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

Phase 1

Terminated

Conditions: Locally Advanced Metastatic BRAF Mutant Melanoma

Interventions: Drug: LEE011
Drug: LGX818

Registration Number: NCT01777776

Lead Sponsor: Array BioPharma

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 28

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase Ib	LGX818	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	LEE011	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 2	LGX818	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.
Phase II arm 1a	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 Ib	LEE011	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 1b	LGX818	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	LEE011	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.

Primary Outcome Measures

Name	Time	Method
Phase II - Objective Response Rate (ORR)	Approximately 23 months after enrollment	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.
Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1	Cycle 1 (approximately 28 days)	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)	Approximately 23 months after enrollment	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.

Secondary Outcome Measures

Name	Time	Method
Phase II - Overall Survival (OS)	Approximately 23 months after enrollment	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: Cmin	28-day cycles	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 - Plasma Concentration-time Profiles	28-day cycles	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)	Approximately 23 months after enrollment	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)	Approximately 23 months after enrollment	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 - Pharmacokinetic Parameters: Tmax	28-day cycles	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	28-day cycles	Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Phase I - Number of Subjects Experiencing at Least One Adverse Event (AE).	Approximately 23 months after enrollment
Phase Ib/II - Pharmacokinetic Parameters: Cmax	28-day cycles	Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.
Phase I - Number of Subjects Experiencing at Least One Serious Adverse Event (SAE).	Approximately 23 months after enrollment
Phase Ib/II - Duration Of Response (DOR)	Approximately 23 months after enrollment	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 Ib/II - Pharmacokinetic Parameters: AUCtau	28-day cycles	Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed.

Trial Locations

Locations (6): Memorial Sloan Kettering Cancer Center Dept Oncology
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NY, New York, United States
Karmanos Cancer Institute Dept of Oncology
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Detroit, Michigan, United States
Oregon Health & Science University Dept. of OHSU (3)
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Portland, Oregon, United States
Novartis Investigative Site
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Utrecht, Netherlands
Vanderbilt University Medical Center SC - Dept of Oncology .
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Nashville, Tennessee, United States
University of Colorado Dept of Oncology
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Aurora, Colorado, United States