This phase II trial studies how well cabozantinib s-malate works in treating patients with endometrial cancer that has come back (recurrent) or has spread to other places in the body (metastatic). Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PRIMARY OBJECTIVES:

I. Determine efficacy of single agent cabozantinib s-malate (cabozantinib) in women previously receiving one line of chemotherapy for metastatic endometrial cancer or with progression within 12 months of completing adjuvant therapy, with co-primary endpoints of objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and progression-free-survival at 12 weeks (PFS).

SECONDARY OBJECTIVES:

I. Correlation of clinical response with baseline molecular status of archival tumor (hepatocyte growth factor receptor [c-met] amplification & mutation status) and overall survival.

OUTLINE:

Patients receive cabozantinib s-malate orally (PO) once daily (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 4 weeks or every 6 months.

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed metastatic endometrial cancer; eligible histologies for the experimental cohort are: endometrioid or serous; eligible histologies for the exploratory cohort are: carcinosarcoma, clear cell, mixed, adenosquamous and any other rare sub-type of endometrial cancer
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 10 mm with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam and >= 15 mm in short axis for nodal lesions; patients must have radiographic evidence of disease progression following the most recent line of treatment
• Prior therapy: Eligible subjects must have had 1 line of systemic cytotoxic treatment; this may be adjuvant therapy with documented progression within 12 months of completion, or 1 line of cytotoxic therapy for metastatic disease; NOTE: eligible patients are allowed up to 2 lines of systemic cytotoxic treatment, of which only 1 line is allowed for metastatic disease; the acceptance of progression within 12 months of adjuvant is part inclusion to not require patient to re-challenge with chemotherapy (chemo) if they progressed soon after adjuvant therapy; prior hormonal therapy for metastatic/recurrent disease is also allowed; prior targeted therapy not directed against cMET or vascular endothelial growth factor (VEGF) pathways is allowed
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Life expectancy of greater than 3 months
• Absolute neutrophil count >= 1.5 x 10^9/L
• Platelets >= 100 x 10^9/L
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 X institutional upper limit of normal
• Creatinine =< 1.5 x ULN OR creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• Hemoglobin >= 90 g/L
• Serum albumin >= 28 g/L
• Lipase < 2.0 x ULN; no radiologic/clinical evidence of pancreatitis
• Urine protein/creatinine ratio (UPCR) =< 1
• Serum phosphorus, calcium, magnesium and potassium >= lower limit of normal (LLN)
• Women of childbearing potential must have a negative pregnancy test at screening; women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopausal is defined as amenorrhea >= 12 consecutive months; note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible reason
• Women of child-bearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately; sexually active subjects must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used; all subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s)
• Patients must consent to analysis on archival tissue; if archival sample is not available, a sufficient tumor biopsy can be performed a minimum of 28 days prior to start of treatment if felt to be clinically reasonable
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients who have had chemotherapy (including investigational cytotoxic chemotherapy), biologic agents (e.g., cytokines or antibodies) or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) before the first dose of study treatment or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier

• Prior treatment with cabozantinib

• The subject has received radiation therapy:

  • To bone metastasis within 14 days before the first dose of study treatment
  • To any other site(s) within 28 days before the first dose of study treatment

• The subject has received radionuclide treatment within 6 weeks of the first dose of study treatment

• The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment

• The subject has received any other type of investigational agent within 28 days before the first dose of study treatment

• The subject has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1 from related toxicity to all prior therapies except alopecia and other non-clinically significant adverse events (AEs)

• Any other prior malignancy from which the patient has been disease free for less than 3 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of any site or any other cancer

• Patients with known brain metastases should be excluded from this clinical trial

• The subject has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test >= 1.3 x the laboratory ULN =< 7 days before the first dose of study treatment

• Therapeutic anticoagulation with warfarin, antiplatelet agents (e.g., clopidogrel), thrombin, or Factor Xa inhibitors is not allowed; therapeutic anticoagulation with low molecular weight heparin (LMWH) is allowed as well as prophylactic anticoagulation using low dose aspirin (=< 81 mg/day), low-dose warfarin (=< 1 mg/day), and LMWH

• The subject requires chronic concomitant treatment of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort)

• The subject has experienced any of the following:

  • Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
  • Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment
  • Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment

• The subject has tumor in contact with, invading or encasing any major blood vessels

• The subject has evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib

• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

  • Cardiovascular disorders including:

    • Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening

    • Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mmHg systolic, or > 90 mmHg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment

    • Any history of congenital long QT syndrome

    • Any of the following within 6 months before the first dose of study treatment:

      • Unstable angina pectoris
      • Clinically-significant cardiac arrhythmias
      • Stroke (including transient ischemic attack [TIA], or other ischemic event)
      • Myocardial infarction
      • Thromboembolic event requiring therapeutic anticoagulation (note: subjects with a venous filter [e.g. vena cava filter] are not eligible for this study)

• Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:

  • Any of the following within 28 days before the first dose of study treatment

    • Intra-abdominal tumor/metastases invading GI mucosa
    • Active peptic ulcer disease,
    • Inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
    • Malabsorption syndrome

  • Any of the following within 6 months before the first dose of study treatment:

    • Abdominal fistula
    • Gastrointestinal perforation
    • Bowel obstruction or gastric outlet obstruction
    • Intra-abdominal abscess; note: complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 6 months before the first dose of study treatment

• Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy

• Other clinically significant disorders such as:

  • Active uncontrolled infection requiring intravenous systemic treatment within 14 days before the first dose of study treatment

  • Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment

  • History of organ transplant

  • Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment

  • History of major surgery as follows:

    • Major surgery within 3 months of the first dose of cabozantinib if there were no wound healing complications or within 6 months of the first dose of cabozantinib if there were wound complications

    • Minor surgery within 1 month of the first dose of cabozantinib if there were no wound healing complications or within 3 months of the first dose of cabozantinib if there were wound complications

      • In addition, complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of cabozantinib irrespective of the time from surgery

• The subject is unable to swallow tablets

• The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms =< 7 days before the first dose of study treatment

• The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to XL184

• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with XL184

• Known human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible