Neoplasms

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Mesothelioma

Mesothelioma, Malignant

Adenoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Mesothelial

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Pleural Neoplasms

Lung Diseases

Respiratory Tract Diseases

Malignant Mesothelioma

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Anetumab ravtansine

Maytansine

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Tubulin Modulators

Antimitotic Agents

Immunoconjugates

Immunologic Factors

Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Upon radiologic documentation of disease progression, patients may cross over to Group II.

Patients receive anetumab ravtansine IV over 1 hour and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 12 months for anetumab ravtansine and up to 24 months for pembrolizumab in the absence of disease progression or unacceptable toxicity.

Anetumab Ravtansine

Laboratory Biomarker Analysis

Pharmacological Study

Aaron S Mansfield

This phase I/II trial studies the side effects and how well pembrolizumab with or without anetumab ravtansine works in treating patients with mesothelin-positive pleural mesothelioma. Anetumab ravtansine is a monoclonal antibody, called anetumab, linked to a chemotherapy drug, called ravtansine. Anetumab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as mesothelin receptors, and delivers ravtansine to kill them. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving pembrolizumab and anetumab ravtansine may work better in treating patients with mesothelin-positive pleural mesothelioma.

PRIMARY OBJECTIVES:

I. Determine the dose of anetumab ravtansine that is safe in combination with pembrolizumab to be used in the randomized phase 2 study. (Phase I safety lead-in) II. Determine if the overall response rate of the combination of anetumab ravtansine and pembrolizumab is superior to pembrolizumab alone. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the progression free survival of anetumab ravtansine and pembrolizumab compared to pembrolizumab alone.

II. To evaluate the pharmacodynamic effects of anetumab ravtansine and pembrolizumab on soluble megakaryocyte potentiating factor (MPF).

III. To evaluate the pharmacokinetics of anetumab ravtansine and pembrolizumab. IV. To evaluate mononuclear phagocyte system (MPS) function, FcgammaRs, hormone and chemokine mediators as methods to evaluate factors affecting the pharmacokinetics and pharmacodynamics of these agents.

V. To determine the incidence of antibodies directed against anetumab ravtansine.

CORRELATIVE STUDY OBJECTIVES:

I. To determine whether elevations in Bim in tumor-reactive T cells (TTR) predict responses to treatment and whether its detection is dynamic with treatment.

II. To determine whether soluble PD-L1 predicts responses to treatment and whether its detection is dynamic with treatment.

III. To evaluate PD-L1 expression in archival tissue as a predictive marker of response to pembrolizumab-based therapy.

IV. To explore the symptomatic adverse events (AE) for tolerability of each treatment group using Patient Reported Outcomes (PRO)-Common Terminology Criteria for Adverse Events (CTCAE).

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Upon radiologic documentation of disease progression, patients may cross over to Group II.

GROUP II: Patients receive anetumab ravtansine IV over 1 hour and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 12 months for anetumab ravtansine and up to 24 months for pembrolizumab in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 12 months.

Pembrolizumab With or Without Anetumab Ravtansine in Treating Patients With Mesothelin-Positive Pleural Mesothelioma

Phase 1 Safety Run-In and Phase 2 Randomized Clinical Trial of Anetumab Ravtansine and Pembrolizumab (MK-3475) Compared to Pembrolizumab Alone for Mesothelin-Positive Malignant Pleural Mesothelioma

Measurements of Bim in TTR as a predictor of responses to treatment. Is anticipated that a non-parametric test such as the Mann-Whitney test should be used to compare Bim in TTR between subjects that do and do not respond to therapy.

Measurements of soluble PD-L1 as a predictor of responses to treatment. Is anticipated that a non-parametric test such as the Mann-Whitney test should be used to compare soluble PD-L1 between subjects that do and do not respond to therapy.

PD-L1 expression in archival tissue as a predictive marker of response to pembrolizumab-based therapy. Will compare whether there is a difference in the number of responders with 50% or greater PD-L1 tumor cell expression and those without with the Chi-square test (or Fisher's exact test if the data in the contingency table is sparse).

