Testing the Addition of Targeted Radiation Therapy to Surgery and the Usual Chemotherapy Treatment (Pemetrexed and Cisplatin [or Carboplatin]) for Stage I-IIIA Malignant Pleural Mesothelioma
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| ClinicalTrials.gov Identifier: NCT04158141 |
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Recruitment Status :
Recruiting
First Posted : November 8, 2019
Last Update Posted : March 28, 2023
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Sponsor:
NRG Oncology
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology
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Brief Summary:
This trial studies how well the addition of targeted radiation therapy to surgery and the usual chemotherapy treatment works for the treatment of stage I-IIIA malignant pleural mesothelioma. Targeted radiation therapy such as intensity-modulated radiation therapy or pencil beam scanning uses high energy rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as pemetrexed, cisplatin, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving targeted radiation therapy in addition to surgery and chemotherapy may work better than surgery and chemotherapy alone for the treatment of malignant pleural mesothelioma.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Pleural Biphasic Mesothelioma Pleural Epithelioid Mesothelioma Stage I Pleural Malignant Mesothelioma AJCC v8 Stage IA Pleural Malignant Mesothelioma AJCC v8 Stage IB Pleural Malignant Mesothelioma AJCC v8 Stage II Pleural Malignant Mesothelioma AJCC v8 Stage IIIA Pleural Malignant Mesothelioma AJCC v8 | Drug: Carboplatin Drug: Cisplatin Procedure: Decortication Radiation: Intensity-Modulated Radiation Therapy Drug: Pemetrexed Drug: Pemetrexed Disodium Radiation: Pencil Beam Scanning Procedure: Pleurectomy Other: Quality-of-Life Assessment Other: Questionnaire Administration | Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 150 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase III Randomized Trial of Pleurectomy/Decortication Plus Systemic Therapy With or Without Adjuvant Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) for Malignant Pleural Mesothelioma (MPM) |
| Actual Study Start Date : | January 29, 2020 |
| Estimated Primary Completion Date : | July 1, 2025 |
| Estimated Study Completion Date : | July 1, 2030 |
Resource links provided by the National Library of Medicine
MedlinePlus related topics:
Mesothelioma
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm I (Step 1: chemotherapy, P/D: Step 2: no treatment)
STEP 1: Patients undergo P/D then within 4 to 8 weeks receive pemetrexed IV over 10 minutes and cisplatin or carboplatin IV over 60 minutes on day 1. Patients may instead receive pemetrexed IV over 10 minutes and cisplatin or carboplatin IV over 60 minutes on day 1 then undergo P/D within 4 to 8 weeks after chemotherapy. The order of surgery and chemotherapy is at the discretion of the treating physician. STEP 2: Patients receive no treatment. |
Drug: Carboplatin
Given IV
Other Names:
Drug: Cisplatin Given IV
Other Names:
Procedure: Decortication Undergo decortication Drug: Pemetrexed Given IV
Other Names:
Drug: Pemetrexed Disodium Given IV
Other Names:
Procedure: Pleurectomy Undergo pleurectomy
Other Name: Excision of Pleura Other: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies |
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Experimental: Arm II (Step 1: chemotherapy, P/D, Step 2: IMRT/PBS)
STEP 1: Patients undergo P/D then within 4 to 8 weeks receive pemetrexed IV over 10 minutes and cisplatin or carboplatin IV over 60 minutes on day 1. Patients may instead receive pemetrexed IV over 10 minutes and cisplatin or carboplatin IV over 60 minutes on day 1 then undergo P/D within 4 to 8 weeks after chemotherapy. The order of surgery and chemotherapy is at the discretion of the treating physician. STEP 2: Within 4-8 weeks from the end of Step 1 treatment, patients undergo 25-28 fractions IMRT or PBS proton therapy 5 days per week over 6 weeks. |
Drug: Carboplatin
Given IV
Other Names:
Drug: Cisplatin Given IV
Other Names:
Procedure: Decortication Undergo decortication Radiation: Intensity-Modulated Radiation Therapy Undergo IMRT
Other Names:
Drug: Pemetrexed Given IV
Other Names:
Drug: Pemetrexed Disodium Given IV
Other Names:
Radiation: Pencil Beam Scanning Undergo PBS Procedure: Pleurectomy Undergo pleurectomy
Other Name: Excision of Pleura Other: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies |
Primary Outcome Measures :
- Overall survival (OS) [ Time Frame: From the date of randomization and the date of death due to any cause, assessed up to 5 years ]Will compare the distributions of OS between treatment arms using a one-sided stratified log-rank test (using stratification factors as strata). The rates at various timepoints (e.g., every 6 months after randomization) and medians of OS for each arm will be estimated using the Kaplan-Meier method. The associated 90% confidence interval (CI) will be calculated using Greenwood?s formula and based on a log-log transformation applied on the survival function. Hazard ratios will be estimated using a stratified Cox regression model.
Secondary Outcome Measures :
- Local-failure-free survival (LFFS) [ Time Frame: From randomization to local disease progression or death due to any cause, whichever occurs first, assessed up to 5 years ]Will compare the distributions of LFFS between treatment arms using a one-sided stratified log-rank test (using stratification factors as strata). The rates at various timepoints (e.g., every 6 months after randomization) and medians of LFFS for each arm will be estimated using the Kaplan-Meier method (1958). The associated 95% CI will be calculated using Greenwood?s formula and based on a log-log transformation applied on the survival function. Hazard ratios for LFFS will be estimated using a stratified Cox regression model.
- Distant-metastases-free survival (DMFS) [ Time Frame: From randomization to distant metastases or death due to any cause, whichever occurs first, assessed up to 5 years ]Will compare the distributions of DMFS between treatment arms using a one-sided stratified log-rank test (using stratification factors as strata). The rates at various timepoints (e.g., every 6 months after randomization) and medians of DMFS for each arm will be estimated using the Kaplan-Meier method (1958). The associated 95% CI will be calculated using Greenwood?s formula and based on a log-log transformation applied on the survival function. Hazard ratios for PFS will be estimated using a stratified Cox regression model.
- Progression-free survival (PFS) [ Time Frame: From randomization to any documented progression or death due to any cause, whichever occurs first, assessed up to 5 years ]Will compare the distributions of PFS between treatment arms using a one-sided stratified log-rank test (using stratification factors as strata). The rates at various timepoints (e.g., every 6 months after randomization) and medians of PFS for each arm will be estimated using the Kaplan-Meier method (1958). The associated 95% CI will be calculated using Greenwood?s formula and based on a log-log transformation applied on the survival function. Hazard ratios for PFS will be estimated using a stratified Cox regression model.
- Incidence of treatment-related toxicity [ Time Frame: Up to 5 years ]Adverse events (AEs) will be graded with Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All adverse events, adverse events leading to withdrawal, interruption or modification of protocol treatment, grade >= 3 adverse events, and serious adverse events will be summarized. Deaths and cause of death will be summarized. The rate of treatment-related adverse events will be reported with the frequency and severity (e.g., type, grade, and attribution) by arm.
- Quality of Life (QOL)/patient-reported Outcome (PRO) [ Time Frame: Up to 5 years ]Measured by European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaires.
Other Outcome Measures:
- Degree of under-staging, concordant and upstaging between centrally-reviewed clinical staging and pathologic staging [ Time Frame: Up to 5 years ]For each subject, the centrally-reviewed clinical staging (based on positron emission tomography, computed tomography and/or magnetic resonance imaging) will be compared with pathologic staging to determine whether it is under-staging (clinical staging is more extensive than pathologic staging), concordant (clinical staging is same as pathologic staging), or upstaging (clinical staging is less extensive than pathologic staging). The proportion of under-staging, concordant and upstaging, along with the associated 95% confidence intervals, will be reported.
- Association between radiation dose to gross residual disease and local control [ Time Frame: Up to 5 years ]Gross residual disease and local failure will be analyzed as competing risk data (death without gross residual disease or death without local failure as the respective competing event). Association between radiation dose to gross residual disease and local failure will be evaluated similarly in multivariable analyses using Fine-Gray regression model.
- Rate of R0/R1 and R2 resections, by type of procedures (extended pleurectomy/decortication (P/D), P/D and partial pleurectomy) [ Time Frame: Up to 5 years ]Proportions of R0/R1 and R2 resections, by type of procedures (extended pleurectomy/decortication (P/D), P/D and partial pleurectomy), along with 95% confidence intervals, will be reported.
