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Completed

NCT Number: NCT01781572

A Phase Ib/II Study of LEE011 in Combination With MEK162 in 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.

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Key information

Conditions

Locally Advanced or Metastatic NRAS Mutant Melanoma

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Pfizer Investigative Site 1003, North Sydney, New South Wales, Australia

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

LEE011

Drug

LEE011 will be administered orally once daily

MEK162

Drug

MEK162 will be administered orally twice daily

Primary outcomes

  1. Number of Dose Limiting Toxicities (Phase Ib)

    Time frame: first 28 days of treatment

    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.

  2. Objective Response Rate (ORR) (Phase II)

    Time frame: Approximately 12 months after the FPFV

    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.

Secondary outcomes

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

    Time frame: Cycle 1 Day 1

    To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).

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

    Time frame: Cycle 1 Day 1

    To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).

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

    To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).

  4. Plasma Concentration-time Profile (AUCtau,ss) of MEK162 (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

    To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).

  5. Plasma Concentration-time Profile (Cmin,ss) of LEE011 (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

    To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).

  6. Plasma Concentration-time Profile (Cmin,ss) of MEK162 (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

    To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).

  7. Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib)

    Time frame: Cycle 1 Day 1

    To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).

  8. Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib)

    Time frame: Cycle 1 Day 1

    To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).

  9. Plasma Concentration-time Profile (Cmax,ss) of LEE011 (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

    To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).

  10. Plasma Concentration-time Profile (Cmax,ss) of MEK162 (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

    To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).

  11. Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib)

    Time frame: Cycle 1 Day 1

    To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).

  12. Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib)

    Time frame: Cycle 1 Day 1

    To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).

  13. Plasma Concentration-time Profile (Tmax,ss) of LEE011 (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

    To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).

  14. Plasma Concentration-time Profile (Tmax,ss) of MEK162 (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

    To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).

  15. Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (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

    To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).

  16. Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (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

    To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).

  17. Plasma Concentration-time Profile (T1/2,ss) of LEE011 (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

    To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).

  18. Plasma Concentration-time Profile (T1/2,ss) of MEK162 (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

    To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).

  19. Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib)

    Time frame: Cycle 1 Day 1

    To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).

  20. Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib)

    Time frame: Cycle 1 Day 1

    To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).

  21. Number of Participants With Adverse Drug Reactions

    Time frame: Approximately 12 months after FPFV

    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.

  22. Duration of Response (DoR) - Phase 2

    Time frame: Approximately 12 months after the FPFV

    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.

  23. Time to Progression (TTP) - Phase 2

    Time frame: Approximately 12 months after the FPFV

    To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer.

  24. Progression Free Survival (PFS) - Phase 1b and Phase 2

    Time frame: Approximately 12 months after the FPFV

    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.

  25. Overall Survival (OS) - Phase ll

    Time frame: Approximately 12 months after the FPFV

    To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer.

  26. Best Overall Response (BOR) - Phase II

    Time frame: Approximately 12 months after the FPFV

    To assess clinical safety according to RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer.

Sponsors and collaborators

Lead sponsor

Pfizer

Industry

Registry information

Official study title

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

Important dates

Study start
2013
Primary completion
2018
Study completion
2018
First posted
Feb 1, 2013
Registry last updated
Dec 7, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.