An early safety analysis will be performed after the first 6 patients have been accrued to the safety lead-in portion of the study at dose level 1 and observed for one cycle. If 2 or more of the first 6 patients experience a dose limiting toxicities, then the starting dose level will be adjusted and additional cohorts may be evaluated. All patients that have received any amount of the combination anetumab ravtansine and pembrolizumab will be evaluable for toxicity.

Will be assessed using Response Evaluation Criteria in Solid Tumors version 1.1 criteria. The proportion of successes will be estimated in each group by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated in each arm. Comparison of confirmed response rates between the two treatment groups will be performed using a one-sided z-test with pooled variance at significance level 0.10.

Will be defined as evaluable patients who achieved noted to be a partial response or complete response based Response Evaluation Criteria in Solid Tumors version 1.1 criteria. Will be estimated using the method of Kaplan-Meier. The comparison of duration of response between two treatment arms will be based on the log-rank test. This calculation will start with the date of start of treatment.

Will be estimated using the method of Kaplan-Meier. The comparison of overall survival between two treatment arms will be based on the log-rank test.

Will be estimated using the method of Kaplan-Meier. The comparison of progression-free survival between two treatment arms will be based on the log-rank test.

Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed for each arm to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. The overall adverse event rates for grade 3 or higher hematologic and non-hematologic adverse events at least possibly related to treatment will be compared between the two treatment groups using the Chi-square test (or Fisher's exact test if the data in the contingency table is sparse).

Will be largely descriptive. Changes over time will be plotted and assessed for each patient.

Relative changes in biomarker levels will be compared by best overall response groups using the non-parametric Wilcoxon rank-sum test. Also, the associations between changes in megakaryocyte potentiating factor levels and ordered response categories (i.e. complete response-partial response-stable disease-progressive disease) will be assessed with the Jonckheere-Terpstra test for trend.

The mean equivalent soluble fluorophore and antibody bound to cell (ABC) will be determined for each specimen. Linear regression will be used to explore the linear relationship between the continuous values of these mononuclear phagocyte system-FcgammaRs probes and anetumab ravtansine levels. The concentrations of CCL2 and CCL5 will be determined for each specimen. Linear regression will be used to explore the linear relationship between the continuous values of these chemokines and anetumab ravtansine levels.

National Cancer Institute (NCI)

Blood and Lymph Conditions

Pleural Diseases

Thymoma

Thymus Neoplasms

Lymphatic Diseases

Patients with (strong suspicion of) intrathoracic malignancy and an indication for tissue collection by CT-guided, transthoracic or thoracoscopic approach undergo additional imaging with confocal laser endomicroscopy (CLE).

Confocal laser endomicroscopy

L Wijmans, MD

M van de Pol, PhD

Maria Disselhorst, MD

Paul Baas, MD, PhD

Lizzy Wijmans, MD

Marianne van de Pol, MD, PhD

Jouke Annema, MD PhD

Jouke Annema, MD,PhD

To date, the different biopsy methods, such as CT-guided pleural biopsy, mediastinal biopsy, endosonography and thoracoscopy have their limitations in diagnosing pleural malignancies, such as mesothelioma. Sampling errors frequently occur resulting in the common histological finding of 'non-specific pleuritic/fibrosis', which presents a great uncertainty for clinicians and patients. Confocal laser endomicroscopy (CLE) provides real-time imaging on a cellular level, however data of CLE in pleural malignancies are lacking.

