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

NCT01781572 | Completed Phase 1 Results

• 2 other identifiers: CMEK162X2114C4211005
• Study Type: interventional
• Target: 102
• Locations: 5 countries
• Sites: 17

Brief Summary

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.

Conditions

Locally Advanced or Metastatic NRAS Mutant Melanoma

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (26)

• Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib)

  Cycle 1 Day 1

• Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib)

  Cycle 1 Day 1

• Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (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)

  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)

  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

Study Arms (2)

Phase Ib

EXPERIMENTAL

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; Drug: MEK162

Phase II

EXPERIMENTAL

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; Drug: MEK162

Interventions

LEE011 DRUG

LEE011 will be administered orally once daily

Phase II; Phase Ib

MEK162 DRUG

MEK162 will be administered orally twice daily

Phase II; Phase Ib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Pfizer: lead

Study Sites (17)

University of California, Dept of Oncology

San Francisco, California, 94101, United States

Location

California Pacific Medical Center Onc Dept

San Francisco, California, 94120-7999, United States

Location

Karmanos Cancer Institute Dept of Oncology

Detroit, Michigan, 48201, United States

Location

Memorial Sloan Kettering Cancer Center Dept Oncology

New York, New York, 10021, United States

Location

Columbia University Medical Center- New York Presbyterian Onc Dept.

New York, New York, 10032, United States

Location

Vanderbilt University Medical Center SC - Dept of Oncology .

Nashville, Tennessee, 37232, United States

Location

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

Houston, Texas, 77030-4009, United States

Location

Pfizer Investigative Site 1003

North Sydney, New South Wales, 2060, Australia

Location

Pfizer Investigative Site 1002

Westmead, New South Wales, 2145, Australia

Location

Pfizer Investigator Site 1001

East Melbourne, Victoria, Australia

Location

Pfizer Investigative Site 1050

Essen, 45147, Germany

Location

Pfizer Investigative Site 1053

Gera, 07548, Germany

Location

Pfizer Investigative Site 1052

Hanover, 30625, Germany

Location

Pfizer Investigative Site 1051

München, 80336, Germany

Location

Pfizer Investigative Site 1101

Napoli, 80131, Italy

Location

Pfizer Investigative Site 1151

Utrecht, The Netherlands, 3508 GA, Netherlands

Location

Pfizer Investigative Site 1150

Nijmegen, 6525 GA, Netherlands

Location

Related Publications (1)

• 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.

  PMID: 35294522 DERIVED

MeSH Terms

Interventions

ribociclib; binimetinib

Results Point of Contact

• Title: Study Director
• Organization: Pfizer

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 24, 2013
• First Posted: February 1, 2013
• Study Start: June 1, 2013
• Primary Completion: January 15, 2018
• Study Completion: February 20, 2018
• Last Updated: December 7, 2020
• Results First Posted: August 12, 2020

Record last verified: 2020-11

Locations

IT (1); DE (4); AU (3); NL (2); US (7)