Papaverine in Combination With Radiation Therapy for the Treatment of Locally Advanced Rectal Cancer, DINOMITE Trial

Inclusion Criteria:

* Documented informed consent of the participant and/or legally authorized representative
* Willingness to participate in all correlative studies: fMRI, and tissue collection of tumor and normal rectum (ribonucleic acid \[RNA\]/deoxyribonucleic acid \[DNA\]/protein), blood (plasma/peripheral blood mononuclear cell \[PBMC\]) draws and stool collection
* Age: ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) ≤ 2
* Histologically confirmed rectal adenocarcinoma
* Patient wants to pursue an organ preservation/non-operative management (NOM) approach after completion of total neoadjuvant therapy (TNT)
* Locally advanced rectal cancer (T3-4 or node+, M0)
* Tumor is microsatellite stable (MSS) (defined as not microsatellite instability-high \[MSI-H\] or mismatch repair deficient \[dMMR\])
* Absolute neutrophil count (ANC) ≥ 1,500/mm\^3 (within 30 days of start). NOTE: Growth factor is not permitted within 14 days of ANC assessment unless cytopenia is secondary to disease involvement
* Platelets ≥ 100,000/mm\^3 (within 30 days of start). NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement
* Hemoglobin ≥ 9g/dL (within 30 days of start). NOTE: Red blood cell transfusions are not permitted within 14 days of hemoglobin assessment unless cytopenia is secondary to disease involvement
* Total bilirubin ≤ 1.5 X upper limit of normal (ULN) (within 30 days of start)
* Aspartate aminotransferase (AST) =\< 2.5 x ULN (within 30 days of start)
* Alanine aminotransferase (ALT) =\< 2.5 x ULN (within 30 days of start)
* Creatinine clearance of ≥ 50 mL/min per 24 hour urine test or the Cockcroft-Gault formula (within 30 days of start)
* For patients with known infections only: seropositive for HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), nucleic acid quantitation must be performed. Viral load must be undetectable. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial (within 28 days of start)
* Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (within 30 days of start)
* Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 4 months after the last dose of protocol therapy

  * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)

Exclusion Criteria:

* Chemotherapy, biological therapy, immunotherapy within 14 days or five half-lives (whichever is shorter) prior to day 1 of protocol therapy
* Prior pelvic irradiation resulting in overlapping fields
* Use of levodopa in the last 30 days
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
* Unable to undergo MRI and endoscopic procedures
* History of complete atrioventricular block, hepatic dysfunction (e.g. cirrhosis), or priapism
* Other active malignancy. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
* Females only: Pregnant or breastfeeding
* Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
* Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)