Trametinib With GSK2141795 in BRAF Wild-type Melanoma

The recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.

Verified February 2015 by Adil Daud, University of California, San Francisco.
Recruitment status was: Active, not recruiting

Sponsor:

Collaborator:

National Comprehensive Cancer Network

Information provided by (Responsible Party):

Adil Daud, University of California, San Francisco

ClinicalTrials.gov Identifier:

NCT01941927

First received: August 30, 2013

Last updated: February 17, 2015

Last verified: February 2015

History of Changes

Purpose

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	Intervention	Phase
Melanoma	Drug: Trametinib (GSK1120212) Drug: GSK2141795	Phase 2


Study Type:	Interventional
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

Resource links provided by NLM:

MedlinePlus related topics: Melanoma

Drug Information available for: Trametinib

Genetic and Rare Diseases Information Center resources: Carcinoid Tumor Neuroepithelioma

U.S. FDA Resources

Further study details as provided by Adil Daud, University of California, San Francisco:

Primary Outcome Measures:

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:

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.

Other Outcome Measures:

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 ]


Enrollment:	20
Study Start Date:	September 2013
Estimated Study Completion Date:	May 2016
Primary Completion Date:	December 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.

Arms

Assigned Interventions

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.

Eligibility


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

Criteria

Inclusion Criteria:

Age ≥ 18 years.
Histologically or cytologically confirmed Malignant Melanoma.
Unresectable Stage III or Stage IV disease.
Measureable disease by RECIST 1.1
ECOG performance status 0-2
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.
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.
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:

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.
Congestive Heart Failure with significant limitation of activity New York Heart Association (NYHA) class III or IV
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.
QTc >480 mSec , unless presence of bundle branch block. In this case, observed QTc - (QRS-150) should be ≤ 480 msec.
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.
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.
Prior treatment with any AKT or MEK inhibitor
Retinal or Fundal disease (including macular degeneration, retinal vein occlusion, hypertensive or diabetic retinopathy).
Inflammatory Bowel Disease, malabsorption syndrome or diarrhea > Grade 1.
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.
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

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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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


Responsible Party:	Adil Daud, Clinical Professor, University of California, San Francisco
ClinicalTrials.gov Identifier:	NCT01941927 History of Changes
Other Study ID Numbers:	13855
Study First Received:	August 30, 2013
Last Updated:	February 17, 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

ClinicalTrials.gov processed this record on June 26, 2017

To Top