Regorafenib in Reducing Recurrence in Patients With Non-metastatic Rectal Cancer Who Have Completed Curative-Intent Treatment

Inclusion Criteria:

* Histologically or cytologically confirmed adenocarcinoma of the rectum that was clinically staged T3, T4 or node-positive (defined as \>= N1 per American Joint Committee on Cancer \[AJCC\] 7th edition) that was treated with the following treatment with curative intent:

  * Curative surgical resection
  * Pre- or post-operative chemoradiation; and at least 3 months of adjuvant systemic chemotherapy (equivalent to 6 cycles of leucovorin calcium, fluorouracil, and oxaliplatin \[FOLFOX\] or infusional fluorouracil \[5FU\])
* No evidence of cancer within 28 days prior to start of study treatment; this should be determined by imaging of the chest, abdomen and pelvis by computed tomography (CT) and/or magnetic resonance imaging (MRI); staging of the chest using chest x-ray in lieu of CT and/or MRI should not be used for this purpose
* Have an Eastern Cooperative Oncology Group (ECOG) performance status of =\< 1
* Consent to allowing his/her archival tumor tissues to be requested and analyzed; however, the non-availability or inadequate amount samples for analysis will not exclude the patient
* Platelet count \>= 100,000/mm\^3; blood transfusion to meet the inclusion criteria will not be allowed
* Hemoglobin (Hb) \>= 9 g/dL; blood transfusion to meet the inclusion criteria will not be allowed
* Absolute neutrophil count (ANC) 1500/mm\^3; blood transfusion to meet the inclusion criteria will not be allowed
* Total bilirubin =\< 1.5 x the upper limits of normal (ULN)
* Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) =\< 2.5 x ULN
* Alkaline phosphatase limit =\< 2.5 x ULN
* Lipase =\< 1.5 x the ULN
* Serum creatinine =\< 1.5 times the ULN
* International normalized ratio (INR) of prothrombin time (PT; PT-INR) and activated partial thromboplastin time (aPTT) =\< 1.5: subjects who are prophylactically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists per medical history; close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care
* Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study drug; post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test
* Patients of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry and, until at least 3 months after the last dose of the study drug; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
* Patient is willing and able to take oral medications and to comply with scheduled visits, treatment plan, and study related procedures

Exclusion Criteria:

* Evidence of recurrence of rectal cancer prior to the start of study treatment
* Any previously untreated or concurrent cancer that is distinct in primary site or histology from rectal cancer except cervical cancer in-situ, treated basal cell carcinoma, or superficial bladder tumor; subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before starting study drug are allowed; all cancer treatments must be completed at least 3 years prior to study entry (i.e., signature date of the informed consent form)
* Anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) within 4 weeks prior to entering the study (signing of consent form) or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier; patients on hormonal or bisphosphonate treatment for non-cancer related conditions are eligible
* Inability to start study treatment within 12 weeks following the completion of curative intent therapy for rectal adenocarcinoma
* Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication; minor procedures such as diagnostic laparoscopy, percutaneous biopsy and paracentesis within 14 days before start of study medication
* Patients who have not recovered from the surgical resection of rectal cancer such as wound dehiscence, non-healing wound, wound infection and fistula
* Prior use of regorafenib
* Gastrointestinal conditions that may significantly affect the absorption of regorafenib
* Uncontrolled hypertension (systolic pressure \> 140 mmHg or diastolic pressure \> 90 mmHg on repeated measurement) despite optimal medical management
* Evidence or history of bleeding diathesis or coagulopathy
* Any hemorrhage or bleeding event \>= Common Terminology Criteria for Adverse Events (CTCAE) grade 3 within 4 weeks prior to start of study medication
* Have had arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within 3 months prior to the initiation of study treatment
* Patients with phaeochromocytoma
* Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection requiring treatment with antiviral therapy
* Ongoing infection \> CTCAE grade 2
* Patients with seizure disorder requiring medication
* Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
* Pleural effusion or ascites that causes respiratory compromise (\>= grade 2 dyspnea CTCAE)
* History of organ allograft (including corneal transplant)
* Pregnant or nursing female patients
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association \> class II), unstable angina pectoris (defined as anginal symptoms at rest, new-onset angina within 3 months before study treatment initiation, or myocardial infarction within 6 months before study treatment initiation), cardiac arrhythmia (which require anti-arrhythmic therapy other than beta blockers or digoxin), active coronary artery disease, or psychiatric illness/social situations that would limit compliance with study requirements
* Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
* Therapeutic anticoagulation with vitamin-K antagonists (e.g., warfarin) or with heparins and heparinoids; however, prophylactic anticoagulation as described below is allowed:

  * Low dose warfarin (1 mg orally, once daily) with PT-INR =\< 1.5 is permitted; infrequent bleeding or elevations in PT-INR have been reported in some subjects taking warfarin while on regorafenib therapy; therefore, subjects taking concomitant warfarin should be monitored regularly for changes in PT, PT-INR or clinical bleeding episodes
  * Low dose aspirin (=\< 100 mg daily)
  * Prophylactic doses of heparin
* Are taking strong cytochrome P (cytochrome P450, family 3, subfamily A, polypeptide 4 \[CYP3A4\]) inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin, St. John's wort/Hypericum perforatum)
* Unwilling or unable to follow protocol requirements
* Any condition which in the investigator's opinion deems the patient an unsuitable candidate to receive study drug
* Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results