Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Metastatic Triple-Negative Breast Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01964924
• Collaborator: GlaxoSmithKline (Industry)
• Enrollment: 37
• Locations: 8
• Arm: 1
• Actual Duration (Months): 54.7
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase II trial studies how well trametinib and v-akt murine thymoma viral oncogene homolog 1 (Akt) inhibitor GSK2141795 work in treating patients with triple-negative breast cancer (breast cancer cells that do not have estrogen receptors, progesterone receptors, or large amounts of human epidermal growth factor receptor 2 [HER2/neu] protein) that has spread to other places in the body. Trametinib and Akt inhibitor GSK2141795 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Estrogen Receptor Negative; HER2/Neu Negative; Invasive Breast Carcinoma; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma	Drug: Akt Inhibitor GSK2141795; Other: Laboratory Biomarker Analysis; Drug: Trametinib	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess the anti-tumor activity associated with trametinib monotherapy in patients with triple negative breast cancer (TNBC).

SECONDARY OBJECTIVES:

1. To assess the anti-tumor activity associated with trametinib in combination with AKT inhibitor GSK2141795 after progression on trametinib in patients with metastatic TNBC.

2. To determine the progression-free survival following the initiation of treatment with trametinib monotherapy in patients with metastatic TNBC.

3. To determine the progression-free survival following the initiation of treatment with trametinib in combination with GSK2141795 in patients with metastatic TNBC.

4. To determine the overall survival following the initiation of treatment with trametinib with GSK214179 in patients with metastatic TNBC.

5. To determine the nature and degree of toxicities associated with trametinib monotherapy and trametinib in combination with GSK2141795 in patients with metastatic TNBC.

6. To determine the biomarker potential of phosphatase and tensin homolog (PTEN) to predict response to single agent trametinib.

7. To determine molecular markers of sensitivity and resistance to trametinib monotherapy and trametinib in combination with GSK2141795 in patients with metastatic TNBC.

OUTLINE:

PART 1: 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. Patients who experience disease progression continue to Part 2.

PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO 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 every 3 months for 52 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single Arm, Phase II Study of Single Agent Trametinib Followed by Trametinib in Combination With GSK2141795 in Patients With Advanced Triple Negative Breast Cancer
• Actual Study Start Date: Oct 2, 2013
• Actual Primary Completion Date: Jan 20, 2017
• Actual Study Completion Date: Apr 23, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (trametinib, Akt inhibitor GSK2141795) PART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2. PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Akt Inhibitor GSK2141795; Given PO; Other Names: GSK2141795 Oral Akt Inhibitor GSK2141795 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Trametinib; Given PO; Other Names: GSK1120212 JTP-74057 MEK Inhibitor GSK1120212 Mekinist

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (ORR), Defined as the Proportion of Patients Who Have Had a Partial Response (PR) or Complete Response (CR) (RECIST 1.1 Based) Within the First 6 Months After Initiation of Therapy With Trametinib [6 months]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Secondary Outcome Measures

1. Clinical Benefit Rate (CBR = CR+PR+Stable Disease [SD]) [Up to 52 weeks]

   The clinical benefit rate (CR+PR+SD) will be reported for patients after Part 1 and after Part 2.

2. Duration of Objective Response [up to 52 weeks]

   Summary statistics of duration of response for patients with objective response

3. Incidence of Adverse Events That Are Classified as Either Possibly, Probably, or Definitely Related to Study Treatment [Up to 52 weeks]

   Incidence of adverse events for patients that are classified as either possibly, probably, or definitely related to study treatment graded by National Cancer Institute (NCI) CTCAE v4.0

4. Incidence of Severe (Grade 3+) Adverse Events or Toxicities Graded Per NCI CTCAE Version 4.0 [Up to 52 weeks]

   NCI CommonTerminology Criteria for Adverse Events (CTCAE) version 4.0 was utilized for grading incidence of toxicities (grade 3+).

5. Overall Survival [Start date of the treatment to the date of the event (i.e., death) or the date of last follow-up to evaluate that event, assessed up to 52 weeks]

   The Kaplan-Meier method will be used to estimate overall survival distribution.

6. Progression-free Survival [The duration of time from start of treatment to time of progression or death, whichever comes first, assessed up to 52 weeks]

   The Kaplan-Meier method will be used to estimate progression-free survival distribution.

7. Proportion of Patients Who go Off Treatment Due to Adverse Reactions [Up to 52 weeks]

   The proportion of patients who go off treatment due to adverse reactions or even those who refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial was captured. These tolerability measures were assessed within each of the treatment parts independently. All patients who have received at least one dose of any of the therapeutic agents was evaluable for toxicity and tolerability.

8. Proportion of Patients Who Refuse Further Treatment for Lesser Toxicities That Inhibit Their Willingness to Continue Participation on the Trial [Up to 52 weeks]

9. Tolerability of the Regimen Defined as the Number of Patients Who Required Dose Modifications and/or Dose Delays [Up to 52 weeks]

Other Outcome Measures

1. Predictive Value of PTEN and Other Biomarkers on Patient Outcome (Survival, ORR, and CBR) [At time of disease progression, assessed up to 52 weeks]

2. Protein Intensity Fold-change Ratios Assessed by Reverse Phase Protein Assay Intensity Values [Up to 52 weeks]

   Ratios between tumors sampled prior to initiating trametinib single agent treatment and at time of progression (TOP) on either single agent trametinib or the combination (TOP/pre-treat ratio), will be calculated. These ratios will be median-centered and clustered using Cluster 2.0 software. Student's t-test for differences between average protein intensity ratios at these intervals will be calculated using Microsoft Excel by grouping all the ratios for individual clusters.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed metastatic invasive breast cancer that is negative for the estrogen receptor (ER), progesterone receptor (PR) and HER2 by institutional guidelines

• Patients must have measurable disease (Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1])

• Patients must have had exposure to at least 1 and no more than 3 prior chemotherapy regimens for the treatment of metastatic breast cancer

• Patients must consent to both a pretreatment and a post-treatment mandatory research biopsy prior to enrolling on trial, and therefore, must have tissue (excluding bone or brain) that is amenable to biopsy

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• 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 version 4 (CTCAE v4) grade =< 1 (except alopecia) at the time of enrollment

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 75,000/mcL

• Total bilirubin =< 1.5 × institutional upper limit of normal

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 × institutional upper limit of normal

• Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)

• Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min

• Patients must have controlled blood pressure with a systolic blood pressure < 140 mmHg and diastolic < 90 mmHg; anti-hypertensive medications are permitted

• Patients must be at least 4 weeks from last radiation dose; patients must be at least 4 weeks from last chemotherapy, targeted therapy, or biologic therapy (exception allowed for a 2 week washout for patients who were on chemotherapy at less than a standard of care dose, as long as all other eligibility criteria are met); patients must be at least 4 weeks from last surgical procedure and recovered from all post-operative complications

• 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; 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 monotherapy or in combination with GSK2141795 administration

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• History of another malignancy

• Exception: patients 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, are eligible

• History of interstitial lung disease or pneumonitis

• History of type I diabetes mellitus; if a patient has type II diabetes, they must have a hemoglobin (hemoglobin A1C) =< 8%; patients with a screening fasting glucose > 120 mg/dL will be excluded

• Uncontrolled hypothyroidism; patients must have a normal thyroid-stimulating hormone (TSH) per institutional standards at baseline

• Patients who are receiving any other investigational agents

• Individuals with symptomatic or progressive brain metastases are ineligible; subjects with treated brain metastases are eligible if they have no radiographic or other signs of progression in the brain for >= 3 weeks after completion of local therapy; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 3 weeks prior to study enrollment

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to trametinib monotherapy or trametinib in combination with GSK2141795

• Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:

• Other anti-cancer therapy while on study treatment (megestrol if used as an appetite stimulant is allowed)

• The concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], gingko biloba, yohimbe, saw palmetto, or ginseng)

• Patients receiving strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible

• History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, history of hyperviscosity or hypercoagulability syndromes; visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure > 21 mm Hg

• 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

• Pregnant women are excluded from this study, breastfeeding should be discontinued if the mother is treated with trametinib monotherapy or trametinib in combination with GSK2141795

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
2	Moffitt Cancer Center	Tampa	Florida	United States	33612
3	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
4	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
5	Case Western Reserve University	Cleveland	Ohio	United States	44106
6	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
7	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
8	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298

Sponsors and Collaborators

• National Cancer Institute (NCI)
• GlaxoSmithKline

Investigators

• Principal Investigator: Bhuvaneswari Ramaswamy, MD, Ohio State University Comprehensive Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 30, 2018

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01964924
• Other Study ID Numbers: NCI-2013-01895; NCI-2013-01895; 2013C0069; OSU 13117; 9455; 9455; N01CM00070; N01CM00100; P30CA016058; UM1CA186712; UM1CA186716
• First Posted: Oct 17, 2013
• Last Update Posted: Sep 20, 2019
• Last Verified: Aug 1, 2019

• Additional relevant MeSH terms: Carcinoma; Breast Neoplasms; Triple Negative Breast Neoplasms; Trametinib

Study Results

Participant Flow

Pre-assignment Detail	Patients on Part 1: trametinib monotherapy until progression and then will continue on to Part 2: trametinib combined with GSK2141795.

Arm/Group Title	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 1:	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 2:
Arm/Group Description	PART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression in Part 1 continue to Part 2.	PART 2: Patients who experience disease progression in Part 1 continue to Part 2. Patients receive trametinib and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Akt Inhibitor GSK2141795: Given PO Laboratory Biomarker Analysis: Correlative studies Trametinib: Given PO
Period Title: Trametinib Monotherapy
STARTED	37	0
COMPLETED	18	0
NOT COMPLETED	19	0
Period Title: Trametinib Monotherapy
STARTED	0	19
COMPLETED	0	19
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Treatment (Trametinib, Akt Inhibitor GSK2141795)
Arm/Group Description	PART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2. PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Akt Inhibitor GSK2141795: Given PO Laboratory Biomarker Analysis: Correlative studies Trametinib: Given PO
Overall Participants	37
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	57
Sex: Female, Male (Count of Participants)
Female	37 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	37 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	4 10.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 5.4%
White	31 83.8%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	37 100%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR), Defined as the Proportion of Patients Who Have Had a Partial Response (PR) or Complete Response (CR) (RECIST 1.1 Based) Within the First 6 Months After Initiation of Therapy With Trametinib
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Trametinib, Akt Inhibitor GSK2141795)
Arm/Group Description	PART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2. PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Akt Inhibitor GSK2141795: Given PO Laboratory Biomarker Analysis: Correlative studies Trametinib: Given PO
Measure Participants	37
Count of Participants [Participants]	2 5.4%

2. Secondary Outcome

Title	Clinical Benefit Rate (CBR = CR+PR+Stable Disease [SD])
Description	The clinical benefit rate (CR+PR+SD) will be reported for patients after Part 1 and after Part 2.
Time Frame	Up to 52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 1:	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 2:
Arm/Group Description	PART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2.	PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Akt Inhibitor GSK2141795: Given PO Laboratory Biomarker Analysis: Correlative studies Trametinib: Given PO
Measure Participants	37	19
Count of Participants [Participants]	8 21.6%	6 NaN

3. Secondary Outcome

Title	Duration of Objective Response
Description	Summary statistics of duration of response for patients with objective response
Time Frame	up to 52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 1:	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 2:
Arm/Group Description	PART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2.	PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Akt Inhibitor GSK2141795: Given PO Laboratory Biomarker Analysis: Correlative studies Trametinib: Given PO
Measure Participants	8	6
Mean (Standard Deviation) [days of response]	162.75 (149.26)	87.00 (62.86)

4. Secondary Outcome

Title	Incidence of Adverse Events That Are Classified as Either Possibly, Probably, or Definitely Related to Study Treatment
Description	Incidence of adverse events for patients that are classified as either possibly, probably, or definitely related to study treatment graded by National Cancer Institute (NCI) CTCAE v4.0
Time Frame	Up to 52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 1:	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 2:
Arm/Group Description	PART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2.	PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	37	19
Number [number of adverse events]	227	204

5. Secondary Outcome

Title	Incidence of Severe (Grade 3+) Adverse Events or Toxicities Graded Per NCI CTCAE Version 4.0
Description	NCI CommonTerminology Criteria for Adverse Events (CTCAE) version 4.0 was utilized for grading incidence of toxicities (grade 3+).
Time Frame	Up to 52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 1:	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 2:
Arm/Group Description	PART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2.	PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	37	19
Number [number of adverse events]	68	29

6. Secondary Outcome

Title	Overall Survival
Description	The Kaplan-Meier method will be used to estimate overall survival distribution.
Time Frame	Start date of the treatment to the date of the event (i.e., death) or the date of last follow-up to evaluate that event, assessed up to 52 weeks

Outcome Measure Data

Analysis Population Description

overall survival analyzed for all patients regardless of (part 1 only) or (part 1 and 2) participation

Arm/Group Title	Treatment (Trametinib, Akt Inhibitor GSK2141795)
Arm/Group Description	PART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2. PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Akt Inhibitor GSK2141795: Given PO Laboratory Biomarker Analysis: Correlative studies Trametinib: Given PO
Measure Participants	37
Median (95% Confidence Interval) [weeks]	43.143

7. Secondary Outcome

Title	Progression-free Survival
Description	The Kaplan-Meier method will be used to estimate progression-free survival distribution.
Time Frame	The duration of time from start of treatment to time of progression or death, whichever comes first, assessed up to 52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 1:	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 2:
Arm/Group Description	PART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2.	PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Akt Inhibitor GSK2141795: Given PO Laboratory Biomarker Analysis: Correlative studies Trametinib: Given PO
Measure Participants	37	19
Median (95% Confidence Interval) [weeks]	7.71	7.86

8. Secondary Outcome

Title	Proportion of Patients Who go Off Treatment Due to Adverse Reactions
Description	The proportion of patients who go off treatment due to adverse reactions or even those who refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial was captured. These tolerability measures were assessed within each of the treatment parts independently. All patients who have received at least one dose of any of the therapeutic agents was evaluable for toxicity and tolerability.
Time Frame	Up to 52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Trametinib, Akt Inhibitor GSK2141795)	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 2:
Arm/Group Description	PART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2. PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Akt Inhibitor GSK2141795: Given PO Laboratory Biomarker Analysis: Correlative studies Trametinib: Given PO	PART 2: Patients who experience disease progression in Part 1 continue to Part 2. Patients receive trametinib and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Akt Inhibitor GSK2141795: Given PO Laboratory Biomarker Analysis: Correlative studies Trametinib: Given PO
Measure Participants	37	19
Count of Participants [Participants]	4 10.8%	0 NaN

9. Secondary Outcome

Title	Proportion of Patients Who Refuse Further Treatment for Lesser Toxicities That Inhibit Their Willingness to Continue Participation on the Trial
Time Frame	Up to 52 weeks

Outcome Measure Data

Analysis Population Description

The proportion of patients who refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial was in Part I

Arm/Group Title	Treatment (Trametinib, Akt Inhibitor GSK2141795)	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 2:
Arm/Group Description	PART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2. PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Akt Inhibitor GSK2141795: Given PO Laboratory Biomarker Analysis: Correlative studies Trametinib: Given PO	PART 2: Patients who experience disease progression in Part 1 continue to Part 2. Patients receive trametinib and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Akt Inhibitor GSK2141795: Given PO Laboratory Biomarker Analysis: Correlative studies Trametinib: Given PO
Measure Participants	37	0
Count of Participants [Participants]	2 5.4%	0 NaN

10. Secondary Outcome

Title	Tolerability of the Regimen Defined as the Number of Patients Who Required Dose Modifications and/or Dose Delays
Time Frame	Up to 52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Trametinib, Akt Inhibitor GSK2141795)	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 2:
Arm/Group Description	PART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2. PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Akt Inhibitor GSK2141795: Given PO Laboratory Biomarker Analysis: Correlative studies Trametinib: Given PO	PART 2: Patients who experience disease progression in Part 1 continue to Part 2. Patients receive trametinib and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Akt Inhibitor GSK2141795: Given PO Laboratory Biomarker Analysis: Correlative studies Trametinib: Given PO
Measure Participants	37	19
Count of Participants [Participants]	35 94.6%	0 NaN

11. Other Pre-specified Outcome

Title	Predictive Value of PTEN and Other Biomarkers on Patient Outcome (Survival, ORR, and CBR)
Time Frame	At time of disease progression, assessed up to 52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Other Pre-specified Outcome

Title	Protein Intensity Fold-change Ratios Assessed by Reverse Phase Protein Assay Intensity Values
Description	Ratios between tumors sampled prior to initiating trametinib single agent treatment and at time of progression (TOP) on either single agent trametinib or the combination (TOP/pre-treat ratio), will be calculated. These ratios will be median-centered and clustered using Cluster 2.0 software. Student's t-test for differences between average protein intensity ratios at these intervals will be calculated using Microsoft Excel by grouping all the ratios for individual clusters.
Time Frame	Up to 52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Up to 1 year patients will be evaluated for toxicities from the time of their first treatment until they are off study.
Adverse Event Reporting Description	Adverse Event grading was done using NCI CTCAE version 4.0
Arm/Group Title	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 1:		Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 2:
Arm/Group Description	PART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2.		PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 1:		Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 2:
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/37 (35.1%)		12/19 (63.2%)
Serious Adverse Events
	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 1:		Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 2:
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/37 (81.1%)		15/19 (78.9%)
Blood and lymphatic system disorders
Anemia	1/37 (2.7%)	1	0/19 (0%)	0
Leukocytosis	1/37 (2.7%)	1	0/19 (0%)	0
Cardiac disorders
Cardiac arrest	1/37 (2.7%)	1	0/19 (0%)	0
Ear and labyrinth disorders
Vertigo	1/37 (2.7%)	1	0/19 (0%)	0
Gastrointestinal disorders
Diarrhea	0/37 (0%)	0	2/19 (10.5%)	2
Dysphagia	1/37 (2.7%)	1	0/19 (0%)	0
Enterocolitis	0/37 (0%)	0	1/19 (5.3%)	1
Vomiting	0/37 (0%)	0	1/19 (5.3%)	1
General disorders
Death NOS	1/37 (2.7%)	1	4/19 (21.1%)	4
Edema face	1/37 (2.7%)	1	0/19 (0%)	0
Edema limbs	1/37 (2.7%)	1	0/19 (0%)	0
Fever	1/37 (2.7%)	1	1/19 (5.3%)	1
General disorders and administration site conditions - Other, specify	1/37 (2.7%)	1	0/19 (0%)	0
Infections and infestations
Infections and infestations - Other, specify	0/37 (0%)	0	1/19 (5.3%)	1
Sepsis	2/37 (5.4%)	2	0/19 (0%)	0
Skin infection	1/37 (2.7%)	1	0/19 (0%)	0
Investigations
Alkaline phosphatase increased	1/37 (2.7%)	1	0/19 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/37 (0%)	0	1/19 (5.3%)	1
Hypoalbuminemia	1/37 (2.7%)	1	0/19 (0%)	0
Hypocalcemia	1/37 (2.7%)	1	0/19 (0%)	0
Hypoglycemia	1/37 (2.7%)	1	0/19 (0%)	0
Musculoskeletal and connective tissue disorders
Pain in extremity	1/37 (2.7%)	1	0/19 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	8/37 (21.6%)	8	3/19 (15.8%)	3
Nervous system disorders
Hypoglossal nerve disorder	1/37 (2.7%)	1	0/19 (0%)	0
Syncope	1/37 (2.7%)	1	0/19 (0%)	0
Renal and urinary disorders
Renal and urinary disorders - Other, specify	1/37 (2.7%)	1	0/19 (0%)	0
Reproductive system and breast disorders
Breast pain	1/37 (2.7%)	1	0/19 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/37 (2.7%)	1	1/19 (5.3%)	1
Pleural effusion	1/37 (2.7%)	1	0/19 (0%)	0
Pneumonitis	0/37 (0%)	0	1/19 (5.3%)	1
Vascular disorders
Hypertension	1/37 (2.7%)	1	0/19 (0%)	0
Thromboembolic event	1/37 (2.7%)	1	0/19 (0%)	0
Other (Not Including Serious) Adverse Events
	Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 1:		Treatment (Trametinib, Akt Inhibitor GSK2141795) PART 2:
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/37 (100%)		19/19 (100%)
Blood and lymphatic system disorders
Anemia	7/37 (18.9%)	7	8/19 (42.1%)	8
Cardiac disorders
Heart failure	1/37 (2.7%)	1	1/19 (5.3%)	1
Left ventricular systolic dysfunction	1/37 (2.7%)	1	1/19 (5.3%)	1
Sinus tachycardia	3/37 (8.1%)	3	0/19 (0%)	0
Ventricular tachycardia	1/37 (2.7%)	1	1/19 (5.3%)	1
Endocrine disorders
Hyperthyroidism	2/37 (5.4%)	2	1/19 (5.3%)	1
Hypothyroidism	1/37 (2.7%)	1	2/19 (10.5%)	2
Eye disorders
Blurred vision	1/37 (2.7%)	1	2/19 (10.5%)	2
Gastrointestinal disorders
Abdominal distension	1/37 (2.7%)	1	1/19 (5.3%)	1
Abdominal pain	3/37 (8.1%)	3	0/19 (0%)	0
Colitis	0/37 (0%)	0	1/19 (5.3%)	1
Constipation	5/37 (13.5%)	5	0/19 (0%)	0
Diarrhea	11/37 (29.7%)	11	16/19 (84.2%)	16
Dry mouth	4/37 (10.8%)	4	1/19 (5.3%)	1
Dyspepsia	4/37 (10.8%)	4	0/19 (0%)	0
Dysphagia	2/37 (5.4%)	2	5/19 (26.3%)	5
Esophageal pain	0/37 (0%)	0	1/19 (5.3%)	1
Gastroesophageal reflux disease	0/37 (0%)	0	1/19 (5.3%)	1
Gastrointestinal disorders - Other, specify	2/37 (5.4%)	2	2/19 (10.5%)	2
Mucositis oral	4/37 (10.8%)	4	12/19 (63.2%)	13
Nausea	12/37 (32.4%)	12	5/19 (26.3%)	6
Vomiting	6/37 (16.2%)	6	3/19 (15.8%)	3
General disorders
Edema face	4/37 (10.8%)	4	1/19 (5.3%)	1
Edema limbs	11/37 (29.7%)	11	4/19 (21.1%)	4
Edema trunk	2/37 (5.4%)	2	0/19 (0%)	0
Facial pain	1/37 (2.7%)	1	1/19 (5.3%)	1
Fatigue	11/37 (29.7%)	11	6/19 (31.6%)	6
Fever	3/37 (8.1%)	3	0/19 (0%)	0
Flu like symptoms	2/37 (5.4%)	2	1/19 (5.3%)	1
Localized edema	1/37 (2.7%)	1	1/19 (5.3%)	1
Neck edema	2/37 (5.4%)	2	0/19 (0%)	0
Non-cardiac chest pain	2/37 (5.4%)	2	3/19 (15.8%)	3
Pain	4/37 (10.8%)	4	2/19 (10.5%)	2
Infections and infestations
Infections and infestations - Other, specify	1/37 (2.7%)	1	3/19 (15.8%)	4
Paronychia	1/37 (2.7%)	1	2/19 (10.5%)	2
Skin infection	2/37 (5.4%)	2	0/19 (0%)	0
Urinary tract infection	2/37 (5.4%)	2	1/19 (5.3%)	1
Injury, poisoning and procedural complications
Bruising	0/37 (0%)	0	1/19 (5.3%)	1
Fall	2/37 (5.4%)	2	0/19 (0%)	0
Vascular access complication	0/37 (0%)	0	1/19 (5.3%)	1
Investigations
Alanine aminotransferase increased	7/37 (18.9%)	7	2/19 (10.5%)	2
Alkaline phosphatase increased	6/37 (16.2%)	6	3/19 (15.8%)	3
Aspartate aminotransferase increased	13/37 (35.1%)	13	4/19 (21.1%)	4
Creatinine increased	4/37 (10.8%)	4	3/19 (15.8%)	3
Ejection fraction decreased	0/37 (0%)	0	1/19 (5.3%)	1
Electrocardiogram QT corrected interval prolonged	0/37 (0%)	0	2/19 (10.5%)	2
INR increased	0/37 (0%)	0	1/19 (5.3%)	1
Investigations - Other, specify	0/37 (0%)	0	2/19 (10.5%)	3
Lymphocyte count decreased	6/37 (16.2%)	6	4/19 (21.1%)	4
Neutrophil count decreased	1/37 (2.7%)	1	2/19 (10.5%)	3
Platelet count decreased	7/37 (18.9%)	7	3/19 (15.8%)	3
Weight gain	3/37 (8.1%)	3	1/19 (5.3%)	1
Weight loss	1/37 (2.7%)	1	3/19 (15.8%)	4
White blood cell decreased	5/37 (13.5%)	5	6/19 (31.6%)	7
Metabolism and nutrition disorders
Anorexia	5/37 (13.5%)	5	2/19 (10.5%)	2
Dehydration	1/37 (2.7%)	1	5/19 (26.3%)	5
Hypercalcemia	0/37 (0%)	0	1/19 (5.3%)	1
Hyperglycemia	7/37 (18.9%)	7	6/19 (31.6%)	8
Hypoalbuminemia	9/37 (24.3%)	9	7/19 (36.8%)	8
Hypocalcemia	3/37 (8.1%)	3	4/19 (21.1%)	5
Hypoglycemia	0/37 (0%)	0	1/19 (5.3%)	1
Hypokalemia	3/37 (8.1%)	3	2/19 (10.5%)	6
Hypomagnesemia	1/37 (2.7%)	1	1/19 (5.3%)	1
Hyponatremia	3/37 (8.1%)	3	1/19 (5.3%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	2/37 (5.4%)	2	0/19 (0%)	0
Back pain	3/37 (8.1%)	3	4/19 (21.1%)	4
Flank pain	1/37 (2.7%)	1	1/19 (5.3%)	1
Generalized muscle weakness	3/37 (8.1%)	3	2/19 (10.5%)	2
Neck pain	0/37 (0%)	0	1/19 (5.3%)	1
Pain in extremity	4/37 (10.8%)	4	2/19 (10.5%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps-Other	1/37 (2.7%)	1	2/19 (10.5%)	2
Tumor pain	1/37 (2.7%)	1	1/19 (5.3%)	1
Nervous system disorders
Dizziness	3/37 (8.1%)	3	1/19 (5.3%)	1
Dysgeusia	0/37 (0%)	0	2/19 (10.5%)	2
Dysphasia	0/37 (0%)	0	2/19 (10.5%)	2
Headache	4/37 (10.8%)	4	0/19 (0%)	0
Movements involuntary	0/37 (0%)	0	1/19 (5.3%)	1
Peripheral motor neuropathy	0/37 (0%)	0	1/19 (5.3%)	1
Peripheral sensory neuropathy	5/37 (13.5%)	5	4/19 (21.1%)	4
Presyncope	0/37 (0%)	0	1/19 (5.3%)	2
Psychiatric disorders
Anxiety	4/37 (10.8%)	4	0/19 (0%)	0
Depression	4/37 (10.8%)	4	0/19 (0%)	0
Insomnia	2/37 (5.4%)	2	2/19 (10.5%)	2
Renal and urinary disorders
Hematuria	0/37 (0%)	0	1/19 (5.3%)	1
Urinary frequency	2/37 (5.4%)	2	2/19 (10.5%)	2
Reproductive system and breast disorders
Breast pain	1/37 (2.7%)	1	1/19 (5.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	3/37 (8.1%)	3	2/19 (10.5%)	2
Dyspnea	9/37 (24.3%)	9	8/19 (42.1%)	8
Epistaxis	1/37 (2.7%)	1	3/19 (15.8%)	3
Hoarseness	0/37 (0%)	0	1/19 (5.3%)	1
Hypoxia	2/37 (5.4%)	2	0/19 (0%)	0
Nasal congestion	2/37 (5.4%)	2	0/19 (0%)	0
Pleural effusion	5/37 (13.5%)	5	0/19 (0%)	0
Pneumonitis	0/37 (0%)	0	3/19 (15.8%)	3
Sore throat	2/37 (5.4%)	2	0/19 (0%)	0
Voice alteration	0/37 (0%)	0	1/19 (5.3%)	1
Skin and subcutaneous tissue disorders
Alopecia	3/37 (8.1%)	3	1/19 (5.3%)	1
Dry skin	5/37 (13.5%)	5	4/19 (21.1%)	4
Nail ridging	2/37 (5.4%)	2	0/19 (0%)	0
Palmar-plantar erythrodysesthesia syndrome	0/37 (0%)	0	1/19 (5.3%)	1
Pruritus	6/37 (16.2%)	6	3/19 (15.8%)	5
Rash acneiform	10/37 (27%)	10	3/19 (15.8%)	5
Rash maculo-papular	6/37 (16.2%)	6	3/19 (15.8%)	3
Skin and subcutaneous tissue disorders - Other, specify	4/37 (10.8%)	4	3/19 (15.8%)	3
Vascular disorders
Hypertension	5/37 (13.5%)	5	7/19 (36.8%)	9
Hypotension	0/37 (0%)	0	1/19 (5.3%)	1
Lymphedema	5/37 (13.5%)	5	2/19 (10.5%)	2
Thromboembolic event	0/37 (0%)	0	1/19 (5.3%)	1

Limitations/Caveats

[Not Specified]

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.