Novel optical imaging techniques such as confocal laser endomicroscopy (CLE) have emerged in recent years as techniques that actually enable in vivo real-time microscopic analysis of malignancies of the GI-tract and lung cancer. Through recent advances the probe became small enough to fit through a biopsy needle and can be used during CT-guided and endosonographic guided biopsies (EUS-FNA). Patients with intra-thoracic malignancies often require invasive procedures such as bronchoscopy, thoracoscopy, mediastinoscopy, transthoracic needle aspiration or surgical exploration to obtain a diagnosis. Intra thoracic malignancies encompass lung cancers, thymomas and malignant pleural mesothelioma. These tumors often present with pleural thickening, unilateral pleural effusion, mediastinal enlargement or a peripheral located mass in the lungs. Tissue collection of the suspected pleural thickening is required to assess a diagnosis and differentiate between the tumor types, to classify and to stage in a proper manner. To date, the different biopsy methods, such as CT-guided pleural biopsy, mediastinal biopsy, endosonography and thoracoscopy have their limitations in diagnosing these malignancies. Sampling errors frequently occur resulting in the common histological finding of 'non-specific pleuritic/fibrosis', which presents a great uncertainty for clinicians and patients. Novel microscopic imaging techniques such as CLE are capable of real time imaging on a cellular level. Data of CLE in intra-thoracic malignancies are lacking.

Confocal Laser Endomicroscopy in Pleural Malignancies

Confocal Laser Endomicroscopy in Pleural Malignancies: A Comparison With Pathology

Number of successful procedures with evaluable CLE-imaging

Qualitative description of the number of descriptive criteria based on CLE imaging.

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Head of pulmonary endoscopy department

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Phase II, Single-Arm, Multi-Site study. All subjects will receive the investigational agent, GC1008 in 3 week cycles of treatment

GC1008 is a human IgG4 kappa monoclonal antibody capable of neutralizing all mammalian isoforms of TGFbeta (i.e., beta1, beta 2 and beta 3). GC1008 is a high affinity antibody with dissociation constants (Kds) of 1.8 nM, 2.8 nM and 1.4 nM for TGF1,2,and 3, respectively.

GC1008

James Stevenson, MD

This study is being conducted to evaluate the overall safety and effectiveness of an investigational drug, GC1008, in patients with mesothelioma. An investigational drug is one that has not been approved by the FDA. Approximately 40 people will be enrolled on this study at the University of Pennsylvania (Main Institution/Coordinating Site) and the University of Chicago (Participating Institution). We expect about 20 subjects to be enrolled at each institution.

Primary: - To assess progression-free survival rate at three months.

Secondary: - To determine the toxicity and safety of systemic infusion of anti-TGF beta antibody at three-week dosing intervals. - To assess time to progression and overall survival - to assess response rate using Modified RECIST Criteria for Mesothelioma Additional Objectives: - To assess efficacy using serial measurements of serum \[and intrapleural, if indwelling catheter in place\] biomarkers, including serum-mesothelin related peptide (SMRP/Mesomark®) and osteopontin. - To assess systemic \[and intrapleural if indwelling catheter in place\] humoral anti-tumor immune responses after repeated anti-TGF beta antibody instillation. - To assess systemic \[and intrapleural, if indwelling catheter in place\] TGF beta, and other cytokine levels after repeated anti-TGF beta antibody instillation. - To assess biologic response measurements of TGF beta blockade from serum tests and from pleural fluid or biopsy tissue if this is available.

Anti-TGF Monoclonal Antibody (GC1008) in Relapsed Malignant Pleural Mesothelioma

A Phase II Trial of Anti-TGF Monoclonal Antibody (GC1008) in Relapsed Malignant Pleural Mesothelioma (MPM))

Assessment of time to disease progression and overall survival

Response and progression will be evaluated in this study using the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in RECIST. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.

Evaluation of changes after treatment therapy to a number of potential blood biomarkers of TGF-β effect (serum osteopontin, serum hyaluronan, serum MMP-1, serum MMP-7, serum IL-6, plasma CCL18, plasma VEGF, and plasma PAI-1). Animal models predict acute changes in TGF-β levels in blood associated with changes in serum biomarkers.

Comparing antibody bands in pre-treatment versus post-treatment serum

The number of participants with significant change in percentage of circulating CD4+ T regulatory cells, marked by expression of FOXP3 after treatment. TGFβ has been implicated in the formation of T regulatory cells, and the blockade of TGFβ in animal models can inhibit the formation of T regulatory cells.

