A Phase 1 Study of IPdR in Combination With Capecitabine and Radiotherapy in Rectal Cancer

• At diagnosis, patients must have had histologically proven adenocarcinoma of the rectum with no evidence of distant metastases

• At diagnosis, the major portion of the tumor must have been intact, and the following must be documented:

‣ Distance of the lowest tumor margin from the anal verge; and

⁃ Intent for sphincter sparing or non-sphincter sparing surgical resection according to the primary surgeon; and

⁃ The majority of the untreated tumor must be \< 12 cm from the anal verge or below the peritoneal reflection as determined by the treating surgeon

• At diagnosis, the tumor must have been locally advanced stage II (T3-4 N0) or stage III (N positive \[+\]) rectal cancer with at least one of the following:

‣ Distal location (as defined by measurement on magnetic resonance imaging \[MRI\], endorectal ultrasound \[ERUS\]/pelvic computed tomography \[CT\] \[with intravenous (IV) contrast\] scan or palpable on digital rectal exam \[DRE\]): cT3-4 =\< 5 cm from the anal verge, any N

⁃ Bulky: Any cT4 or evidence that the tumor is adjacent to (defined as within 3 mm of) the mesorectal fascia on MRI or ERUS/pelvic CT (with IV contrast) scan

⁃ High risk for metastatic disease with 4 or more regional lymph nodes (cN2). Clinical Nodal or cN status for eligibility includes the total number of nodes (N2 = 4 or more) in the mesorectal and superior rectal stations measuring \>= 1.0 cm in any axis on cross sectional or endoscopic imaging. Nodes must measure 1.0 cm or greater to be considered positive for this eligibility requirement

⁃ Not a candidate for sphincter-sparing surgical resection prior to neoadjuvant therapy (as planned by the primary surgeon)

• Patients must have received 8 cycles of neoadjuvant leucovorin, fluorouracil, and oxaliplatin (mFOLFOX) and must have completed this therapy at least 3 weeks (and no more than 6 weeks) prior to enrollment on this study

• Patients must intend to undergo surgical resection of the rectal primary tumor following chemoradiotherapy

• Age \>= 18 years

‣ Because no dosing or adverse event (AE) data are currently available on the use of IPdR in combination with capecitabine and RT in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials

• Eastern Cooperative Oncology Group performance status =\< 2 (Karnofsky \>= 60%)

• Leukocytes \>= 3,000/mcL

• Absolute neutrophil count \>= 1,200/mcL

• Platelets \>= 100,000/mcL

• Hemoglobin \> 10 g/dL

• Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) =\< 2.5 x institutional ULN

• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional ULN

• Creatinine =\< 1.5 x institutional ULN OR glomerular filtration rate (GFR) \>= 60 mL/min/1.73 m\^2

• Alkaline phosphatase =\< 3 x institutional ULN

• Sodium, potassium, chloride, bicarbonate, and magnesium within institutional normal limits

• Patients with acquired immunodeficiency syndrome (acquired immunodeficiency syndrome \[AIDS\]-related illnesses) or known human immunodeficiency virus (HIV) disease must:

‣ Have a CD4 count \>= 200 cells/uL within 30 days before enrollment,

⁃ Be off all antiretroviral therapy (prophylaxis/treatment) more than 60 days before enrollment, and

⁃ Have no evidence of opportunistic infections

• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured and be receiving no therapy

• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification. To be eligible for this trial, patients should be class 2B or better

• Patients must have the ability to swallow and retain oral medication

• The effects of IPdR on the developing human fetus are unknown. For this reason and because radiosensitizing agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential (WOCBP)\* and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. WOCBP must have a negative urine or serum pregnancy test within 72 hours prior to enrollment. If urine pregnancy results are positive or cannot be confirmed as negative, a serum pregnancy test will be required. 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. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of IPdR administration

‣ Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes

• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible