Papaverine in Combination With Chemoradiation for the Treatment of Stage II-III Non-small Cell Lung Cancer

Inclusion Criteria:

• All prior treatment-related toxicities must be Common Terminology Criteria forAdverse Events (CTCAE) (version 5.0) =< grade 1 (except alopecia) at the time ofenrollment

• 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-hoururine 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) forwhom definitive CRT or RT to the primary and regional lymph nodes isrecommended by the multidisciplinary team, each individual metastatic tumorwould be considered an additional site of disease with the exception of brainmetastases. Up to 10 brain metastases would be considered as 1 site.

• Patients with oligometastatic disease will be allowed to receive adjuvantsystemic therapy at the discretion of the medical oncologist and additionallocal therapy to metastatic sites at the discretion of the multidisciplinaryteam

• Patients must be considered unresectable or medically-inoperable if stage II-IIINSCLC

• Patients with a local or regional recurrence following surgical resection forwhom definitive CRT or RT to disease in the chest is recommended by themultidisciplinary 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 scanof the brain with contrast. Non-contrast MRI scans of the chest/abdomen/pelvis orbrain are permitted for workup if patient has allergy to CT contrast or renalinsufficiency

• Patients must have vital signs, history/physical examination, laboratory studies (complete blood count [CBCP] with differential, chemistries including liver functiontests, creatinine clearance (CrCl) assessment; pregnancy test if needed within 14days 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) andwell-healed before starting treatment

• Ability to provide written informed consent obtained prior to participation in thestudy 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 acceptablepregnancy assessment

• Nursing women may participate only if nursing is discontinued, due to thepossibility of harm to nursing infants from the treatment regimen

• Women/men of reproductive potential must be counselled on contraception/ abstinencewhile receiving the study treatment

• Women of childbearing potential are required to use an effective method ofcontraception from the time of negative serum pregnancy test, throughout thestudy duration, and until 4 years after the last dose of radiation. Should awoman become pregnant or suspect she is pregnant while she or her partner isparticipating in this study, she should inform her treating physicianimmediately

• Men treated or enrolled on this protocol must also agree to use adequatecontraception prior to the study, for the duration of study participation, andfor 6 months after completion of study drug administration

• For patients planning to undergo CRT, patient is suitable to receive standardchemotherapy 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 pulmonaryfibrosis

• History of previous radiation therapy which would result in overlapping radiationfields

• 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 womanbecome pregnant or suspect she is pregnant while participating in this study, sheshould 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 MRISub-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 malignancyexception above), psychiatric disorder, or other conditions that could interferewith subject's safety, obtaining informed consent or compliance to the studyprocedures, in the opinion of the treating physicians. This could include severe,active co-morbidities such as:

• Unstable angina and/or congestive heart failure requiring hospitalizationwithin the last 6 months

• Transmural myocardial infarction within the last 6 months

• Acquired immune deficiency syndrome (AIDS) based upon the current Centers forDisease Control and Prevention (CDC) definition; note, however, that humanimmunodeficiency virus (HIV) testing is not required for entry into thisprotocol. The need to exclude patients with AIDS from this protocol isnecessary because the treatments involved in this protocol may be significantlyimmunosuppressive

• Chronic obstructive pulmonary disease exacerbation or other respiratory illnessrequiring hospitalization or precluding study therapy within 30 days ofregistration

• Patients who are presently receiving nitrates or nitroglycerin, or have receivedthese medications within 30 days of day 1 of protocol treatment

• Patients who are currently taking Sildenafil should agree to discontinue use for 2days prior to initiation of papaverine, during the duration of study, and for 2 daysafter 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 relieveanxiety/claustrophobia

• Patients who use supplemental oxygen and are not able to stop their oxygen for up toa few hours at a time, or who use oxygen because they have breathing when they arelaying down