Safety and Efficacy of LEE011 and LGX818 in Patients With BRAF Mutant Melanoma.

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01777776
First received: January 22, 2013
Last updated: October 14, 2014
Last verified: October 2014
  Purpose

To evaluate the safety, tolerability and efficacy of LEE011 and LGX818 when administered orally to patients with BRAF mutant melanoma.


Condition Intervention Phase
Locally Advanced or Metastatic BRAF Mutant Melanoma
Drug: LEE011
Drug: LGX818
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib/II, Multicenter, Study of LEE011 in Combination With LGX818 in Adult Patients With BRAF 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: Cycle 1 = 28 days ] [ Designated as safety issue: Yes ]
    Dose Limiting Toxicities (DLTs) during the first 28 days of the combination treatment of LEE011 and LGX818.

  • Progression Free Survival (PFS) - Phase II Arms 1 a/b [ Time Frame: 23 months after FPFV ] [ Designated as safety issue: No ]
    As per RECIST v1.1. PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause.

  • Objective Response Rate (ORR) - Phase II Arm 2 [ Time Frame: 23 months after FPFV ] [ Designated as safety issue: No ]
    As per RECIST v1.1. ORR is defined as the proportion of patients with a best overall response of complete response or partial response.


Secondary Outcome Measures:
  • Number of Adverse Events - Phase Ib/II [ Time Frame: Approximately 23 months after FPF ] [ Designated as safety issue: Yes ]
    To assess the safety and tolerability of LEE011 and LGX818 in these patients which includes changes in hematology and chemistry values, vital signs and electrocardiograms (ECG's) assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

  • Number of Serious Adverse Events - Phase Ib/II [ Time Frame: Approximately 23 months after FPFV ] [ Designated as safety issue: Yes ]
    To assess the safety and tolerability of LEE011 and LGX818 in patients which includes changes in hematology and chemistry values, vital signs and ECGs assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

  • Plasma concentration-time profiles - Phase Ib/II [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]
    Plasma PK parameters of LEE011 and plasma PK parameters of LGX818. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 21 and 22; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable). Phase 2: Cycle 1/Days 1, 8, 15, and 21. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Overall Response Rate (ORR) - Phase Ib and Phase II arms 1a/b [ Time Frame: Approximately 23 months after FPFV ] [ Designated as safety issue: No ]
    ORR is defined as the proportion of patients with a best overall response of complete response or partial response.

  • Progression Free Survival (PFS) - Phase Ib and Phase II Arm 2 [ Time Frame: Approximately 23 months after FPFV ] [ Designated as safety issue: No ]
    PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause.

  • Duration Of Response (DOR) - Phase Ib, Phase II arms 1a/1b/2 [ Time Frame: Approximately 23 months after FPFV ] [ Designated as safety issue: No ]
    DOR is calculated as the time from the date of first documented response (complete response (CR) or partial response (PR)) to the first documented date of progression or death due to underlying cancer.

  • Overall Survival (OS) - Phase II arms 1a/1b/2 [ Time Frame: Approximately 23 months after FPFV ] [ Designated as safety issue: No ]
    OS is defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last known date patient alive.

  • Plasma concentration-time profiles: AUCtau - Phase Ib/II [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]
    Plasma PK parameters of LEE011 and plasma PK parameters of LGX818. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 21 and 22; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable). Phase 2: Cycle 1/Days 1, 8, 15, and 21. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Plasma concentration-time profiles: Cmin - Phase Ib/II [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]
    Plasma PK parameters of LEE011 and plasma PK parameters of LGX818. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 21 and 22; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable). Phase 2: Cycle 1/Days 1, 8, 15, and 21. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Plasma concentration-time profiles: Cmax - Phase Ib/II [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]
    Plasma PK parameters of LEE011 and plasma PK parameters of LGX818. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 21 and 22; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable). Phase 2: Cycle 1/Days 1, 8, 15, and 21. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Plasma concentration-time profiles: Tmax - Phase Ib/II [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]
    Plasma PK parameters of LEE011 and plasma PK parameters of LGX818. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 21 and 22; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable). Phase 2: Cycle 1/Days 1, 8, 15, and 21. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Plasma concentration-time profiles: Racc - Phase Ib/II [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]
    Plasma PK parameters of LEE011 and plasma PK parameters of LGX818. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 21 and 22; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable). Phase 2: Cycle 1/Days 1, 8, 15, and 21. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).


