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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05136846
Recruitment Status : Not yet recruiting
First Posted : November 29, 2021
Last Update Posted : November 29, 2021
Sponsor:
Information provided by (Responsible Party):
Jeremy Brownstein, Ohio State University Comprehensive Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Locally Advanced Lung Non-Small Cell Carcinoma Stage II Lung Cancer AJCC v8 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 Drug: Carboplatin Biological: Durvalumab Drug: Paclitaxel Drug: Papaverine Radiation: Radiation Therapy Phase 1

Detailed Description:

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. Patients also receive paclitaxel IV over 1 hour and carboplatin IV once weekly (QW) over 1-6 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.

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Trial Targeting Mitochondrial Metabolism With Papaverine in Combination With Chemoradiation for Stage II-III Non-Small Cell Lung Cancer
Estimated Study Start Date : December 1, 2021
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: Treatment (papaverine, RT, paclitaxel, carboplatin)
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 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
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carboplatinum
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Biological: Durvalumab
Given IV
Other Names:
  • Imfinzi
  • Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
  • MEDI-4736
  • MEDI4736

Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat

Drug: Papaverine
Given IV or SC
Other Names:
  • Cerebid
  • Cerespan
  • Pavabid
  • Pavacap
  • Pavatym
  • Robaxapap

Radiation: Radiation Therapy
Undergo RT
Other Names:
  • Cancer Radiotherapy
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation




Primary Outcome Measures :
  1. Maximally tolerated dose (MTD) of papaverine (PPV) in combination with chemoradiation treatment (CRT) [ Time Frame: 6 weeks ]
    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.


Secondary Outcome Measures :
  1. Primary tumor control rate [ Time Frame: At 12 and 24 months post-treatment ]
    Defined as the absence of primary tumor failure. Will be calculated and 95% exact binomial confidence interval will be provided.

  2. Local control rate [ Time Frame: At 12 and 24 months post-treatment ]
    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.

  3. Time to local-regional progression [ Time Frame: From entry on the study until the time of documented local-regional recurrence or death, assessed at 12 and 24 months post-treatment ]
    Will be summarized using Kaplan-Meier method.

  4. Disease-free survival [ Time Frame: From entry on the study until the time of any documented disease recurrence or death, assessed at 12 and 24 months post-treatment ]
    Will be summarized using Kaplan-Meier method.

  5. Distant-metastasis-free survival [ Time Frame: At 12 and 24 months post-treatment ]
    Will be summarized using Kaplan-Meier method.

  6. Overall survival [ Time Frame: From study entry until the time of death from any cause, assessed at 12 and 24 months post-treatment ]
    Will be summarized using Kaplan-Meier method.

  7. Changes in magnetic resonance imaging (MRI) blood oxygen level dependent (BOLD) response on MRI [ Time Frame: Baseline up to 24 months ]
    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.

  8. Changes in blood-based biomarkers related to predict patients response to PPV + CRT [ Time Frame: Baseline up to 24 months ]
    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

  9. Changes in tissue-based biomarkers related to predict patients response to PPV + CRT [ Time Frame: Baseline up to 24 months ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)
  • Patients must be considered unresectable or medically-inoperable
  • 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)

Exclusion Criteria:

  • Documented or pathologically-proven metastatic disease
  • Presence of nodules considered neoplastic in contralateral lobes (M1a)
  • Patients with history of pneumonectomy
  • Prior cytotoxic chemotherapy or molecularly-targeted agents (e.g. erlotinib, crizotinib), unless > 2 years prior
  • Any concurrent malignancy other than non-melanoma skin cancer, non-invasive bladder cancer, or carcinoma in situ of the cervix. Patients with a previous malignancy without evidence of disease for >= 3 years will be allowed to enter the trial
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05136846


Contacts
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Contact: The Ohio State University Comprehensive Cancer Center 800-293-5066 OSUCCCClinicaltrials@osumc.edu

Locations
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United States, Ohio
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
Contact: Jeremy M. Brownstein, MD       Jeremy.Brownstein@osumc.edu   
Principal Investigator: Jeremy Brownstein, MD         
Sponsors and Collaborators
Ohio State University Comprehensive Cancer Center
Investigators
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Principal Investigator: Jeremey Brownstein, MD Ohio State University Comprehensive Cancer Center
Additional Information:
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Responsible Party: Jeremy Brownstein, Principal Investigator, Ohio State University Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT05136846    
Other Study ID Numbers: OSU-20327
NCI-2021-07691 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: November 29, 2021    Key Record Dates
Last Update Posted: November 29, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Paclitaxel
Carboplatin
Albumin-Bound Paclitaxel
Durvalumab
Papaverine
Immunoglobulins
Antibodies, Monoclonal
Immunoglobulin G
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Immunologic Factors
Physiological Effects of Drugs