A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma

Study Overview
=================
Brief Summary
-----------------
BRF113710 is a Phase II, single-arm, open-label study to assess the efficacy, safety, and tolerability of GSK2118436 administered twice daily as a single agent in subjects with BRAF mutant metastatic melanoma. Subjects will receive 150 mg of GSK2118436 twice daily and continue on treatment until disease progression, death, or unacceptable adverse event.

Official Title
-----------------
A Phase II (BRF113710) Single-arm, Open-label Study of GSK2118436 in BRAF Mutant Metastatic Melanoma

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

Intervention / Treatment
-----------------
* Drug: GSK2118436


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Must be at least 18 years of age Must have histologically confirmed cutaneous metastatic melanoma (Stage IV) that is BRAF mutation-positive (V600 E/K) as determined via central testing with a BRAF mutation assay. Is treatment naive or has received prior treatment for metastatic melanoma. Must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Women of child-bearing potential must have a negative pregnancy test within 14 days prior to the first dose of study treatment. Women with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 4 weeks after the last dose of study medication. Men with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 16 weeks after the last dose of study medication. Must have Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. Adequate organ function. Exclusion Criteria: Previous treatment with a BRAF or MEK inhibitor. Cancer therapy (chemotherapy with delayed toxicity, radiation therapy, immunotherapy, biologic therapy, or major surgery) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks; or use of any investigational anti-cancer or other drug within 28 days or 5 half-lives, whichever is longer, preceding the first dose of GSK2118436. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection. History or evidence of brain metastases on MRI or head CT if MRI is not able to be performed. History of other malignancy. Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Certain cardiac abnormalities.

