A Phase I Trial Targeting Mitochondrial Metabolism With Papaverine in Combination With Chemoradiation for Stage II-III Non-Small Cell Lung Cancer

Inclusion Criteria: * All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0) =\< grade 1 (except alopecia) at the time of enrollment * Absolute neutrophil count \>=1.5 x 10\^9/L * Hemoglobin \>= 9 g/dL * Platelets \>= 100 x 10\^9/L * Total bilirubin =\< 1.5 x upper limit of normal (ULN) * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x ULN * Creatinine \< 1.5 mg/dL or calculated creatinine clearance\* \>= 50 mL/min or 24-hour urine creatinine clearance \>= 50 mL/min * Calculated by the Cockcroft-Gault formula •\>= 18 years old * Non-small cell lung cancer (NSCLC), histologically and/or cytologically proven * Clinical American Joint Committee on Cancer (AJCC) stage II-III NSCLC (T1-4N0-3M0) and select patients with stage IV oligometastatic disease. * For patients with oligometastatic disease (up to 5 total sites of disease) for whom definitive CRT or RT to the primary and regional lymph nodes is recommended by the multidisciplinary team, each individual metastatic tumor would be considered an additional site of disease with the exception of brain metastases. Up to 10 brain metastases would be considered as 1 site. * Patients with oligometastatic disease will be allowed to receive adjuvant systemic therapy at the discretion of the medical oncologist and additional local therapy to metastatic sites at the discretion of the multidisciplinary team * Patients must be considered unresectable or medically-inoperable if stage II-III NSCLC * Patients with a local or regional recurrence following surgical resection for whom definitive CRT or RT to disease in the chest is recommended by the multidisciplinary team will be considered eligible * Patients must have fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)-computed tomography (CT) scan (or CT chest/abdomen/pelvis with IV contrast), and magnetic resonance imaging (MRI) brain with IV contrast (preferred) or CT scan of the brain with contrast. Non-contrast MRI scans of the chest/abdomen/pelvis or brain are permitted for workup if patient has allergy to CT contrast or renal insufficiency * Patients must have vital signs, history/physical examination, laboratory studies (complete blood count \[CBCP\] with differential, chemistries including liver function tests, creatinine clearance (CrCl) assessment; pregnancy test if needed within 14 days of registration) * Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * No history of complete atrioventricular block, hepatic dysfunction (e.g. cirrhosis), glaucoma, or priapism * Patients must be a minimum of 3 weeks from thoracotomy (if performed) and well-healed before starting treatment * Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed * Women of child-bearing potential (WOCBP) must have a negative pregnancy test within 14 days of registration. Urine human chorionic gonadotropin (HCG) is an acceptable pregnancy assessment * Nursing women may participate only if nursing is discontinued, due to the possibility of harm to nursing infants from the treatment regimen * Women/men of reproductive potential must be counselled on contraception/ abstinence while receiving the study treatment * Women of childbearing potential are required to use an effective method of contraception from the time of negative serum pregnancy test, throughout the study duration, and until 4 years after the last dose of radiation. 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 for 6 months after completion of study drug administration * For patients planning to undergo CRT, patient is suitable to receive standard chemotherapy per treating medical oncologist with radiation during study treatment INCLUSION CRITERIA FOR MRI IMAGING SUB-STUDY: •Patients must consent to participate in the main part of this study and be enrolled into the expansion cohort, or consent to participate in the main part of this study and also consent to participate in the optional MRI Imaging study Exclusion Criteria: * Patients with history of pneumonectomy * History of active connective tissue disease (scleroderma) or idiopathic pulmonary fibrosis * History of previous radiation therapy which would result in overlapping radiation fields * Subjects who are breast-feeding and plan to continue breast-feeding during therapy, or have a positive pregnancy test will be excluded from the study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * Hepatic insufficiency resulting in jaundice, or not meeting laboratory values above (albumin, total bilirubin, AST/ALT) * Patients enrolled into the expansion cohort must be able to complete the MRI Sub-study, or at a minimum attempt the first scan of the MRI Sub-study * Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the treating physicians. This could include severe, active co-morbidities such as: * Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months * Transmural myocardial infarction within the last 6 months * Acquired immune deficiency syndrome (AIDS) based upon the current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of registration * Patients who are presently receiving nitrates or nitroglycerin, or have received these medications within 30 days of day 1 of protocol treatment * Patients who are currently taking Sildenafil should agree to discontinue use for 2 days prior to initiation of papaverine, during the duration of study, and for 2 days after last dose of papaverine EXCLUSION CRITERIA FOR MRI IMAGING SUB-STUDY: * Any medical contraindication to MR imaging (e.g. pacemakers, metallic implants, aneurysm clips, pregnancy, nursing mothers, weight greater than 350 pounds) * Severe anxiety/claustrophobia related to MR imaging despite medications to relieve anxiety/claustrophobia * Patients who use supplemental oxygen and are not able to stop their oxygen for up to a few hours at a time, or who use oxygen because they have breathing when they are laying down