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

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

Detailed Description
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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.

Official Title
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A Phase Ib/II, Multicenter, Study of LEE011 in Combination With LGX818 in Adult Patients With BRAF Mutant Melanoma.

Conditions
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Locally Advanced Metastatic BRAF Mutant Melanoma

Intervention / Treatment
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* Drug: LEE011
* Drug: LGX818


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase Ib<br>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<br>* LEE011 will be administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle).<br>* Other names: Ribociclib;Drug: LGX818<br>* LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).<br>* Other names: Encorafenib;|
| Experimental: Phase II arm 1a<br>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<br>* LEE011 will be administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle).<br>* Other names: Ribociclib;Drug: LGX818<br>* LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).<br>* Other names: Encorafenib;|
| Experimental: Phase II arm 1b<br>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<br>* LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).<br>* Other names: Encorafenib;|
| Experimental: Phase II arm 2<br>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<br>* LEE011 will be administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle).<br>* Other names: Ribociclib;Drug: LGX818<br>* LGX818 will be administered orally, once daily on a continuous dosing schedule (28-day cycle).<br>* Other names: Encorafenib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Cycle 1 (approximately 28 days) | 
| 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. | Approximately 23 months after enrollment | 
| 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. | Approximately 23 months after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I - Number of Subjects Experiencing at Least One Adverse Event (AE). |  | Approximately 23 months after enrollment | 
| Phase I - Number of Subjects Experiencing at Least One Serious Adverse Event (SAE). |  | Approximately 23 months after enrollment | 
| 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. | 28-day cycles | 
| 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. | Approximately 23 months after enrollment | 
| 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. | Approximately 23 months after enrollment | 
| 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. | Approximately 23 months after enrollment | 
| 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. | Approximately 23 months after enrollment | 
| 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. | 28-day cycles | 
| 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. | 28-day cycles | 
| 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. | 28-day cycles | 
| 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. | 28-day cycles | 
| 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. | 28-day cycles | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RAF kinase inhibitor, Metastatic melanoma, V600, Open-label dose escalation, BRAF inhibitor, LEE011, CDK4/6, LGX818, BRAF