Clinical Trials /

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

NCT01781572

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

A Phase Ib/II Study of <span class="go-doc-concept go-doc-intervention">LEE011</span> in Combination With MEK162 in Patients With <span class="go-doc-concept go-doc-biomarker">NRAS</span> <span class="go-doc-concept go-doc-keyword">Mutant</span> <span class="go-doc-concept go-doc-disease">Melanoma</span>

Title

  • Brief Title: A Phase Ib/II Study of LEE011 in Combination With MEK162 in Patients With NRAS Mutant Melanoma
  • Official Title: A Phase Ib/II, Multicenter, Open Label, Study of LEE011 in Combination With MEK162 in Adult Patients With NRAS Mutant Melanoma
  • Clinical Trial IDs

    NCT ID: NCT01781572

    ORG ID: CMEK162X2114

    Trial Conditions

    Locally Advanced or Metastatic NRAS Mutant Melanoma

    Trial Interventions

    Drug Synonyms Arms
    LEE011 and MEK162 Dosing Schedule 1 Phase Ib
    LEE011 and MEK162 Phase II
    LEE011 and MEK162 Dosing Schedule 2 Phase Ib
    LEE011 and MEK162 Dosing Schedule 3 Phase Ib

    Trial Purpose

    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.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    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. Patients with either measurable or evaluable disease will be eligible. 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. LEE011 and MEK162, LEE011 and MEK162, LEE011 and 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. Data from enrolled patients will also be used to better characterize the safety, tolerability and PK profile of the two agents. 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. LEE011 and MEK162

    Eligibility Criteria

    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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Incidence of dose limiting toxicities (Phase Ib)

    Objective response rate (ORR) (phase II)

    Secondary Outcome Measures

    Plasma concentration-time profile (AUCtau) of LEE011 and MEK162 (phase Ib)

    Plasma concentration-time profile (AUCtau,ss) of LEE011 and MEK162 (phase Ib)

    Plasma concentration-time profile (Cmin,ss) of LEE011 and MEK162 (phase Ib)

    Plasma concentration-time profiles of LEE011 and MEK162 (phase Ib)

    Plasma concentration-time profile (Cmax) of LEE011 and MEK162 (phase Ib)

    Plasma concentration-time profile (Cmax,ss) of LEE011 and MEK162 (phase Ib)

    Plasma concentration-time profile (Tmax) of LEE011 and MEK162 (phase Ib)

    Plasma concentration-time profile (Tmax,ss) of LEE011 and MEK162 (phase Ib)

    Plasma concentration-time profile (accumulation ration, Racc) of LEE011 and MEK162 (phase Ib)

    Plasma concentration-time profile (T1/2, acc) of LEE011 and MEK162 (phase Ib)

    Plasma concentration-time profile (CL/F) of LEE011 and MEK162 (phase Ib)

    Incidence of adverse drug reactions

    Duration of Response (DoR) - Phase ll

    Time to Progression (TTP) - Phase ll

    Progression Free Survival (PFS) - Phase ll

    Overall Survival (OS) - Phase ll

    Best Overall Response (BOR) - Phase ll

    Trial Keywords