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

This phase I trial finds out the best dose, possible benefits and/or side effects of papaverine when given together with chemoradiation intreating patients with stage II-III non-small cell lung cancer. Papaverine targets mitochondrial metabolism to decrease the cancer growth process. Giving papaverine with chemoradiation may work best to treat patients with non-small cell lung cancer.

PRIMARY OBJECTIVE:

I. To determine the maximally tolerated dose of papaverine (PPV) in combination with chemoradiation (CRT) and immunotherapy in patients with unresectable locally advanced (LA) non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVES:

I. To estimate the rates of primary tumor control, local control, time to local-regional progression, disease-free survival (DFS), and overall survival (OS). II. To assess whether blood oxygen level determination (BOLD) functional magnetic resonance imaging (MRI) studies can predict which patients may respond best to PPV + CRT, and detect changes in oxygenation before and after PPV administration.

III. To assess whether blood-based and tissue-based biomarkers can predict which patients may respond best to PPV + CRT.

OUTLINE: This is a dose-escalation study of PPV.

Patients receive PPV intravenously (IV) or subcutaneously (SC) and undergo 5 fractions of radiation therapy (RT) per week for 6 weeks. Patients also receive paclitaxel IV over 1 hour and carboplatin IV once weekly (QW) over 1-6 weeks or pemetrexed IV over 10 minutes followed by carboplatin IV every 3 weeks in the absence of disease progression or unacceptable toxicity. Beginning 1 month of completing CRT, patients with PD-L1 positive disease receive durvalumab IV every 2 weeks (Q2W) for 12 months. Patients also undergo positron emission tomography/computed tomography (PET/CT) or CT and brain magnetic resonance imaging (MRI) during screening, and blood sample collection and CT scans throughout the trial. Patients may also undergo two additional research MRI scans between day -7 and -1.

After completion of the study treatment, patients are followed for 2 years at 1, 3, 6, 9, 12, 16, 20, and 24 months, then periodically for up to 5 years.

Eligibility Criteria:
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
* \>= 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 patients with oligometastatic disease.

  * For patients with oligometastatic disease (up to 5 total sites of disease) for whom definitive chemoradiation 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

  * Patients with a local or regional recurrence following surgical resection for whom definitive chemoradiation to disease in the chest is recommended by the multidisciplinary team will be considered eligible
* Within 60 days of registration: 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
* Within 30 days of registration: patients must have vital signs, history/physical examination, laboratory studies (CBCP with differential, chemistries including liver function tests, creatinine clearance (CrCl) assessment; pregnancy test if needed within 14 days of registration)
* Absolute neutrophil count \>=1.5 x 10\^9/L (within 30 days of study registration)
* Hemoglobin \>= 9 g/dL (within 30 days of study registration)
* Platelets \>= 100 x10\^9/L (within 30 days of study registration)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) (within 30 days of study registration)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x ULN (within 30 days of study registration)
* Creatinine \< 1.5 mg/dL or calculated creatinine clearance\* \>= 50 mL/min or 24-hour urine creatinine clearance \>= 50 mL/min (within 30 days of study registration)

  * Calculated by the Cockcroft-Gault formula
* If a pleural effusion is present and visible on both CT scan AND chest Xray, the investigator should exclude malignant disease by pleurocentesis to confirm cytologically-negative pleural fluid. If fluid is exudative or cytologically positive for tumor cells, patient is excluded

  * Patients with effusions that are minimal (i.e. not visible on chest x-ray) and that are too small to safely tap are eligible
* Life expectancy of \> 6 months in the opinion of investigator
* Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 30 days of registration
* 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
* Patient is suitable to receive standard chemotherapy with radiation during study treatment (i.e. carboplatin + paclitaxel or carboplatin + pemetrexed)

  * 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.

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
* Uncontrolled neuropathy grade 2 or greater, regardless of cause
* 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
* If patient elects to have two research MRIs during dose-finding phase of trial, medical contraindication to MR imaging (e.g. pacemakers, metallic implants, aneurysm clips, known contrast allergy to gadolinium contrast, pregnancy, nursing mothers, weight greater than 350 pounds) or severe anxiety/claustrophobia related to MR imaging despite medications to relieve anxiety/claustrophobia
* Hepatic insufficiency resulting in jaundice and/or coagulation defects, or not meeting laboratory values above (albumin, total bilirubin, AST/ALT)
* 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
  * Hepatic insufficiency resulting in jaundice and/or coagulation defects