Brentuximab Vedotin in Treating Patients With CD30+ Malignant Mesothelioma That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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This phase II trial studies how well brentuximab vedotin works in treating patients with CD30 positive (+) malignant mesothelioma that cannot be removed by surgery. Monoclonal antibodies, such as brentuximab vedotin, may interfere with the ability of tumor cells to grow and spread.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess 4-month disease control rate (DCR) in pre-treated patients with unresectable malignant pleural mesothelioma (MPM) treated with brentuximab vedotin. SECONDARY OBJECTIVES: I. To evaluate the response rate, progression-free and overall survival, and safety/toxicity of brentuximab vedotin in CD30+ malignant mesothelioma. II. To prospectively evaluate the incidence of CD30+ expression in malignant mesothelioma during the screening process. III. To determine whether CD30+ expression levels in tumor tissue correlate to response to brentuximab vedotin. EXPLORATORY OBJECTIVES: I. To collect archival or new tissue and blood for correlative studies. II. Next generation sequencing (NGS) will be conducted on adequate tumor tissue specimens. III. Exploratory analysis: Bank peripheral blood at baseline for subsequent cytokine or reverse phase protein array (RPPA). OUTLINE: Patients receive brentuximab vedotin intravenously (IV) over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, 3 months, 6 months and then every 6 months thereafter.

Official Title
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Phase II Trial of Adcetris (Brentuximab Vedotin) in CD30+ Malignant Mesothelioma

Conditions
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CD30-Positive Neoplastic Cells Present, Malignant Mesothelioma

Intervention / Treatment
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* Drug: Brentuximab Vedotin
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care Female subject is either: a. post-menopausal for at least one year before the screening visit; or b. surgically sterilized; or c. willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study and at least 6 months after the last dose of brentuximab vedotin Male subject, even if surgically sterilized (i.e., status postvasectomy), agrees to use an acceptable barrier method for contraception (condom with a spermicidal agent), or completely abstain from heterosexual intercourse during the entire study treatment period through 6 months after the last dose of brentuximab vedotin Absolute neutrophil count (ANC) > 1500/mm^3 Platelets > 100,000/mm^3 Hemoglobin (Hgb) > 8.5 g/dL Total bilirubin =< 1.5 x upper limit of normal (ULN) Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 3 x ULN; AST and/or ALT may be up to 5 X ULN if with known liver metastases (mets) Calculated creatinine clearance must be >= 30 mL/minute Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Pathologic diagnosis of malignant mesothelioma (any primary site is acceptable, any histology is acceptable) Have unresectable malignant mesothelioma (any histology) Positive CD30+ immunohistochemical expression Any line of prior therapy - patients may be chemo-naive or chemo-refractory (any line) Patients must have measurable disease by modified Response Evaluation Criteria in Solid Tumors (RECIST) or RECIST; examinations for assessment of measurable disease must have been completed within 28 days prior to registration Exclusion Criteria: Radiation therapy to more than 25% of the bone marrow; whole pelvic radiation is considered to be over 25% Prior allogeneic bone marrow or organ transplantation Female subject who is pregnant or breast-feeding; confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women Patient has received other investigational drugs with 14 days before enrollment Serious medical or psychiatric illness likely to interfere with participation in this clinical study No prior history of malignancy within 2 years, unless cured of a skin cancer or a stage I-III solid tumor; no prior hematologic malignancy within 3 years Known hypersensitivity to brentuximab vedotin components Persons who are incarcerated at time of enrollment (e.g., prisoners) or likely to become incarcerated during the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (brentuximab vedotin)<br>Patients receive brentuximab vedotin IV over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Brentuximab Vedotin<br>* Given IV<br>* Other names: SGN-35;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate (DCR) defined as proportion of patients who had complete response, partial response or stable disease by Response Evaluation Criteria in Solid Tumors version 4.1 | A DCR of 50% or higher is considered as clinically significant. If the trial is not stopped early and all 50 patients are accrued, point estimate along with 95% credible interval will be provided. Logistic regression model will be utilized to assess the effect of patient prognostic factors on the response status if sufficient number of patients with stable disease or better response to the treatment are observed. | At 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor characteristics | Patients' demographic and tumor characteristics will be analyzed, with categorical variables summarized in frequency tables while continuous variables summarized using mean (plus or minus standard deviation) and median (range). The student t-test/Wilcoxon test and analysis of variance (ANOVA)/Kruskal-Wallis test will be used to compare continuous variables between different patient groups. The chi-square test or the Fisher's exact test will be applied to assess the association between two categorical variables. | Up to 5 years | 
| Time to progression | The distribution of time-to-event endpoints will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important patient characteristics will be made using the log-rank test. Cox proportional hazard regression will be employed for multi-covariate analysis on time-to-event outcomes when appropriate. | Up to 5 years | 
| Overall survival | The distribution of time-to-event endpoints will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important patient characteristics will be made using the log-rank test. Cox proportional hazard regression will be employed for multi-covariate analysis on time-to-event outcomes when appropriate. | Up to 5 years | 
| CD30+ expression levels | The student t-test/Wilcoxon test and ANOVA/Kruskal-Wallis test will be used to compare CD30+ expression levels by response status. | Up to 5 years |