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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01781572
First received: January 24, 2013
Last updated: April 2, 2014
Last verified: April 2014

January 24, 2013
April 2, 2014
June 2013
January 2016   (final data collection date for primary outcome measure)
  • Incidence of dose limiting toxicities (Phase Ib) [ Time Frame: first 28 days of treatment ] [ Designated as safety issue: Yes ]
    To estimate the maximum tolerate doses (MTDs) and/or identify the RP2D and schedule of LEE011 and MEK162 combination.
  • Objective response rate (ORR) (phase II) [ Time Frame: Baseline, every 2-4 months ] [ Designated as safety issue: Yes ]
    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.
Same as current
Complete list of historical versions of study NCT01781572 on ClinicalTrials.gov Archive Site
  • Plasma concentration-time profile (AUCtau) of LEE011 and MEK162 (phase Ib) [ Time Frame: up to 24 weeks ] [ Designated as safety issue: Yes ]
    To Characterize the PK profiles of LEE011 and MEK162 as well as any other significant metabolites identified (Phase Ib).
  • Plasma concentration-time profile (AUCtau,ss) of LEE011 and MEK162 (phase Ib) [ Time Frame: up to 24 weeks ] [ Designated as safety issue: Yes ]
    To Characterize the PK profiles of LEE011 and MEK162 as well as any other significant metabolites identified (Phase Ib).
  • Plasma concentration-time profile (Cmin,ss) of LEE011 and MEK162 (phase Ib) [ Time Frame: up to 24 weeks ] [ Designated as safety issue: Yes ]
    To Characterize the PK profiles of LEE011 and MEK162 as well as any other significant metabolites identified (Phase Ib).
  • Plasma concentration-time profiles of LEE011 and MEK162 (phase Ib) [ Time Frame: up to 24 weeks ] [ Designated as safety issue: Yes ]
    Evaluation of PK parameters, including but not limited to AUCtau, AUCtau,ss, Cmin,ss, Cmax, Cmax,ss ,Tmax, Tmax,ss, accumulation ratio (Racc), and T1/2,acc, CL/F in cycle 1-6. (Phase Ib).
  • Plasma concentration-time profile (Cmax) of LEE011 and MEK162 (phase Ib) [ Time Frame: up to 24 weeks ] [ Designated as safety issue: Yes ]
    To Characterize the PK profiles of LEE011 and MEK162 as well as any other significant metabolites identified (Phase Ib).
  • Plasma concentration-time profile (Cmax,ss) of LEE011 and MEK162 (phase Ib) [ Time Frame: up to 24 weeks ] [ Designated as safety issue: Yes ]
    To Characterize the PK profiles of LEE011 and MEK162 as well as any other significant metabolites identified (Phase Ib).
  • Plasma concentration-time profile (Tmax) of LEE011 and MEK162 (phase Ib) [ Time Frame: up to 24 weeks ] [ Designated as safety issue: Yes ]
    To Characterize the PK profiles of LEE011 and MEK162 as well as any other significant metabolites identified (Phase Ib).
  • Plasma concentration-time profile (Tmax,ss) of LEE011 and MEK162 (phase Ib) [ Time Frame: up to 24 weeks ] [ Designated as safety issue: Yes ]
    To Characterize the PK profiles of LEE011 and MEK162 as well as any other significant metabolites identified (Phase Ib).
  • Plasma concentration-time profile (accumulation ration, Racc) of LEE011 and MEK162 (phase Ib) [ Time Frame: up to 24 weeks ] [ Designated as safety issue: Yes ]
    To Characterize the PK profiles of LEE011 and MEK162 as well as any other significant metabolites identified (Phase Ib).
  • Plasma concentration-time profile (T1/2, acc) of LEE011 and MEK162 (phase Ib) [ Time Frame: up to 24 weeks ] [ Designated as safety issue: Yes ]
    To Characterize the PK profiles of LEE011 and MEK162 as well as any other significant metabolites identified (Phase Ib).
  • Plasma concentration-time profile (CL/F) of LEE011 and MEK162 (phase Ib) [ Time Frame: up to 24 weeks ] [ Designated as safety issue: Yes ]
    To Characterize the PK profiles of LEE011 and MEK162 as well as any other significant metabolites identified (Phase Ib).
  • Incidence of adverse drug reactions [ Time Frame: Approximatley 12 months after FPFV ] [ Designated as safety issue: Yes ]
    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.
  • Duration of Response (DoR) - Phase ll [ Time Frame: Approximatley 12 months after the FPFV ] [ Designated as safety issue: Yes ]
    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 to Progression (TTP) - Phase ll [ Time Frame: Approximately 12 months after the FPFV ] [ Designated as safety issue: Yes ]
    To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer.
  • Progression Free Survival (PFS) - Phase ll [ Time Frame: Approximatley 12 months after the FPFV ] [ Designated as safety issue: Yes ]
    To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer.
  • Overall Survival (OS) - Phase ll [ Time Frame: Approximately 12 months after the FPFV ] [ Designated as safety issue: Yes ]
    To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer.
  • Best Overall Response (BOR) - Phase ll [ Time Frame: Approximately 12 months after the FPFV ] [ Designated as safety issue: Yes ]
    To assess clinical safety according to RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer.
Same as current
Not Provided
Not Provided
 
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.

Not Provided
Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Locally Advanced or Metastatic NRAS Mutant Melanoma
  • Drug: LEE011 and MEK162
    MEK162 will be administered orally twice daily on a continuous dosing schedule. LEE011 will be administered orally once daily for 21 days followed by a 1 week break (28-day cycle).
    Other Name: Dosing Schedule 1
  • Drug: LEE011 and MEK162
    Once the MTD(s)/RP2D have been determined for each tested dose schedule, the 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 and MEK162
    MEK162 will be administered orally twice daily and LEE011 will be administered orally once daily for 3 weeks followed by a 1 week break (28-day cycle).
    Other Name: Dosing Schedule 2
  • Drug: LEE011 and MEK162
    MEK162 will be administered orally twice daily and LEE011 will be administered once daily for 2 weeks followed by a 1 week break (21-day cycle).
    Other Name: Dosing Schedule 3
  • 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. 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.
    Interventions:
    • Drug: LEE011 and MEK162
    • Drug: LEE011 and MEK162
    • Drug: LEE011 and MEK162
  • 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. 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.
    Intervention: Drug: LEE011 and MEK162
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
58
January 2016
January 2016   (final data collection date for primary outcome measure)

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.

Both
18 Years and older
No
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals
United States,   Australia,   Germany,   Italy,   Netherlands,   Norway
 
NCT01781572
CMEK162X2114
No
Novartis ( Novartis Pharmaceuticals )
Novartis Pharmaceuticals
Not Provided
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Novartis
April 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP