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

Phase 2

Completed

Conditions: Progesterone Receptor Negative
Recurrent Breast Carcinoma
Stage IV Breast Cancer
Estrogen Receptor Negative
HER2/Neu Negative
Invasive Breast Carcinoma
Triple-Negative Breast Carcinoma

Interventions: Drug: Akt Inhibitor GSK2141795
Other: Laboratory Biomarker Analysis
Drug: Trametinib

Registration Number: NCT01964924

Lead Sponsor: National Cancer Institute (NCI)

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.

Detailed Description: PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

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

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

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

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

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

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

VII. 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 37

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (trametinib, Akt inhibitor GSK2141795)	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.
Treatment (trametinib, Akt inhibitor GSK2141795)	Laboratory Biomarker Analysis	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.
Treatment (trametinib, Akt inhibitor GSK2141795)	Trametinib	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
Duration of Objective Response	up to 52 weeks	Summary statistics of duration of response for patients with objective response
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
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+).
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.
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.
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.
Proportion of Patients Who Refuse Further Treatment for Lesser Toxicities That Inhibit Their Willingness to Continue Participation on the Trial	Up to 52 weeks
Tolerability of the Regimen Defined as the Number of Patients Who Required Dose Modifications and/or Dose Delays	Up to 52 weeks

Trial Locations

Locations (8): Case Western Reserve University
🇺🇸
Cleveland, Ohio, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
Ohio State University Comprehensive Cancer Center
🇺🇸
Columbus, Ohio, United States
Moffitt Cancer Center
🇺🇸
Tampa, Florida, United States
MedStar Georgetown University Hospital
🇺🇸
Washington, District of Columbia, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸
Richmond, Virginia, United States