LGX818 in Combination With Agents (MEK162; BKM120; LEE011; BGJ398; INC280) in Advanced BRAF Melanoma

Study Overview
=================
Brief Summary
-----------------
The primary purpose of the Phase II CLGX818X2102 study is to assess the anti-tumor activity of LGX818 in combination with selected agents.

Detailed Description
-----------------
This is a phase II two part multi-center, open-label study. Part I: LGX818 single agent treatment until progression Part II: Combination treatments of LGX818 + MEK162, or BKM120, or BGJ398, or INC280, or LEE01 to assess the clinical efficacy, to further evaluate the safety of the drug combinations in patients with locally advanced or metastatic BRAF mutant melanoma after relapse on LGX818, and to determine the maximum tolerated dose of the combinations (when not established previously). These drug combinations are selected and assigned to patients based on documentation of molecular resistance mechanism. Patients with BRAF mutant melanoma treated by LGX818 single agent in other studies can be enrolled directly in Part II of CLGX818X2102 after relapse. Dose-escalations in the combination arms for which no MTD has been established will be based on the recommendations of a Bayesian logistic regression model guided by an escalation with overdose control criterion. After careful evaluation of slow enrollment and the BRAF-mutant melanoma treatment landscape, recruitment was permanently halted on 26-Jul-2014. This recruitment halt was not a consequence of any safety concern and patients who were ongoing in the study continued to be treated as per protocol.

Official Title
-----------------
Phase II, Multi-center, Open-label Study of Single-agent LGX818 Followed by a Rational Combination With Agents After Progression on LGX818, in Adult Patients With Locally Advanced or Metastatic BRAF V600 Melanoma

Conditions
-----------------
Melanoma

Intervention / Treatment
-----------------
* Drug: LGX818


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: locally advanced or metastatic melanoma confirmed BRAF V600 mutation patients naïve to a selective BRAF inhibitor fresh tumor biopsy at baseline, and patient agrees for a mandatory biopsy at the time of relapse life expectancy ≥ 3 months World Health Organization (WHO) Performance Status ≤ 2. Exclusion Criteria: Previous treatment with RAF-inhibitor Symptomatic or untreated leptomeningeal disease Symptomatic brain metastases. Known acute or chronic pancreatitis Clinically significant cardiac disease AST/SGOT and ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver metastases are present Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral interventional drug Previous or concurrent malignancy. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation Specific exclusion criteria for each treatment arm: LGX818/MEK162: History or current evidence of retinal disease History of Gilbert's syndrome. LGX818/BKM120: Patients with diabetes mellitus requiring insulin treatment Patient has mood disorders LGX818/BGJ398: History and/or current evidence of ectopic mineralization/ calcification Current evidence of corneal disorder/ keratopathy Patients with current evidence of endocrine alteration of calcium/phosphate homeostasis. History of congenital long QT- syndrome and/or hypokalaemia CTCAE Grade ≥ 3 and/or magnesium levels below the clinically relevant lower limits before study entry. Ionized (i) calcium (Ca) > ULN Serum inorganic phosphorus (Pi) > ULN LGX818/LEE011 History of congenital long QT- syndrome and/or hypokalaemia CTCAE Grade ≥ 3 and/or magnesium levels below the clinically relevant lower limits before study entry.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LGX818 single agent<br>Patients had to have written documentation of a BRAFV600 mutation, which was to have been obtained locally on a fresh tumor biopsy (preferred) or on the most recent archival tumor sample available. | Drug: LGX818<br>* BRAF inhibitor. LGX818 was administered QD orally on a daily schedule (21-day cycles) as a flat-fixed dose and not by body weight or body surface area. LGX818 100 mg capsules and 50 mg capsules.<br>* Other names: encorafenib;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II) | Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: Complete Response (CR) is the Disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. | Baseline through study completion (approximately 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicities (DLTs) (Part II) | Incidence of DLTs in Part II of the study was not evaluated due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study. | Baseline through study completion (approximately 2 years) | 
| Plasma Concentration and Derived Pharmacokinetic Parameters | Assessment of pharmacokinetic (PK) parameters and plasma concentration was not done due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study. | Baseline through study completion (approximately 2 years) | 
| Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I) | Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: Complete Response (CR) is the Disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. | Baseline through completion of Part I of the study (approximately 2 years) | 
| Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II) | Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: Complete Response (CR) is the Disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. One patient with documented PD at study Day 146 entered into Part II of the study and received combination treatment of LGX818 450 mg plus MEK162 45 mg for two weeks. The patient experienced disease progression on Day 22 of Part II and discontinued the study. | Entry to Part II of the study through study completion (approximately 22 days) | 
| Molecular Status of Markers Relevant to the RAP/MEK/ERK and PI3K/AKT Pathways | Molecular status was not evaluated due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study. | Baseline and at progression with LGX818 single agent treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
BRAF inhibitor, open-label study, LGX818, MEK1620, MAPK1/2 inhibitor, Pi3K inhibitor, FGFR, c-Met, CDK4/6, metastatic melanoma, BRAF, V600