Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Acute Myeloid Leukemia

This phase II trial studies how well trametinib and protein kinase B (Akt) inhibitor GSK2141795 work in treating patients with acute myeloid leukemia. Trametinib and Akt inhibitor GSK2141795 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the proportion of patients achieving complete remission (CR) or CR with incomplete recovery of platelets (CRp) as best response within 4 cycles of therapy of trametinib in combination with GSK2141795 (Akt inhibitor GSK2141795) in acute myeloid leukemia (AML) patients with rat sarcoma (RAS) mutations.

SECONDARY OBJECTIVES:

I. To determine the disease-free survival of patients achieving CR/CRp. II. To determine the duration of response of patients achieving CR/CRp. III. To determine the toxicity profile of trametinib in combination with GSK2141795 in this patient population.

IV. To determine the biologic effects of trametinib in combination with GSK2141795 on leukemia cells.

OUTLINE:

Patients receive trametinib orally (PO) once daily (QD) and 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 for 12 weeks.

Eligibility Criteria:
Inclusion Criteria:

* Patients must have histologically or cytologically confirmed AML, other than acute promyelocytic leukemia, as defined by the 2008 World Health Organization (WHO) criteria that have relapsed or refractory to standard chemotherapy; unsuitable for standard chemotherapy or unwilling to undergo standard chemotherapy; subjects \>= 60 years of age with newly diagnosed AML who are not candidates for or have refused standard chemotherapy are eligible
* Patients with prior autologous and allogeneic hematopoietic stem cell transplantation are eligible if patients are off immunosuppression for \> 1 month and have no evidence of active graft versus host disease (GVHD) except grade 1 skin GVHD
* Positive for RAS mutation (neuroblastoma RAS viral \[v-ras\] oncogene homolog \[NRAS\] codon 12, 13, 61 mutation or Kirsten rat sarcoma viral oncogene homolog \[KRAS\] codon 12, 13, 61 mutation) at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory prior to study entry; mutational testing will be performed on bone marrow sample and/or peripheral blood; patients with previously known RAS mutations prior to study entry may be considered positive for RAS mutation for eligibility prior to a CLIA-certified laboratory confirmation of such a mutation at the discretion of the investigator; (appropriate blood and/or bone marrow samples must be taken for RAS determination and submitted to a CLIA-certified laboratory prior to study entry); however, if such a mutation is not confirmed by the M D Anderson Cancer Center (MDACC)/other center's CLIA-certified laboratory, the patient may be permitted to stay on the study if they wish and consent to do so but such patients' data will be analyzed separately
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
* Life expectancy of greater than 4 weeks
* 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 (CTCAE) version (v)4 grade =\< 1 (except alopecia) prior to the first dose of the study drug
* Serum total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (isolated total bilirubin \> 1.5 institutional ULN is acceptable if bilirubin is fractionated and direct bilirubin is \< 35%)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x institutional ULN
* Serum creatinine =\< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) \>= 60 mL/min
* Fasting serum glucose =\< 150 mg/dl (fasting is defined as at least 8 hours without oral intake)
* Left ventricular ejection fraction (LVEF) \>= institutional lower limit of normal (LLN) AND at least 50%; LVEF can be assessed by either echocardiogram (ECHO) or multi gated acquisition scan (MUGA)
* 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, during the study participation, and for four months after the last dose of drug; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment; 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
* 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; consult the Cancer Therapy Evaluation Program (CTEP) Medical Monitor if unsure whether second malignancies meet the requirements specified above
* History of interstitial lung disease or pneumonitis
* Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to randomization; daily or weekly chemotherapy (with the exception of hydroxyurea) without the potential for delayed toxicity within 14 days prior to randomization unless there is evidence of rapidly progressive disease
* Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of trametinib/GSK2141795 and during the study
* Symptomatic or untreated leptomeningeal disease or brain metastases or spinal cord compression
* Patients with abnormal fasting glucose values (\> 150 mg/dl) at screening will be excluded; in addition, patients with type 1 diabetes will also be excluded; however, patients with type 2 diabetes will be allowed if diagnosed \>= 6 months prior to enrollment, and if presenting with regular hemoglobin A1C (HbA1C) =\< 8% at screening
* Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib or excipients or to dimethyl sulfoxide (DMSO) or GSK2141795
* Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:

  * Other anti-cancer therapy while on study treatment; (Note: megestrol \[Megace\] if used as an appetite stimulant is allowed)
  * Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis
  * 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, dehydroepiandrosterone \[DHEA\], yohimbe, saw palmetto, or ginseng)

    * Note: for proliferative disease, hydroxyurea will be allowed during weeks 1 and 2 of cycle 1 of study; hydroxyurea may be started or the dose changed during that 2-week period if it is clinically indicated; if a subject not previously on a stable dose of hydroxyurea needs to begin hydroxyurea or a subject on a stable dose needs to have their dose increased during the first 2 weeks, the investigator will notify the clinical team that this has been initiated
* Drugs that potently inhibit cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) should either be prohibited or used with caution; drugs which are strong inducers of cytochrome P450 family 3, subfamily A (CYP3A) should also be prohibited; drugs that are substrates of CYP3A4 or cytochrome P450 family 2, subfamily C, polypeptide 8 (CYP2C8) with a narrow therapeutic index may be prohibited; drugs that are sensitive substrates of CYP3A4 or CYP2C8 should be used with caution; it is important to regularly consult a frequently-updated list; medical reference texts such as the Physicians' Desk Reference may also provide this information; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
* History or current evidence/risk of retinal vein occlusion (RVO)
* History or evidence of cardiovascular risk including any of the following:

  * LVEF \< institutional LLN or \< 50%
  * A QT interval corrected for heart rate using the Bazett's formula QTcB \>= 480 msec
  * History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for \> 30 days prior to randomization are eligible)
  * History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for \> 30 days prior to study dose are eligible)
  * Patient with symptomatic bradycardia, or a history of clinically significant bradyarrhythmias such as sick sinus syndrome, second (2nd) degree atrioventricular (AV) block (Mobitz type 2)
  * History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to study dose
  * History or evidence of current \>= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system
  * Treatment-refractory hypertension defined as a blood pressure of systolic \> 140 mmHg and/or diastolic \> 90 mmHg which cannot be controlled by anti-hypertensive therapy
  * Patients with intra-cardiac defibrillators
  * Known cardiac metastases
* Known active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection, are eligible); patients with human immunodeficiency virus (HIV) are not eligible if on anti-retroviral medications
* Any serious/and or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures
* The study drug must not be administered to pregnant women or nursing mothers; women of childbearing potential should be advised to avoid pregnancy and use effective methods of contraception; men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib/GSK2141795, the potential hazard to the fetus should be explained to the patient and partner (as applicable)
* HIV-positive patients on combination antiretroviral therapy are ineligible
* Hypoxia (oxygen saturation \< 90% on room air) or in the opinion of the investigator any pulmonary compromise leading to hypoxia, at the time of study entry