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Trametinib With GSK2141795 in BRAF Wild-type Melanoma

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ClinicalTrials.gov Identifier: NCT01941927
Recruitment Status : Completed
First Posted : September 13, 2013
Results First Posted : February 12, 2020
Last Update Posted : February 12, 2020
Sponsor:
Collaborator:
National Comprehensive Cancer Network
Information provided by (Responsible Party):
Adil Daud, University of California, San Francisco

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Melanoma
Interventions Drug: Trametinib (GSK1120212)
Drug: GSK2141795
Enrollment 20
Recruitment Details  
Pre-assignment Details  
Arm/Group Title NRAS Wildtype NRAS Mutant
Hide Arm/Group Description Patients without NRAS (neuroblastoma RAS viral oncogene homolog) exon 1 and 2 mutations Patients with NRAS exon 1 and 2 mutations (NRAS mutant) identified by Sanger sequencing or exon-capture next-generation sequencing
Period Title: Overall Study
Started 10 10
Completed 10 10
Not Completed 0 0
Arm/Group Title NRAS Wildtype NRAS Mutant Total
Hide Arm/Group Description Patients without NRAS exon 1 and 2 mutations Patients with NRAS exon 1 and 2 mutations (NRAS mutant) identified by Sanger sequencing or exon-capture next-generation sequencing Total of all reporting groups
Overall Number of Baseline Participants 10 10 20
Hide Baseline Analysis Population Description
Patients with NRAS exon 1 and 2 mutations (NRAS mutant) identified by Sanger sequencing or exon-capture next-generation equencing and patients without these mutations (wild-type (WT)). The sample size for each arm was based on a Simon 2-stage stage design.
Age, Customized  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 10 participants 10 participants 20 participants
59.3
(40 to 86)
56.8
(19 to 67)
58.5
(19 to 86)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants 10 participants 20 participants
Female
2
  20.0%
3
  30.0%
5
  25.0%
Male
8
  80.0%
7
  70.0%
15
  75.0%
Eastern Cooperative Oncology Group (ECOG) status: 0   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants 10 participants 20 participants
ECOG status 0
6
  60.0%
2
  20.0%
8
  40.0%
ECOG status 1
4
  40.0%
8
  80.0%
12
  60.0%
ECOG status 2
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Description:

Participants were rated using the ECOG Performance Status Scale. Status had to be 0 to 2 in order to be eligible for the study.

Grade 0: Normal activity. Fully active, able to carry on all pre-disease performance without restriction

Grade 1: Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work)

Grade 2: In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours

Stage   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants 10 participants 20 participants
M1a
0
   0.0%
2
  20.0%
2
  10.0%
M1b
0
   0.0%
2
  20.0%
2
  10.0%
M1c
10
 100.0%
6
  60.0%
16
  80.0%
[1]
Measure Description:

Histological confirmation of Malignant Melanoma using the American Joint Committee on Cancer (AJCC) tumor/node/metastasis (TNM) classification and staging system.

M1a: Metastases to skin, soft tissue (including muscle), and/or nonregional lymph nodes

M1b: Lung metastasis, with or without M1a involvement

M1c: Distant metastasis to non-central nervous system (CNS) visceral sites with or without M1a or M1b involvement

