Trametinib With or Without GSK2141795 in Treating Patients With Metastatic Uveal Melanoma
Study Details
Study Description
Brief Summary
This randomized phase II trial studies how well trametinib with or without Akt inhibitor GSK2141795 (GSK2141795) works in treating patients with uveal melanoma that has spread to other parts of the body (metastatic). Trametinib and GSK2141795 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether trametinib is more effective with or without GSK2141795 in treating patients with metastatic uveal melanoma.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVES:
- To compare progression-free survival between those treated with trametinib alone and those treated with the combination of trametinib and GSK2141795.
SECONDARY OBJECTIVES:
-
To compare overall survival between those treated with trametinib alone and those treated with the combination of trametinib and GSK2141795.
-
To compare the overall response rate between those treated with trametinib alone and those treated with the combination of trametinib and GSK2141795.
-
To compare the safety and toxicity between those treated with trametinib alone and those treated with the combination of trametinib and GSK2141795.
TERTIARY OBJECTIVES:
-
To assess clinical outcomes (response rate, progression-free and overall survival) with trametinib and GSK2141795 after progression on trametinib.
-
To assess toxicity with trametinib and GSK2141795 after progression on trametinib.
-
To correlate clinical outcome with Gnaq/11 mutational status. IV. To assess the pharmacodynamic effects of trametinib alone and with GSK2141795, and utilize whole-transcriptome and reverse phase protein array to identify markers of sensitivity and primary resistance to trametinib alone and with GSK2141795.
-
To assess for changes in circulating tumor deoxyribonucleic acid (DNA) with therapy.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM A: Patients receive trametinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who experience objective disease progression may crossover to Arm B. (no patients will be enrolled to Arm B or Crossover therapy as of 11/6/2015)
ARM B: Patients receive trametinib PO QD and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 4 weeks and then every 12 weeks thereafter.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm A (trametinib) Patients receive trametinib PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who experience objective disease progression may crossover to Arm B. (no patients will be enrolled to Arm B or Crossover therapy as of 11/6/2015) |
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Drug: Trametinib
Given PO
Other Names:
|
| Experimental: Arm B (trametinib, Akt inhibitor GSK2141795) Patients receive trametinib PO QD and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. |
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Drug: Trametinib
Given PO
Other Names:
Drug: Uprosertib
Given PO
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Time to Progression (Progression-free Survival [PFS]), Defined From the Date of Randomization to the Date of Documented Progression or Death Per RECIST [from randomization to the earlier date of objective disease progression or death]
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Secondary Outcome Measures
- Number of Participants With Toxicity, Graded According to the National Cancer Institute CTCAE v4.0, Who Were Treated and Did Not Withdraw Consent [From date of randomization until the date of death from any cause or 4 weeks from last treatment of the initial treatment assignment, whichever came first, assessed up to 12 months]
Graded according to the National Cancer Institute CTCAE v4.0. Please see AE/SAE Section for specifics.
- Overall Survival (OS) Per RECIST Criteria [up to 36 months]
OS curves will be generated using Kaplan-Meier methodology.
- Response Rate (Complete Response+ Partial Response) Using the RECIST Criteria [From date of randomization until the date of death from any cause or 4 weeks from last treatment of the initial treatment assignment, whichever came first, assessed up to 12 months]
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI and/or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease (PD); PD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions.
Other Outcome Measures
- Change in Apoptosis in Paired Samples as Assessed by Caspase 3 Cleavage [Baseline to 4 weeks from last treatment]
- Change in Suppression of Phosphorylated (p)-ERK, AKT, and Cyclin-D1 [Baseline to 4 weeks from last treatment]
Association between suppression and response to treatment will be assessed using Fisher's exact test.
- Circulating Tumor DNA Levels [Up to 4 weeks from last treatment]
The numeric data will be summarized by clinical response.
- Gnaq/11 Mutational Status [Up to 4 weeks from last treatment]
Clinical response will be associated with Gnaq/11 mutational status using Wilcoxon rank sum test.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Patients must have metastatic histologically or cytologically confirmed uveal melanoma; if histologic or cytologic confirmation of the primary is not available, confirmation of the primary diagnosis of uveal melanoma by the treating investigator can be clinically obtained, as per standard practice for uveal melanoma; pathologic confirmation of metastatic disease will be performed at Memorial Sloan Kettering (MSK) or at a participating site
-
Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan
-
Patients may not have received prior systemic or hepatic directed infusional/embolization therapies for advanced uveal melanoma; local therapies such as radiofrequency ablation or cryotherapy for metastatic disease are permitted but must have been performed at least 21 days prior to initiation of study therapy; lesions treated with local modalities such as radiofrequency ablation or cryotherapy may not be used as target lesions unless they demonstrate growth over a minimum of 3 months on subsequent imaging studies
-
Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
-
Life expectancy of greater than 3 months
-
Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
-
All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 grade =< 1 (except alopecia) at the time of randomization and crossover
-
Leukocytes >= 3,000/mcL
-
Absolute neutrophil count >= 1,500/mcL
-
Platelets >= 100,000/mcL
-
Hemoglobin >= 9.0 g/dL (not requiring transfusions within the past 2 weeks)
-
Total bilirubin =< 1.5 x institutional upper limit of normal; Note: patients with hyperbilirubinemia clinically consistent with an inherited disorder of bilirubin metabolism (e.g., Gilbert syndrome) will be eligible at the discretion of the treating physician and/or the principal investigator
-
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional upper limit of normal for patients with no concurrent liver metastases, OR =< 2.5 x institutional upper limit of normal for patients with concurrent liver metastases
-
Creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula)
= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min
-
Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA)
-
Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; women of child-bearing potential must have a negative blood pregnancy test within 14 days prior to start of protocol treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of trametinib administration
-
Ability to understand and the willingness to sign a written informed consent document
-
Patients must agree to provide all imaging studies for central radiology review; this central radiology review may be performed retrospectively and will not be utilized for decision making for patients on study
-
ELIGIBILITY CRITERIA FOR CROSSOVER REGISTRATION
-
Previously treated with trametinib on Arm A and experienced objective disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
-
Not removed from trametinib treatment due to the development of unacceptable toxicity that is not manageable with dose reduction
-
No other drug treatment for malignant melanoma administered after completing study treatment with trametinib
-
Meet all eligibility criteria with the exception of:
-
Prior therapy with trametinib will be permitted
-
All laboratory parameters must be met as outlined except for ALT and total bilirubin, which must meet criteria for continued therapy
-
Patients who are eligible for cross-over will not need to undergo another ophthalmologic examination
Exclusion Criteria:
-
History of another malignancy except for those who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies not requiring active therapy, are eligible; consult the study MSK Principal Investigator or the Cancer Therapy Evaluation Program (CTEP) Medical Monitor if unsure whether second malignancies meet the requirements specified above
-
History of interstitial lung disease or pneumonitis
-
Any major surgery or extensive radiotherapy within 21 days prior to randomization and crossover
-
Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of trametinib alone or with GSK2141795 and during the study
-
Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression; treated brain metastases must have been stable for at least 1 month
-
Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib, GSK2141795, or excipients or to dimethyl sulfoxide (DMSO)
-
Current use of a prohibited medication
-
History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED) in the eye unaffected by uveal melanoma
-
Patients with abnormal fasting glucose values (values > upper limit of normal [ULN] or < LLN) at screening will be excluded; in addition, patients with type 1 diabetes will also be excluded; however, patients with type 2 diabetes will be allowed if diagnosed
= 6 months prior to enrollment, and if presenting with a normal fasting glucose value and a regular hemoglobin A1C (HbA1C) =< 8% at screening
-
History or evidence of cardiovascular risk including any of the following:
-
Left ventricular ejection fraction (LVEF) < LLN
-
A QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec
-
History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible)
-
History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization
-
History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system
-
Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy
-
Patients with intra-cardiac defibrillators
-
Known cardiac metastases
-
Known hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible); patients with human immunodeficiency virus (HIV) are not eligible if on anti-retroviral medications
-
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
-
The study drug must not be administered to pregnant women or nursing mothers; women of childbearing potential should be advised to avoid pregnancy and use effective methods of contraception; men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Emory University Hospital/Winship Cancer Institute | Atlanta | Georgia | United States | 30322 |
| 2 | Columbia University/Herbert Irving Cancer Center | New York | New York | United States | 10032 |
| 3 | Memorial Sloan-Kettering Cancer Center | New York | New York | United States | 10065 |
| 4 | Vanderbilt University/Ingram Cancer Center | Nashville | Tennessee | United States | 37232 |
| 5 | M D Anderson Cancer Center | Houston | Texas | United States | 77030 |
| 6 | Institut Curie Paris | Paris | France | 75005 | |
| 7 | The University of Liverpool | Liverpool | United Kingdom | L69 3GA |
Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Alexander Shoushtari, Memorial Sloan Kettering Cancer Center
Study Documents (Full-Text)
More Information
Publications
None provided.- NCI-2013-02091
- NCI-2013-02091
- 13-144
- 9445
- 9445
- N01CM00039
- P30CA008748
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Arm A (Trametinib) | Arm B (Trametinib, Akt Inhibitor GSK2141795) |
|---|---|---|
| Arm/Group Description | Patients receive trametinib PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who experience objective disease progression may crossover to Arm B. (no patients will be enrolled to Arm B or Crossover therapy as of 11/6/2015) Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO | Patients receive trametinib PO QD and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO |
| Period Title: Overall Study | ||
| STARTED | 21 | 21 |
| COMPLETED | 20 | 21 |
| NOT COMPLETED | 1 | 0 |
Baseline Characteristics
| Arm/Group Title | Arm A (Trametinib) | Arm B (Trametinib, Akt Inhibitor GSK2141795) | Total |
|---|---|---|---|
| Arm/Group Description | Patients receive trametinib PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who experience objective disease progression may crossover to Arm B. (no patients will be enrolled to Arm B or Crossover therapy as of 11/6/2015) Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO | Patients receive trametinib PO QD and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO | Total of all reporting groups |
| Overall Participants | 21 | 21 | 42 |
| Age (years) [Mean (Full Range) ] | |||
| Mean (Full Range) [years] |
59
|
59.6
|
59.3
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
10
47.6%
|
9
42.9%
|
19
45.2%
|
| Male |
11
52.4%
|
12
57.1%
|
23
54.8%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
0
0%
|
0
0%
|
0
0%
|
| Not Hispanic or Latino |
21
100%
|
21
100%
|
42
100%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
1
4.8%
|
0
0%
|
1
2.4%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
| White |
20
95.2%
|
21
100%
|
41
97.6%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
21
100%
|
21
100%
|
42
100%
|
Outcome Measures
| Title | Time to Progression (Progression-free Survival [PFS]), Defined From the Date of Randomization to the Date of Documented Progression or Death Per RECIST |
|---|---|
| Description | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Time Frame | from randomization to the earlier date of objective disease progression or death |
Outcome Measure Data
| Analysis Population Description |
|---|
| This assessment corresponds to the participants' initial treatment assignment. |
| Arm/Group Title | Arm A (Trametinib) | Arm B (Trametinib, Akt Inhibitor GSK2141795) |
|---|---|---|
