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Study to Investigate the Objective Response Rate of Dabrafenib in Combination With Trametinib in Subjects With BRAF V600 Mutation-Positive Melanoma

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ClinicalTrials.gov Identifier: NCT02083354
Recruitment Status : Completed
First Posted : March 11, 2014
Results First Posted : March 17, 2021
Last Update Posted : May 13, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Cancer
Melanoma
Interventions Drug: Dabrafenib
Drug: Trametinib
Enrollment 77
Recruitment Details  
Pre-assignment Details 77 participants were enrolled in the study.
Arm/Group Title Arm 1
Hide Arm/Group Description All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Period Title: Overall Study
Started 77
Completed [1] 36
Not Completed 41
Reason Not Completed
Lost to Follow-up             1
Adverse Event             3
Withdrawal by Subject             5
Disease progression             32
[1]
treatment ongoing
Arm/Group Title Arm 1
Hide Arm/Group Description All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Overall Number of Baseline Participants 77
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 77 participants
50.6  (13.08)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 77 participants
Female
42
  54.5%
Male
35
  45.5%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 77 participants
American Indian or Alaska Native
0
   0.0%
Asian
77
 100.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
0
   0.0%
White
0
   0.0%
More than one race
0
   0.0%
Unknown or Not Reported
0
   0.0%
1.Primary Outcome
Title Objective Response Rate (ORR)
Hide Description To determine ORR of dabrafenib in combination with trametinib in subjects with BRAF V600 mutation-positive, unresectable or metastatic melanoma. ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 and as assessed by the investigator.
Time Frame Up to 35 months
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set
Arm/Group Title Arm 1
Hide Arm/Group Description:
All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Overall Number of Participants Analyzed 77
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
61
(49.2 to 72.0)
2.Secondary Outcome
Title To Evaluate the Antitumor Activity by Assessing the Progression-free Survival (PFS)
Hide Description PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause
Time Frame Up to 36 months
Outcome Measure Data Not Reported
3.Secondary Outcome
Title To Evaluate the Antitumor Activity by Assessing the Duration of Response
Hide Description Duration of response is defined as the time from first documented evidence of CR or PR until the earliest date of documented radiological progression or death due to any cause among subjects who achieved a confirmed CR or PR
Time Frame Up to 36 months
Outcome Measure Data Not Reported
4.Secondary Outcome
Title To Evaluate the Antitumor Activity by Assessing the Overall Survival (OS)
Hide Description OS defined as the interval from first dose of study treatment to the date of death, irrespective of the cause of death; subjects still alive will be censored at the date of the last contact
Time Frame Approximately 5 years
Outcome Measure Data Not Reported
5.Secondary Outcome
Title To Assess Exposures to Dabrafenib, Dabrafenib Metabolites, and Trametinib, and Characterize the Population Pharmacokinetics of Dabrafenib and Trametinib
Hide Description PK parameters will include maximum peak concentration (Cmax), Time to Cmax (tmax), Predose concentration (Ctau), Area under the concentration-time curve (AUC) from time 0 to last time of quantifiable concentration (AUC [0-t]), and from time 0 to 8 hours of quantifiable concentration (AUC[0-8]); AUC from time 0 to 12 hours of quantifiable concentration (AUC[0-12]) (dabrafenib and metabolites only), AUC (0-24) (trametinib only) and the metabolite to dabrafenib ratio of AUC(0-t). Population PK parameters will include, apparent clearance following oral dosing (CL/F), volume of distribution (V/F), and absorption rate constant (Ka) for dabrafenib and trametinib
Time Frame Pre-dose (within 30 minutes prior to dosing) and 1, 2, 4, 6, and 8 hours after dosing on Day 15. For subjects in China: Pre-dose (within 30 minutes prior to dosing) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours after dosing on Day 1 and Day 15
Outcome Measure Data Not Reported
6.Secondary Outcome
Title Safety and Tolerability of Dabrafenib and Trametinib as Assessed by Physical Examinations
Hide Description Complete physical examination will include assessments of eyes, neurological and cardiovascular systems, lungs, abdomen, and any other areas with signs and symptoms of disease, and of the head, neck, ears, nose, mouth, throat, thyroid, lymph nodes, extremities, and a full skin exam to assess cutaneous malignancies and proliferative skin diseases. Also, thorough genitourinary (pelvic) and rectal examinations to assess secondary malignancies
Time Frame Screening, every 4 weeks and at treatment discontinuation (approximately 1 year but can be up to 5 years)
Outcome Measure Data Not Reported
7.Secondary Outcome
Title Safety and Tolerability of Dabrafenib and Trametinib as Assessed by Vital Signs
Hide Description Vital sign measurements will include systolic and diastolic blood pressure, body temperature, pulse rate, body weight, and height (only at Screening)
Time Frame Screening, every 4 weeks and at treatment discontinuation (approximately 1 year but can be up to 5 years)
Outcome Measure Data Not Reported
8.Secondary Outcome
Title Safety and Tolerability of Dabrafenib and Trametinib as Assessed by 12-lead Electrocardiograms (ECG), Echocardiogram (ECHO)
Hide Description Clinical assessments including 12-lead (ECG, ECHO will be done to assess cardiac safety
Time Frame ECG Screening, Day 15, Week 4, 8 and 12, every 12 weeks after Week 12 and treatment Discontinuation(approximately 1 year but can be up to 5 years). ECHO Screening, Week 4 and every 12 weeks
Outcome Measure Data Not Reported
9.Secondary Outcome
Title Safety and Tolerability of Dabrafenib and Trametinib as Assessed by Eye Examinations
Hide Description Safety as measured by clinical assessments including eye exams
Time Frame Screening and Week 4 and as clinically warranted
Outcome Measure Data Not Reported
10.Secondary Outcome
Title Safety and Tolerability of Dabrafenib and Trametinib by Laboratory Assessments
Hide Description Laboratory assessments will include clinical chemistry and hematology parameters
Time Frame Screening, every 4 weeks and at treatment Discontinuation (approximately 1 year but can be up to 5 years)
Outcome Measure Data Not Reported
11.Secondary Outcome
Title Safety and Tolerability of Dabrafenib and Trametinib as Assessed Adverse Events (AEs)
Hide Description [Not Specified]
Time Frame From the first dose of study treatment until 30 days after discontinuation of study treatment (approximately 1 year but can be up to 5 years)
Outcome Measure Data Not Reported
Time Frame Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 35 months (for both dabrafenib and also trametinib).
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title All Patients
Hide Arm/Group Description All Patients
All-Cause Mortality
All Patients
Affected / at Risk (%)
Total   11/77 (14.29%) 
Hide Serious Adverse Events
All Patients
Affected / at Risk (%)
Total   12/77 (15.58%) 
Eye disorders   
Uveitis  1  1/77 (1.30%) 
Gastrointestinal disorders   
Pneumoperitoneum  1  1/77 (1.30%) 
General disorders   
Pyrexia  1  1/77 (1.30%) 
Hepatobiliary disorders   
Liver injury  1  1/77 (1.30%) 
Infections and infestations   
Arthritis infective  1  1/77 (1.30%) 
Diarrhoea infectious  1  1/77 (1.30%) 
Pneumonia  1  1/77 (1.30%) 
Post procedural sepsis  1  1/77 (1.30%) 
Pyelonephritis acute  1  1/77 (1.30%) 
Septic shock  1  1/77 (1.30%) 
Soft tissue infection  1  1/77 (1.30%) 
Injury, poisoning and procedural complications   
Femur fracture  1  1/77 (1.30%) 
Investigations   
Ejection fraction decreased  1  1/77 (1.30%) 
Metabolism and nutrition disorders   
Hyperglycaemia  1  1/77 (1.30%) 
Hypoglycaemia  1  1/77 (1.30%) 
Psychiatric disorders   
Confusional state  1  1/77 (1.30%) 
Respiratory, thoracic and mediastinal disorders   
Haemoptysis  1  1/77 (1.30%) 
Interstitial lung disease  1  1/77 (1.30%) 
Pulmonary embolism  1  1/77 (1.30%) 
Pulmonary haemorrhage  1  1/77 (1.30%) 
1
Term from vocabulary, MedDRA (23.1)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
All Patients
Affected / at Risk (%)
Total   73/77 (94.81%) 
Blood and lymphatic system disorders   
Anaemia  1  33/77 (42.86%) 
Gastrointestinal disorders   
Constipation  1  11/77 (14.29%) 
Diarrhoea  1  10/77 (12.99%) 
Nausea  1  21/77 (27.27%) 
Vomiting  1  15/77 (19.48%) 
General disorders   
Asthenia  1  5/77 (6.49%) 
Chest discomfort  1  4/77 (5.19%) 
Chills  1  15/77 (19.48%) 
Fatigue  1  6/77 (7.79%) 
Malaise  1  5/77 (6.49%) 
Oedema peripheral  1  6/77 (7.79%) 
Pyrexia  1  43/77 (55.84%) 
Infections and infestations   
Nasopharyngitis  1  19/77 (24.68%) 
Investigations   
Alanine aminotransferase increased  1  15/77 (19.48%) 
Aspartate aminotransferase increased  1  20/77 (25.97%) 
Blood alkaline phosphatase increased  1  19/77 (24.68%) 
Blood lactate dehydrogenase increased  1  17/77 (22.08%) 
Gamma-glutamyltransferase increased  1  6/77 (7.79%) 
Neutrophil count decreased  1  27/77 (35.06%) 
Platelet count decreased  1  14/77 (18.18%) 
Weight decreased  1  10/77 (12.99%) 
Weight increased  1  12/77 (15.58%) 
White blood cell count decreased  1  32/77 (41.56%) 
Metabolism and nutrition disorders   
Decreased appetite  1  12/77 (15.58%) 
Hyperglycaemia  1  31/77 (40.26%) 
Hypoalbuminaemia  1  5/77 (6.49%) 
Hypokalaemia  1  7/77 (9.09%) 
Hyponatraemia  1  5/77 (6.49%) 
Musculoskeletal and connective tissue disorders   
Arthralgia  1  6/77 (7.79%) 
Myalgia  1  9/77 (11.69%) 
Pain in extremity  1  5/77 (6.49%) 
Nervous system disorders   
Dizziness  1  16/77 (20.78%) 
Headache  1  12/77 (15.58%) 
Respiratory, thoracic and mediastinal disorders   
Cough  1  15/77 (19.48%) 
Skin and subcutaneous tissue disorders   
Erythema  1  4/77 (5.19%) 
Panniculitis  1  5/77 (6.49%) 
Pruritus  1  5/77 (6.49%) 
Rash  1  26/77 (33.77%) 
1
Term from vocabulary, MedDRA (23.1)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: + 1 862 778 8300
EMail: Novartis.email@Novartis.com
Layout table for additonal information
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT02083354    
Other Study ID Numbers: 200104
CDRB436B2205 ( Other Identifier: Novartis )
First Submitted: February 13, 2014
First Posted: March 11, 2014
Results First Submitted: February 15, 2021
Results First Posted: March 17, 2021
Last Update Posted: May 13, 2021