Trametinib With GSK2141795 in BRAF Wild-type Melanoma
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.
|Study Design:||Intervention Model: Single Group Assignment
Masking: 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|
- 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 ]
- Progression-Free Survival of patients treated with the combination of trametinib and GSK 2141795 [ Time Frame: Up to 2 years ]
- Overall Survival of patients treated with the combination of trametinib and GSK 2141795 [ Time Frame: Up to 2 years ]
- Time-to-Progression of patients treated with the combination of trametinib and GSK 2141795 [ Time Frame: Up to 2 years ]
- 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.
- Biomarkers of response in biopsy tissue from patients on trial [ Time Frame: Up to 2 years ]
- Biomarkers of response in peripheral blood from patients on trial [ Time Frame: Up to 2 years ]
- Biomarkers of resistance in biopsy tissue from patients on trial [ Time Frame: Up to 2 years ]
- Biomarkers of resistance in peripheral blood from patients on trial [ Time Frame: Up to 2 years ]
|Study Start Date:||September 2013|
|Estimated Study Completion Date:||May 2016|
|Primary Completion Date:||December 2014 (Final data collection date for primary outcome measure)|
Experimental: Trametinib, GSK2141795
Drug: Trametinib (GSK1120212)
Trametinib is a highly selective allosteric inhibitor of MEK1 andMEK2 activation and kinase activity.
Other Name: MEKINISTDrug: 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01941927
|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|
|Principal Investigator:||Adil Daud, M.D.||University of California, San Francisco|