Symptoms and General Pathology

All Conditions

Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Recurrence

Mesothelioma

Mesothelioma, Malignant

Lung Neoplasms

Disease Attributes

Adenoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Mesothelial

Respiratory Tract Neoplasms

Thoracic Neoplasms

Pleural Neoplasms

Lung Diseases

Respiratory Tract Diseases

Malignant Mesothelioma

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Antibodies

Tin Fluorides

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients may be eligible for up to 1 year of additional pembrolizumab therapy if they progress after stopping pembrolizumab.

Laboratory Biomarker Analysis

Pharmacogenomic Study

Hedy Kindler

This phase II trial studies how well pembrolizumab works in treating patients with malignant mesothelioma, a cancer of the linings around the lungs (pleura) or abdomen (peritoneum). Monoclonal antibodies, such as pembrolizumab, work by blocking a protein called programmed cell death 1 (PD-1) which may stimulate an immune response and kill tumor cells.

PRIMARY OBJECTIVES:

I. To determine the objective response rate of patients with malignant mesothelioma treated with pembrolizumab in A) an unselected patient population, as well as B) in a programmed cell death ligand 1 (PD-L1) positive population (should the trial proceed to Part B, and PD-L1 expression correlate with improved efficacy).

II. To determine the optimal threshold for PD-L1 expression using the 22C3 antibody based immunohistochemistry (IHC) assay in correlation to tumor response.

SECONDARY OBJECTIVES:

I. To determine the progression-free survival of patients with malignant mesothelioma in A) an unselected patient population and B) a PD-L1 positive population when treated with pembrolizumab.

II. To determine the overall survival of patients with malignant mesothelioma in A) an unselected patient population and B) a PD-L1 positive population when treated with pembrolizumab.

III. To determine the disease control rate (complete response \[CR\] + partial response \[PR\] + stable disease \[SD\]) of patients with malignant mesothelioma who are treated with pembrolizumab in A) an unselected patient population and B) a PD-L1 positive population.

IV. To determine toxicity in patients with malignant mesothelioma who are treated with pembrolizumab.

V. To determine percentage of patients with mesothelioma who have PD-L1 tumor expression, and the distribution of PD-L1 expression (percent positivity of tumor cells/stroma staining).

TERTIARY OBJECTIVES:

I. To characterize the T-cell inflamed phenotype in mesothelioma patients via presence of cluster of differentiation (CD)8 tumor infiltrating lymphocytes (TILs) and/or use of a gene expression signature (Nanostring).

II. To evaluate other immune escape mechanisms including indoleamine-pyrrole 2,3-dioxygenase (IDO) expression, regulatory T cells (Tregs) (forkhead box P3 \[FOXP3\] expression), myeloid-derived suppressor cells (MDSCs) and other checkpoints by immunohistochemistry (or other methods e.g. flow cytometry).

III. To determine PD-L1 expression by mass spectrometry and correlate with tumor response, PD-L1 expression by IHC, and the T-cell inflamed phenotype.

IV. To determine the immune cell populations present in fresh tumor (when available), via tumor digests and mass spectrometry-based flow cytometric analysis (e.g. using CyTOF) in a multiplex fashion in patients with fresh tumor tissue.

V. To characterize the T-cell receptor repertoire of TILs compared to circulating T-cells in mesothelioma patients with available fresh frozen tissue (spectrotyping, T-cell repertoire sequencing \[e.g. using the Adaptive platform\]).

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients may be eligible for up to 1 year of additional pembrolizumab therapy if they progress after stopping pembrolizumab.

After completion of study treatment, patients are followed up for 30 days (up to 90 days for serious adverse events), every 8 weeks until patient experiences confirmed disease progression or starts a new anti-cancer therapy, and then every 12 weeks for 3 years.

Pembrolizumab in Treating Patients With Malignant Mesothelioma

A Phase II Study of the Anti-PD-1 Antibody Pembrolizumab in Patients With Malignant Mesothelioma

CD8 levels will be correlated with PD-L1 expression using Pearson or Spearman rank correlation coefficients.

Other immune escape mechanisms including MDSCs and other checkpoints will be assessed by immunohistochemistry (0 - 3+) or flow cytometry counting the number and percentage of positive cells. Levels will be correlated with PD-L1 expression and other biomarkers.

PD-L1 expression by mass spectrometry and correlation with PD-L1 expression by IHC as well as tumor response, and the T-cell inflamed phenotype will be performed. Multivariate logistic regression will be performed to determine whether these biomarkers or combinations of biomarkers are predictive of response. Exact logistic regression models will be fit given the small number of responders expected (4 from part A and 7-8 from part B).

Mass spectrometry-based flow cytometric analysis (CyTOF) will be descriptive based on number and percentage of certain cell populations.