Enrollment: 28
Study Start Date: July 2013
Estimated Study Completion Date: February 2016
Estimated Primary Completion Date: February 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase Ib
Phase Ib will randomize 18 patients with BRAF mutant melanoma, who are naïve or who have progressed on prior therapy to evaluate the safety and tolerability of the combination of LEE011 and LGX818.
Drug: LEE011
LEE011 will be administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle).
Drug: LGX818
LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).
Experimental: Phase II arm 1a
Phase II arm 1a will randomize 60 patients that are naïve to prior BRAF inhibitor therapy to LGX818+LEE011 to evaluate the effect of adding LEE011 to a BRAFi in this population.
Drug: LEE011
LEE011 will be administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle).
Drug: LGX818
LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).
Experimental: Phase II arm 1b
Phase II arm 1b will randomize 30 patients to LGX818. Single agent anti-tumor activity of LGX818 is comparable to other BRAFi that are either approved or in clinical trials. This single agent anti-tumor activity will be compared to that of the combination (LEE011 + LGX818) in the BRAFi naïve patient population.
Drug: LGX818
LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).
Experimental: Phase II arm 2
Phase II arm 2 will evaluate a single arm LEE011+LGX818 in 40 patients resistant to prior BRAF inhibitor therapy. Single agent LGX818 has shown limited activity in patients with melanoma who have failed prior BRAF inhibitor treatment; the contribution of LEE011 in this combination will be evaluated.
Drug: LEE011
LEE011 will be administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle).
Drug: LGX818
LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).

  Eligibility

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

Inclusion Criteria:

  • Age ≥18 years.
  • Diagnosis of locally advanced or metastatic melanoma along with written documentation of BRAF V600 mutation.
  • ECOG performance status of 0 - 2.
  • Patients enrolled into Phase Ib must have evidence of evaluable and/or measurable disease as determined by RECIST v1.1.
  • Patients enrolled into Phase II (BRAFi naïve and resistant) must have evidence of measurable disease as determined by RECIST v1.1.
  • Archival tumor tissue must be obtained for patients enrolled in Phase Ib and Phase II arm 1a/b- BRAFi naïve patients. If an archival tumor tissue is not available, a fresh tumor sample is acceptable.
  • For patients enrolled in the phase II arm 2, patients must agree to undergo a fresh tumor biopsy unless one was collected prior to study entry but at the time of disease relapse from the most recent BRAFi treatment.

Exclusion Criteria:

  • Symptomatic brain metastases.
  • Symptomatic or untreated leptomeningeal disease.
  • Patients with inadequate laboratory values during screening.
  • In the phase II BRAFi naïve arms (1a/b), prior exposure to CDK4/6 inhibitor (e.g., PD 0332991)
  • Impaired cardiac function or clinically significant cardiac diseases.
  • Impairment of gastro-intestinal (GI) function or GI disease that may significantly alter the absorption of LEE011 or LGX818.
  • Patients with concurrent severe and/or uncontrolled concurrent medical conditions.
  • Previous or concurrent malignancy.
  • Major surgery < 2 weeks before starting study treatment
  • Known diagnosis of human immunodeficiency virus (HIV) or hepatitis C.

Other protocol-defined 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: NCT01777776

Locations
United States, Colorado
University of Colorado Dept of Oncology
Aurora, Colorado, United States, 80045
United States, Michigan
Wayne State University/Karmanos Cancer Institute Dept of Oncology
Detroit, Michigan, United States, 48201
United States, New York
Memorial Sloan Kettering Cancer Center Dept Oncology
New York, New York, United States, 10021
United States, Oregon
Oregon Health & Science University Dept. of OHSU (3)
Portland, Oregon, United States, 97239
United States, Tennessee
Vanderbilt University Medical Center SC - Dept of Oncology .
Nashville, Tennessee, United States, 37232
Australia, New South Wales
Novartis Investigative Site
Westmead, New South Wales, Australia, 2145
Canada, Quebec
Novartis Investigative Site
Montreal, Quebec, Canada, H2X 3J4
Netherlands
Novartis Investigative Site
Utrecht, Netherlands, 3584CX
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: NCT01777776     History of Changes
Other Study ID Numbers: CLEE011X2105
Study First Received: January 22, 2013
Last Updated: October 14, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
Open-label dose escalation; BRAF inhibitor; LEE011; CDK4/6; LGX818; RAF kinase inhibitor; metastatic melanoma; BRAF; V600

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

ClinicalTrials.gov processed this record on October 23, 2014