A Phase Ib/II Study of LGX818 in Combination With MEK162 in Adult Patients With BRAF Dependent Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a multi-center, open-label, dose finding, Phase Ib dose escalation study to estimate the MTD(s) and/or RP2D(s) for the dual combination of LGX818 and MEK162 and the triple combination of LGX818 and MEK162 and LEE011, followed each independently by a Phase II part to assess the clinical efficacy and to further assess the safety of the combinations in selected patient populations. Oral LGX818 and MEK162 will be administered on a continuous schedule. Oral LEE011 will be administered once daily on a three weeks on, one week off schedule. Patients will be treated until progression of disease, unacceptable toxicity develops, or withdrawal of informed consent, whichever occurs first. A cycle is defined as 28 days. The dose escalation parts of the trial will be conducted in adult patients with BRAF V600-dependent advanced solid tumors and is expected to enroll at least 18 patients for the dual combination and at least 12 patients for the triple combination. The dose escalation will be guided by a Bayesian logistic regression model (BLRM). Following MTD/RP2D declaration, patients will be enrolled in three Phase II arms for the dual combination and one Phase II arm for the triple combination. All patients will be followed for 30 days for safety assessments after study drugs discontinuation. All patients enrolled in the Phase II part of the study will be followed for survival.

Official Title
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A Phase Ib/II, Multicenter, Open-label, Dose Escalation Study of LGX818 in Combination With MEK162 in Adult Patients With BRAF V600 - Dependent Advanced Solid Tumors

Conditions
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Solid Tumors Harboring a BRAF V600 Mutation

Intervention / Treatment
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* Drug: LGX818
* Drug: MEK162
* Drug: LEE011


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC]), or confirmed diagnosis of non-resectable advanced metastatic colorectal cancer (mCRC), or any other indication upon agreement with the Sponsor, whose disease has progressed despite previous antineoplastic therapy or for whom no further effective standard therapy is available Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation Evidence of measurable disease as determined by RECIST v1.1 World Health Organization (WHO) Performance Status ≤ 2 Negative serum pregnancy test within 72 hours prior to the first study dose in all women of childbearing potential Exclusion Criteria: Progressive disease following prior treatment with RAF-inhibitors in combination with MEK-inhibitors Symptomatic or untreated leptomeningeal disease Symptomatic brain metastases. Patients are not permitted to receive enzyme inducing anti-epileptic drugs Known acute or chronic pancreatitis History or current evidence of retinal disease, retinal vein occlusion or ophthalmopathy Clinically significant cardiac disease Patients with abnormal laboratory values at Screening/baseline Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LGX818/MEK162 Previous or concurrent malignancy Pregnant or nursing (lactating) women For addition of LEE011 in the triple combination, congenital long QT syndrome or family history of unexpected sudden cardiac death and/or hypokalemia CTCAE Grade ≥ 3, brain metastases at baseline, abnormal coagulation results PT/INR >1.5 x ULN or aPTT >1.5 x ULN. 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: Other
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dual combination<br>LGX818 QD and MEK162 BID | Drug: LGX818<br> <br> Drug: MEK162<br> <br> |
| Experimental: triple combination<br>LGX818 QD and MEK162 BID and LEE011 QD 3 weeks on, 1 week off. | Drug: LGX818<br> <br> Drug: MEK162<br> <br> Drug: LEE011<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib: Estimation of Maximum Tolerated Dose (MTD) by measuring incidence of dose limiting toxicities (DLT) | To estimate the MTD(s) and/or recommended phase 2 dose(s) (RP2D(s)) of oral LGX818 in combination with oral MEK162, and of oral LGX818 in combination with oral MEK162 and oral LEE011 in patients with BRAF V600-dependent advanced solid tumors by measuring the incidence of DLTs as defined by the protocol. | up to 8 months | 
| Phase II: Clinical efficacy | Assess clinical efficacy of the LGX818 and MEK162 dual combination and LGX818 and MEK162 and LEE011 triple combination in the Phase II populations by evaluating the disease control rate (DCR) and objective response rate (ORR) as per RECIST 1.1 | up to 14 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of LGX818 and MEK162 dual combination, and LGX818 and MEK162 and LEE011 triple combination by evaluating the incidence and severity of adverse events (AE). | To characterize the safety and tolerability of LGX818 and MEK162 in combination, and LGX818 and MEK162 and LEE011 in combination by evaluating the incidence and severity (as per CTCAE grading) of AEs in all patients enrolled in the study. | up to 17 months | 
| Determination of single and multiple dose of Pharmacokinetics (PK) profile by measuring plasma concentrations versus time after study drug combination dosing (Phase Ib) | To determine the single and multiple dose PK profile of the LGX818 and MEK162 combination and LGX818 and MEK162 and LEE011 combination, by measuring plasma concentrations of MEK162 and LGX818 and LEE011 resp. at different timepoints prior and post study drug combination dosing on several days within cycle 1 and subsequent cycles. | up to 8 months | 
| Preliminary clinical anti-tumor activity by evaluating the objective response rate (Phase Ib) | To assess preliminary anti-tumor activity of the LGX818 and MEK162 combination, and the LGX818 and MEK162 and LEE011 combination by evaluating the ORR as per RECIST 1.1. Safety Issue?: (FDAAA) No | up to 8 months | 
| Further clinical efficacy (phase II) | To further assess clinical efficacy of the LGX818 and MEK162 combination and the LGX818 and MEK162 and LEE011 combination in the Phase II populations by measuring progression free survival (PFS) as per RECIST 1.1 | up to 14 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced solid tumor,, BRAF V600 mutation