ClinicalTrials.gov
ClinicalTrials.gov Menu

Trametinib With GSK2141795 in BRAF Wild-type Melanoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01941927
Recruitment Status : Unknown
Verified February 2015 by Adil Daud, University of California, San Francisco.
Recruitment status was:  Active, not recruiting
First Posted : September 13, 2013
Last Update Posted : February 19, 2015
Sponsor:
Collaborator:
National Comprehensive Cancer Network
Information provided by (Responsible Party):
Adil Daud, University of California, San Francisco

Study Description
Go to 
Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Brief Summary:

This is a multicenter phase II clinical study of trametinib in combination with GSK2141795 in patients with BRAF wild-type mutation melanoma. All patients will receive continuous dosing of trametinib (2 mg) in combination with GSK2141795 (25 mg) oral daily until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity. Imaging (CT or MRI) will be performed within 7 days prior to day 1 of Odd Cycles, starting with Cycle 3.

Patients may continue treatment with trametinib in combination with GSK2141795 on trial until disease progression or the development of unacceptable toxicity that does not improve with maximal supportive care or dose reduction per protocol.

Treatment-associated adverse events will be assessed based on clinical and laboratory findings using the Common Toxicity Criteria for Adverse Events, version 4.0. Adverse event assessments will be performed every week through cycle 3 day 1, and on day 1 for every cycle thereafter. AEs and SAEs will be monitored by UCSF's Data Safety Monitoring Committee.

Safety assessments will include medical history, physical examination, CBC with differential, chemistries panel, thyroid function and pregnancy tests, ECGs, and ophthalmology evaluations. Screening assessments will also include a transthoracic echocardiogram or MUGA scan, and brain imaging.

It is estimated that 48 patients will complete the study.


Condition or disease Intervention/treatment Phase
Melanoma Drug: Trametinib (GSK1120212) Drug: GSK2141795 Phase 2

Study Design
Go to 
Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Clinical Trial of the MEK Inhibitor Trametinib With the AKT Inhibitor GSK2141795 in BRAF Wild-type Melanoma
Study Start Date : September 2013
Actual Primary Completion Date : December 2014
Estimated Study Completion Date : May 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma
Drug Information available for: Trametinib
U.S. FDA Resources

Arms and Interventions
Go to 
Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm Intervention/treatment
Experimental: Trametinib, GSK2141795

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
 Drug: Trametinib (GSK1120212)
Trametinib is a highly selective allosteric inhibitor of MEK1 andMEK2 activation and kinase activity.
Other Name: MEKINIST
Drug: GSK2141795
GSK 2141795 is an ATP competitive subnanomolar pan-AKT inhibitor. In order to measure the true potency of GSK 2141795, potency (Ki*) values were determined in a filter binding assay using lower enzyme concentrations (0.1, 0.7, and 0.2 nM for human AKT1, AKT2, and AKT3, respectively). Using a sandwich ELISA, GSK 2141795 inhibited phosphorylation of GSK-3β in BT474 and LNCaP cell lines with EC50 values of 143 and 34 nM, respectively. Sincephosphorylation of GSK-3β can be modulated by other enzymes (PKA, PKC, and RSK),cellular activity of GSK 2141795 was evaluated using a phospho-PRAS40 ELISA.GSK 2141795 inhibited the phosphorylation of PRAS40 with EC50 values of 39 and 55 nM for BT474 and LNCaP cells, respectively.


Outcome Measures
Go to 
Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :
  1. Objective Response Rate (ORR) in patients with either mutated NRAS or wild-type NRAS/wild-type BRAF melanoma treated with the combination of trametinib and GSK 2141795 [ Time Frame: Up to 2 years ]

Secondary Outcome Measures :
  1. Progression-Free Survival of patients treated with the combination of trametinib and GSK 2141795 [ Time Frame: Up to 2 years ]
  2. Overall Survival of patients treated with the combination of trametinib and GSK 2141795 [ Time Frame: Up to 2 years ]
  3. Time-to-Progression of patients treated with the combination of trametinib and GSK 2141795 [ Time Frame: Up to 2 years ]
  4. Number of severe adverse events (Grade 3 and 4) reported by patients related with the treatment of Trametinib and GSK2141795. [ Time Frame: Up to 2 years ]
    SAEs will be collected to assess the tolerability, safety and toxicity profile of this treatment.


