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.

Study Overview

• Status: Completed
• Conditions: Locally Advanced or Metastatic NRAS Mutant Melanoma
• Intervention / Treatment: Drug: LEE011; Drug: MEK162

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • North Sydney, New South Wales, Australia, 2060
      • Pfizer Investigative Site 1003
    • Westmead, New South Wales, Australia, 2145
      • Pfizer Investigative Site 1002
  • Victoria
    • East Melbourne, Victoria, Australia
      • Pfizer Investigator Site 1001
• Germany
  • Essen, Germany, 45147
    • Pfizer Investigative Site 1050
  • Gera, Germany, 07548
    • Pfizer Investigative Site 1053
  • Hannover, Germany, 30625
    • Pfizer Investigative Site 1052
  • Muenchen, Germany, 80336
    • Pfizer Investigative Site 1051
• Italy
  • Napoli, Italy, 80131
    • Pfizer Investigative Site 1101
• Netherlands
  • Nijmegen, Netherlands, 6525 GA
    • Pfizer Investigative Site 1150
  • The Netherlands
    • Utrecht, The Netherlands, Netherlands, 3508 GA
      • Pfizer Investigative Site 1151
• United States
  • California
    • San Francisco, California, United States, 94120-7999
      • California Pacific Medical Center Onc Dept
    • San Francisco, California, United States, 94101
      • University of California, Dept of Oncology
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute Dept of Oncology
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center- New York Presbyterian Onc Dept.
    • New York, New York, United States, 10021
      • Memorial Sloan Kettering Cancer Center Dept Oncology
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center SC - Dept of Oncology .
  • Texas
    • Houston, Texas, United States, 77030-4009
      • University of Texas/MD Anderson Cancer Center Dept of Onc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase Ib; 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; LEE011 will be administered orally once daily; Drug: MEK162; MEK162 will be administered orally twice daily
Experimental: Phase II; 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; LEE011 will be administered orally once daily; Drug: MEK162; MEK162 will be administered orally twice daily

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Schuler M, Zimmer L, Kim KB, Sosman JA, Ascierto PA, Postow MA, De Vos FYFL, van Herpen CML, Carlino MS, Johnson DB, Berking C, Reddy MB, Harney AS, Berlin JD, Amaria RN. Phase Ib/II Trial of Ribociclib in Combination with Binimetinib in Patients with NRAS-mutant Melanoma. Clin Cancer Res. 2022 Jul 15;28(14):3002-3010. doi: 10.1158/1078-0432.CCR-21-3872.

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): January 15, 2018
• Study Completion (Actual): February 20, 2018

Study Registration Dates

• First Submitted: January 24, 2013
• First Submitted That Met QC Criteria: January 30, 2013
• First Posted (Estimate): February 1, 2013

Study Record Updates

• Last Update Posted (Actual): December 7, 2020
• Last Update Submitted That Met QC Criteria: November 23, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma
• Other Study ID Numbers: CMEK162X2114; C4211005 (Other Identifier: Pfizer)