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

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