A Phase I Study of Oral LGX818 in Adult Patients With Advanced or Metastatic BRAF Mutant Melanoma

Study Overview
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Brief Summary
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CLGX818X2101 is a first-time in-human, phase I study to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of daily administered LGX818 (daily, twice daily and/or every-other-day), a RAF kinase inhibitor. Patients with locally advanced or metastatic melanoma harboring the BRAF V600 mutation (during dose escalation phase and expansion phase) and patients with metastatic colorectal cancer harboring the BRAF V600 mutation (during the expansion phase) will be enrolled. The study consists of a dose escalation part were cohorts of patients will receive escalating oral doses of LGX818, followed by a safety dose expansion part were patients will be treated with oral dose of LGX818 given at the MTD or RP2D.

Official Title
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A Phase I, Multicenter, Open-label, Dose-escalation Study of Oral LGX818 in Adult Patients With Locally Advanced or Metastatic BRAF Mutant Melanoma

Conditions
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Melanoma and Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: LGX818


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For the dose escalation phase: Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC]). For the dose expansion phase: (i) Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC]), or (ii) confirmed diagnosis and non-resectable advanced metastatic colorectal cancer (mCRC) for which no further effective standard therapy exists. Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation. Evidence of measurable disease Exclusion Criteria: Previous therapy with a MEK inhibitor. Symptomatic or untreated leptomeningeal disease. Symptomatic or untreated brain metastasis.Patients previously treated for these conditions that are asymptomatic in the absence of corticosteroid therapy are allowed to enroll. Brain metastasis must be stable with verification by imaging. Known acute or chronic pancreatitis. Clinically significant cardiac disease Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LGX818 Previous or concurrent malignancy. Exceptions to this exclusion criteria include: adequately treated basal cell or squamous cell skin cancer; in situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 3 years prior to study entry; or other solid tumor treated curatively, and without evidence of recurrence for at least 3 years prior to study entry. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL). History of thromboembolic or cerebrovascular events within the last 6 months 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LGX818 - Dose escalation<br> | Drug: LGX818<br> <br> |
| Experimental: LGX818 - Dose Expansion at MTD or RP2D<br> | Drug: LGX818<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicities |  | Approximately every 8 weeks (up to 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and nature of Adverse events and clinical activity |  | Approximately 3 years | 
| Pharmacokinetic profile of LGX818 | LGX818 Plasma concentration | Approximately 2 years | 
| Tumor response per RECIST | This includes duration of response, time to response, progression free survival and overall survival. | Approximately 3 years | 
| Baseline molecular status | Baseline molecular status (mutation/ amplification/ expression) in tumor tissue of potential predictive markers | Approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BRAF mutant,, BRAF mutated,, melanoma,, metastatic,, advanced,, RAF kinase inhibitor, BRAF V600 mutation