Trametinib With GSK2141795 in BRAF Wild-type Melanoma
This study is ongoing, but not recruiting participants.
Sponsor:
Adil Daud
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
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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: | Endpoint Classification: Efficacy Study 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:
Further study details as provided by 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 ] [ Designated as safety issue: Yes ]
Secondary Outcome Measures:
- Progression-Free Survival of patients treated with the combination of trametinib and GSK 2141795 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
- Overall Survival of patients treated with the combination of trametinib and GSK 2141795 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
- Time-to-Progression of patients treated with the combination of trametinib and GSK 2141795 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
- 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 ] [ Designated as safety issue: Yes ]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 ] [ Designated as safety issue: No ]
- Biomarkers of response in peripheral blood from patients on trial [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
- Biomarkers of resistance in biopsy tissue from patients on trial [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
- Biomarkers of resistance in peripheral blood from patients on trial [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
| 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)
GSK2141795
|
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 |
| Genders Eligible for Study: | Both |
| 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
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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
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
No publications provided
| 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 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by University of California, San Francisco:
|
Melanoma Wild-type BRAF |
Additional relevant MeSH terms:
|
Melanoma Neoplasms Neoplasms by Histologic Type Neoplasms, Germ Cell and Embryonal Neoplasms, Nerve Tissue Neuroectodermal Tumors Neuroendocrine Tumors Nevi and Melanomas |
Trametinib Antineoplastic Agents Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Protein Kinase Inhibitors Therapeutic Uses |
ClinicalTrials.gov processed this record on March 03, 2015