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
  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.


Condition Intervention Phase
Locally Advanced or Metastatic NRAS Mutant Melanoma
Drug: LEE011 and MEK162
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib/II, Multicenter, Open Label, Study of LEE011 in Combination With MEK162 in Adult Patients With NRAS Mutant Melanoma

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Estimated Enrollment: 58
Study Start Date: June 2013
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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
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 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.
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01781572

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals

Locations
United States, California
University of California San Francisco Dept of Onc Not yet recruiting
San Francisco, California, United States, 94101
Contact: Kathryn Takamura    415-885-7837    takamuraK@cc.ucsf.edu   
Principal Investigator: Adil Daud         
United States, Florida
H. Lee Moffitt Cancer Center & Research Institute SC - 7 Not yet recruiting
Tampa, Florida, United States, 33612
Contact: Amber Isley    813-745-7631    Amber.Isley@moffitt.org   
Principal Investigator: Geoffrey Gibney         
United States, Michigan
Wayne State University/Karmanos Cancer Institute Dept of Oncology Recruiting
Detroit, Michigan, United States, 48201
Contact: Gail Newth    313-576-9371      
Principal Investigator: Muaiad Kittaneh         
United States, New York
Memorial Sloan Kettering Cancer Center Dept Oncology Recruiting
New York, New York, United States, 10021
Contact: Angelica Bialczak    646-888-4339    bialczaa@mskcc.org   
Principal Investigator: Michael K. Postow         
Columbia University Medical Center- New York Presbyterian Onc Dept. Not yet recruiting
New York, New York, United States, 10032
Contact: Biljana Popvic    212-305-3846    bp2304@columbia.edu   
Principal Investigator: Gary K. Schwartz         
United States, Tennessee
Vanderbilt University Medical Center SC - Dept of Oncology . Recruiting
Nashville, Tennessee, United States, 37232
Contact: Barbara J Broome    615-936-5867    Barbara.j.broome@vanderbilt.edu   
Principal Investigator: Jeffrey A. Sosman         
United States, Texas
University of Texas/MD Anderson Cancer Center Dept of Onc. Recruiting
Houston, Texas, United States, 77030-4009
Contact: Shelia Lister    713-563-0536    slister@mdanderson.org   
Principal Investigator: Kevin B. Kim         
United States, Washington
Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Dept of Oncology Not yet recruiting
Seattle, Washington, United States, 98109-1023
Contact: Daniel Leatham    206-288-7370    dleatham@uwashington.edu   
Principal Investigator: Kim Margolin         
Australia, New South Wales
Novartis Investigative Site Not yet recruiting
North Sydney, New South Wales, Australia, 2060
Novartis Investigative Site Recruiting
Westmead, New South Wales, Australia, 2145
Australia, Victoria
Novartis Investigative Site Not yet recruiting
Heidelberg, Victoria, Australia, 3084
Novartis Investigative Site Not yet recruiting
Melbourne, Victoria, Australia, 3002
Germany
Novartis Investigative Site Not yet recruiting
Essen, Germany, 45147
Novartis Investigative Site Not yet recruiting
Gera, Germany, 07548
Novartis Investigative Site Not yet recruiting
Hannover, Germany, 30625
Novartis Investigative Site Not yet recruiting
Muenchen, Germany, 80336
Italy
Novartis Investigative Site Not yet recruiting
Napoli, Italy, 80131
Netherlands
Novartis Investigative Site Recruiting
Utrecht, the Netherlands, Netherlands, 3508 GA
Novartis Investigative Site Not yet recruiting
Maastricht, Netherlands, 5800
Novartis Investigative Site Recruiting
Nijmegen, Netherlands, 6525 GA
Norway
Novartis Investigative Site Not yet recruiting
Oslo, Norway, NO-0379
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01781572     History of Changes
Other Study ID Numbers: CMEK162X2114
Study First Received: January 24, 2013
Last Updated: April 2, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas

ClinicalTrials.gov processed this record on August 19, 2014