LGX818 for Patients With BRAFV600 Mutated Tumors

Study Overview
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Brief Summary
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The purpose of this signal seeking study is to determine whether treatment with LGX818 demonstrates sufficient efficacy in select pathway-activated solid tumors and/or hematologic malignancies to warrant further study

Official Title
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Modular Phase II Study to Link Targeted Therapy to Patients With Pathway Activated Tumors: Module 4 - LGX818 for Patients With BRAFV600 Mutated Tumors

Conditions
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Solid Tumor, Hematologic Malignancies

Intervention / Treatment
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* Drug: LGX818


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patient has a confirmed diagnosis of a select solid tumor (except with a primary diagnosis of melanoma and colorectal cancer (CRC)) or hematologic malignancies and is in need of treatment because of progression or relapse. Patient's tumor has been evaluated and pre-identified as having a tumor with a BRAFV600 mutation at a CLIA certified laboratory. Patient must have received at least one prior treatment for recurrent, metastatic and /or locally advanced disease and for whom no standard therapy options are anticipated to result in a durable remission. Patient must have progressive and measurable disease per RECIST 1.1. or other appropriate hematological response criteria. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 Exclusion Criteria: Patient has received prior treatment with LGX818. Patients with Central Nerve System (CNS) metastasis or leptomeningeal carcinomatosis. Patient has received chemotherapy or other anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug. Patients with acute or chronic pancreatitis. Patients with impaired cardiac function or clinically significant cardiac diseases. Patients with another primary malignancy within 3 years prior to starting study treatment, with the exception of adequately treated basal cell carcinoma, squamous cell carcinoma or other non-melanomatous skin cancer, or in-situ carcinoma of the uterine cervix.

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
Intervention Model: Single Group Assignment


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LGX818<br>LGX818 will be dosed on a flat scale of 300 mg (e.g., 3 x 100 mg capsules) once daily on a continuous dosing cycle. A complete treatment cycle is defined as 28 days. There will be no breaks between dosing cycles. | Drug: LGX818<br>* LGX818 will be dosed on a flat scale of 300 mg (e.g., 3 x 100 mg capsules) once daily on a continuous dosing cycle. A complete treatment cycle is defined as 28 days. There will be no breaks between dosing cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (CBR) for Solid Tumors as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | CBR for solid tumors was defined as percentage of participants with complete response (CR) or partial response (PR), or stable disease (SD) for greater than or equal to (>=) 16 weeks. As per RECIST v1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor markers. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeter (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. PD was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. | Up to 13.3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) for Solid Tumors as Per RECIST Version 1.1 | ORR for solid tumors was defined as the percentage of participants achieving an overall best response of CR or PR as assessed per RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions and normalization of tumor markers. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From the first dose study treatment until the first documented CR or PR (maximum up to 13.3 months) | 
| Progression-Free Survival (PFS) for Solid Tumors as Per RECIST Version 1.1 | PFS for solid tumors was defined as the time from the date of first dose of study drug to the date of first documented disease progression (PD) or relapse or death due to any cause within 30 days of the last dose. PD was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. Participants who had no event were censored at the date of last adequate tumor assessment. | From the date of first dose until the first documentation of PD, relapse, censored date or death, whichever occurred first (maximum up to 13.3 months) | 
| Overall Survival (OS) for Solid Tumors | OS for solid tumors was defined as the time from the date of first dose of study drug to the date of death due to any cause. For participants who were alive at the time of analysis, the data was censored at the date of last contact. | From date of the first dose until the date of death, censored date (maximum up to 13.3 months) | 
| Duration of Response (DOR) for Solid Tumors as Per RECIST Version 1.1 | DOR for solid tumors was defined as the time from the first documented response (CR or PR) to the date of first documented PD or relapse or death due to any cause, whichever occurred first. As per RECIST v1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor markers. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | From first documentation of response to first documentation of PD or relapse or death (maximum up to 13.3 months) | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) Graded According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 | Adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated. TEAE was defined as event with onset dates occurring during the on-treatment period. CTCAE Grade 5 (death) was not used in this study. | Screening up to 30 days after the last dose of study treatment (maximum up to 13.3 months) | 
| Change From Baseline in Systolic and Diastolic Blood Pressure | Change from baseline in systolic and diastolic blood pressure in millimeter of mercury (mmHg) in sitting position was reported. | Baseline, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 (each cycle of 28 days), and End of treatment (up to 7 days after study treatment discontinuation) | 
| Change From Baseline in Sitting Pulse Rate | Change from baseline in pulse rate in beats per minute (bpm) in sitting position was reported. | Baseline, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 (each cycle of 28 days), and End of treatment (up to 7 days after study treatment discontinuation) | 
| Change From Baseline in Body Temperature | Change from baseline in body temperature in degree Celsius was reported. | Baseline, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 (each cycle of 28 days), and End of treatment (up to 7 days after study treatment discontinuation) | 
| Change From Baseline in Respiratory Rate | Change from baseline in respiratory rate in breaths per minute was reported. | Baseline, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 (each cycle of 28 days), and End of treatment (up to 7 days after study treatment discontinuation) | 
| Change From Baseline in Body Weight | Change from baseline in body weight in kilogram (Kg) was reported | Baseline, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 (each cycle of 28 days), and End of treatment (up to 7 days after study treatment discontinuation) | 
| Number of Participants With Shifts From Baseline in Hematology and Serum Chemistry Laboratory Abnormalities | Number of participants with shifts from baseline in hematology and serum chemistry laboratory parameters, were graded and reported as low, normal and high as assessed by Common terminology criteria for adverse events (CTCAE) v4.03. 'Low' refers to participants with values that were below lower limit of normal with no observation above the upper limit of normal; 'High' refers to participants with values that were above the upper limit of normal with no observation below the lower limit of normal; 'Low and High' refers to participants with values that were below the lower limit of normal and values that were above the upper limit of normal. | Baseline up to maximum of 30 days after the last dose of study treatment (up to 13.3 months) | 
| Change From Baseline in QT Interval Corrected According to the Formula of Fridericia (QTcF), QT, QRS, and PR Duration | Change from baseline in QTcF, QT, QRS, and PR duration were reported. QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QRS interval is the time from electrocardiogram Q wave to the end of the S wave, corresponding to ventricle depolarization. PR interval is the time between the beginning of the P wave and the start of the QRS interval, corresponding to the end of atrial depolarization and onset of ventricular depolarization. | Baseline, Day 15 of Cycle 1, 2, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 (each cycle of 28 days), and End of treatment (up to 7 days after study treatment discontinuation) | 
| Change From Baseline in Heart Rate | Change from baseline in heart rate in terms of beats per minute was reported. | Baseline, Day 15 of Cycle 1, 2, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 (each cycle of 28 days), and End of treatment (up to 7 days after study treatment discontinuation) |