Lactate Dehydrogenase (LDH) level  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants 10 participants 20 participants
LDH normal
2
  20.0%
2
  20.0%
4
  20.0%
LDH elevated
8
  80.0%
8
  80.0%
16
  80.0%
Genotype  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants 10 participants 20 participants
Genotype NRAS Q61H
0
   0.0%
1
  10.0%
1
   5.0%
Genotype NRAS Q61K
0
   0.0%
3
  30.0%
3
  15.0%
Genotype NRAS Q61L
0
   0.0%
1
  10.0%
1
   5.0%
Genotype NRAS Q61R
0
   0.0%
5
  50.0%
5
  25.0%
BRAF Wild Type (WT) /NRAS WT
10
 100.0%
0
   0.0%
10
  50.0%
Subtype  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants 10 participants 20 participants
Cutaneous
6
  60.0%
0
   0.0%
6
  30.0%
Mucosal
0
   0.0%
8
  80.0%
8
  40.0%
Acral
1
  10.0%
2
  20.0%
3
  15.0%
Uveal
3
  30.0%
0
   0.0%
3
  15.0%
1.Primary Outcome
Title Objective Response Rate (ORR)
Hide Description Only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response These participants will have their response classified according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) method, where the baseline target lesion sum of longest diameter (LD) will be used as reference by which to characterize the objective tumor response. An objective response is defined as an overall response of complete response (CR), partial response (PR), or stable disease (SD) with a confirmatory scan or evaluation at time of final disease response determination.
Time Frame Up to 2 years from beginning of therapy
Hide Outcome Measure Data
Hide Analysis Population Description
Reported here are a number of participants that achieved the best objective response defined as stable disease
Arm/Group Title NRAS Wildtype NRAS Mutant
Hide Arm/Group Description:
Patients without NRAS exon 1 and 2 mutations
Patients with NRAS exon 1 and 2 mutations (NRAS mutant) identified by Sanger sequencing or exon-capture next-generation sequencing
Overall Number of Participants Analyzed 10 10
Measure Type: Count of Participants
Unit of Measure: Participants
5
  50.0%
4
  40.0%
2.Secondary Outcome
Title Progression-Free Survival of Patients Treated With the Combination of Trametinib and GSK 2141795
Hide Description Time from randomization to objective tumor progression or death. Participants who die without documentation of disease progression and before it was time to conduct the first tumor reassessment, will be considered inevaluable or not assessed adequately
Time Frame Up to 2 years from beginning of therapy
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title NRAS Wildtype NRAS Mutant
Hide Arm/Group Description:
Patients without NRAS exon 1 and 2 mutations
Patients with NRAS exon 1 and 2 mutations (NRAS mutant) identified by Sanger sequencing or exon-capture next-generation sequencing
Overall Number of Participants Analyzed 10 10
Median (95% Confidence Interval)
Unit of Measure: months
2.8
(2.6 to 2.9)
2.3
(2.1 to 2.5)
3.Secondary Outcome
Title Overall Survival of Patients Treated With the Combination of Trametinib and GSK 2141795
Hide Description [Not Specified]
Time Frame Up to 2 years from beginning of therapy
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title NRAS Wildtype NRAS Mutant
Hide Arm/Group Description:
Patients without NRAS exon 1 and 2 mutations
Patients with NRAS exon 1 and 2 mutations (NRAS mutant) identified by Sanger sequencing or exon-capture next-generation sequencing
Overall Number of Participants Analyzed 10 10
Median (95% Confidence Interval)
Unit of Measure: months
3.5
(0.6 to 6.4)
4
(0.9 to 7)
4.Secondary Outcome
Title Time-to-Progression (TTP) of Patients Treated With the Combination of Trametinib and GSK 2141795
Hide Description Time from treatment initiation until objective tumor progression observed. Only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. Participants who exhibit objective disease progression prior to the end of Cycle 1 will be considered evaluable. Response will also be considered inevaluable for any participants receiving treatment (regardless of how much was received) who did not have any follow-up assessment completed before initiation of alternative treatment or participants who die without documentation of disease progression and before it was time to conduct the first tumor reassessment, will be considered inevaluable or not assessed adequately
Time Frame Up to 2 years from beginning of therapy
Hide Outcome Measure Data
Hide Analysis Population Description
The drug combination failed to produce objective responses in participants with either NRAS mutant or NRAS wild-type melanoma in TTP evaluable patient population. No objective responses for progression in TTP specific evaluable participants population were observed so endpoint could not be calculated.
Arm/Group Title NRAS Wildtype NRAS Mutant
Hide Arm/Group Description:
Patients without NRAS exon 1 and 2 mutations
Patients with NRAS exon 1 and 2 mutations (NRAS mutant) identified by Sanger sequencing or exon-capture next-generation sequencing
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
5.Secondary Outcome
Title Number of Severe Adverse Events (Grade 3 and 4) Reported by Patients Related With the Treatment of Trametinib and GSK2141795.
Hide Description [Not Specified]
Time Frame Up to 2 years from beginning of therapy
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Trametinib, GSK2141795
Hide Arm/Group Description:

Trametinib (GSK1120212)

  • Oral
  • 2 mg
  • Daily
  • Number of Cycles: until progression or unacceptable toxicity develops

GSK2141795

  • Oral
  • 25 mg
  • Daily
  • Number of Cycles: until progression or unacceptable toxicity develops
Overall Number of Participants Analyzed 10
Measure Type: Number
Unit of Measure: Severe Adverse Events
6
Time Frame Patient toxicity will be collected from time of first treatment at weekly scheduled study visits. Patients will be followed for toxicity for 30 days after last dose of study drug or removal from study, or until death, whichever occurs first. Patients removed from study for unacceptable treatment related adverse event(s) will be followed additionally until resolution or stabilization of all treatment related adverse events to Grade 2 or lower
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Trametinib, GSK2141795
Hide Arm/Group Description

