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

Pfizer102 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

102

Conditions

Locally Advanced or Metastatic NRAS Mutant Melanoma

Interventions

LEE011DRUG

LEE011 will be administered orally once daily

MEK162DRUG

MEK162 will be administered orally twice daily

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (17)

University of California, Dept of Oncology

San Francisco, California, United States

California Pacific Medical Center Onc Dept

San Francisco, California, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: Approximately 12 months after the FPFV

Secondary Outcomes

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).

Time frame: 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).

Time frame: 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).

Time frame: 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

Data from ClinicalTrials.gov

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Karmanos Cancer Institute Dept of Oncology

Detroit, Michigan, United States

Memorial Sloan Kettering Cancer Center Dept Oncology

New York, New York, United States

Columbia University Medical Center- New York Presbyterian Onc Dept.

New York, New York, United States

Vanderbilt University Medical Center SC - Dept of Oncology .

Nashville, Tennessee, United States

University of Texas/MD Anderson Cancer Center Dept of Onc.

Houston, Texas, United States

Pfizer Investigative Site 1003

North Sydney, New South Wales, Australia

Pfizer Investigative Site 1002

Westmead, New South Wales, Australia

Pfizer Investigator Site 1001

East Melbourne, Victoria, Australia

...and 7 more locations

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).

Time frame: 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).

Time frame: 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).

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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Approximately 12 months after the FPFV