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Trametinib With GSK2141795 in BRAF Wild-type Melanoma

Primary Purpose

Melanoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Trametinib (GSK1120212)
GSK2141795
Sponsored by
Adil Daud
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Melanoma focused on measuring Melanoma, Wild-type, BRAF

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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. Eastern Cooperative Oncology Group (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 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.

  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
    • 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:

  1. 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.
  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 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

Sites / Locations

  • University of California, San Francisco
  • Memorial Sloan-Kettering Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Trametinib, GSK2141795

Arm Description

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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
Overall Survival of Patients Treated With the Combination of Trametinib and GSK 2141795
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
Number of Severe Adverse Events (Grade 3 and 4) Reported by Patients Related With the Treatment of Trametinib and GSK2141795.

Full Information

First Posted
August 30, 2013
Last Updated
January 31, 2020
Sponsor
Adil Daud
Collaborators
National Comprehensive Cancer Network
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1. Study Identification

Unique Protocol Identification Number
NCT01941927
Brief Title
Trametinib With GSK2141795 in BRAF Wild-type Melanoma
Official Title
Phase II Clinical Trial of the MEK Inhibitor Trametinib With the AKT Inhibitor GSK2141795 in BRAF Wild-type Melanoma
Study Type
Interventional

2. Study Status

Record Verification Date
January 2020
Overall Recruitment Status
Completed
Study Start Date
September 10, 2013 (Actual)
Primary Completion Date
October 14, 2014 (Actual)
Study Completion Date
May 3, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Adil Daud
Collaborators
National Comprehensive Cancer Network

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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 (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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Melanoma
Keywords
Melanoma, Wild-type, BRAF

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Trametinib, GSK2141795
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Trametinib (GSK1120212)
Other Intervention Name(s)
MEKINIST
Intervention Description
Trametinib is a highly selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity.
Intervention Type
Drug
Intervention Name(s)
GSK2141795
Intervention Description
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.
Primary Outcome Measure Information:
Title
Objective Response Rate (ORR)
Description
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.
Time Frame
Up to 2 years from beginning of therapy
Secondary Outcome Measure Information:
Title
Progression-Free Survival of Patients Treated With the Combination of Trametinib and GSK 2141795
Description
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
Time Frame
Up to 2 years from beginning of therapy
Title
Overall Survival of Patients Treated With the Combination of Trametinib and GSK 2141795
Time Frame
Up to 2 years from beginning of therapy
Title
Time-to-Progression (TTP) of Patients Treated With the Combination of Trametinib and GSK 2141795
Description
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
Time Frame
Up to 2 years from beginning of therapy
Title
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 from beginning of therapy

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Adil Daud, M.D.
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Memorial Sloan-Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
28921907
Citation
Algazi AP, Esteve-Puig R, Nosrati A, Hinds B, Hobbs-Muthukumar A, Nandoskar P, Ortiz-Urda S, Chapman PB, Daud A. Dual MEK/AKT inhibition with trametinib and GSK2141795 does not yield clinical benefit in metastatic NRAS-mutant and wild-type melanoma. Pigment Cell Melanoma Res. 2018 Jan;31(1):110-114. doi: 10.1111/pcmr.12644. Epub 2017 Nov 2.
Results Reference
result

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Trametinib With GSK2141795 in BRAF Wild-type Melanoma

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