Neoplasms

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Mesothelioma

Mesothelioma, Malignant

Lung Neoplasms

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

peritoneal malignant mesothelioma of grade 1

peritoneal malignant mesothelioma of grade 2

peritoneal malignant mesothelioma of grade 3

No intervention

Anne HOORENS, MD

Nazim Benzerdkeb, MD

Wiebke Solass Wiebke Solass, MD

Loma Parikh Loma Parikh, MD

Ben Davidson Ben Davidson, MD

Mireia Castillo-Martin Mireia Castillo-Martin, MD

Malignant peritoneal mesothelioma is a rare neoplasm. The most common type, the epithelioid type, has been further divided into histological patterns of tubulo-papillary, acinar, adenomatoid, micropapillary, or solid. Its prognosis is improved by the use of a locoregional treatment combining extensive cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), which increases survival up to 50 months. Histology is one of the most important prognostic variable that, forms the basis for treatment decisions. However, the prognostic of the epithelioid type varies greatly due to its tumor heterogeneity. It is therefore necessary to find prognostic factors of malignant epithelioid peritoneal mesothelioma in order to better define the therapeutic strategy. Among histological factors, solid growth, tumor necrosis, nuclear atypia, and mitotic count were found to be independent prognostic factors in epithelioid malignant pleural mesothelioma. However, in epithelioid malignant peritoneal mesothelioma (EMPM), these factors were studied in small and heterogeneous series in terms of histological growth and definitions used for histological factors. The present large study was conducted to investigate the prognostic impact of several histologic factors in EMPM. Their prognosis impacts were assessed using overall survival (OS) and progression-free survival (PFS) in EMPM.

Assessment of Histologic Prognostic Factors in Peritoneal Malignant Mesothelioma

Hospices Civils de Lyon

Symptoms and General Pathology

Recurrence

Disease Attributes

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

Vitamins

Antibodies, Monoclonal

Carboplatin

Bevacizumab

Pemetrexed

Immunomodulating Agents

Atezolizumab

Immunoglobulin G

Endothelial Growth Factors

Mitogens

Immunoglobulins, Intravenous

Folic Acid Antagonists

Angiogenesis Inhibitors

Growth Inhibitors

Immunologic Factors

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folinic Acid

Folate

Vitamin B9

Patients receive atezolizumab IV over 60 minutes, bevacizumab IV over 30-90 minutes, carboplatin IV over 30 minutes, and pemetrexed IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks, patients undergo cytoreductive surgery and HIPEC. Patients not eligible for surgery may receive atezolizumab and bevacizumab in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan and PET scan on study. Patients also undergo blood and tissue sample collection on study.

Patients receive bevacizumab IV over 30-90 minutes, carboplatin IV over 30 minutes, and pemetrexed IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks, patients undergo cytoreductive surgery and HIPEC. Patients not eligible for surgery may receive bevacizumab with or without atezolizumab at the discretion of the investigator in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan and PET scan on study. Patients also undergo blood and tissue sample collection on study.

Undergo blood and tissue sample collection

Biospecimen Collection

Computed Tomography

Cytoreductive Surgery

Hyperthermic Intraperitoneal Chemotherapy

Positron Emission Tomography

Site Public Contact

Hedy L. Kindler

Suparna Mantha

Aaron S. Mansfield

Daniel Almquist

Daniel M. Anderson

John L. Hays

Hassan Hatoum

Liza C. Villaruz

Kanwal P. Raghav

Matthias Weiss

Michael Husak

Aaron S Mansfield

This phase II trial compares the usual treatment alone to using immunotherapy (atezolizumab) plus the usual treatment in treating patients with peritoneal mesothelioma. The usual treatment consists of surgery or chemotherapy. Chemotherapy drugs, such as carboplatin and pemetrexed, 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. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving atezolizumab with usual treatment may work better than usual treatment alone.

PRIMARY OBJECTIVE:

I. To determine whether frontline treatment with carboplatin, pemetrexed, bevacizumab and atezolizumab results in a superior best response rate than carboplatin, pemetrexed and bevacizumab in patients with peritoneal mesothelioma as determined by Response Evaluation Criteria in Solid Tumors (RECIST).

SECONDARY OBJECTIVES:

I. To determine the safety, major pathologic response rates, and completeness of cytoreduction of patients treated with neoadjuvant carboplatin, pemetrexed, bevacizumab and atezolizumab or carboplatin, pemetrexed and bevacizumab.

II. To determine the safety of patients treated with palliative carboplatin, pemetrexed, bevacizumab and atezolizumab or carboplatin, pemetrexed and bevacizumab.

III. To determine whether frontline treatment with carboplatin, pemetrexed, bevacizumab and atezolizumab results in a superior metabolic response rate than carboplatin, pemetrexed and bevacizumab as determined by Positron Emission Tomography (PET) Response Criteria in Solid Tumors.

IV. Explore the value that analysis of secondary computed tomography (CT) findings and quantitative fludeoxyglucose F-18 (FDG)-PET imaging adds to prognostic information and response assessment in this disease.

V. Determine the number of patients who were deemed to have unresectable disease who are able to undergo surgery following treatment with carboplatin, pemetrexed, bevacizumab and atezolizumab or carboplatin, pemetrexed and bevacizumab due to dramatic response.

VI. To compare the progression-free survival and overall survival between arms. VII. Results of the primary analysis will be examined for consistency, while taking into account the stratification factors and/or covariates of baseline quality of life (QOL) and fatigue.

EXPLORATORY OBJECTIVE:

I. To determine whether blood-based biomarkers including our recently described cell-free chromosomal junctions, soluble mesothelin-related peptides and megakaryocyte potentiating factor correlate with clinical outcomes data (i.e. overall survival \[OS\], progression-free survival \[PFS\], recurrence, response, etc.).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive atezolizumab intravenously (IV) over 60 minutes, bevacizumab IV over 30-90 minutes, carboplatin IV over 30 minutes, and pemetrexed IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks, patients undergo cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Patients not eligible for surgery may receive atezolizumab and bevacizumab in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive bevacizumab IV over 30-90 minutes, carboplatin IV over 30 minutes, and pemetrexed IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks, patients undergo cytoreductive surgery and HIPEC. Patients not eligible for surgery may receive bevacizumab with or without atezolizumab at the discretion of the investigator in the absence of disease progression or unacceptable toxicity.

Patients undergo computed tomography (CT) scan and positron emission tomography (PET) scan on study. Patients also undergo blood and tissue sample collection on study.

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

Chemotherapy With or Without Immunotherapy for Peritoneal Mesothelioma

Phase 2 Randomized Trial of Neoadjuvant or Palliative Chemotherapy With or Without Immunotherapy for Peritoneal Mesothelioma

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Will be correlated with clinical endpoints including confirmed response, overall survival, PFS, recurrence, and adverse events. Statistical and graphical techniques will be used to explore the relationships between the translational and clinical data. For time-to-event endpoints, will use Cox proportional hazards models, and for confirmed response will use Logistic regression models. In addition, will use the Chi-square or Fisher's exact tests to test the association between categorical marker data and confirmed response/adverse events.

The proportion of patients with a pathologic response will be calculated and compared between arms and 95% confidence intervals reported. The chi-square test will be used to compare the rates between arms.

Will estimate the conversion rate to surgical resection among those not deemed to be surgical candidates prior to treatment and provide the 95% confidence interval as well.

Will be estimated using the Kaplan-Meier method, where the log-rank test will be used to compare the 2 treatment arms.

The maximum grade for each type of adverse event will be summarized using Common Terminology Criteria for Adverse Events version 5.0. The frequency and percentage of grade 3+ adverse events will be compared between the 2 treatment arms. Comparisons between arms will be made by using either the Chi-square or Fisher's Exact test.

Pharmaceutical Solutions

Paclitaxel

Albumin-Bound Paclitaxel

Tubulin Modulators

Antimitotic Agents

According to standard of care work-up for CRS-HIPEC, patients will undergo diagnostic laparoscopy to determine the feasibility of complete cytoreduction with HIPEC. In case CRS-HIPEC is not considered feasible, a peritoneal port-a-cath (PAC) system will be placed. Through this PAC, 8-16 weekly cycles of intraperitoneal chemotherapy will be administered.

Weekly cycles of intraperitoneal paclitaxel monotherapy

Intraperitoneal Paclitaxel Solution (Ml)

Michelle Dietz, MD

Patients primary malignant peritoneal mesothelioma (MPM), without extra-abdominal disease, that are not eligible (or willing) to undergo cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) can be included in this study. Patients will be treated with intraperitoneal (IP) chemotherapy (paclitaxel) in weekly cycles. The primary aim of this study is to determine the maximum tolerable dose (MTD) of IP monotherapy with paclitaxel for patients with MPM. The secondary aims are to assess safety and feasibility of this strategy, and to study the pharmacokinetics of paclitaxel in this setting.

Malignant Peritoneal Mesothelioma (MPM) is a rare, but unfortunately very aggressive cancer with a poor prognosis. Currently, the only possibly curative treatment is cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). However, the majority of patients are not eligible to undergo this treatment, mainly due to extensive local disease. Currently, a palliative treatment with low morbidity is not available. Overall response rates to systemic chemotherapy are low, though morbidity rates are high. Immunotherapy presents similar shortcomings, as the morbidity rate is comparable to that of systemic chemotherapy, while its benefit for MPM patients is not proven. Especially given the high morbidity rate, and the limited effectiveness of systemic treatment with either immunotherapy or chemotherapy, there is lack of treatments suitable as palliative treatment for patients with MPM. Thereby, the majority of MPM patients currently receive no anti-tumor treatment.

