Trametinib With GSK2141795 in BRAF Wild-type Melanoma

Study Overview
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Brief Summary
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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 (AE) assessments will be performed every week through cycle 3 day 1, and on day 1 for every cycle thereafter. AEs and Serious adverse events (SAE)s will be monitored by UCSF's Data Safety Monitoring Committee. Safety assessments will include medical history, physical examination, Complete Blood Count (CBC) with differential, chemistries panel, thyroid function and pregnancy tests, ECGs, and ophthalmology evaluations. Screening assessments will also include a transthoracic echocardiogram or multiple-gated acquisition (MUGA) scan, and brain imaging. It is estimated that 48 patients will complete the study.

Official Title
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Phase II Clinical Trial of the MEK Inhibitor Trametinib With the AKT Inhibitor GSK2141795 in BRAF Wild-type Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Trametinib (GSK1120212)
* Drug: GSK2141795


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years. Histologically or cytologically confirmed Malignant Melanoma. Unresectable Stage III or Stage IV disease. Measureable disease by RECIST 1.1 Eastern Cooperative Oncology Group (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 Wild-Type (WT)/BRAF WT. BRAF genotype must be determined by a CLIA-approved assay. NRAS genotyping may be determined by Sanger sequencing, melting point polymerase chain reaction (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 aspartate aminotransferase (AST) /alanine aminotransferase (ALT) ≤ 5 times the upper limit of normal if liver metastasis present or ≤2.5 X upper limit of normal (ULN) if no liver metastases are present. Creatinine ≤ 2 mg/dL Exclusion Criteria: Progressive central nervous system (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 Squamous cell carcinoma (SCC), Basal Cell, cervical cancer, early stage prostate cancer, ductal carcinoma in situ (DCIS) or melanoma (second primary) are allowed even if <5 years from diagnosis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trametinib, GSK2141795<br>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)<br>* Trametinib is a highly selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity.<br>* Other names: MEKINIST;Drug: GSK2141795<br>* 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. Since phosphorylation 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | 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. | Up to 2 years from beginning of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival of Patients Treated With the Combination of Trametinib and GSK 2141795 | 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 | Up to 2 years from beginning of therapy | 
| Overall Survival of Patients Treated With the Combination of Trametinib and GSK 2141795 |  | Up to 2 years from beginning of therapy | 
| Time-to-Progression (TTP) of Patients Treated With the Combination of Trametinib and GSK 2141795 | 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 | Up to 2 years from beginning of therapy | 
| Number of Severe Adverse Events (Grade 3 and 4) Reported by Patients Related With the Treatment of Trametinib and GSK2141795. |  | Up to 2 years from beginning of therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, Wild-type, BRAF