Trametinib (GSK1120212)

  • Oral, 2 mg Daily
  • Number of Cycles: until progression or unacceptable toxicity develops

GSK2141795

  • Oral, 25 mg Daily
  • Number of Cycles: until progression or unacceptable toxicity develops
All-Cause Mortality
Trametinib, GSK2141795
Affected / at Risk (%)
Total   12/20 (60.00%) 
Hide Serious Adverse Events
Trametinib, GSK2141795
Affected / at Risk (%)
Total   5/20 (25.00%) 
Gastrointestinal disorders   
diarrhea  1  1/20 (5.00%) 
General disorders   
failure to thrive  1  1/20 (5.00%) 
Infections and infestations   
decubitus ulcer  1  1/20 (5.00%) 
Sepsis  1  1/20 (5.00%) 
Respiratory, thoracic and mediastinal disorders   
pleural effusion  1  1/20 (5.00%) 
pulmonary embolism  1  1/20 (5.00%) 
pneumonia  1  1/20 (5.00%) 
Skin and subcutaneous tissue disorders   
rash maculo-papular  1  1/20 (5.00%) 
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Trametinib, GSK2141795
Affected / at Risk (%)
Total   17/20 (85.00%) 
Blood and lymphatic system disorders   
Blood and lymphatic system disorders - Other, specify  1  1/20 (5.00%) 
Gastrointestinal disorders   
Diarrhea  1  12/20 (60.00%) 
Nausea  1  5/20 (25.00%) 
Constipation  1  4/20 (20.00%) 
Mucositis oral  1  3/20 (15.00%) 
Vomiting  1  3/20 (15.00%) 
Abdominal pain  1  2/20 (10.00%) 
Oral pain  1  2/20 (10.00%) 
Anal fistula  1  1/20 (5.00%) 
Dyspepsia  1  1/20 (5.00%) 
Dysphagia  1  1/20 (5.00%) 
General disorders   
Fatigue  1  4/20 (20.00%) 
Fever  1  3/20 (15.00%) 
Chills  1  1/20 (5.00%) 
Malaise  1  1/20 (5.00%) 
Infections and infestations   
Rash pustular  1  2/20 (10.00%) 
Bladder infection  1  1/20 (5.00%) 
Investigations   
Alkaline phosphatase increased  1  2/20 (10.00%) 
Alanine aminotransferase increased  1  1/20 (5.00%) 
Creatinine increased  1  1/20 (5.00%) 
Metabolism and nutrition disorders   
Anorexia  1  1/20 (5.00%) 
Dehydration  1  1/20 (5.00%) 
Hyperglycemia  1  1/20 (5.00%) 
Musculoskeletal and connective tissue disorders   
Back pain  1  1/20 (5.00%) 
Nervous system disorders   
Headache  1  2/20 (10.00%) 
Dizziness  1  1/20 (5.00%) 
Dysgeusia  1  1/20 (5.00%) 
Peripheral sensory neuropathy  1  1/20 (5.00%) 
Sinus pain  1  1/20 (5.00%) 
Reproductive system and breast disorders   
Vaginal discharge  1  1/20 (5.00%) 
Respiratory, thoracic and mediastinal disorders   
Cough  1  3/20 (15.00%) 
Nasal congestion  1  2/20 (10.00%) 
Dyspnea  1  1/20 (5.00%) 
Epistaxis  1  1/20 (5.00%) 
Sore throat  1  1/20 (5.00%) 
Skin and subcutaneous tissue disorders   
Rash acneiform  1  6/20 (30.00%) 
Rash maculo-papular  1  5/20 (25.00%) 
Dry skin  1  2/20 (10.00%) 
Skin and subcutaneous tissue disorders - Other, specify  1  2/20 (10.00%) 
Alopecia  1  1/20 (5.00%) 
Pruritus  1  1/20 (5.00%) 
Scalp pain  1  1/20 (5.00%) 
Vascular disorders   
Hypertension  1  2/20 (10.00%) 
Thromboembolic event  1  1/20 (5.00%) 
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT 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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Adil Daud, MD
Organization: University of California, San Francisco
Phone: (415) 353-7392
EMail: Adil.Daud@ucsf.edu
Layout table for additonal information
Responsible Party: Adil Daud, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01941927    
Other Study ID Numbers: 13855
NCI-2013-01849 ( Registry Identifier: NCI Clinical Trials Reporting Program (CTRP) )
First Submitted: August 30, 2013
First Posted: September 13, 2013
Results First Submitted: February 28, 2018
Results First Posted: February 12, 2020
Last Update Posted: February 12, 2020