Obligate use of a cardiac pacemaker or implantable cardioverter defibrillator 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase Ib<br>The phase Ib is the dose escalation part where successive cohorts of 3-6 newly enrolled patients receiving various dose pairs considering the recommendation from an adaptive BLRM incorporating the EWOC principle until MTD(s)/RP2D is defined. If multiple alternate dosing schedules are explored in parallel, the allocation of patients will proceed in an alternating fashion. Approximately 40 patients are expected to be treated during the phase Ib part of the study. Dosing Schedule 1: MEK162 administered orally twice daily on a continuous dosing schedule. LEE011 administered orally once daily for 21 days followed by a 1 week break (28-day cycle). Dosing Schedule 2: MEK162 administered orally twice daily and LEE011 administered orally once daily for 3 weeks followed by a 1 week break (28-day cycle). Dosing Schedule 3: MEK162 administered orally twice daily and LEE011 administered once daily for 2 weeks followed by a 1 week break (21-day cycle). | Drug: LEE011<br>* LEE011 will be administered orally once daily<br>Drug: MEK162<br>* MEK162 will be administered orally twice daily<br>|
| Experimental: Phase II<br>The Phase II part will begin once the MTD(s)/RP2D have been determined in the Phase Ib in order to assess antitumor activity of the LEE011and MEK162 combination. Patients enrolled in the Phase II part of the study are required to have measurable disease. Approximately 40 patients will be treated in this part. Phase II part will begin at the RP2D on the chosen schedule in order to assess antitumor activity of the LEE011 and MEK162 combination. | Drug: LEE011<br>* LEE011 will be administered orally once daily<br>Drug: MEK162<br>* MEK162 will be administered orally twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Dose Limiting Toxicities (Phase Ib) | To estimate the maximum tolerate doses (MTDs) and/or identify the RP2D and schedule of LEE011 and MEK162 combination. A dose-limiting toxicity (DLT) was defined as an AE or clinically significant abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the first cycle of treatment with ribociclib and binimetinib. | first 28 days of treatment | 
| Objective Response Rate (ORR) (Phase II) | ORR is the proportion of patients with best overall response of complete response (CR) or partial response (PR) by month 2 assessed according to RECIST 1.1 criteria. ORR is done to describe the anti-tumor activity of LEE011 and MEK162 combination. The primary analysis of the ORR was based on the Investigator's assessment of overall lesion responses per RECIST 1.1. | Approximately 12 months after the FPFV | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib) | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). | Cycle 1 Day 1 | 
| Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib) | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). | Cycle 1 Day 1 | 
| Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (Phase Ib) | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | 
| Plasma Concentration-time Profile (AUCtau,ss) of MEK162 (Phase Ib) | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | 
| Plasma Concentration-time Profile (Cmin,ss) of LEE011 (Phase Ib) | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). | For the 28-day schedule the steady-state parameter time frame was predose on Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was predose on Cycle 1 Day 14 | 
| Plasma Concentration-time Profile (Cmin,ss) of MEK162 (Phase Ib) | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). | For the 28-day schedule the steady-state parameter time frame was predose on Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was predose on Cycle 1 Day 14 | 
| Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib) | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). | Cycle 1 Day 1 | 
| Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib) | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). | Cycle 1 Day 1 | 
| Plasma Concentration-time Profile (Cmax,ss) of LEE011 (Phase Ib) | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | 
| Plasma Concentration-time Profile (Cmax,ss) of MEK162 (Phase Ib) | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | 
| Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib) | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). | Cycle 1 Day 1 | 
| Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib) | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). | Cycle 1 Day 1 | 
| Plasma Concentration-time Profile (Tmax,ss) of LEE011 (Phase Ib) | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | 
| Plasma Concentration-time Profile (Tmax,ss) of MEK162 (Phase Ib) | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | 
| Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (Phase Ib) | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | 
| Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (Phase Ib) | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | 
| Plasma Concentration-time Profile (T1/2,ss) of LEE011 (Phase Ib) | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | 
| Plasma Concentration-time Profile (T1/2,ss) of MEK162 (Phase Ib) | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | 
| Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib) | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). | Cycle 1 Day 1 | 
| Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib) | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). | Cycle 1 Day 1 | 
| Number of Participants With Adverse Drug Reactions | Safety and tolerability will be characterized through the incidence and severity of adverse drug reactions, serious adverse drug reactions, changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, dose reduction and dose intensity. | Approximately 12 months after FPFV | 
| Duration of Response (DoR) - Phase 2 | To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer. Please note: As clinicaltrials.gov only allows numerical data entry, the value of 999 indicates not estimable for confidence interval. | Approximately 12 months after the FPFV | 
| Time to Progression (TTP) - Phase 2 | To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer. | Approximately 12 months after the FPFV | 
| Progression Free Survival (PFS) - Phase 1b and Phase 2 | To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer. In the Phase 1b part, patients were combined for purposes of PFS analyses based on schedule received, since too few patients received any individual dose level to allow for valid PFS estimates within the respective dose levels. This is how the data were analyses and presented for the clinical study report. | Approximately 12 months after the FPFV | 
| Overall Survival (OS) - Phase ll | To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer. | Approximately 12 months after the FPFV | 
| Best Overall Response (BOR) - Phase II | To assess clinical safety according to RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer. | Approximately 12 months after the FPFV |