| Arm/Group Description | Patients receive trametinib PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who experience objective disease progression may crossover to Arm B. (no patients will be enrolled to Arm B or Crossover therapy as of 11/6/2015) Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO | Patients receive trametinib PO QD and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO |
| Measure Participants | 20 | 21 |
| Median (Full Range) [weeks] |
16.6
|
15.6
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A (Trametinib), Arm B (Trametinib, Akt Inhibitor GSK2141795) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.74 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Title | Number of Participants With Toxicity, Graded According to the National Cancer Institute CTCAE v4.0, Who Were Treated and Did Not Withdraw Consent |
|---|---|
| Description | Graded according to the National Cancer Institute CTCAE v4.0. Please see AE/SAE Section for specifics. |
| Time Frame | From date of randomization until the date of death from any cause or 4 weeks from last treatment of the initial treatment assignment, whichever came first, assessed up to 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| This assessment corresponds to the participants' initial treatment assignment. |
| Arm/Group Title | Arm A (Trametinib) | Arm B (Trametinib, Akt Inhibitor GSK2141795) |
|---|---|---|
| Arm/Group Description | Patients receive trametinib PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who experience objective disease progression may crossover to Arm B. (no patients will be enrolled to Arm B or Crossover therapy as of 11/6/2015) Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO | Patients receive trametinib PO QD and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO |
| Measure Participants | 21 | 21 |
| Count of Participants [Participants] |
21
100%
|
21
100%
|
| Title | Overall Survival (OS) Per RECIST Criteria |
|---|---|
| Description | OS curves will be generated using Kaplan-Meier methodology. |
| Time Frame | up to 36 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| This assessment corresponds to the participants' initial treatment assignment. |
| Arm/Group Title | Arm A (Trametinib) | Arm B (Trametinib, Akt Inhibitor GSK2141795) |
|---|---|---|
| Arm/Group Description | Patients receive trametinib PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who experience objective disease progression may crossover to Arm B. (no patients will be enrolled to Arm B or Crossover therapy as of 11/6/2015) Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO | Patients receive trametinib PO QD and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO |
| Measure Participants | 20 | 21 |
| Median (Full Range) [weeks] |
69
|
88
|
| Title | Response Rate (Complete Response+ Partial Response) Using the RECIST Criteria |
|---|---|
| Description | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI and/or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease (PD); PD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions. |
| Time Frame | From date of randomization until the date of death from any cause or 4 weeks from last treatment of the initial treatment assignment, whichever came first, assessed up to 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| This assessment corresponds to the participants' initial treatment assignment. |
| Arm/Group Title | Arm A (Trametinib) | Arm B (Trametinib, Akt Inhibitor GSK2141795) |
|---|---|---|
| Arm/Group Description | Patients receive trametinib PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who experience objective disease progression may crossover to Arm B. (no patients will be enrolled to Arm B or Crossover therapy as of 11/6/2015) Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO | Patients receive trametinib PO QD and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO |
| Measure Participants | 19 | 18 |
| Partial Response |
2
9.5%
|
1
4.8%
|
| Progression of Disease |
8
38.1%
|
4
19%
|
| Stable Disease |
9
42.9%
|
13
61.9%
|
| Title | Change in Apoptosis in Paired Samples as Assessed by Caspase 3 Cleavage |
|---|---|
| Description | |
| Time Frame | Baseline to 4 weeks from last treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| The size of the cores from the acquired samples in almost all participants were small and the quality was insufficient to analyze across the sample set. |
| Arm/Group Title | Arm A (Trametinib) | Arm B (Trametinib, Akt Inhibitor GSK2141795) |
|---|---|---|
| Arm/Group Description | Patients receive trametinib PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who experience objective disease progression may crossover to Arm B. (no patients will be enrolled to Arm B or Crossover therapy as of 11/6/2015) Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO | Patients receive trametinib PO QD and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO |
| Measure Participants | 0 | 0 |
| Title | Change in Suppression of Phosphorylated (p)-ERK, AKT, and Cyclin-D1 |
|---|---|
| Description | Association between suppression and response to treatment will be assessed using Fisher's exact test. |
| Time Frame | Baseline to 4 weeks from last treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| The size of the cores from the acquired samples in almost all participants were small and the quality was insufficient to analyze across the sample set. |
| Arm/Group Title | Arm A (Trametinib) | Arm B (Trametinib, Akt Inhibitor GSK2141795) |
|---|---|---|
| Arm/Group Description | Patients receive trametinib PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who experience objective disease progression may crossover to Arm B. (no patients will be enrolled to Arm B or Crossover therapy as of 11/6/2015) Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO | Patients receive trametinib PO QD and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO |
| Measure Participants | 0 | 0 |
| Title | Circulating Tumor DNA Levels |
|---|---|
| Description | The numeric data will be summarized by clinical response. |
| Time Frame | Up to 4 weeks from last treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data were not analyzed due to lack of funding. |
| Arm/Group Title | Arm A (Trametinib) | Arm B (Trametinib, Akt Inhibitor GSK2141795) |
|---|---|---|
| Arm/Group Description | Patients receive trametinib PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who experience objective disease progression may crossover to Arm B. (no patients will be enrolled to Arm B or Crossover therapy as of 11/6/2015) Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO | Patients receive trametinib PO QD and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO |
| Measure Participants | 0 | 0 |
| Title | Gnaq/11 Mutational Status |
|---|---|
| Description | Clinical response will be associated with Gnaq/11 mutational status using Wilcoxon rank sum test. |
| Time Frame | Up to 4 weeks from last treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis across the sample set unable to be completed due to patient-specific issues (participants skipped biopsy for safety, insufficient cores for extra DNA extraction) |
| Arm/Group Title | Arm A (Trametinib) | Arm B (Trametinib, Akt Inhibitor GSK2141795) |
|---|---|---|
| Arm/Group Description | Patients receive trametinib PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who experience objective disease progression may crossover to Arm B. (no patients will be enrolled to Arm B or Crossover therapy as of 11/6/2015) Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO | Patients receive trametinib PO QD and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO |
| Measure Participants | 0 | 0 |
Adverse Events
| Time Frame | From date of randomization until the date of death from any cause or 4 weeks from removal of the study, whichever came first, assessed up to 12 months | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | AE's and SAE's for Arm A, Arm B, and the crossover group were collected. | |||||
| Arm/Group Title | Arm A (Trametinib) | Arm B (Trametinib, Akt Inhibitor GSK2141795) | Crossover Arm | |||
| Arm/Group Description | Patients receive trametinib PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who experience objective disease progression may crossover to Arm B. (no patients will be enrolled to Arm B or Crossover therapy as of 11/6/2015) Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO | Patients receive trametinib PO QD and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO | Participants had progression of disease on Arm A and were then treated on Arm B. | |||
All Cause Mortality |
||||||
| Arm A (Trametinib) | Arm B (Trametinib, Akt Inhibitor GSK2141795) | Crossover Arm | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 5/20 (25%) | 13/21 (61.9%) | 8/11 (72.7%) | |||
Serious Adverse Events |
||||||
| Arm A (Trametinib) | Arm B (Trametinib, Akt Inhibitor GSK2141795) | Crossover Arm | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 8/20 (40%) | 12/21 (57.1%) | 11/11 (100%) | |||
| Cardiac disorders | ||||||
| Atrial Fibrillation | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Myocardial infarction | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Pericardial Effusion | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Endocrine disorders | ||||||
| Adrenal insufficiency | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Eye disorders | ||||||
| Retinal vascular disorder | 0/20 (0%) | 0/21 (0%) | 1/11 (9.1%) | |||
| Eye disorders - Other, specify | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Gastrointestinal disorders | ||||||