As MPM very rarely disseminates outside the abdominal-cavity, the use of intraperitoneal (IP) chemotherapy seems a logical and promising step. This therapy can be delivered through an IP port-a-cath (PAC), and potentially has major advantages over systemic treatment. A higher, more effective dose of chemotherapy can directly be delivered at the site of disease, while systemic uptake is limited likely resulting in fewer toxicity. In rare cases where metastases do develop, a switch can be made to systemic treatment. By first applying local treatment, most patients will be spared a toxic and often ineffective systemic therapy. Another major advantage of the suggested approach is that ascites, a common MPM-symptom that causes major morbidity, can be drained through the same PAC-system. Paclitaxel is a well-known chemotherapeutic agent and is considered extremely favorable for IP use.

The aim of this study is to determine the maximum tolerable dose (MTD) of IP monotherapy with paclitaxel for patients with MPM, and to assess safety and feasibility of this strategy. The investigators will conduct a classic three-plus-three dose escalation study with three dose Three patients are initially enrolled into a given dose cohort. If there is no dose limiting toxicity (DLT) observed in any of these patients, the trial proceeds to enroll additional patients to the next higher dose cohort. If one patient develops a DLT at a specific dose level, three additional subjects are enrolled into that same dose cohort. Development of a DLT in more than 1 patient in a specific dose cohort (≥33%) suggests that the MTD has been exceeded, and further dose escalation is not pursued. The previous dose is considered the MTD. When the MTD is found, an expansion of 3-6 more patients in that dose cohort will be performed, to achieve a total number of 9 patients treated at the MTD-level.

Patients undergo a diagnostic laparoscopy (DLS) according to standard work-up for CRS-HIPEC. If the disease is considered not resectable, a peritoneal PAC will be placed during DLS. Through this PAC intraperitoneal paclitaxel will be administered weekly (dosage according to dose-escalation schedule). The number of cycles depends on toxicity and response to the treatment. The first response evaluation is scheduled after 8 cycles. There is no limit to the number of cycles, in case of continuing response to treatment. During the first and the fourth cycle, additional blood samples and IP-fluid samples will be collected for pharmacokinetic analysis.

A prospective, open-label, single-center, phase-1/2 study with a classic three-plus-three dose escalation design.

Intraperitoneal Paclitaxel for Patients With Primary Malignant Peritoneal Mesothelioma

Intraperitoneal Paclitaxel for Patients With Primary Malignant Peritoneal Mesothelioma - a Phase I/II Dose Escalation and Safety Study

The primary endpoint of the study is to determine the maximum tolerable dose (MTD) of intraperitoneal (IP) paclitaxel monotherapy, for patients with malignant peritoneal mesothelioma (MPM) who are not eligible to undergo CRS-HIPEC.

Safety determined by toxicity assessment according to CTCAE version 5.0

The treatment will be considered feasible if at least 50% of patients are able to finish 75% (i.e. 6) of total planned cycles (i.e. 8)

The 24-hour AUC will be calculated for systemic and intraperitoneal paclitaxel by obtaining blood and intraperitoneal fluid samples during the first and fourth treatment cycle, at time points prior to infusion, at the end of peritoneal infusion as well as every hour up to patients discharge.

The Cmax will be calculated by obtaining blood and intraperitoneal fluid samples during the first and fourth treatment cycle, at time points prior to infusion, at the end of peritoneal infusion as well as every hour up to patients discharge.

The t1/2 will be calculated by obtaining blood and intraperitoneal fluid samples during the first and fourth treatment cycle, at time points prior to infusion, at the end of peritoneal infusion as well as every hour up to patients discharge.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Assessment of Histologic Prognostic Factors in Peritoneal Malignant Mesothelioma	NCT05193006	Peritoneal Mali...	No intervention	18 Years - 80 Years	Hospices Civils de Lyon
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
Chemotherapy With or Without Immunotherapy for Peritoneal Mesothelioma	NCT05001880	Peritoneal Mali...	Atezolizumab Bevacizumab Biospecimen Col... Carboplatin Computed Tomogr... Cytoreductive S... Hyperthermic In... Pemetrexed Positron Emissi...	18 Years -	National Cancer Institute (NCI)
Intraperitoneal Paclitaxel for Patients With Primary Malignant Peritoneal Mesothelioma	NCT05449366	Peritoneal Mali...	Intraperitoneal...	18 Years -	Erasmus Medical Center
Chemotherapy With or Without Immunotherapy for Peritoneal Mesothelioma	NCT05001880	Peritoneal Mali...	Atezolizumab Bevacizumab Biospecimen Col... Carboplatin Computed Tomogr... Cytoreductive S... Hyperthermic In... Pemetrexed Positron Emissi...	18 Years -	National Cancer Institute (NCI)
Assessment of Histologic Prognostic Factors in Peritoneal Malignant Mesothelioma	NCT05193006	Peritoneal Mali...	No intervention	18 Years - 80 Years	Hospices Civils de Lyon

Spots Global Cancer Trial Database for peritoneal malignant mesothelioma