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 |
| --- | --- |
| Other: All patients<br>Subjects will receive 150 mg of GSK2118436 twice daily and continue on treatment until disease progression, death, or unacceptable adverse event. | Drug: GSK2118436<br>* Subjects will receive 150 mg of GSK2118436 twice daily and continue on treatment until disease progression, death, or unacceptable adverse event.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR) as Assessed by the Investigator for Participants Who Had a BRAF V600E Mutation | A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 millimeter (mm) in the short axis.) or PR (at least a 30 percent decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). To be assigned a status of PR or CR, a confirmatory disease assessment was required at Week 12 if an initial response was seen at the Week 6 scan. Initial responses (CR/PR) that occured at Week 12 or later were required to be confirmed not less than 4 weeks and not more than 6 weeks after the criteria for response were first met. The analysis was performed on Primary efficacy Population which comprised of all participants who received at least one dose of GSK2118436 (All Treated Participants Population) and had a BRAF V600E mutation. | Up to 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Best Overall Response of CR or PR as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600K Mutation | A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30 percent decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). To be assigned a status of PR or CR, a confirmatory disease assessment had to have been performed at Week 12 if an initial response was seen at the Week 6 scan. Initial responses (CR/PR) that occured at Week 12 or later should have been confirmed not less than 4 weeks and not more than 6 weeks after the criteria for response were first met. The analysis was performed on Secondary efficacy analysis Population which comprised of all participants who received at least one dose of GSK2118436 (All Treated Participants Population) and had a BRAF V600K mutation. | Up to 60 months | 
| Progression-free Survival (PFS) as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600E Mutation | PFS is defined as the interval between the first dose of study medication and the earliest date of disease progression or death due to any cause. The length of this interval is estimated as the date of death or progression minus date of first dose plus 1 day. Kaplan-Meier model was used to estimate the median and 95 percent confidence interval (CI). For participants who received subsequent anti-cancer therapy prior to the date of documented progression or death, PFS was censored at the last adequate assessment. For participants who did not have a documented date of progression or death, PFS was censored at the date of last adequate assessment. | Up to 60 months | 
| Progression-free Survival (PFS) as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600K Mutation | PFS is defined as the interval between the first dose of study medication and the earliest date of disease progression or death due to any cause. The length of this interval is estimated as the date of death or progression minus date of first dose plus 1 day. Kaplan-Meier model was used to estimate the median and 95 percent CI. For participants who received subsequent anti-cancer therapy prior to the date of documented progression or death, PFS was censored at the last adequate assessment. For participants who did not have a documented date of progression or death, PFS was censored at the date of last adequate assessment. | Up to 60 months | 
| Duration of Response as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600E Mutation | Duration of response for participants with either a CR or PR is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression or death due to any cause. Duration of response was estimated using Kaplan-Meier model and the median and 95 percent CI was presented. The analysis was performed on Primary efficacy Population and only those participants who had a CR or PR were analyzed. | Up to 60 months | 
| Duration of Response as Assessed by the Investigator and an Independent Reviewer for Participants Who Had a BRAF V600K Mutation | Duration of response for participants with either a CR or PR is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression or death due to any cause. Duration of response was estimated using Kaplan-Meier model and the median and 95 percent CI was presented. The analysis was performed on Secondary efficacy Population and only those participants who had a CR or PR were analyzed. | Up to 60 months | 
| Overall Survival for Participants Who Had a BRAF V600E Mutation | Overall survival is defined as the time from the first dose of study medication until death due to any cause. For participants who did not die, overall survival was censored at the date of last contact. Overall survival was estimated using kaplan-Meier model and median and 95 percent CI was presented. | Up to 60 months | 
| Overall Survival for Participants Who Had a BRAF V600K Mutation | Overall survival is defined as the time from the first dose of study medication until death due to any cause. For participants who did not die, overall survival was censored at the date of last contact. Overall survival was estimated using Kaplan-Meier model and median and 95 percent CI was presented. | From the first dose to death due to any cause (up to 60 months) | 
| Number of Participants With AEs and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs including systemic allergic and non-allergic reactions as well as local site injection-related reactions were counted throughout treatment phase and follow up phase. Systemic allergic reactions included facial paralysis, flushing, hypersensitivity and rash pruritic. Injection related reactions were considered as systemic non-allergic reactions. Local site reactions included injection site bruising, erythema, pain and reaction. The analysis was performed on All treated Population which comprised of all participants that receive at least one dose of dabrafenib. | Up to 60 months | 
| Number of Participants With Change From Baseline in Clinical Chemistry and Hematology Toxicity Grades | Blood samples were collected from participants for evaluation of change from Baseline in toxicity grades in clinical chemistry and hematology parameters. The clinical chemistry parameters included alkaline phosphatase, Alanine amino transferase (ALT), Aspartate amino transferase (AST), total bilirubin, creatinine, glucose, potassium, magnesium, sodium and phosphorus. The hematology parameters included hemoglobin, total neutrophils, platelets and white blood cells (WBC). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. The change from Baseline was calculated as visit value minus Baseline value and was presented in the form of worst case post-baseline value which was the maximum toxicity grade for a participant after the first dose of study drug over the treatment period. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). | Up to 60 months | 
| Number of Participants With Change From Baseline in Temperature and Pulse Rate | Number of participants with change from Baseline in temperature and pulse rate were evaluated from the first dose of study treatment till discontinuation due to any reason. Change from Baseline in worst-case post Baseline value was presented as decrease to <=35, change to normal or no change and increase to >=38. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. The change from Baseline was calculated as visit value minus Baseline value and was presented in the form of worst case post-baseline value which was the maximum toxicity grade for a participant after the first dose of study drug over the treatment period. | Up to 60 months | 
| Number of Participants With Increase From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Number of participants with increase from Baseline in SBP and DBP were evaluated from the first dose of study treatment till discontinuation due to any reason. Change from Baseline in worst-case post Baseline value was presented as any increase to >=80 and increase to >=100 for DBP and as any increase to >=120 and increase to >=160 for SBP. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. The change from Baseline was calculated as visit value minus Baseline value and was presented in the form of worst-case post Baseline value which was the maximum toxicity grade for a participant after the first dose of study drug over the treatment period. One participant out of the 92 participants (76 BRAF V600E patients + 16 BRAF V600K patients) did not have SBP and DBP collected after baseline. | Up to 60 months | 
| Number of Participants With Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Levels | LVEF was defined as the percentage of blood pumped out of the left ventricle. Change from Baseline in worst-case post Baseline was presented as no change or any increase and any decrease values. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. The change from Baseline was calculated as visit value minus Baseline value and was presented in the form of worst-case post Baseline value which was the maximum toxicity grade for a participant after the first dose of study drug over the treatment period. | Up to 60 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Metastatic melanoma, BRAF mutant, Melanoma, BRAF mutant metastatic melanoma