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

This study has been terminated.
(Study was withdrawn due to scientific and business considerations.)
Sponsor:
Information provided by (Responsible Party):
Array BioPharma
ClinicalTrials.gov Identifier:
NCT01777776
First received: January 22, 2013
Last updated: July 27, 2016
Last verified: July 2016
  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 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 Array BioPharma:

Primary Outcome Measures:
  • Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 [ Time Frame: Cycle 1 (approximately 28 days) ] [ Designated as safety issue: Yes ]

    Dose Limiting Toxicities (DLTs) during the first 28 days of the combination treatment of LEE011 and LGX818.

    Due to the halt of enrollment, no Maximum Tolerated Dose (MTD) was formally declared during the study.


  • Phase II - Progression Free Survival (PFS) [ Time Frame: Approximately 23 months after enrollment ] [ 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.

    Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to efficacy were not performed.


  • Phase II - Objective Response Rate (ORR) [ Time Frame: Approximately 23 months after enrollment ] [ 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.

    Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to efficacy were not performed.



Secondary Outcome Measures:
  • Phase I - Number of Subjects Experiencing at Least One Adverse Event (AE). [ Time Frame: Approximately 23 months after enrollment ] [ Designated as safety issue: No ]
  • Phase I - Number of Subjects Experiencing at Least One Serious Adverse Event (SAE). [ Time Frame: Approximately 23 months after enrollment ] [ Designated as safety issue: No ]
  • Phase Ib/II - Plasma Concentration-time Profiles [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]
    Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to plasma concentration time profiles were not performed.

  • Phase Ib/II - Overall Response Rate (ORR) [ Time Frame: Approximately 23 months after enrollment ] [ Designated as safety issue: No ]

    ORR is defined as the proportion of patients with a best overall response of complete response or partial response.

    Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed.


  • Phase Ib/II - Progression Free Survival (PFS) [ Time Frame: Approximately 23 months after enrollment ] [ 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.

    Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed.


  • Phase Ib/II - Duration Of Response (DOR) [ Time Frame: Approximately 23 months after enrollment ] [ 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.

    Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed.


  • Phase II - Overall Survival (OS) [ Time Frame: Approximately 23 months after enrollment ] [ 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.

    Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed.


  • Phase Ib/II - Pharmacokinetic Parameters: AUCtau [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]
    Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.

  • Phase Ib/II - Pharmacokinetic Parameters: Cmin [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]
    Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.

  • Phase Ib/II - Pharmacokinetic Parameters: Cmax [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]
    Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.

  • Phase Ib/II - Pharmacokinetic Parameters: Tmax [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]
    Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.

  • Phase Ib/II - Pharmacokinetic Parameters: Racc [ Time Frame: 28-day cycles ] [ Designated as safety issue: No ]
    Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.


Enrollment: 28
Study Start Date: July 2013
Study Completion Date: April 2015
Primary Completion Date: April 2015 (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).
Other Name: Ribociclib
Drug: LGX818
LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).
Other Name: Encorafenib
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).
Other Name: Ribociclib
Drug: LGX818
LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).
Other Name: Encorafenib
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).
Other Name: Encorafenib
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).
Other Name: Ribociclib
Drug: LGX818
LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).
Other Name: Encorafenib

Detailed Description:
In response to developments in the treatment of melanoma, the sponsor reviewed the data from the ongoing study and decided to halt further enrollment of patients in the Phase Ib part of the study. Consequently, the Phase II part of the study was not performed. Early termination of the study was not due to any safety concerns.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
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
Karmanos Cancer Institute Dept of Oncology
Detroit, Michigan, United States, 48201
United States, New York
Memorial Sloan Kettering Cancer Center Dept Oncology
NY, New York, United States, 90033
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
Australia, South Australia
Novartis Investigative Site
Woodville, South Australia, Australia, 5011
Canada, Quebec
Novartis Investigative Site
Montreal, Quebec, Canada, H2X 3J4
Netherlands
Novartis Investigative Site
Utrecht, Netherlands, 3584CX
Sponsors and Collaborators
Array BioPharma
Investigators
Study Director: Array BioPharma 303-381-6604
  More Information

Responsible Party: Array BioPharma
ClinicalTrials.gov Identifier: NCT01777776     History of Changes
Other Study ID Numbers: CLEE011X2105 
Study First Received: January 22, 2013
Results First Received: April 13, 2016
Last Updated: July 27, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Array BioPharma:
Open-label dose escalation
BRAF inhibitor
LEE011
CDK4/6
LGX818
RAF kinase inhibitor
Metastatic melanoma
BRAF
V600

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 December 02, 2016