Number of participants who demonstrated upregulation of NK cell receptors 3 weeks after treatment. There are data that show anti-TGFβ antibodies can upregulate NK cell receptors in patients with chronic viral infections. TGFβ blockade was measured in samples of serum tests and from pleural fluid or biopsy if available.

The fraction of subjects surviving 3 months without disease progression.

The toxicity and safety of systemic infusion of anti-TGF antibody at three-week dosing intervals. Number subjects with Grade 2 and Grade 3/4 treatment related toxicities.

Abramson Cancer Center at Penn Medicine

Phase II, Single-Arm, Multi-Site study. All subjects will receive the investigational agent, GC1008 in 3 week cycles of treatment.

GC1008: GC1008 is a human IgG4 kappa monoclonal antibody capable of neutralizing all mammalian isoforms of TGFbeta (i.e., beta1, beta 2 and beta 3). GC1008 is a high affinity antibody with dissociation constants (Kds) of 1.8 nM, 2.8 nM and 1.4 nM for TGF1,2,and 3, respectively.

Investigational Drug infusion-for Safety and Effectiveness

Phase II, Single-Arm, Multi-Site study. All subjects will receive the investigational agent, GC1008 in 3 week cycles of treatment

GC1008: GC1008 is a human IgG4 kappa monoclonal antibody capable of neutralizing all mammalian isoforms of TGFbeta (i.e., beta1, beta 2 and beta 3). GC1008 is a high affinity antibody with dissociation constants (Kds) of 1.8 nM, 2.8 nM and 1.4 nM for TGF1,2,and 3, respectively.

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

Limitations of the trial include small sample size and lack of post-tumor treatment samples.

James Robinson

Outcome analysis presented in manuscript of results of trial based on 13 participants.

3-month Progression Free Survival Rate

Grade 2 Treatment Related Toxicities

Grade 3/4 Treatment Related Toxicities

Toxicity and Safety of Systemic Infusion of Anti-TGF Antibody

Time to Progression

Overall Survival

Time to Progression and Overall Survival

Response Rate Using Modified RECIST Criteria for Mesothelioma

Change in serum osteopontin after treatment

Change in serum hyaluronan after treatment

Change in serum MMP-1 after treatment

Change in serum MMP-7 after treatment

Change in serum IL-6 V after treatment

Change in plasma CCL18 v after treatment

Change in plasma VEGF after treatment

Change in plasma PAI-1 after treatment

Number of Participants With a Change of Serum Biomarkers After Therapy

Number of Participants With Systemic Humoral Anti-tumor Immune Response After Repeated Anti-TGFβ Antibody Instillation

Assessment of Systemic TGFβ After Repeated Anti-TGFβ Antibody Installation

Biologic Response Measurements of TGFβ Blockade

Overall Study

Symptoms and General Pathology

Recurrence

Disease Attributes

Tin Fluorides

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.

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.

University of Chicago

Micronutrients

Hematinics

Amino Acids

Vitamins

Pemetrexed

Cisplatin

Maleic acid

Cediranib

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Protein Kinase Inhibitors

Glutamic Acid

Folinic Acid

Folate

Vitamin B9

Patients receive pemetrexed disodium IV over 10 minutes and cisplatin IV over 2 hours on day 1 and cediranib maleate PO QD on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive cediranib maleate alone PO QD in the absence of disease progression or unacceptable toxicity.

Patients receive pemetrexed disodium and cisplatin as in arm I and placebo PO QD on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive placebo alone PO QD in the absence of disease progression or unacceptable toxicity.

Cediranib Maleate

Pemetrexed Disodium

Placebo Administration

Anne S Tsao

This randomized phase I/II trial is studying the side effects and best dose of cediranib maleate when given together with pemetrexed disodium and cisplatin and to see how well it works in treating patients with malignant pleural mesothelioma. Drugs used in chemotherapy, pemetrexed disodium and cisplatin, 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. Cediranib maleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving pemetrexed disodium and cisplatin together with cediranib maleate may kill more tumor cells.

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose (MTD) and the recommended phase II dose of cediranib maleate (cediranib) in combination with cisplatin and pemetrexed disodium (pemetrexed). (Phase I) II. To assess the safety and toxicity of the regimen. (Phase I) III. To assess whether cisplatin/pemetrexed plus cediranib as compared to cisplatin/pemetrexed plus placebo improves progression-free survival in patients with malignant pleural mesothelioma. (Phase II) IV. To compare overall survival in patients treated with cisplatin/pemetrexed plus cediranib to those treated with cisplatin/pemetrexed plus placebo. (Phase II) V. To assess the safety and toxicity profile of the regimen. (Phase II) VI. To assess response rate (confirmed and unconfirmed, complete and partial responses) and disease control rate (response or stable disease) in the subset of patients with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. (Phase II) VII. To assess response rate and disease control rate using modified RECIST criteria for pleural tumors in the subset of patients with measurable disease by modified RECIST criteria for pleural tumors. (Phase II) VIII. To assess the rate of agreement between local and central pathology review of mesothelioma and its histologic subtypes. (Phase II) IX. To collect specimens for banking for use in future research studies. (Phase II)

OUTLINE: This is a phase I dose-escalation study of cediranib maleate followed by a phase II study.

PHASE I (CLOSED): Patients receive pemetrexed disodium intravenously (IV) over 10 minutes and cisplatin IV over 2 hours on day 1 and cediranib maleate orally (PO) once daily (QD) on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive cediranib maleate alone PO QD in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive pemetrexed disodium IV over 10 minutes and cisplatin IV over 2 hours on day 1 and cediranib maleate PO QD on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive cediranib maleate alone PO QD in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive pemetrexed disodium and cisplatin as in arm I and placebo PO QD on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive placebo alone PO QD in the absence of disease progression or unacceptable toxicity.

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

Pemetrexed Disodium and Cisplatin With or Without Cediranib Maleate in Treating Patients With Malignant Pleural Mesothelioma

A Phase I/Randomized Phase II Study of Cediranib (NSC#732208) Versus Placebo in Combination With Cisplatin and Pemetrexed in Chemonaive Patients With Malignant Pleural Mesothelioma

MTD was determined by testing dose-de-escalation to 20mg PO daily on dose de-escalation cohort 1 to 2 with 3 to 6 patients each. MTD reflects the highest dose of drug that did not cause a Dose-Limiting Toxicity (DLT) in \> 33% of participants. Toxicities will be graded according to the CTEP Active Version of the NCI Common Terminology Criteria for Adverse Events. Dose-limiting toxicities (DLT) apply only during Cycle 1 and must be drug-related (i.e. possibly, probably or definitely related to one of the 3 study drugs). The following events occurring in the first cycle of treatment are considered dose limiting.

1. Febrile neutropenia
2. Grade 4 neutrophil count decrease for more than 7 days' duration
3. Grade 4 platelet count decrease
4. Grade 3 or 4 non-hematologic toxicity (excluding alopecia)

From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression free are censored at date of last contact. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v 1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesions, or the appearance of new lesions.

From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): Complete Response (CR), Disappearance of all measurable and non-measurable disease; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

All target measurable lesions must be assessed using the same techniques as baseline.

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): Complete Response (CR), Disappearance of all measurable and non-measurable disease; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (STA): Does not qualify for CR, PR, Progression or Symptomatic Deterioration. Disease Control Rate (DCR) = CR + PR + STA

All target measurable lesions must be assessed using the same techniques as baseline.

Per modified RECIST for Pleural Tumors. In addition to RECIST1.1, for modified RECIST, measurements based on the sum of 6 CT cuts in the pleural perpendicular to the chest wall are applied to standard RECIST criterial (sum of 6 = one univariate diameter). Complete Response (CR), Disappearance of all measurable and non-measurable disease; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

All target measurable lesions must be assessed using the same techniques as baseline.

Per modified RECIST for Pleural Tumors. In addition to RECIST1.1, for modified RECIST, measurements based on the sum of 6 CT cuts in the pleural perpendicular to the chest wall are applied to standard RECIST criterial (sum of 6 = one univariate diameter). Complete Response (CR), Disappearance of all measurable and non-measurable disease; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (STA), does not qualify for CR, PR, Progression or Symptomatic Deterioration. Disease Control Rate (DCR) = CR + PR + STA.