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| Ages Eligible for Study: | 18 Years to 80 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
PRIOR TO STEP 1 REGISTRATION INCLUSION CRITERIA
- Pathologically (histologically or cytologically) confirmed diagnosis of epithelioid or biphasic malignant pleural mesothelioma (MPM) within 90 days prior to Step 1 Registration
- Imaging proof of clinical stage (American Joint Committee on Cancer [AJCC] 8th edition) I-IIIA MPM by PET/CT within 42 days prior to Step 1 Registration
- MPM is amenable to resection by P/D as determined by a thoracic surgeon within 42 days prior to Step 1 Registration
- History/physical examination within 42 days prior to Step 1 Registration
- Karnofsky performance status >= 80 within 42 days prior to Step 1 Registration
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Pulmonary function tests within 42 days prior to Step 1 Registration:
- >= 40% predicted post-forced expiratory volume in 1 second (FEV1);
- >= 40% predicted post-operative diffusion capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin [Hgb])
- Leukocytes >= 3000 cells/mm^3 (within 30 days prior to Step 1 Registration)
- Absolute neutrophil count >= 1500 cells/mm^3 (within 30 days prior to Step 1 Registration)
- Platelets >= 100,000 cells/mm^3 (within 30 days prior to Step 1 Registration)
- Serum total bilirubin =< 1.5 X upper limit of normal (ULN) (within 30 days prior to Step 1 Registration)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 X ULN (within 30 days prior to Step 1 Registration)
- Glomerular filtration rate (GFR): >= 50 mL/min/1.73 m^2 (must be calculated using estimated creatinine clearance [CrCl] by the Cockcroft-Gault [C-G] equation [Nephron 1976;16:31-41]) (within 30 days prior to Step 1 Registration)
- Negative serum pregnancy test within 14 days of Step 1 Registration for pre-menopausal women of childbearing potential
- The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
- EORTC QLQ-C30 and QLQ-LC13 within 42 days prior to Step 1 Registration PRIOR TO STEP 2 RANDOMIZATION INCLUSION CRITERIA
- Patients must have received at least 2 cycles of pemetrexed/platinum chemotherapy and undergone a pleurectomy/decortication with the goal of macroscopic complete resection following step 1 Registration
- Karnofsky performance status >= 70 within 30 days prior to Step 2 Randomization
- History/physical examination within 30 days prior to Step 2 Randomization
- EORTC QLQ-C30 and QLQ-LC13 within 30 days prior to Step 2 Randomization
Exclusion Criteria:
PRIOR TO STEP 1 REGISTRATION EXCLUSION CRITERIA
- Pregnant or lactating women, or sexually active men or women not using effective contraception (risk for fetal defects from teratogenic chemotherapy and radiation therapy) within 14 days prior to Step 1 Registration
- Diagnosis of sarcomatoid mesothelioma
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Severe, active co-morbidity defined as follows:
- New York Heart Association (NYHA) class III or IV heart failure
- Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid therapy of > 10 mg prednisone daily or equivalent at the time of registration. Inhaled corticosteroids are allowed;
- Unstable angina requiring hospitalization and/or transmural myocardial infarction within the last 3 months;
- Interstitial lung disease;
- Hemodialysis or peritoneal dialysis;
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Concurrent active malignancy (with the exception of current or prior non-melanomatous skin cancer or low-grade malignancies followed observantly for which treatment has not or does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen)
- If evidence of disease < 3 years, institution must consult with the principal investigator, Andreas Rimner, Doctor of Medicine (MD)
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Hepatic impairment defined by ChildPugh class (ChildPugh class B & C);
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy within 30 days prior to registration, if indicated. Note: HBV viral testing is not required for eligibility for this protocol
- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load within 30 days prior to registration
- Active tuberculosis
- Patients on immunosuppressive therapy, for example history of organ or bone marrow transplant or chronic lymphocytic leukemia (CLL);
- CD4 count < 200 cells/microliter. Note that patients who are human immunodeficiency virus (HIV) positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior to registration. Note also that HIV testing is not required for eligibility for this protocol
- Prior nephrectomy on the contralateral side of MPM
- Ipsilateral thoracic electronic implant, e.g. pacemaker, defibrillator, unless switched to the contralateral side prior to initiation of radiation therapy (RT)
- Prior thoracic radiation therapy (patients with prior thoracic RT cannot be planned to 50-60 Gy without exceeding normal tissue constraints)
PRIOR TO STEP 2 RANDOMIZATION EXCLUSION CRITERIA
- Progressive disease
- Supplemental oxygen use
- Third space fluid that cannot be controlled by drainage or insufficient lung expansion after P/D (this prevents targeting the pleura without exceeding normal tissue constraints)
- Prior intrapleural therapy (i.e. intrapleural chemotherapy, photodynamic therapy); pleurodesis is permitted
- Bulky residual disease in the major fissure preventing pleural IMRT
- Patients who have undergone extrapleural pneumonectomy
- Patients with active infection that requires systemic I.V. antibiotics, antiviral, or antifungal treatments
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): NCT04158141
Locations
Show 27 study locations
Sponsors and Collaborators
NRG Oncology
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Andreas Rimner, MD | NRG Oncology |
| Responsible Party: | NRG Oncology |
| ClinicalTrials.gov Identifier: | NCT04158141 |
| Other Study ID Numbers: |
NRG-LU006 NCI-2019-07141 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) NRG-LU006 ( Other Identifier: NRG Oncology ) NRG-LU006 ( Other Identifier: CTEP ) U10CA180868 ( U.S. NIH Grant/Contract ) |
| First Posted: | November 8, 2019 Key Record Dates |
| Last Update Posted: | March 28, 2023 |
| Last Verified: | March 2023 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by NRG Oncology:
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Mesothelioma IMPRINT |
Additional relevant MeSH terms:
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Mesothelioma Mesothelioma, Malignant Lung Neoplasms Adenoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Neoplasms, Mesothelial Respiratory Tract Neoplasms Thoracic Neoplasms Neoplasms by Site |
Pleural Neoplasms Lung Diseases Respiratory Tract Diseases Cisplatin Carboplatin Pemetrexed Antineoplastic Agents Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Folic Acid Antagonists Nucleic Acid Synthesis Inhibitors |