Cabozantinib in Treating Patients With Locally Advanced or Metastatic Unresectable Adrenocortical Carcinoma

Inclusion Criteria:

* Histological confirmation of adrenocortical carcinoma (ACC) based on either: i). Weiss Score of \>= 3 in patients who had earlier surgical resection OR ii). biopsy results compatible with ACC in the context of clinical setting highly suggestive of ACC (adrenal mass \> 4 cm invading surrounding organs or associated with distant metastases).
* Locally advanced or metastatic disease not amenable to surgery with curative intent with measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as determined by the investigator based on an assessment of all known disease sites by computerized tomography (CT) scan or magnetic resonance imaging (MRI) of chest/abdomen/pelvis within 28 days before the first dose of cabozantinib. In patients with intravenous (IV) contrast allergy or borderline renal function, CT without IV contrast or 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) CT may be used as clinically indicated.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
* Recovery to baseline or =\< grade 1 CTCAE v.4.0 from toxicities related to any prior treatments, unless adverse events (AEs) are clinically nonsignificant and/or stable on supportive therapy.
* Life expectancy of at least 3 months.
* Absolute neutrophil count (ANC) \>= 1500/mm\^3 without colony stimulating factor support (obtained within 28 days prior to the first dose of cabozantinib).
* Platelets \>= 100,000/mm\^3 (obtained within 28 days prior to the first dose of cabozantinib).
* Hemoglobin \>= 9 g/dL (obtained within 28 days prior to the first dose of cabozantinib).
* Bilirubin =\< 1.5 x the upper limit of normal (ULN). For subjects with known Gilbert's disease, bilirubin =\< 3.0 mg/dL (obtained within 28 days prior to the first dose of cabozantinib).
* Serum albumin \>= 2.8 g/dl (obtained within 28 days prior to the first dose of cabozantinib).
* Serum creatinine =\< 1.5 x ULN or creatinine clearance (CrCl) \>= 50 mL/min. For creatinine clearance estimation, the Cockcroft and Gault equation should be used (obtained within 28 days prior to the first dose of cabozantinib).
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3.0 x ULN (obtained within 28 days prior to the first dose of cabozantinib).
* Lipase =\< 2.0 x the upper limit of normal and no radiologic or clinical evidence of pancreatitis (obtained within 28 days prior to the first dose of cabozantinib).
* Urine protein/creatinine ratio (UPCR) =\< 1 (obtained within 28 days prior to the first dose of cabozantinib).
* Serum phosphorus \>= 2.5 mg/dl (obtained within 28 days prior to the first dose of cabozantinib).
* Calcium \>= 8 mg/dL (obtained within 28 days prior to the first dose of cabozantinib).
* Magnesium \>= 1.2 mg/dL (obtained within 28 days prior to the first dose of cabozantinib).
* Potassium \>= 3.0 meq/L (obtained within 28 days prior to the first dose of cabozantinib).
* Capable of understanding and complying with the protocol requirements and has signed the informed consent document.
* Sexually active patients (men and women) 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 sexually active 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).
* 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. Postmenopause 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, anti-estrogens, ovarian suppression or any other reversible reason.

Exclusion Criteria:

* Received cytotoxic chemotherapy, radiation therapy, or targeted therapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 28 days of study enrollment.
* For patients who received mitotane within 6 months of consenting, mitotane should have been stopped at least 28 days prior to study enrollment AND to have mitotane serum level of \< 2 mg/L.
* Prior treatment with cabozantinib or other cMET inhibitors.
* Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before the first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment.
* The subject has not recovered to baseline or CTCAE =\< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs.
* Prothrombin time (PT)/ international normalized ratio (INR) or partial thromboplastin time (PTT) test \>= 1.3 x the laboratory ULN within 28 days before the first dose of study treatment.
* Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin and Factor Xa inhibitors), platelet inhibitors (e.g., clopidogrel) or therapeutic doses of low molecular weight heparins (LMWH). Low dose aspirin for cardioprotection (per local applicable guidelines) and low-dose LMWH are permitted. Anticoagulation with therapeutic doses of LMWH is allowed in subjects who are on a stable dose of LMWH for at least 6 weeks before the first dose of study treatment, and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor.
* Severe and uncontrolled Cushing syndrome despite medical management (e.g., systolic blood pressure \> 160 mmHg or hyperglycemia with fasting glucose above 300 mg/dL).
* The use of strong CYP3A4 inhibitor (with the exception of ketoconazole).
* The subject has experienced any of the following: a. clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment; b. hemoptysis \>= 0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment; c. any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment. Tumor invading any major blood vessel at the time of study enrollment.
* 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, or the subject with radiographic evidence of cavitating pulmonary lesion(s); or subjects with tumor invading or encasing any major blood vessels.
* Uncontrolled, significant concurrent or recent illness including, but not limited to, the following conditions: a. Cardiovascular disorders including i. congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening ii. concurrent uncontrolled hypertension defined as sustained blood pressure (BP) \> 150 mm Hg systolic, or \> 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment iii. any history of congenital long QT syndrome or iv. 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) within 90 days of the first dose of study treatment, myocardial infarction, clinically significant thromboembolic event within 42 days of randomization requiring therapeutic anticoagulation.
* (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this study) b. gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including: i. 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; patients must be completely recovered, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), acute pancreatitis, pancreatic duct or common bile duct obstruction, acute diverticulitis, acute cholecystitis, symptomatic cholangitis or recent appendicitis within 1 month of first dose of cabozantinib; patients must be completely recovered from these conditions, clinically significant malabsorption syndrome, c. endocrine disorders, uncontrolled Cushing syndrome despite of adequate medical therapy.
* 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 90 days before the first dose of study therapy.
* Other clinically significant disorders such as: i. active infection requiring systemic antibiotic treatment within 14 days before the first dose of study treatment ii. serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment iii. history of organ transplant iv. concurrent uncompensated hypothyroidism or thyroid dysfunction (thyroid-stimulating hormone \[TSH\] above 10) within 28 days before the first dose of study treatment v. major surgery within 12 weeks before the first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before the first dose of study treatment. Minor surgery within 28 days before the first dose of study treatment with complete wound healing at least 10 days before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
* Unable to swallow tablets.
* A corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 milliseconds within 28 days before first dose of study treatment.
* Pregnant or breastfeeding.
* A previously identified allergy or hypersensitivity to components of the study treatment formulation.
* Unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.
* Evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment except for breast ductal carcinoma-in situ, cured non-melanoma skin cancer, or cured in situ cervical carcinoma.
* Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality which, in the judgment of the investigator, would have made the patient inappropriate for entry into this study.