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 authorizedrepresentative

• Willingness to participate in all correlative studies: fMRI, and tissue collectionof tumor and normal rectum (ribonucleic acid [RNA]/deoxyribonucleic acid [DNA]/protein), blood (plasma/peripheral blood mononuclear cell [PBMC]) draws andstool 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: Growthfactor is not permitted within 14 days of ANC assessment unless cytopenia issecondary to disease involvement

• Platelets ≥ 100,000/mm^3 (within 30 days of start). NOTE: Platelet transfusions arenot permitted within 14 days of platelet assessment unless cytopenia is secondary todisease involvement

• Hemoglobin ≥ 9g/dL (within 30 days of start). NOTE: Red blood cell transfusions arenot permitted within 14 days of hemoglobin assessment unless cytopenia is secondaryto 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-Gaultformula (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. Viralload must be undetectable. HIV-infected patients on effective anti-retroviraltherapy 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. Ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required (within 30 days of start)

• Agreement by females and males of childbearing potential to use an effective methodof birth control or abstain from heterosexual activity for the course of the studythrough at least 4 months after the last dose of protocol therapy

• Childbearing potential defined as not being surgically sterilized (men andwomen) 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 orbiologic composition to study agent

• Unable to undergo MRI and endoscopic procedures

• History of complete atrioventricular block, hepatic dysfunction (e.g. cirrhosis), orpriapism

• Other active malignancy. Patients with a prior or concurrent malignancy whosenatural history or treatment does not have the potential to interfere with thesafety or efficacy assessment of the investigational regimen are eligible for thistrial

• Females only: Pregnant or breastfeeding

• Any other condition that would, in the investigator's judgment, contraindicate thepatient's participation in the clinical study due to safety concerns with clinicalstudy procedures

• Prospective participants who, in the opinion of the investigator, may not be able tocomply with all study procedures (including compliance issues related tofeasibility/logistics)