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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Stage II Lung Cancer AJCC v8, Locally Advanced Lung Non-Small Cell Carcinoma, Stage IIA Lung Cancer AJCC v8, Stage IIB Lung Cancer AJCC v8, Stage III Lung Cancer AJCC v8, Stage IIIA Lung Cancer AJCC v8, Stage IIIB Lung Cancer AJCC v8, Stage IIIC Lung Cancer AJCC v8, Unresectable Lung Non-Small Cell Carcinoma

Intervention / Treatment
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* Drug: Carboplatin
* Biological: Durvalumab
* Drug: Paclitaxel
* Drug: Papaverine
* Radiation: Radiation Therapy
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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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) 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (papaverine, RT, paclitaxel, carboplatin)<br>Patients receive PPV IV or SC and undergo 5 fractions of RT per week. Patients also receive paclitaxel IV over 1 hour and carboplatin IV 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 Q2W for 12 months. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Drug: Papaverine<br>* Given IV or SC<br>* Other names: Robaxapap;Radiation: Radiation Therapy<br>* Undergo RT<br>* Other names: Therapy, Radiation;Drug: Pemetrexed<br>* Given IV<br>* Other names: Pemfexy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximally tolerated dose (MTD) of papaverine (PPV) in combination with chemoradiation treatment (CRT) | Will employ the Bayesian optimal interval (BOIN) design to find the MTD. Treatment-related toxicity will be assessed based on Common Terminology Criteria for Adverse Events version 5.0 criteria. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary tumor control rate | Defined as the absence of primary tumor failure. Will be calculated and 95% exact binomial confidence interval will be provided. | At 12 and 24 months post-treatment | 
| Local control rate | Defined as the absence of local failure, which is a combination of primary tumor and involved lobe failure. Will be calculated and 95% exact binomial confidence interval will be provided. | At 12 and 24 months post-treatment | 
| Time to local-regional progression | Will be summarized using Kaplan-Meier method. | From entry on the study until the time of documented local-regional recurrence or death, assessed at 12 and 24 months post-treatment | 
| Disease-free survival | Will be summarized using Kaplan-Meier method. | From entry on the study until the time of any documented disease recurrence or death, assessed at 12 and 24 months post-treatment | 
| Distant-metastasis-free survival | Will be summarized using Kaplan-Meier method. | At 12 and 24 months post-treatment | 
| Overall survival | Will be summarized using Kaplan-Meier method. | From study entry until the time of death from any cause, assessed at 12 and 24 months post-treatment | 
| Changes in magnetic resonance imaging (MRI) blood oxygen level dependent (BOLD) response on MRI | Images pre and post PPV will be analyzed for stability of baseline and treatment signals. Percent BOLD change will be determined for maximal and overall signal changes. Comparisons between the distributions of pre and post PPV will be valuated using Earth Mover's Distance. | Baseline up to 24 months | 
| Changes in blood-based biomarkers related to predict patients response to PPV + CRT | Will acquire measurements of circulating serum microRNAs that can indicate tumor hypoxia or response to therapeutic intervention, and alterations in immune cell subsets that are suggestive of immune system activation or suppression with the experimental therapy | Baseline up to 24 months | 
| Changes in tissue-based biomarkers related to predict patients response to PPV + CRT | When biopsy tissue is available, will acquire gene expression profiles by Affymetrix gene chip for indications of tumor hypoxia or response to therapeutic intervention, and correlating tumor mutations in genes involved in the anti-oxidant response pathway with outcomes. | Baseline up to 24 months |