Trametinib in Treating Patients With Advanced Melanoma With BRAF Non-V600 Mutations

• Sponsor: Vanderbilt-Ingram Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02296112
• Collaborator: National Cancer Institute (NCI) (NIH), National Comprehensive Cancer Network (Other)
• Enrollment: 9
• Locations: 4
• Arm: 1
• Duration (Months): 75.5
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase II trial studies trametinib in treating patients with melanoma with v-Raf murine sarcoma viral oncogene homolog B (BRAF) non-V600 mutations that has spread to other places in the body. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Melanoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Melanoma	Drug: trametinib; Other: laboratory biomarker analysis; Other: pharmacological study	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the clinical efficacy of trametinib in advanced BRAF nonV600mutation (MUT) melanoma ("high activity" group).

SECONDARY OBJECTIVES:

1. To characterize the safety of trametinib. II. To evaluate the progression-free survival (PFS) and overall survival (OS) of trametinib in advanced BRAF nonV600MUT melanoma.

TERTIARY OBJECTIVES:

1. To determine the clinical efficacy of trametinib in advanced BRAF nonV600MUT melanoma ("low activity/unknown" group).

2. Identify mechanisms of resistance to trametinib in this patient population.

OUTLINE:

Patients receive trametinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 28 days.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Open-Label, Two-Arm Study of the MEK Inhibitor, Trametinib, to Investigate the Safety and Anti-Cancer Activity in Subjects With Melanoma With BRAF Non-V600 Mutations
• Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Aug 1, 2018
• Actual Study Completion Date: Apr 16, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (trametinib) Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: trametinib; Given PO; Other Names: GSK1120212 JTP-74057 Mekinist ; Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate in "High Affinity" Group [Up to 12 months]

   Per RECIST criteria version (v.) 1.1: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions.

Secondary Outcome Measures

1. Progression-Free Survival All Patients [On-study date to lesser of date of progression or date of death from any cause (assessed up to 3 years)]

   Progression of disease as defined by RECIST 1.1 criteria will be reported. Time from on treatment to progression or death (whichever comes first). For those did not progress or die, they were censored at the last follow up or off study date(if they do not have a last date of follow up).

2. Duration of Response in "High Affinity" Group [Date of first partial or complete response as defined by RECIST 1.1 criteria to date of progression up to 3 years]

   Estimated probable duration from date of objective response to date of disease progression, using the Kaplan-Meier method with censoring (see analysis population description for additional details). Disease progression is defined under RECIST v1.1 as >= 20% increase in sum of longest diameters of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions.

3. Clinical Benefit (Complete Response [CR] + Partial Response [PR] + Stable Disease [SD]) Per RECIST v. 1.1 in "High Affinity" Group [Up to 12 months]

   Per RECIST criteria v. 1.1: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions.

4. Overall Survival [On-study date to date of death from any cause (assessed up to 3 years)]

   Estimated probable duration of life from on-study date to date of death from any cause, using the Kaplan-Meier method with censoring.

5. Number of Patients With Each Worst-Grade Toxicity [On-study date to 30 days following final dose of study drug, up to 3 years]

   Safety profile shown by count of patients according to the worst-grade toxicity experienced by each, where worst-grade toxicity is per National Cancer Institute (NCI) common toxicity criteria: grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life-threatening; grade 5, death.

6. Overall Response Rate in "Low Affinity" Group [Up to 12 months]

   Per RECIST criteria v. 1.1: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions.

Other Outcome Measures

1. Duration of Response in "Low Affinity" Group [Up to 3 years]

   Estimated probable duration from date of first partial or complete response as defined by RECIST 1.1 criteria to date of disease progression, using the Kaplan-Meier method with censoring (see analysis population description for additional details). Disease progression is defined under RECIST v1.1 as >= 20% increase in sum of longest diameters of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions.

2. Clinical Benefit (CR + PR + SD) Per RECIST v. 1.1 in "Low Affinity" Group [Up to 12 months]

   Per RECIST criteria v. 1.1: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions.

3. Molecular Characteristics of Patient Samples, Including Archival Samples [Up to 3 years]

   Molecular characterization of tumor tissue will be performed to identify markers that correlate with clinical responsiveness to treatment with trametinib. Optional on-treatment biopsies will be used to evaluate pharmacodynamic and other molecular effects of treatment, which will be compared to clinical outcomes. Optional post-progression samples will be analyzed to identify mechanisms of resistance.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed written informed consent

• Histologically or cytologically confirmed diagnosis of melanoma

• BRAF mutation in loci other than V600 (BRAF nonV600 MUT) or BRAF fusion detected by genetic testing of the primary tumor or regional/distant metastasis

• Subjects must provide either a fresh or archived tumor sample for correlative study analyses

• For subjects with melanoma, archived or freshly biopsied tumor tissue (preferred) must be obtained prior to enrollment. Tissue shipment tracking information should be provided before administration of study treatment is initiated. However, if shipping will be delayed and tissue shipment tracking information is unavailable, study drug may be administered prior to tissue receipt pending discussion with principal investigator.

• Measurable disease (i.e., present with at least one measurable lesion per Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1)

• All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values) must be =< grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0) at the time of randomization. Subjects with endocrinopathies (e.g. hypopituitarism, hypothyroidism, hypoadrenalism) caused by immune therapies currently on adequate hormone replacement WILL be permitted.

• Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels

• Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception

• Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception

• An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Absolute neutrophil count (ANC) > or = 1.0 × 10^9/L

• Hemoglobin > or = 9 g/dL

• Platelet count > or = 75 x 10^9/L

• Prothrombin time (PT)/international normalized ratio (INR)* = or < 1.3 x upper limit of normal (ULN)

• Subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization; PT and partial thromboplastin time (PTT) > 1.5 x ULN are permitted in these subjects

• PTT =or < 1.3 x ULN

• Albumin >or = 2.5 g/dL

• Total bilirubin = or < 1.5 x ULN

• Alanine aminotransferase (ALT) = or < 2.5 x ULN

• Creatinine = or < 1.5 ULN or calculated creatinine clearance* > or = 50 mL/min

• Calculate creatinine clearance using standard Cockcroft-Gault formula; creatinine clearance must be > or = 50 mL/min to be eligible

• Left ventricular ejection fraction (LVEF) > or = lower limit of normal (LLN) by echocardiogram (ECHO)

Exclusion Criteria:

• No prior therapy with inhibitors affecting the mitogen-activated protein kinase (MAPK) pathways at any level (BRAF, mitogen-activated protein [MAP]/extracellular signal-related kinase [ERK] kinase [MEK], neuroblastoma RAS viral [v-ras] oncogene homolog [NRAS], ERK inhibitors) for unresectable stage IIIC or stage IV (metastatic) melanoma; no limit to other therapies (immunotherapy or chemotherapy); prior systemic treatment in the adjuvant setting is allowed; (note: ipilimumab treatment must end at least 8 weeks prior to study day 1)

• BRAFV600 mutation positive

• NRAS codon 12, 13, or 61 mutation

• Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to study day 1, or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to study day 1

• Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to study day 1

• Current use of a prohibited medication as described

• History of another malignancy

• Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected, non-melanoma skin cancer, or subjects with indolent second malignancies are eligible. T1a melanoma and melanoma in situ are permitted. Consult Medical Monitor if unsure whether second malignancies meet requirements specified above.

• Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject's safety, obtaining informed consent, or compliance with study procedures

• Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV infection will be permitted)

• History of leptomeningeal disease or spinal cord compression secondary to metastasis

• Brain metastasis, unless previously treated with surgery or stereotactic radiosurgery and the disease has been confirmed stable (i.e., no increase in lesion size) for at least 6 weeks with two consecutive magnetic resonance imaging (MRI) scans using contrast prior to study day 1; enzyme inducing anticonvulsants are not allowed while patients are on study treatment

• A history or evidence of cardiovascular risk including any of the following:

• A QT interval corrected for heart rate using the Bazett's formula (QTc) > or = 480 msec

• A history or evidence of current clinically significant uncontrolled arrhythmias

• Exception: subjects with atrial fibrillation controlled for > 30 days prior to study day 1

• History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to study day 1

• A history or evidence of current >= class I congestive heart failure as defined by the New York Heart Association (NYHA) guidelines

• Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy

• Patients with intra-cardiac defibrillators or permanent pacemakers

• Known cardiac metastases

• A history or current evidence of retinal vein occlusion (RVO) including:

• History of RVO or

• Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO such as:

• Evidence of new optic disc cupping

• Evidence of new visual field defects

• Intraocular pressure > 21 mmHg as measured by tonography

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO)

• History of interstitial lung disease or pneumonitis

• Females who are pregnant or nursing

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Georgetown University Medical Center	Washington	District of Columbia	United States	20007
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
3	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
4	M D Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• Vanderbilt-Ingram Cancer Center
• National Cancer Institute (NCI)
• National Comprehensive Cancer Network

Investigators

• Principal Investigator: Douglas Johnson, Vanderbilt-Ingram Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 12, 2016

More Information

Additional Information:

• Vanderbilt-Ingram Cancer Center, Find a Clinical Trial

Publications

None provided.

• Responsible Party: Douglas Johnson, Principal Investigator, Vanderbilt-Ingram Cancer Center
• ClinicalTrials.gov Identifier: NCT02296112
• Other Study ID Numbers: VICC MEL 1457; NCI-2014-02185; MEL1457; GSK1120212; VICC MEL 1457; P30CA068485
• First Posted: Nov 20, 2014
• Last Update Posted: May 28, 2021
• Last Verified: May 1, 2021

• Additional relevant MeSH terms: Melanoma; Trametinib

Study Results

Participant Flow

Arm/Group Title	Treatment (Trametinib)
Arm/Group Description	Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. trametinib: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies
Period Title: Overall Study
STARTED	9
COMPLETED	0
NOT COMPLETED	9

Baseline Characteristics

Arm/Group Title	Treatment (Trametinib)
Arm/Group Description	Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. trametinib: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies
Overall Participants	9
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	7 77.8%
>=65 years	2 22.2%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	52.111111111111 (5.546381313885)
Sex: Female, Male (Count of Participants)
Female	3 33.3%
Male	6 66.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	7 77.8%
More than one race	0 0%
Unknown or Not Reported	2 22.2%
Region of Enrollment (participants) [Number]
United States	9 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate in "High Affinity" Group
Description	Per RECIST criteria version (v.) 1.1: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

patients with advanced melanoma with High Activity BRAF Mutations or Fusion Events.

Arm/Group Title	Treatment (Trametinib) "High Activity"
Arm/Group Description	Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. trametinib: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies
Measure Participants	2
Mean (95% Confidence Interval) [Proportion of participants]	0.5 5.6%

2. Secondary Outcome

Title	Progression-Free Survival All Patients
Description	Progression of disease as defined by RECIST 1.1 criteria will be reported. Time from on treatment to progression or death (whichever comes first). For those did not progress or die, they were censored at the last follow up or off study date(if they do not have a last date of follow up).
Time Frame	On-study date to lesser of date of progression or date of death from any cause (assessed up to 3 years)

Outcome Measure Data

Analysis Population Description

Patients with advanced melannoma with BRAF non-V600 mutations and received treatment

Arm/Group Title	Treatment (Trametinib)
Arm/Group Description	Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. trametinib: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies
Measure Participants	9
Median (95% Confidence Interval) [months]	7.5

3. Secondary Outcome

Title	Duration of Response in "High Affinity" Group
Description	Estimated probable duration from date of objective response to date of disease progression, using the Kaplan-Meier method with censoring (see analysis population description for additional details). Disease progression is defined under RECIST v1.1 as >= 20% increase in sum of longest diameters of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions.
Time Frame	Date of first partial or complete response as defined by RECIST 1.1 criteria to date of progression up to 3 years

Outcome Measure Data

Analysis Population Description

Patients with advanced melanoma with BRAF "high activity"

Arm/Group Title	Treatment (Trametinib) "High Activity"
Arm/Group Description	Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. trametinib: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies
Measure Participants	2
Median (95% Confidence Interval) [months]	NA

4. Secondary Outcome

Title	Clinical Benefit (Complete Response [CR] + Partial Response [PR] + Stable Disease [SD]) Per RECIST v. 1.1 in "High Affinity" Group
Description	Per RECIST criteria v. 1.1: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

patients with advanced melanoma with High Activity BRAF Mutations or Fusion Events.

Arm/Group Title	Treatment (Trametinib) "High Activity"
Arm/Group Description	Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. trametinib: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies
Measure Participants	2
Mean (95% Confidence Interval) [Proportion of participants]	0.5 5.6%

5. Secondary Outcome

Title	Overall Survival
Description	Estimated probable duration of life from on-study date to date of death from any cause, using the Kaplan-Meier method with censoring.
Time Frame	On-study date to date of death from any cause (assessed up to 3 years)

Outcome Measure Data

Analysis Population Description

All patients on study

Arm/Group Title	Treatment (Trametinib)
Arm/Group Description	Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. trametinib: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies
Measure Participants	9
Median (95% Confidence Interval) [months]	27.6

6. Secondary Outcome

Title	Number of Patients With Each Worst-Grade Toxicity
Description	Safety profile shown by count of patients according to the worst-grade toxicity experienced by each, where worst-grade toxicity is per National Cancer Institute (NCI) common toxicity criteria: grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life-threatening; grade 5, death.
Time Frame	On-study date to 30 days following final dose of study drug, up to 3 years

Outcome Measure Data

Analysis Population Description

All patients on study.

Arm/Group Title	Treatment (Trametinib) Worst Grade 1	Worst Grade 2	Worst Grade 3
Arm/Group Description	Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. trametinib: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies	Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in ...	Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in ...
Measure Participants	9	9	9
Number [participants]	2 22.2%	3 NaN	3 NaN

7. Secondary Outcome

Title	Overall Response Rate in "Low Affinity" Group
Description	Per RECIST criteria v. 1.1: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

Patients on study with low activity

Arm/Group Title	Low Activity
Arm/Group Description	Patients with low activity of BRAF mutations
Measure Participants	7
Mean (95% Confidence Interval) [proportion]	0.14

8. Other Pre-specified Outcome

Title	Duration of Response in "Low Affinity" Group
Description	Estimated probable duration from date of first partial or complete response as defined by RECIST 1.1 criteria to date of disease progression, using the Kaplan-Meier method with censoring (see analysis population description for additional details). Disease progression is defined under RECIST v1.1 as >= 20% increase in sum of longest diameters of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients on study with low activity

Arm/Group Title	Low Activity
Arm/Group Description	Patients with low activity of BRAF mutations
Measure Participants	7
Median (95% Confidence Interval) [months]	NA

9. Other Pre-specified Outcome

Title	Clinical Benefit (CR + PR + SD) Per RECIST v. 1.1 in "Low Affinity" Group
Description	Per RECIST criteria v. 1.1: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Molecular Characteristics of Patient Samples, Including Archival Samples
Description	Molecular characterization of tumor tissue will be performed to identify markers that correlate with clinical responsiveness to treatment with trametinib. Optional on-treatment biopsies will be used to evaluate pharmacodynamic and other molecular effects of treatment, which will be compared to clinical outcomes. Optional post-progression samples will be analyzed to identify mechanisms of resistance.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	39 months
Arm/Group Title	Treatment (Trametinib)
Arm/Group Description	Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. trametinib: Given PO laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies
All Cause Mortality
	Treatment (Trametinib)
	Affected / at Risk (%)	# Events
Total	3/9 (33.3%)
Serious Adverse Events
	Treatment (Trametinib)
	Affected / at Risk (%)	# Events
Total	4/9 (44.4%)
Gastrointestinal disorders
Diarrhea	1/9 (11.1%)	1
Oral pain	1/9 (11.1%)	1
General disorders
Limb edema	1/9 (11.1%)	1
Investigations
Alanine aminotransferase increased	1/9 (11.1%)	1
Aspartate aminotransferase increased	1/9 (11.1%)	1
Rash	1/9 (11.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/9 (11.1%)	1
Skin and subcutaneous tissue disorders
Skin infection	2/9 (22.2%)	3
Other (Not Including Serious) Adverse Events
	Treatment (Trametinib)
	Affected / at Risk (%)	# Events
Total	9/9 (100%)
Blood and lymphatic system disorders
Anemia	3/9 (33.3%)	7
Hypokalemia	1/9 (11.1%)	1
Leukocytosis	1/9 (11.1%)	1
Thrombotic thrombocytopenic purpura	1/9 (11.1%)	2
Hypoalbuminemia	1/9 (11.1%)	3
Hypomagnesemia	1/9 (11.1%)	2
Hypergylcemia	1/9 (11.1%)	1
ALT 402 U/L	1/9 (11.1%)	1
AST 170 U/L	1/9 (11.1%)	1
Cardiac disorders
Shortness of breath	1/9 (11.1%)	1
Eye disorders
Blurred vision	2/9 (22.2%)	2
Dry eye	1/9 (11.1%)	1
Gastrointestinal disorders
Diarrhea	7/9 (77.8%)	20
Constipation	2/9 (22.2%)	3
Dry mouth	2/9 (22.2%)	2
Nausea	2/9 (22.2%)	2
Vomiting	2/9 (22.2%)	3
Abdominal pain	1/9 (11.1%)	1
Anal hemorrhage	1/9 (11.1%)	1
Bloating	1/9 (11.1%)	1
Colitis	1/9 (11.1%)	1
Flatulence	1/9 (11.1%)	1
Xerosis	1/9 (11.1%)	1
Oral hemorrhage	1/9 (11.1%)	1
Oral pain	1/9 (11.1%)	2
Pain in right side chest	1/9 (11.1%)	1
Mucositis	1/9 (11.1%)	1
Xerostemia	1/9 (11.1%)	1
General disorders
Fatigue	6/9 (66.7%)	9
Feeling cold all the time	1/9 (11.1%)	1
face edema	2/9 (22.2%)	2
Pain	2/9 (22.2%)	3
Chills	1/9 (11.1%)	1
Fever	1/9 (11.1%)	1
Flu-like symptoms	1/9 (11.1%)	1
Irritability	1/9 (11.1%)	2
Localized edema	1/9 (11.1%)	1
Burning sensation on the hands and ears	1/9 (11.1%)	1
Dry skin	1/9 (11.1%)	1
Depression	1/9 (11.1%)	1
Anxiety	1/9 (11.1%)	1
Dyspnea	1/9 (11.1%)	1
Alopecia	1/9 (11.1%)	1
Bloating	1/9 (11.1%)	1
Bloating and gas pain	1/9 (11.1%)	1
Bruising	1/9 (11.1%)	1
Bumps in mouth	1/9 (11.1%)	2
Bumps in nose	1/9 (11.1%)	2
Dry mouth	1/9 (11.1%)	1
Headache	1/9 (11.1%)	1
Lumbar nerve root injury	1/9 (11.1%)	3
Lymphedema	1/9 (11.1%)	1
Infections and infestations
Tonsil infection	1/9 (11.1%)	2
Toe fungus	1/9 (11.1%)	1
Thrush	1/9 (11.1%)	1
Injury, poisoning and procedural complications
Fall	2/9 (22.2%)	2
Bruising	1/9 (11.1%)	1
Seroma	1/9 (11.1%)	1
Investigations
Alkaline phosphatase increased	2/9 (22.2%)	3
Creatinine increased	2/9 (22.2%)	4
GGT increased	1/9 (11.1%)	1
Lymphocyte count decreased	1/9 (11.1%)	2
LDH Elevated	3/9 (33.3%)	4
Platelet count decreased	1/9 (11.1%)	1
Platelets elevated	1/9 (11.1%)	2
Hyperlipidemia	1/9 (11.1%)	1
Vitamin D deficiency	1/9 (11.1%)	1
Metabolism and nutrition disorders
Hyperglycemia	4/9 (44.4%)	7
Hypoalbuminemia	3/9 (33.3%)	6
Anorexia	2/9 (22.2%)	2
Hypermagnesemia	1/9 (11.1%)	2
Hyperuricemia	1/9 (11.1%)	1
Hypocalcemia	1/9 (11.1%)	2
Hypokalemia	1/9 (11.1%)	1
Hypomagnesemia	1/9 (11.1%)	2
Hyponatremia	1/9 (11.1%)	1
Hypophosphatemia	1/9 (11.1%)	3
Musculoskeletal and connective tissue disorders
Pain in extremity	3/9 (33.3%)	5
Arthralgia	1/9 (11.1%)	1
Back pain	1/9 (11.1%)	1
Joint range of motion decreased	1/9 (11.1%)	1
Right shoulder pain (arm pit dull pain)	1/9 (11.1%)	1
Myalgia	1/9 (11.1%)	2
Myositis	1/9 (11.1%)	1
Pain in left upper extremity	1/9 (11.1%)	1
Soft tissue infection in left arm	1/9 (11.1%)	1
3rd finger amputation	1/9 (11.1%)	1
Leg spasm	1/9 (11.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/9 (11.1%)	1
New basal cell carcinoma right flank	1/9 (11.1%)	1
Nervous system disorders
Headache	3/9 (33.3%)	3
Loss of consciousness (for less than a minute during a fall)	1/9 (11.1%)	1
Dizziness	1/9 (11.1%)	1
Involuntary movements	1/9 (11.1%)	1
Intermittent head pressure	1/9 (11.1%)	1
Psychiatric disorders
Confusion	1/9 (11.1%)	2
Anxiety	3/9 (33.3%)	3
Depression	1/9 (11.1%)	1
Insomnia	1/9 (11.1%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/9 (33.3%)	7
Epistaxis	1/9 (11.1%)	1
Nasal congestion	1/9 (11.1%)	1
Skin and subcutaneous tissue disorders
Rash acneiform	7/9 (77.8%)	11
Rash, maculo-papular	5/9 (55.6%)	9
Dry skin	4/9 (44.4%)	4
Alopecia	3/9 (33.3%)	3
Basal cell carcinoma	1/9 (11.1%)	1
Pruritus	2/9 (22.2%)	3
Skin ulceration	1/9 (11.1%)	1
New skin lesion	2/9 (22.2%)	2
Toe fungus	1/9 (11.1%)	1
Red elevated papule under the right axilla	1/9 (11.1%)	1
Vascular disorders
Lymphedema	3/9 (33.3%)	4
Hypertension	1/9 (11.1%)	1
Thromboembolic event	1/9 (11.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.