Trametinib in Treating Patients With Recurrent or Progressive Low-Grade Ovarian Cancer or Peritoneal Cavity Cancer

Inclusion Criteria:

• Patients age greater than 18 with the following tumors are included in the study:

• Patients initially diagnosed with low-grade serous ovarian or peritonealcarcinoma that recur as low-grade serous carcinoma (invasive micropapillaryserous carcinoma or invasive grade I serous carcinomas as defined by GOG,Federation of Obstetricians and Gynecologists [FIGO], World Health Organization [WHO] or Silverberg)

• Patients initially diagnosed with serous borderline ovarian or peritonealcarcinoma that recur as low-grade serous carcinoma (invasive micropapillaryserous carcinoma or invasive grade I serous carcinomas as defined by GOG, FIGOWHO or Silverberg)

• At least 4 weeks must have elapsed since the patient underwent any major surgery (e.g. MAJOR: laparotomy, laparoscopy, thoracotomy, VATS [video assisted thorascopicsurgery]); there is no restriction on MINOR procedures: (e.g. central venouscatheter placement, ureteral stent placement or exchange, tumor core or fine-needleaspirate [FNA] biopsy)

• Patients must have documented low-grade serous carcinoma; confirmation must occur byprospective pathology review prior to study entry; the prospective pathology reviewcan be done on tissue from the recurrent carcinoma or from original diagnosticspecimen

• All patients must have measurable disease as defined by Response Evaluation Criteriain Solid Tumors (RECIST) 1.1; measurable disease is defined as at least one targetlesion that can be accurately measured in at least one dimension (longest diameterto be recorded); each lesion must be >= 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI), or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes must be >= 15 mm in short axiswhen measured by CT or MRI; all imaging studies must be performed within 28 daysprior to registration

• Prior therapy

• Patients must have recurred or progressed following at least one platinum-basedchemotherapy regimen

• Patients may have received an unlimited number of prior therapy regimens

• Patients may not have received all of the five choices in the "standardtherapy" arm

• Any hormonal therapy directed at the malignant tumor must be discontinued atleast one week prior to registration

• Any other prior therapy directed at the malignant tumor, including chemotherapyand radiation therapy, must be discontinued at least 4 weeks prior toregistration; any investigational agent must be discontinued at least 28 daysprior to registration

• Trametinib, can cause fetal harm when administered to a pregnant woman; women ofchild-bearing potential (i.e. patients whose reproductive organs remain in place andwho have not passed menopause) and men must agree to use a highly effective methodof contraception (e.g. hormonal, intrauterine device or; abstinence*) prior to studyentry, during the study participation, and for six months after the last dose of thedrug; women of child-bearing potential must have a negative serum pregnancy testwithin 14 days prior to randomization, cannot be breast-feeding, and must agree touse a highly effective form of contraception throughout the treatment period and for 6 months after the last dose of study treatment; should a woman become pregnant orsuspect she is pregnant while she or her partner is participating in this study, sheshould inform her treating physician immediately

• Abstinence is only acceptable when this is in line with the preferred and usuallifestyle of the patient

• Patients must have the ability to understand and sign an approved informed consentand authorization permitting release of personal health information

• Patients must have a GOG performance status of 0 or 1

• Able to swallow and retain orally-administered medication and does not have anyclinically significant gastrointestinal abnormalities that may alter absorption,such as malabsorption syndrome, bowel obstruction, or major resection of the stomachor bowel

• All prior treatment-related toxicities must be CTCAE v4 grade =< 1 (except alopecia)at the time of randomization

• Patients must have a left ventricular ejection fraction >= lower limit of normal byechocardiogram (ECHO) or multigated acquisition scan (MUGA)

• Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gaultformula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min (within 14days prior to treatment)

• Bilirubin =< 1.5 times upper limit of normal (within 14 days prior to treatment)

• Alanine aminotransferase (ALT) =< 2.5 times upper limit of normal (within 14 daysprior to treatment)

• Aspartate aminotransferase (AST) =< 2.5 times upper limit of normal (within 14 daysprior to treatment)

• Albumin >= 2.5 g/dL (within 14 days prior to treatment)

• Prothrombin time (PT) and activated partial thromboplastin time (APTT) =< 1.5 timesupper limit of normal (within 14 days prior to treatment)

• Neutrophil count >= 1.5 x 10^9/L (within 14 days prior to treatment)

• Platelet count >= 100 x 10^9/L (within 14 days prior to treatment)

• Hemoglobin >= 9.0 g/dL (within 14 days prior to treatment)

• If letrozole is selected as the control therapy, patients must be postmenopausal,either following bilateral oophorectomy or at least 5 years after spontaneousmenopause; patients within 5 years of spontaneous menopause or who have had ahysterectomy without bilateral oophorectomy must have postmenopausal luteinizinghormone (LH) and follicle stimulating hormone (FSH) levels; patients on hormonereplacement therapy (HRT) must agree to withdrawal of hormone therapy beforeletrozole is started

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks fornitrosoureas or mitomycin C) prior to entering the study or those who have notrecovered from adverse events due to agents administered more than 4 weeks earlier

• Use of other investigational drugs within 28 days (or five half-lives, whichever isshorter; with a minimum of 14 days from the last dose) preceding the first dose oftrametinib or standard of care agent

• If patients have had a potential index lesion radiated, it must have progressed postradiation therapy to be used as a measurable eligibility lesion

• Patients may not have received prior MEK, v-Ki-ras2 Kirsten rat sarcoma viraloncogene homolog (KRAS), or v-raf murine sarcoma viral oncogene homolog B1 (BRAF)inhibitor therapy

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

• Patients may not be receiving any other anti-cancer or investigational agents

• Because the composition, PK, and metabolism of many herbal supplements areunknown, the concurrent use of all herbal supplements is prohibited during thestudy (including, but not limited to St. John's wort, kava, ephedra [ma huang],gingko biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, orginseng)

• Patients with known leptomeningeal or brain metastases or spinal cord compressionshould be excluded from this clinical trial because of their poor prognosis andbecause they often develop progressive neurologic dysfunction that would confoundthe evaluation of neurologic and other adverse events

• Patients with a bowel obstruction or any other gastrointestinal condition that mightaffect absorption of the oral drug should be excluded; this would include patientswith inability to swallow and retain orally-administered medication, malabsorptionsyndrome, or those with a major resection of the stomach or bowels

• Patients with a history of interstitial lung disease or pneumonitis

• Patients with a previous or current malignancy at other sites should be excluded,with the exception of:

• Curatively treated local tumors such as carcinoma-in-situ of the cervix, basalor squamous cell carcinoma of the skin

• Tumors for which no relapse has been observed within 5 years

• Known hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients withchronic or cleared HBV and HCV infection are eligible); patients with humanimmunodeficiency virus (HIV) are not eligible if on anti-retroviral medications

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugschemically related to trametinib, or excipients, or to dimethyl sulfoxide (DMSO), orto Cremophor EL (polyoxyethylated castor oil); please note, exclusion for Cremophoris unnecessary unless paclitaxel is the only agent available and the patientrandomizes to the conventional therapy option

• Patients with a history or evidence of cardiovascular risk, including any of thefollowing:

• Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN)

• Bazett's corrected QT (QTcB) >= 480 msec

• History or evidence of current clinically significant uncontrolled arrhythmias

• Exception: Subjects with controlled atrial fibrillation for > 30 days prior torandomization are eligible

• History of (within 6 months prior to randomization) acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, orstenting

• History or evidence of current >= class II congestive heart failure as definedby New York Heart Association (NYHA)

• Treatment refractory hypertension defined as a blood pressure of systolic > 140mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensivetherapy

• Patients with intra-cardiac defibrillators or permanent pacemakers

• Known cardiac metastases

• Patients with a history or current evidence/risk of retinal vein occlusion (RVO)

• Any serious and/or unstable pre-existing medical disorder (aside from malignancyexception above), psychiatric disorder, or other conditions that could interferewith subject's safety, obtaining informed consent or compliance to the studyprocedures

• Patients who require use of a concomitant medication that can prolong the QTinterval

• Animal reproductive studies have not been conducted with trametinib; therefore, thestudy drug must not be administered to pregnant women or nursing mothers; women ofchildbearing potential should be advised to avoid pregnancy and use effectivemethods of contraception; if a female patient or a female partner of a patientbecomes pregnant while the patient receives trametinib, the potential hazard to thefetus should be explained to the patient and partner (as applicable)