Symptoms and General Pathology

All Conditions

Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Recurrence

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

Patients receive tivantinib 360 PO BID. Treatment continues in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Tivantinib

Hedy Kindler

This phase II trial studies how well tivantinib works in treating patients with previously treated malignant mesothelioma. Tivantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the objective response rate of patients with malignant mesothelioma who are treated with ARQ 197 (tivantinib).

SECONDARY OBJECTIVES:

I. To determine the progression-free survival of patients with malignant mesothelioma who are treated with ARQ 197.

II. To determine the toxicity experienced by patients with malignant mesothelioma who are treated with ARQ 197.

III. To determine median and overall survival of patients with malignant mesothelioma who are treated with ARQ 197.

TERTIARY OBJECTIVES:

I. To determine the frequency of mesenchymal-epithelial transition (MET) gene amplification in malignant mesothelioma patient tumor samples, and to correlate the results with MET immunohistochemistry (IHC).

II. To determine whether MET gene amplification results in increased sensitivity to ARQ 197 as observed by improved clinical outcomes (response rate \[RR\] and progression free survival \[PFS\]) compared to those without MET gene over-expression/amplification.

III. To determine whether high baseline serum hepatocyte growth factor (HGF), as well as changes in serum HGF during treatment at pre-defined early time points, correlate with treatment efficacy and clinical outcome, as measured by response rate and progression-free survival.

IV. To identify mutations by sequencing of specific areas of the MET gene in tumor samples (semaphorin \[SEMA\], jumonji \[JM\] and tyrosine kinase domains).

V. To perform immunohistochemistry (IHC) of mesothelioma tumors for HGF, MET and phosphorylated (p)-MET (pY1003 and pY1230/34/35).

VI. To assess serum HGF and serum soluble MET levels by enzyme linked immunosorbent assay (ELISA) (R\&D systems) pre-treatment, after 2 cycles and at disease progression.

OUTLINE:

Patients receive tivantinib orally (PO) twice daily (BID). Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

Tivantinib in Treating Patients With Previously Treated Malignant Mesothelioma

A Phase 2 Study of ARQ 197 in Patients With Previously-Treated Malignant Mesothelioma

Fisher's exact test will be performed for binary variables (e.g., presence/absence of MET gene amplification). Paired t-tests or Wilcoxon signed-ranks test, whichever is appropriate, will be used to examine the changes with treatment in the laboratory correlates that are continuous and McNemar's test will be used for binary markers.

Will be evaluated by Spearman's rank correlation coefficient.

Will be evaluated using the Cox regression model.

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

Grade 3 or higher AE of any type, regardless of attribution.

Time to disease progression or death from any cause. Analyzed using the Kaplan-Meier method.

National Cancer Institute (NCI)

Treatment (Tivantinib)

Patients receive tivantinib 360 mg PO BID. Treatment continues in the absence of disease progression or unacceptable toxicity.

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Hedy Kindler, MD

Note: Study terminated for futility due to insufficient number of objective responders in first stage.

Objective Radiologic Response Rate (Complete or Partial Response) Assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

Incidence of Adverse Events, Graded Per NCI CTCAE Version 4

Overall Survival

Progression-free Survival

Change in Baseline Levels of Continuous or Ordinal Markers (e.g., Serum HGF/MET IHC) Between Responders and Non-responders

Change in Serum HGF or MET IHC and Tumor Size Change (Percent Reduction in Sum of Longest Diameters)

Association Between Baseline HGF, MET Gene Amplification, MET IHC and PFS

Overall Study

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.

Pharmacogenomic Study

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

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.

SWOG statistician

All participants from Phase I who are eligible for DLT. Patients will be considered evaluable for DLT if they received at least 14 doses of cediranib at the assigned dose during Cycle 1 and at least one dose each of pemetrexed and cisplatin, or if they developed a DLT. If a patient does not develop a DLT but does not complete at least 14 doses of cediranib and one dose each of pemetrexed and cisplatin during Cycle 1 due to any reason, the patient will be considered not evaluable for DLT and will be replaced.

All Phase I Participants

Maximum Tolerated Dose of Cediranib in Combination With Cisplatin and Pemetrexed (Phase I)

Only eligible and analyzable patients were included.

Progression-free Survival (Phase II)

Only eligible and analyzable patients are included in the analysis.

Overall Survival (Phase II)

Only eligible patients with baseline measurable disease per RECIST 1.1 were included in the analysis.

Response Rate by RECIST1.1 (Phase II)

Eligible patients with baseline eligible disease per RECIST 1.1 were included in the analysis.

Disease Control Rate by RECIST 1.1 (Phase II)

Eligible patients with baseline measurable disease per modified RECIST were included in the analysis.

Response Rate by Modified RECIST (Phase II)

Disease Control Rate by Modified RECIST (Phase II)

Abdominal pain

Anemia

Constipation

Dehydration

Diarrhea

Dyspnea

Fatigue

Gastrointestinal disorders - Other, specify

Heart failure

Hypertension

Hypokalemia

Hypomagnesemia

Hyponatremia

Irregular menstruation

Lymphocyte count decreased

Mucositis oral

Nausea

Nervous system disorders - Other, specify

Neutrophil count decreased

Palmar-plantar erythrodysesthesia syndrome

Peripheral sensory neuropathy

Platelet count decreased

Pulmonary hypertension

Vomiting

Weight loss

White blood cell decreased

Patients who received at least one dose of protocol treatment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Tivantinib in Treating Patients With Previously Treated Malignant Mesothelioma	NCT01861301	Epithelioid Mes... Recurrent Malig... Sarcomatoid Mes... Stage II Pleura... Stage III Pleur... Stage IV Pleura...	Laboratory Biom... Tivantinib	18 Years -	National Cancer Institute (NCI)
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
Tivantinib in Treating Patients With Previously Treated Malignant Mesothelioma	NCT01861301	Epithelioid Mes... Recurrent Malig... Sarcomatoid Mes... Stage II Pleura... Stage III Pleur... Stage IV Pleura...	Laboratory Biom... Tivantinib	18 Years -	National Cancer Institute (NCI)
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)
Tivantinib in Treating Patients With Previously Treated Malignant Mesothelioma	NCT01861301	Epithelioid Mes... Recurrent Malig... Sarcomatoid Mes... Stage II Pleura... Stage III Pleur... Stage IV Pleura...	Laboratory Biom... Tivantinib	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for sarcomatoid mesothelioma