Copanlisib in Treating Patients With Persistent or Recurrent Endometrial Cancer

Inclusion Criteria:

* Patients must have the psychological ability and general health that permits completion of the study requirements and required follow-up
* Women of child-bearing potential (WOCBP) must agree to use adequate contraception when sexually active; patients should continue contraception for 6 months after finishing study drug
* Submission of tumor tissue is required for all patients; investigators should check with their site pathology department regarding release of biospecimens before approaching patients about participation in the trial
* Patients must have recurrent or persistent endometrial cancer (endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, mixed epithelial carcinoma or adenocarcinoma not otherwise specified \[NOS\]); histologic confirmation of the primary tumor is required
* All patients must have a somatic PIK3CA gene mutation (i.e., R88Q in exon 1, N345K in exon 4, C420R in exon 7, E542K, E545X \[E545A, E545D, E545G, and E545K\], Q546X \[Q546E, Q546K, Q546L, and Q546R\] in exon 9, and M1043I, H1047X \[H1047L, H1047R, and H1047Y\], or G1049R in exon 20) in a representative primary or metastatic tumor sample confirmed by the Roche COBAS PIK3CA Mutation Test at Q\^2 Solutions
* All patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to 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 axis when measured by CT or MRI
* Patients must have at least one "target lesion" to be used to assess response on this protocol as defined by RECIST 1.1; tumors within a previously irradiated field will be designated as 'non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy
* Patients must have recovered from effects of recent surgery, radiotherapy, or chemotherapy; at least 4 weeks must have elapsed since the patient underwent any major surgery (e.g., major: laparotomy, laparoscopy); there is no delay required for minor procedures (e.g., tumor fine-needle aspiration \[FNA\] or core biopsy, venous access device placement)
* Patients may have received prior radiation therapy for treatment of endometrial cancer; prior radiation therapy may have included pelvic radiation therapy, extended field pelvic/para-aortic radiation therapy, intravaginal brachytherapy and/or palliative radiation therapy; all radiation therapy must be completed at least 4 weeks prior to registration
* Patients may have received prior hormonal therapy for treatment of endometrial carcinoma; all hormonal therapy must be discontinued at least 4 weeks prior to registration
* Patients may have received prior therapy (including chemotherapy, biologic/targeted therapy and immunotherapy) for treatment of endometrial cancer; all therapy must be discontinued at least 4 weeks prior to registration; any investigational agent must be discontinued at least 30 days prior to registration
* Patients must have had at least one prior chemotherapeutic regimen for management of endometrial carcinoma; initial treatment may include chemotherapy, chemotherapy and radiation therapy, or consolidation/maintenance therapy; chemotherapy administered in conjunction with primary radiation as a radio-sensitizer WILL be counted as a systemic chemotherapy regimen

  * Patients are allowed to receive, but not required to receive, up to a total of 3 lines of chemotherapy
* Appropriate stage for study entry based on the following diagnostic workup:

  * History/physical examination within 28 days prior to registration
  * Imaging of target lesion(s) within 28 days prior to registration
  * Completion of pre-study protocol specific assessments as required
* Performance status (Eastern Cooperative Oncology Group \[ECOG\]/Karnofsky) of 0, 1 or 2 within 28 days prior to registration
* Absolute neutrophil count (ANC) \>= 1,500/mcl
* Platelets \>= 75,000/mcl
* Hemoglobin (Hgb) \>= 8 g/dL
* Creatinine =\< 1.5 x upper limit of normal (ULN)
* Bilirubin =\< 1.5 x ULN (=\< 3 x ULN for patients with Gilbert syndrome)
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3 x ULN
* Left ventricular ejection fraction (LVEF) \>= 50%
* Fasting cholesterol less than or equal to 300 mg/dl; fasting triglycerides less than or equal to 300 mg/dl
* Prothrombin time (PT) such that international normalized ratio (INR) is less than or equal to 1.5 x ULN (or an in range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) and a partial thromboplastin time (PTT) less than or equal to 1.5 times the upper limit of normal
* The patient must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
* Diabetic patients (type I or II diabetes mellitus) must have baseline hemoglobin (Hb)A1c levels NOT higher than 8.5% at study entry
* Patients with hypertension on medical management must have systolic blood pressure \< 150 mmHG or diastolic pressure \< 90 mmHG at study entry
* Note: ULN is institutional or laboratory upper limit of normal
* Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test within 28 days of registration; the patient and her sexual partner(s) must agree to use adequate contraception when sexually active for the duration of the study and for 6 months after finishing study drug; a woman is considered of childbearing potential following menarche and until becoming post-menopausal unless permanently sterile; permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy; a postmenopausal state is defined as no menses for 12 months without an alternative medical cause; a high follicle stimulating hormone (FSH) level in the postmenopausal range maybe used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy

Exclusion Criteria:

* Patients who have had prior therapy with any phosphatidylinositol 3 kinase (PI3K)/v-akt murine thymoma viral oncogene homolog 1 (AKT)/mammalian target of rapamycin (mTor) pathway inhibitor
* Patients who have the following histologies: mucinous, squamous, sarcomas, carcinosarcomas, clear cell
* Congestive heart failure \> New York Heart Association (NYHA) class II
* Myocardial infarction or unstable angina less than 6 months before registration
* Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before registration
* Non-healing wound, ulcer or bone fracture
* Active, clinically serious infections \> Common Terminology Criteria for Adverse Events (CTCAE) grade 2
* History of, or current autoimmune disease
* Human immunodeficiency virus (HIV) infection
* Hepatitis B (HBV) or hepatitis C (HCV); all patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel; patients with active HBV or hepatitis C infection are not eligible for enrollment; patients with serologic markers of HBV immunization due to known vaccination (hepatitis B surface antigen \[HBsAg\] negative, anti-hepatitis B core \[HBc\] negative and anti-hepatitis B surface \[HBs\] positive) will be eligible
* Previous or concurrent history of malignancies within 5 years prior to study treatment except for curatively treated:

  * Cervical carcinoma in situ
  * Non-melanoma skin cancer
  * Superficial bladder cancer (Ta \[non-invasive tumor\], Tis \[carcinoma in situ\] and T1 \[tumor invades lamina propria\])
* Patients with seizure disorder requiring medication
* Patients with evidence or history of bleeding diathesis; any hemorrhage or bleeding event \>= CTCAE grade 3 within 4 weeks prior to registration
* Proteinuria of CTCAE grade 3 or higher (estimated by urine protein: creatinine ratio \>= 3.5 on a random urine sample); patients who recently (i.e., at least 30 days prior to registration) discontinued an anti-angiogenic therapy which caused proteinuria (ie, grade 2 (\> 2 to \> 3 g of protein or 1-3.5 g/24 hours \[h\]) or grade 3 proteinuria (\> 4 of protein or \> 3.5 g/24 h) are not eligible for enrollment until proteinuria improves to \< 2 g of protein per 24 h
* History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator)
* Concurrent diagnosis of pheochromocytoma
* Unresolved toxicity higher than CTCAE grade 1 attributed to any prior therapy/procedure, excluding alopecia
* Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the formulation
* Strong CYP3A4 inhibitors and inducers; concomitant use of strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir), and inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) are not permitted within two weeks prior to start of study treatment and for the duration of treatment with copanlisib
* Grapefruit and grapefruit juice (CYP3A4 inhibitor), Seville oranges and star fruit consumption is not permitted during the study
* Anti-arrhythmic therapy other than beta blockers or digoxin
* Systemic continuous corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent is not allowed; patients may be using topical or inhaled corticosteroids
* Concomitant therapy with any anticancer agents, immunosuppressive agents, other investigational anticancer therapies
* Concomitant radiotherapy
* Women who are breast feeding