Other Outcome Measures:
  1. Biomarkers of response in biopsy tissue from patients on trial [ Time Frame: Up to 2 years ]
  2. Biomarkers of response in peripheral blood from patients on trial [ Time Frame: Up to 2 years ]
  3. Biomarkers of resistance in biopsy tissue from patients on trial [ Time Frame: Up to 2 years ]
  4. Biomarkers of resistance in peripheral blood from patients on trial [ Time Frame: Up to 2 years ]

Eligibility Criteria
Go to 
Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 years.
  2. Histologically or cytologically confirmed Malignant Melanoma.
  3. Unresectable Stage III or Stage IV disease.
  4. Measureable disease by RECIST 1.1
  5. ECOG performance status 0-2
  6. Resolution of all acute toxic effects of prior radiotherapy, chemotherapy or surgical procedures to NCI CTCAE Version 4.0 grade ≤1. At least 2 weeks must have elapsed since the end of prior systemic treatment, radiotherapy, or major surgical procedure.
  7. Evidence of tumor DNA showing either NRAS mutation or NRAS WT/BRAF WT. BRAF genotype must be determined by a CLIA-approved assay. NRAS genotyping may be determined by Sanger sequencing, melting point PCR assay, Sequenome, or NextGen sequencing.

  8. Adequate Bone Marrow and Organ function as defined:

    • Hemoglobin ≥ 9 g/dL
    • Absolute neutrophil count ≥ 1,500/mm3
    • Platelet count ≥ 100,000/mm3
    • Bilirubin ≤ 1.5 times normal limit
    • AST/ALT ≤ 5 times the upper limit of normal if liver metastasis present or ≤2.5 X ULN if no liver metastases are present.
    • Creatinine ≤ 2 mg/dL

Exclusion Criteria:

  1. Progressive CNS metastatic disease. Patients with CNS metastases are allowed only if previously treated and stable for 8 weeks or more, and patient is neurologically intact off steroids. The stability must be documented by MRI/CT over a period of 8 weeks or greater.
  2. Congestive Heart Failure with significant limitation of activity New York Heart Association (NYHA) class III or IV
  3. Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism.
  4. QTc >480 mSec , unless presence of bundle branch block. In this case, observed QTc - (QRS-150) should be ≤ 480 msec.
  5. More than 1 prior chemotherapy regimen. Patients may have had any prior immunotherapy regimens but must be at least 6 weeks out from anti-CTLA4 or anti-PD-1 antibody treatment and show progression based on immune response evaluation criteria.
  6. Pregnancy or breastfeeding. Female subjects must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy and for 4 months following last dose.
  7. Prior treatment with any AKT or MEK inhibitor
  8. Retinal or Fundal disease (including macular degeneration, retinal vein occlusion, hypertensive or diabetic retinopathy).
  9. Inflammatory Bowel Disease, malabsorption syndrome or diarrhea > Grade 1.
  10. Need for treatment with drugs that are known potent CYP3A inhibitors. Current use or anticipated need for treatment with drugs that are known potent CYP3A or CYP1A2 inducers.
  11. Prior malignancy will be allowed as long as the patient is known to be free of disease for at least 5 years. Prior SCC, Basal Cell, cervical cancer, early stage prostate cancer, DCIS or melanoma (second primary) are allowed even if <5 years from diagnosis
Contacts and Locations
Go to 
Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01941927


Locations
United States, California
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94115
United States, New York
Memorial Sloan-Kettering Cancer Center
New York City, New York, United States, 10065
Sponsors and Collaborators
Adil Daud
National Comprehensive Cancer Network
Investigators
Principal Investigator: Adil Daud, M.D. University of California, San Francisco
More Information
Go to 
Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party: Adil Daud, Clinical Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01941927     History of Changes
Other Study ID Numbers: 13855
First Posted: September 13, 2013    Key Record Dates
Last Update Posted: February 19, 2015
Last Verified: February 2015

Keywords provided by Adil Daud, University of California, San Francisco:
Melanoma
Wild-type
BRAF

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
 Nevi and Melanomas
Trametinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action