Back to resultsSafety and Efficacy of LEE011 and LGX818 in Patients With BRAF Mutant Melanoma.
Primary Purpose
Locally Advanced Metastatic BRAF Mutant Melanoma
Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
LEE011
LGX818
Sponsored by
About this trial
This is an interventional treatment trial for Locally Advanced Metastatic BRAF Mutant Melanoma focused on measuring Open-label dose escalation, BRAF inhibitor, LEE011, CDK4/6, LGX818, RAF kinase inhibitor, Metastatic melanoma, BRAF, V600
Eligibility 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.
Sites / Locations
- University of Colorado Dept of Oncology
- Karmanos Cancer Institute Dept of Oncology
- Memorial Sloan Kettering Cancer Center Dept Oncology
- Oregon Health & Science University Dept. of OHSU (3)
- Vanderbilt University Medical Center SC - Dept of Oncology .
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Experimental
Arm Label
Phase Ib
Phase II arm 1a
Phase II arm 1b
Phase II arm 2
Arm Description
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.
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.
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.
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.
Outcomes
Primary Outcome Measures
Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1
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)
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)
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).
Phase I - Number of Subjects Experiencing at Least One Serious Adverse Event (SAE).
Phase Ib/II - Plasma Concentration-time Profiles
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)
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)
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)
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)
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
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
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
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
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
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01777776
Brief Title
Safety and Efficacy of LEE011 and LGX818 in Patients With BRAF Mutant Melanoma.
Official Title
A Phase Ib/II, Multicenter, Study of LEE011 in Combination With LGX818 in Adult Patients With BRAF Mutant Melanoma.
Study Type
Interventional
2. Study Status
Record Verification Date
July 2016
Overall Recruitment Status
Terminated
Why Stopped
Study was withdrawn due to scientific and business considerations.
Study Start Date
July 2013 (undefined)
Primary Completion Date
April 2015 (Actual)
Study Completion Date
April 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Array BioPharma
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
To evaluate the safety, tolerability and efficacy of LEE011 and LGX818 when administered orally to patients with BRAF mutant melanoma.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Locally Advanced Metastatic BRAF Mutant Melanoma
Keywords
Open-label dose escalation, BRAF inhibitor, LEE011, CDK4/6, LGX818, RAF kinase inhibitor, Metastatic melanoma, BRAF, V600
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
28 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Phase Ib
Arm Type
Experimental
Arm Description
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.
Arm Title
Phase II arm 1a
Arm Type
Experimental
Arm Description
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.
Arm Title
Phase II arm 1b
Arm Type
Experimental
Arm Description
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.
Arm Title
Phase II arm 2
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
LEE011
Other Intervention Name(s)
Ribociclib
Intervention Description
LEE011 will be administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle).
Intervention Type
Drug
Intervention Name(s)
LGX818
Other Intervention Name(s)
Encorafenib
Intervention Description
LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).
Primary Outcome Measure Information:
Title
Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1
Description
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.
Time Frame
Cycle 1 (approximately 28 days)
Title
Phase II - Progression Free Survival (PFS)
Description
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.
Time Frame
Approximately 23 months after enrollment
Title
Phase II - Objective Response Rate (ORR)
Description
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.
Time Frame
Approximately 23 months after enrollment
Secondary Outcome Measure Information:
Title
Phase I - Number of Subjects Experiencing at Least One Adverse Event (AE).
Time Frame
Approximately 23 months after enrollment
Title
Phase I - Number of Subjects Experiencing at Least One Serious Adverse Event (SAE).
Time Frame
Approximately 23 months after enrollment
Title
Phase Ib/II - Plasma Concentration-time Profiles
Description
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.
Time Frame
28-day cycles
Title
Phase Ib/II - Overall Response Rate (ORR)
Description
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.
Time Frame
Approximately 23 months after enrollment
Title
Phase Ib/II - Progression Free Survival (PFS)
Description
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.
Time Frame
Approximately 23 months after enrollment
Title
Phase Ib/II - Duration Of Response (DOR)
Description
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.
Time Frame
Approximately 23 months after enrollment
Title
Phase II - Overall Survival (OS)
Description
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.
Time Frame
Approximately 23 months after enrollment
Title
Phase Ib/II - Pharmacokinetic Parameters: AUCtau
Description
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Time Frame
28-day cycles
Title
Phase Ib/II - Pharmacokinetic Parameters: Cmin
Description
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Time Frame
28-day cycles
Title
Phase Ib/II - Pharmacokinetic Parameters: Cmax
Description
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Time Frame
28-day cycles
Title
Phase Ib/II - Pharmacokinetic Parameters: Tmax
Description
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Time Frame
28-day cycles
Title
Phase Ib/II - Pharmacokinetic Parameters: Racc
Description
Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Time Frame
28-day cycles
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Array BioPharma
Organizational Affiliation
303-381-6604
Official's Role
Study Director
Facility Information:
Facility Name
University of Colorado Dept of Oncology
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Karmanos Cancer Institute Dept of Oncology
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center Dept Oncology
City
NY
State/Province
New York
ZIP/Postal Code
90033
Country
United States
Facility Name
Oregon Health & Science University Dept. of OHSU (3)
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Vanderbilt University Medical Center SC - Dept of Oncology .
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Novartis Investigative Site
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
Novartis Investigative Site
City
Woodville
State/Province
South Australia
ZIP/Postal Code
5011
Country
Australia
Facility Name
Novartis Investigative Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H2X 3J4
Country
Canada
Facility Name
Novartis Investigative Site
City
Utrecht
ZIP/Postal Code
3584CX
Country
Netherlands
12. IPD Sharing Statement
Learn more about this trial
Safety and Efficacy of LEE011 and LGX818 in Patients With BRAF Mutant Melanoma.
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