| Ascites | 0/20 (0%) | 0/21 (0%) | 1/11 (9.1%) | |||
| Dysphagia | 0/20 (0%) | 0/21 (0%) | 1/11 (9.1%) | |||
| Esophagitis | 0/20 (0%) | 0/21 (0%) | 1/11 (9.1%) | |||
| Pancreatitis | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Abdominal pain | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Nausea | 0/20 (0%) | 1/21 (4.8%) | 1/11 (9.1%) | |||
| Vomiting | 0/20 (0%) | 0/21 (0%) | 1/11 (9.1%) | |||
| General disorders | ||||||
| Edema face | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Fever | 0/20 (0%) | 0/21 (0%) | 2/11 (18.2%) | |||
| Hepatobiliary disorders | ||||||
| Hepatic hemorrhage | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Infections and infestations | ||||||
| Infections and infestations - Other, specify | 1/20 (5%) | 0/21 (0%) | 1/11 (9.1%) | |||
| Urinary tract infection | 0/20 (0%) | 0/21 (0%) | 1/11 (9.1%) | |||
| Endocarditis infective | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Sepsis | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Injury, poisoning and procedural complications | ||||||
| Hip fracture | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Investigations | ||||||
| Alanine aminotransferase increased | 1/20 (5%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Aspartate aminotransferase increased | 1/20 (5%) | 1/21 (4.8%) | 1/11 (9.1%) | |||
| Alkaline phosphatase increased | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Blood bilirubin increased | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Metabolism and nutrition disorders | ||||||
| Hyperglycemia | 0/20 (0%) | 0/21 (0%) | 1/11 (9.1%) | |||
| Hyponatremia | 1/20 (5%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Dehydration | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Neoplasms ben/mal/unk (inc cyst/polyp) Other, specify | 1/20 (5%) | 9/21 (42.9%) | 1/11 (9.1%) | |||
| Nervous system disorders | ||||||
| Syncope | 1/20 (5%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Stroke | 0/20 (0%) | 1/21 (4.8%) | 9/11 (81.8%) | |||
| Psychiatric disorders | ||||||
| Confusion | 0/20 (0%) | 1/21 (4.8%) | 1/11 (9.1%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Dyspnea | 0/20 (0%) | 0/21 (0%) | 1/11 (9.1%) | |||
| Hypoxia | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Pleural Effusion | 0/20 (0%) | 2/21 (9.5%) | 1/11 (9.1%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Rash maculo-papular | 0/20 (0%) | 0/21 (0%) | 1/11 (9.1%) | |||
| Vascular disorders | ||||||
| Hypertension | 0/20 (0%) | 2/21 (9.5%) | 0/11 (0%) | |||
| Thromboembolic event | 0/20 (0%) | 3/21 (14.3%) | 0/11 (0%) | |||
| Vascular disorders - Other, specify | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Arm A (Trametinib) | Arm B (Trametinib, Akt Inhibitor GSK2141795) | Crossover Arm | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 20/20 (100%) | 21/21 (100%) | 11/11 (100%) | |||
| Blood and lymphatic system disorders | ||||||
| Anemia | 0/20 (0%) | 0/21 (0%) | 3/11 (27.3%) | |||
| Cardiac disorders | ||||||
| Myocardial infarction | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Ear and labyrinth disorders | ||||||
| Vertigo | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Eye disorders | ||||||
| Blurred vision | 2/20 (10%) | 0/21 (0%) | 0/11 (0%) | |||
| Retinal Vein Occlusion | 0/20 (0%) | 0/21 (0%) | 1/11 (9.1%) | |||
| Gastrointestinal disorders | ||||||
| Diarrhea | 0/20 (0%) | 1/21 (4.8%) | 6/11 (54.5%) | |||
| Dyspepsia | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Mucositis oral | 0/20 (0%) | 2/21 (9.5%) | 5/11 (45.5%) | |||
| Nausea | 0/20 (0%) | 4/21 (19%) | 6/11 (54.5%) | |||
| Stomach pain | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Vomiting | 0/20 (0%) | 2/21 (9.5%) | 4/11 (36.4%) | |||
| Abdominal pain | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Constipation | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Gastroesophageal reflux disease | 0/20 (0%) | 2/21 (9.5%) | 0/11 (0%) | |||
| Dry Mouth | 0/20 (0%) | 0/21 (0%) | 5/11 (45.5%) | |||
| Esophagitis | 0/20 (0%) | 0/21 (0%) | 1/11 (9.1%) | |||
| Dysphagia | 0/20 (0%) | 0/21 (0%) | 1/11 (9.1%) | |||
| General disorders | ||||||
| Chills | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Edema limbs | 0/20 (0%) | 1/21 (4.8%) | 2/11 (18.2%) | |||
| Fatigue | 0/20 (0%) | 6/21 (28.6%) | 6/11 (54.5%) | |||
| Localized edema | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Edema trunk | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Infections and infestations | ||||||
| Bronchial infection | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Infections and infestations - Other, specify | 2/20 (10%) | 0/21 (0%) | 0/11 (0%) | |||
| Paronychia | 1/20 (5%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Skin infection | 2/20 (10%) | 2/21 (9.5%) | 0/11 (0%) | |||
| Upper respiratory infection | 2/20 (10%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Urinary tract infection | 2/20 (10%) | 2/21 (9.5%) | 0/11 (0%) | |||
| Lip infection | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Nail infection | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Tooth infection | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Vaginal infection | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Vulval infection | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Investigations | ||||||
| Alanine aminotransferase increased | 0/20 (0%) | 5/21 (23.8%) | 5/11 (45.5%) | |||
| Alkaline phosphatase increased | 3/20 (15%) | 6/21 (28.6%) | 2/11 (18.2%) | |||
| Aspartate aminotransferase increased | 4/20 (20%) | 7/21 (33.3%) | 0/11 (0%) | |||
| Blood bilirubin increased | 3/20 (15%) | 3/21 (14.3%) | 0/11 (0%) | |||
| CPK increased | 2/20 (10%) | 0/21 (0%) | 0/11 (0%) | |||
| Cholesterol high | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Ejection fraction decreased | 4/20 (20%) | 1/21 (4.8%) | 0/11 (0%) | |||
| INR increased | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Neutrophil count decreased | 2/20 (10%) | 0/21 (0%) | 0/11 (0%) | |||
| Platelet count decreased | 0/20 (0%) | 0/21 (0%) | 1/11 (9.1%) | |||
| White blood cell decreased | 2/20 (10%) | 0/21 (0%) | 0/11 (0%) | |||
| Creatinine increased | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Electrocardiogram QT corrected interval prolonged | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Lymphocyte count decreased | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Weight loss | 0/20 (0%) | 0/21 (0%) | 4/11 (36.4%) | |||
| WBC Decreased | 0/20 (0%) | 0/21 (0%) | 2/11 (18.2%) | |||
| Metabolism and nutrition disorders | ||||||
| Anorexia | 1/20 (5%) | 2/21 (9.5%) | 0/11 (0%) | |||
| Dehydration | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Hyperglycemia | 0/20 (0%) | 3/21 (14.3%) | 4/11 (36.4%) | |||
| Hypoalbuminemia | 4/20 (20%) | 3/21 (14.3%) | 0/11 (0%) | |||
| Hypocalcemia | 4/20 (20%) | 2/21 (9.5%) | 0/11 (0%) | |||
| Hyponatremia | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Hypophosphatemia | 2/20 (10%) | 2/21 (9.5%) | 0/11 (0%) | |||
| Hyperkalemia | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Hypoglycemia | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Musculoskeletal & conn tissue disorder Other, spec | 2/20 (10%) | 0/21 (0%) | 0/11 (0%) | |||
| Pain | 3/20 (15%) | 2/21 (9.5%) | 0/11 (0%) | |||
| Chest wall pain | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Nervous system disorders | ||||||
| Dizziness | 1/20 (5%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Headache | 1/20 (5%) | 2/21 (9.5%) | 0/11 (0%) | |||
| Syncope | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Psychiatric disorders | ||||||
| Confusion | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Renal and urinary disorders | ||||||
| Urinary frequency | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Reproductive system and breast disorders | ||||||
| Dyspareunia | 0/20 (0%) | 0/21 (0%) | 1/11 (9.1%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Cough | 2/20 (10%) | 0/21 (0%) | 0/11 (0%) | |||
| Dyspnea | 1/20 (5%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Nasal congestion | 4/20 (20%) | 0/21 (0%) | 0/11 (0%) | |||
| Pneumothorax | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Sore throat | 0/20 (0%) | 2/21 (9.5%) | 0/11 (0%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Alopecia | 1/20 (5%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Pruritus | 0/20 (0%) | 2/21 (9.5%) | 7/11 (63.6%) | |||
| Rash acneiform | 9/20 (45%) | 2/21 (9.5%) | 0/11 (0%) | |||
| Rash maculo-papular | 1/20 (5%) | 4/21 (19%) | 6/11 (54.5%) | |||
| Skin & subcutaneous tissue disorders Other, spec | 1/20 (5%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Dry skin | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Hyperhidrosis | 0/20 (0%) | 1/21 (4.8%) | 0/11 (0%) | |||
| Surgical and medical procedures | ||||||
| Surgical and medical procedures - Other, specify | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Vascular disorders | ||||||
| Hematoma | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Hypertension | 4/20 (20%) | 10/21 (47.6%) | 2/11 (18.2%) | |||
| Superficial thrombophlebitis | 1/20 (5%) | 0/21 (0%) | 0/11 (0%) | |||
| Thromboembolic event | 2/20 (10%) | 1/21 (4.8%) | 0/11 (0%) | |||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Dr. Alexander Shoushtari |
|---|---|
| Organization | Memorial Sloan Kettering Cancer Center |
| Phone | 646-888-4161 |
| shoushta@mskcc.org |
- NCI-2013-02091
- NCI-2013-02091
- 13-144
- 9445
- 9445
- N01CM00039
- P30CA008748