Analysis of T-cell receptor repertoire from TILs will be descriptive looking for presence or absence of oligoclonal T-cell population.

Toxicities will be summarized in tabular form by type and severity and incidence rates generated.

Based on the results from Part A, the Youden Index methodology will be used to determine the optimal threshold for PD-L1 expression in correlation with tumor response, and if a correlation is identified this threshold will be used for Part B. The overall ability of PD-L1 to predict response will be assessed using the area under the receiver operating characteristic curve (area under the curve). If the area is significantly greater than 0.5, part B will begin using the optimum cutpoint as determined from the Youden index.

Kaplan-Meier curves will be generated for OS. Median OS will be estimated along with 90% confidence intervals using the method of Brookmeyer and Crowley.

Kaplan-Meier curves will be generated for PFS. Median PFS will be estimated along with 90% confidence intervals using the method of Brookmeyer and Crowley.

The disease control rate (CR+PR+SD) and 90% confidence interval will also be determined.

National Cancer Institute (NCI)

University of Chicago

Micronutrients

Hematinics

Amino Acids

Vitamins

Carboplatin

Pemetrexed

Cisplatin

Folic Acid Antagonists

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Glutamic Acid

Folinic Acid

Folate

Vitamin B9

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.

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.

Decortication

Intensity-Modulated Radiation Therapy

Pemetrexed Disodium

Pencil Beam Scanning

Pleurectomy

Quality-of-Life Assessment

Questionnaire Administration

Andreas Rimner, MD

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.

PRIMARY OBJECTIVE:

I. To detect an improvement in overall survival with the addition of adjuvant hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) to surgery and chemotherapy compared to surgery and chemotherapy alone.

SECONDARY OBJECTIVES:

I. To determine local failure-free survival, distant-metastases-free survival, and progression-free survival with the addition of adjuvant hemithoracic IMPRINT to surgery and chemotherapy compared to surgery and chemotherapy alone.

II. To evaluate the treatment-related toxicities in both arms per Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.

III. To detect a clinically meaningful 10-point change in global health status mean scores at 9 months after randomization with the addition of adjuvant IMPRINT as compared to surgery and chemotherapy alone.

EXPLORATORY OBJECTIVES:

I. To evaluate the degree of under-staging, concordant and upstaging between centrally-reviewed clinical staging (based on positron emission tomography \[PET\], computed tomography \[CT\] and/or magnetic resonance imaging \[MRI\]) and pathologic staging.

II. To identify immunologic and pathologic biomarkers as predictors of response and potential targets for future combination trials.

III. To determine the magnitude of radiation dose escalation to gross residual disease based on combined modality imaging and associated local control rates with dose-painting intensity-modulated radiation therapy (IMRT).

IV. To determine the rate of R0/R1 and R2 resections, and type of procedures (extended pleurectomy/decortication \[P/D\], P/D and partial pleurectomy).

V. To evaluate the trajectory of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-Q30) and lung cancer specific module (LC13) symptoms in patients treated with IMPRINT by comparing the proportion of patients who respond with "quite a bit" or "very much" LC13 symptoms at 9-12 months post-randomization compared to at 3 months post-randomization.

VI. To evaluate changes in health-related quality of life, functional domains, and symptoms over time with the addition of adjuvant IMPRINT as compared to surgery and chemotherapy alone.

OUTLINE:

STEP 1: Patients undergo P/D then within 4 to 8 weeks receive pemetrexed intravenously (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 to 8 weeks from the end of Step 1 treatment, patients are randomized to 1 of 2 arms.

ARM I: Patients receive no treatment.

ARM II: Patients undergo 25-28 fractions IMRT or pencil beam scanning (PBS) proton therapy 5 days per week over 6 weeks.

After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years.

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

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)

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.

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.

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.

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.

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.

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.

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.

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.

Measured by European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaires.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Pembrolizumab in Treating Patients With Malignant Mesothelioma	NCT02399371	Biphasic Mesoth... Epithelioid Mes... Peritoneal Mali... Pleural Biphasi... Pleural Epithel... Pleural Maligna... Pleural Sarcoma... Recurrent Perit... Recurrent Pleur... Sarcomatoid Mes...	Pembrolizumab Laboratory Biom... Pharmacogenomic...	18 Years -	University of Chicago
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	NCT04158141	Pleural Biphasi... Pleural Epithel... Stage I Pleural... Stage IA Pleura... Stage IB Pleura... Stage II Pleura... Stage IIIA Pleu...	Carboplatin Cisplatin Decortication Intensity-Modul... Pemetrexed Pemetrexed Diso... Pencil Beam Sca... Pleurectomy Quality-of-Life... Questionnaire A...	18 Years - 80 Years	NRG Oncology

Spots Global Cancer Trial Database for pleural epithelioid mesothelioma