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Report for Clinical Trial NCT01584648

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Phase III, Randomized, Double-blinded Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to Dabrafenib and Placebo as First-line Therapy in Subjects With Unresectable (Stage IIIC) or Metastatic (Stage IV) BRAF V600E/K Mutation-positive Cutaneous Melanoma

This is a two-arm, double-blinded, randomized, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy to dabrafenib administered with a trametinib placebo (dabrafenib monotherapy). Subjects with histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV, and BRAF V600E/K mutation positive will be screened for eligibility. Subjects who have had prior systemic anti-cancer treatment in the advanced or metastatic setting will not be eligible although prior systemic treatment in the adjuvant setting will be allowed. Approximately 340 subjects will be randomized 1:1 (combination therapy: dabrafenib monotherapy). Subjects will be stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus less than or equal to the ULN) and BRAF mutation (V600E versus V600K). The primary endpoint is investigator-assessed, progression-free survival for subjects receiving the combination therapy compared with those receiving dabrafenib monotherapy. Subjects will be followed for overall survival; crossover will not be permitted.

NCT01584648 Melanoma
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

3 Interventions

Name: dabrafenib

Description: dabrafenib 150 mg twice daily
Type: Drug
Group Labels: 1

Combination

Name: dabrafenib plus trametinib placebo

Description: dabrafenib 150 mg twice daily and trametinib placebo
Type: Drug
Group Labels: 1

Dabrafenib monotherapy

Name: Trametinib

Description: trametinib 2 mg once daily
Type: Drug
Group Labels: 1

Combination


Primary Outcomes

Description: Progression-free survival (PFS) is defined as the time (in months) from the date of randomization to the first documented occurrence of PD or death. Investigator PFS was summarized per response evaluation criteria in solid tumors (RECIST, version 1.1) which is a set of published criteria defining when cancer patients improve (respond), stay the same (stable) or worsen (progress). PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5mm or the appearance of one or more new lesions, or the worsening of non target lesions significant enough to require study treatment discontinuation. For participants who had not progressed or died at the time of the analysis, censoring was performed at the last adequate disease assessment.

Measure: Progression-Free Survival (PFS) as Assessed by the Investigator

Time: From randomization until the earliest date of disease progression (PD) or death due to any cause (average of 9 study months)

Secondary Outcomes

Description: OS is defined as the interval of time (in months) between the date of randomization and the date of death due to any cause. For participants who did not die, time of death was censored at the date of last contact.

Measure: Overall Survival (OS)

Time: From randomization until death due to any cause (average of 9 study months)

Description: A participant was defined as a responder if he/she sustained a complete response (CR: the disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm).

Measure: Number of Participants With a Confirmed Response (Complete Response or Partial Response)

Time: From randomization until the first documented complete response or partial response (average of 9 study months)

Description: Duration of response is defined as the time (in months) from the first documented complete response (CR: the disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm) until disease progression (PD). PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5mm or the appearance of one or more new lesions, or the worsening of non target lesions significant enough to require study treatment discontinuation. PD was based on the radiological evidence by investigator.

Measure: Duration of Response for Participants With a Confirmed Response (Complete Response or Partial Response)

Time: From the time of the first documented response (CR or PR) until disease progression (average of 9 study months)

Description: An AE is defined as any untoward medical occurrence in a par., temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Protocol specific SAEs included: ALT≥3XULN and total bilirubin ≥2XULN (35% direct) or ALT ≥3XULN and INR >1.5 (if INR is measured); any new malignancy with a histology different from the primary tumor; left ventricular ejection fraction that met stopping criteria; central serous retinopathy or retinal vein occlusion; pyrexia accompanied by ≥grade 3 hypotension, or hypotension that is clinically significant as judged by the investigator, dehydration requiring IV fluids, or severe rigor/chills. Refer to the general AE/SAE module for a list of AEs and SAEs.

Measure: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

Time: From the time the first dose of study treatment administered until 30 days after discontinuation of study treatment (average of 9 study months)

Description: Clinical chemistry data were summarized according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe or disabling; Grade 4, Life-threatening; Grade 5, Death related to AE. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Clinical chemistry tests where the toxicity grade is defined by NCI-CTCAE includes albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, calcium, glucose, potassium, sodium, creatinine and phosphate. Participants with missing Baseline grades were assumed to have a Baseline grade of 0. Only those participants with laboratory values for worst-case on-therapy are presented. Worst-case on-therapy included both scheduled and unscheduled visits.

Measure: Number of Participants With a Worst-case On-therapy Grade Change From Baseline to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters

Time: From Baseline up to Week 64

Description: Hematology data were summarized according to NCI-CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe, or disabling; Grade 4, Life-threatening; Grade 5, Death related to AE. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Hematology tests where the toxicity grade is defined by NCI-CTCAE includes hemoglobin, lymphocytes, neutrophils, platelets and leukocytes. Participants with missing Baseline grades were assumed to have a Baseline grade of 0. Only those participants with laboratory values for worst-case on-therapy are presented. Worst-case on-therapy included both scheduled and unscheduled visits.

Measure: Number of Participants With a Worst-case On-therapy Grade Change From Baseline to Grade 3 and 4 for the Indicated Hematology Parameters

Time: From Baseline up to Week 64

Description: Hematology tests where the toxicity grade is not defined by NCI-CTCAE includes basophils, eosinophils and monocytes. Change from Baseline is categorized as a decrease to low, change to normal or no change, increase to high in reference to the normal range. Only those participants with laboratory values for worst-case on-therapy are presented. For the worst-case on-therapy, participants were counted twice if the participant lab value decreased to low and increased to high during the on-therapy period.

Measure: Number of Participants With a Worst-case On-therapy Change From Baseline With Respect to the Normal Range for the Indicated Hematology Parameters

Time: From Baseline up to Week 64

Description: Clinical chemistry tests where the toxicity grade is not defined by NCI-CTCAE includes chloride, creatinine clearence, lactate dehydrogenase, urea, protein and carbon dioxide. Change from Baseline is categorized as decrease to low, change to normal or no change, increase to high in reference to the normal range. Only those participants with laboratory values for worst-case on-therapy are presented. For the worst-case on-therapy, participants were counted twice if the participant lab value decreased to low and increased to high during the on-therapy period.

Measure: Number of Participants With a Worst-case On-therapy Change From Baseline With Respect to the Normal Range for the Indicated Clinical Chemistry Parameters

Time: From Baseline up to Week 64

Description: Change from Baseline in heart rate is categorized as decrease to <60 beats per minute (bpm), change to normal or no change, and increase to >100 bpm. Participants with a missing Baseline value are assumed to have a normal Baseline value. Participants were counted twice if the participant heart rate value decreased to <60 bpm and increased to >100 bpm post-Baseline. Only those participants with heart rate values for worst-case on-therapy are presented.

Measure: Number of Participants With a Worst-case On-therapy Change From Baseline in Heart Rate

Time: From Baseline up to Week 64

Description: Change from Baseline in systolic blood pressure (SBP) is categorized as: Grade 0 (<120 millimeters of mercury [mmHg]), Grade 1 (120-139 mmHg), Grade 2 (140-159 mmHg), and Grade 3 (>=160 mmHg). Change from Baseline in diastolic blood pressure (DBP) is categorized as: Grade 0 (<80 mmHg), Grade 1 (80-89 mmHg), Grade 2 (90-99 mmHg), and Grade 3 (>=100 mmHg). An increase is defined as an increase in the CTCAE grade relative to the Baseline grade. Participants with missing Baseline values were assumed to have a Baseline value of grade 0. Only those participants with blood pressure values for worst-case on-therapy are presented.

Measure: Number of Participants With a Worst-case On-therapy Change From Baseline in Systolic and Diastolic Blood Pressure to Grade 2 or Grade 3

Time: From Baseline up to Week 64

Description: Change from Baseline in temperature is categorized as a decrease to <=35 degrees celsius (C), change to normal or no change as 35-38 degrees C, and increase to >=38 degrees C. Participants with a missing Baseline value are assumed to have a normal Baseline value. Participants were counted twice if the participant temperature value decreased to <=35 degrees C and increased to >=38 degrees C post-Baseline. Only those participants with temperature values for worst-case on-therapy are presented.

Measure: Number of Participants With a Worst-case On-therapy Change From Baseline in Temperature

Time: From Baseline up to Week 64

Description: The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. Bazett's QTc is categorized as: Grade 0 (<450 milliseconds [msec]), Grade 1 (450-480 msec), Grade 2 (481-500 msec), and Grade 3 (>=501 msec). An increase is defined as an increase in the CTCAE grade relative to the Baseline grade. Participants with missing Baseline values were assumed to have a Baseline value of grade 0. Only those participants with Bazett's QTc values for worst-case on-therapy are presented.

Measure: Number of Participants With a Worse-case On-therapy Change From Baseline in the Bazett's QTc to Grade 2 or Grade 3

Time: From Baseline up to Week 60

Description: Absolute change from Baseline in LVEF were summarized at each scheduled assessment time and in the worst-case post Baseline. Only the post Baseline assessments that used the same method (ECHO or Multi Gated Acquisition Scan [MUGA]) as the Baseline assessments were used to derive the change from Baseline. The change from Baseline was categorized as any increase; no change; and any decrease and as 0-10 decrease, 10 - 19 decrease, >= 20 decrease, >=10 decrease and >= lower limit of normal (LLN), >=10 decrease and 10 decrease and = 20 decrease and >= LLN, >= 20 decrease and Measure: Number of Participants With Worst-case On-therapy Change From Baseline in Left Ventricular Ejection Fraction (LVEF) as Assessed by Echocardiogram

Time: From Baseline up to Week 60

Description: Participants were evaluated for the event of squamous cell carcinoma including Keratoacanthoma.

Measure: Number of Participants With Incidence of Squamous Cell Carcinoma

Time: From Baseline up to end of study (average of 9 study months)

Description: Blood samples were collected for Pharmacokinetic (PK) analysis in all participants. Three blood samples were collected at Week 8: pre-dose, 1-3 hours post dose, and 4-6 hours post dose. One pre-dose blood sample was obtained at Weeks 16 and 24.

Measure: Plasma Concentrations of Trametinib

Time: Week 8: pre-dose, 1-3 hours and 4-6 hours post dose; Week 16 pre-dose and Week 24 pre-dose

Description: Blood samples were collected for PK analysis in all participants. Three blood samples were collected at Week 8: pre-dose, 1-3 hours post dose, and 4-6 hours post dose. One pre-dose blood sample was obtained at Weeks 16 and 24. Plasma concentrations of dabrafenib (GSK2118436) and its metabolites (GSK2285403, GSK2298683, and GSK2167542) were determined using the currently approved analytical methodology.

Measure: Plasma Concentrations of Dabrafenib and Its Metabolites

Time: Week 8: pre-dose, 1-3 hours and 4-6 hours post dose; Week 16 pre-dose and Week 24 pre-dose

Purpose: Treatment

Allocation: Randomized


There are 2 SNPs

SNPs


1 V600E

A Phase III, Randomized, Double-blinded Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to Dabrafenib and Placebo as First-line Therapy in Subjects With Unresectable (Stage IIIC) or Metastatic (Stage IV) BRAF V600E/K Mutation-positive Cutaneous Melanoma. --- V600E ---

Subjects with histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV, and BRAF V600E/K mutation positive will be screened for eligibility. --- V600E ---

Subjects will be stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus less than or equal to the ULN) and BRAF mutation (V600E versus V600K). --- V600E ---

Plasma concentrations of dabrafenib (GSK2118436) and its metabolites (GSK2285403, GSK2298683, and GSK2167542) were determined using the currently approved analytical methodology.. Inclusion Criteria: - Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive using the bioMerieux (bMx) investigational use only (IUO) THxID BRAF Assay (IDE: G120011). --- V600E ---

(Note: Ipilimumab treatment must end at least 8 weeks prior to randomization.) - The subject has received major surgery or certain tyes of cancer therapy with 21 days of starting treatment - Current use of prohibited medication listed in the protocol - Left ventricular ejection fraction less than the lower limit of normal - Uncontrolled blood pressurl - History or current evidence of retinal vein occlusion or central serous retinopathy - Brain metastases unless previously treated with surgery or stereotactic radiosurgery and the disease has been stable for at least 12 weeks - The subject is pregnant or nursing Inclusion Criteria: - Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive using the bioMerieux (bMx) investigational use only (IUO) THxID BRAF Assay (IDE: G120011). --- V600E ---


2 V600K

Subjects will be stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus less than or equal to the ULN) and BRAF mutation (V600E versus V600K). --- V600E --- --- V600K ---



HPO Nodes


HPO: