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