Testing the Addition of the AKT Inhibitor, Ipatasertib, to Treatment With the Hormonal Agent Megestrol Acetate for Recurrent or Metastatic Endometrial Cancers

Inclusion Criteria:

• Patients must have grade 1 or 2 recurrent or metastatic endometrioid endometrialcancer

• Patients must have measurable disease according to RECIST version (v)1.1. Measurabledisease is defined as at least one lesion that can be accurately measured in atleast one dimension (longest diameter to be recorded). Each lesion must be >= 10 mmwhen measured by CT or MRI. Lymph nodes must be >= 15 mm in short axis when measuredby CT or MRI. Previously irradiated lesions can be considered as measurable diseaseonly if progressive disease has been unequivocally documented at that site sinceradiation

• Patients may have received unlimited prior lines of therapy. If patient receivedprior hormonal therapy (e.g., megestrol acetate, medroxyprogesterone acetate,aromatase inhibitor, tamoxifen, fulvestrant) it must have completed at least 6months prior to registration

• Age >= 18

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2

• Platelets >= 100,000/mcl within 14 days prior to registration

• Absolute neutrophil count (ANC) >= 1,500/mcl within 14 days prior to registration

• Hemoglobin >= 9 g/dL within 14 days prior to registration

• Glomerular filtration rate (GFR) >= 60 mL/min/1.73m^2 measured using Cockcroft-Gaultequation or the estimated glomerular filtration rate from the Modification of Dietin Renal Disease Study within 14 days prior to registration

• Total bilirubin =< 1.5 x the upper limit of normal (ULN) within 14 days prior toregistration

• Patients with known Gilbert syndrome who have bilirubin =< 3 x ULN may beenrolled

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN within 14 days prior to registration

• Albumin >= 3 g/dL within 14 days prior to registration

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• The effects of ipatasertib on the developing human fetus are unknown. For thisreason and because AKT inhibitor agents as well as other therapeutic agents used inthis trial are known to be teratogenic, participants of child-bearing potential mustagree to use adequate contraception (hormonal or barrier method of birth control;abstinence) during study therapy and for 28 days following the last dose of studytherapy. Should a participant become pregnant or suspect pregnancy whileparticipating in this study, they should inform their treating physician immediately

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• For patients with known human immunodeficiency virus (HIV), hepatitis B virus (HBV),and/or hepatitis C virus (HCV) infection:

• HIV-infected patients on effective anti-retroviral therapy with undetectableviral load within 6 months of registration are eligible for this trial

• Patients with evidence of chronic hepatitis B virus (HBV) infection must havean undetectable HBV viral load on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have beentreated and cured. For patients with HCV infection who are currently ontreatment, they are eligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression

• Patients must be able to swallow and retain oral medications and not havegastrointestinal illnesses that would preclude absorption of megestrol acetate oripatasertib as judged by the treating physician

• The patient or a legally authorized representative must provide study-specificinformed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

Exclusion Criteria:

• Patients who have had prior treatment with an AKT inhibitor (Prior treatment withPI3K or mTOR inhibitors is allowed)

• Patients who have received treatment with strong CYP3A inhibitors or inducers within 14 days or 5 drug-elimination half-lives, whichever is longer, prior to studyregistration

• Because the lists of these agents are constantly changing, it is important toregularly consult a frequently-updated medical reference. As part of theenrollment/informed consent procedures, the patient will be counseled on therisk of interactions with other agents, and what to do if new medications needto be prescribed or if the patient is considering a new over-the-countermedicine or herbal product

• Patients with diabetes either requiring insulin therapy or with a baseline fastingglucose > 160 mg/dL and/or high glycosylated hemoglobin A1c (HbA1c) (> 8),suggesting poorly controlled diabetes. Fasting is defined as abstaining from foodand drink (with the exception of water) for at least 8 hours

• Patients who require chronic corticosteroid therapy of > 10 mg of prednisone per dayor an equivalent dose of other anti-inflammatory corticosteroids orimmunosuppressant agents for a chronic disease

• Patients with grade 2 or greater uncontrolled or untreated hypercholesterolemia (> 300 mg/dL) or hypertriglyceridemia (> 300 mg/dL)

• Patients with a history of known or active inflammatory bowel disease (e.g., Crohndisease and ulcerative colitis) or active bowel inflammation (e.g., diverticulitis)

• Patients with a history of or presence of an abnormal electrocardiogram (ECG) thatis clinically significant in the investigator's opinion (including complete leftbundle branch block, second- or third-degree heart block, or evidence of priormyocardial infarction)

• Patients with known clinically significant history of liver disease consistent withChild-Pugh class B or C, including active viral or other hepatitis, current drug oralcohol abuse, or cirrhosis

• Patients with lung disease: Grade 2 or greater pneumonitis, grade 2 or greaterinterstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis,aspergillosis, active tuberculosis, or history of opportunistic infections (pneumocystis pneumonia or cytomegalovirus pneumonia) within the past 6 months

• No active infection requiring parenteral antibiotics

• Women who are pregnant or unwilling to discontinue nursing