MelanomaPhase 2NCT01941927
Trametinib With GSK2141795 in BRAF Wild-type Melanoma
A Phase 2 study testing Trametinib (GSK1120212) and GSK2141795 in people with Melanoma, run by Adil Daud at 2 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma
- What is being tested?
- Trametinib (GSK1120212) and GSK2141795
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 2 sitesUnited States
- Study dates
- 10 Sep 2013to 3 May 2017
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Show all 14Show fewer
- 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
Who cannot join
- 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.
Show all 11Show fewer
- 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
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Memorial Sloan-Kettering Cancer Center
New York, New York, 10065
University of California, San Francisco
San Francisco, California, 94115
About this study
Official title: Phase II Clinical Trial of the MEK Inhibitor Trametinib With the AKT Inhibitor 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.
Read more
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.
- Conditions
- Melanoma
- Being tested
- Trametinib (GSK1120212), GSK2141795
- Keywords
- Melanoma, Wild-type, BRAF
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Trametinib (GSK1120212)Drug
Also called MEKINIST
Trametinib is a highly selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity.
GSK2141795Drug
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.
| Study group | Role | What they receive |
|---|---|---|
| Trametinib, GSK2141795 | Experimental | 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 Receives: Drug: Trametinib (GSK1120212); Drug: GSK2141795 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Up to 2 years from beginning of therapy
Secondary outcomes (4)
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
Measured: Up to 2 years from beginning of therapy
Overall Survival of Patients Treated With the Combination of Trametinib and GSK 2141795
Measured: 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
Measured: 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.
Measured: Up to 2 years from beginning of therapy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Sep 2013 (estimated)
- Study start10 Sep 2013
- Primary completion14 Oct 2014
- Study completion3 May 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for MelanomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Adil Daud
- Sponsor type
- University, hospital or other
- Collaborators
- National Comprehensive Cancer Network
- Responsible party
- Sponsor-investigator, Adil Daud, University of California, San Francisco
- Investigators
- Adil Daud, M.D., Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01941927
- Sponsor's protocol ID
- 13855
- Other IDs
- NCI-2013-01849
- Status last verified
- Jan 2020
- First submitted
- 30 Aug 2013
- Last updated
- 12 Feb 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 28921907
Study at a glance
From the registry record, last updated by the sponsor on 12 Feb 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Clinical Trial of the MEK Inhibitor Trametinib With the AKT Inhibitor GSK2141795 in BRAF Wild-type Melanoma
- ClinicalTrials.gov ID
- NCT01941927
- Acronym / sponsor ID
- 13855
- Conditions
- Melanoma
- Keywords
- Melanoma, Wild-type, BRAF
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Adil DaudUniversity, hospital or other
- Collaborators
- National Comprehensive Cancer Network
- Study start
- 10 Sep 2013 (actual)
- Primary completion
- 14 Oct 2014 (actual)
- Study completion
- 3 May 2017 (actual)
- First posted
- 13 Sep 2013 (estimated)
- Results
- Posted 12 Feb 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Trametinib, GSK2141795 | Experimental | Drug: Trametinib (GSK1120212), Drug: GSK2141795Trametinib (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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- 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
Key exclusion criteria (11 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Trametinib (GSK1120212)Also: MEKINISTTrametinib is a highly selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity. | Drug | Trametinib, GSK2141795 |
| GSK2141795GSK 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. | Drug | Trametinib, GSK2141795 |
Primary outcome
Objective Response Rate (ORR)
Time frame: Up to 2 years from beginning of therapy
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.
4 secondary outcomes
Progression-Free Survival of Patients Treated With the Combination of Trametinib and GSK 2141795
Time frame: Up to 2 years from beginning of therapy
Overall Survival of Patients Treated With the Combination of Trametinib and GSK 2141795
Time frame: Up to 2 years from beginning of therapy
Time-to-Progression (TTP) of Patients Treated With the Combination of Trametinib and GSK 2141795
Time frame: 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.
Time frame: Up to 2 years from beginning of therapy
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Feb 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 28921907Algazi 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.
- Individual participant dataSharing planned: No
Related trials for Melanoma
RecruitingPhase 1/2
Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)
Solid Tumor, Non-Small Cell Lung Cancer
RecruitingPhase 1
IL-17 Blockade to Decrease irAEs (REPLAY)
Metastatic Melanoma
Enrolling by invitationObservational study
Natural History Study of Early Life Exposures in Agriculture (ELEA)
Prostate Cancer, Leukemia
RecruitingPhase 1
A Feasibility Study Utilizing Immune Recall to Increase Response to Checkpoint Therapy
Melanoma
Active, not recruitingPhase 1/2
A Study of Dapansutrile Plus Pembrolizumab in Patients With PD-1 Refractory Advanced Melanoma
Melanoma
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Adil Daud, M.D. principal investigator
University of California, San Francisco
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Trametinib (GSK1120212) and GSK2141795 in people with Melanoma, run by Adil Daud at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Feb 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Objective Response Rate (ORR) (time frame: Up to 2 years from beginning of therapy). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01941927, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Feb 2020.