All target measurable lesions must be assessed using the same techniques as baseline.

Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.

For Adverse Event assessment, we include patients who are eligible and evaluable for adverse events (e.g., received at least one dose of protocol treatment) in the analysis. For all-cause mortality, we include all eligible patients in the analysis.

Phase I Cisplatin-pemetrexed Cediranib 30mg

Phase I Cisplatin-pemetrexed Cediranib 20mg

Phase II Cisplatin-pemetrexed Cediranib 20mg

Phase II Cisplatin-pemetrexed Placebo

Phase I All Participants

Patients receive pemetrexed disodium IV over 10 minutes and cisplatin IV over 2 hours on day 1 and cediranib maleate PO QD on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive cediranib maleate alone PO QD in the absence of disease progression or unacceptable toxicity.

Cediranib Maleate: Given orally

Cisplatin: Given IV

Laboratory Biomarker Analysis: Correlative studies

Pemetrexed Disodium: Given IV

Patients receive pemetrexed disodium IV over 10 minutes and cisplatin IV over 2 hours on day 1 and placebo PO QD on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive placebo alone PO QD in the absence of disease progression or unacceptable toxicity.

Placebo: Given orally

Cisplatin: Given IV

Laboratory Biomarker Analysis: Correlative studies

Pemetrexed Disodium: Given IV

Total

Age, Continuous

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Patients will be graded according to the Zubrod Performance Status Scale:

0: Fully active, able to carry on all pre-disease performance without restriction.

1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work.
2. Ambulatory and capable of self-care but unable to carry out any work activities; up and about more than 50% of waking hours.

The higher grade is, the worse performance status is.

Zubrod Performance Status

Histology

Prior history of radiation

Prior history of definitive surgery

Measurable Disease per RECIST 1.1

Measurable Disease per Modified RECIST for Pleural Tumors

117 participants were enrolled, only 112 participants were included in the analysis: 5 patients were either not eligible or not analyzable. Thus these 5 patients were excluded from any analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pembrolizumab With or Without Anetumab Ravtansine in Treating Patients With Mesothelin-Positive Pleural Mesothelioma	NCT03126630	Pleural Maligna...	Anetumab Ravtan... Laboratory Biom... Pembrolizumab Pharmacological...	18 Years -	National Cancer Institute (NCI)
Confocal Laser Endomicroscopy in Pleural Malignancies	NCT03290183	Pleural Maligna... Thymoma Pleural Disease...	Confocal laser ...	18 Years -	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Confocal Laser Endomicroscopy in Pleural Malignancies	NCT03290183	Pleural Maligna... Thymoma Pleural Disease...	Confocal laser ...	18 Years -	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Anti-TGF Monoclonal Antibody (GC1008) in Relapsed Malignant Pleural Mesothelioma	NCT01112293	Pleural Maligna...	GC1008	18 Years -	Abramson Cancer Center at Penn Medicine
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
Pembrolizumab With or Without Anetumab Ravtansine in Treating Patients With Mesothelin-Positive Pleural Mesothelioma	NCT03126630	Pleural Maligna...	Anetumab Ravtan... Laboratory Biom... Pembrolizumab Pharmacological...	18 Years -	National Cancer Institute (NCI)
Anti-TGF Monoclonal Antibody (GC1008) in Relapsed Malignant Pleural Mesothelioma	NCT01112293	Pleural Maligna...	GC1008	18 Years -	Abramson Cancer Center at Penn Medicine
Pemetrexed Disodium and Cisplatin With or Without Cediranib Maleate in Treating Patients With Malignant Pleural Mesothelioma	NCT01064648	Epithelioid Mes... Pleural Maligna... Recurrent Malig... Sarcomatoid Mes...	Cediranib Malea... Cisplatin Laboratory Biom... Pemetrexed Diso... Placebo Adminis...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for pleural malignant mesothelioma