Randomized, Double-blind Study Comparing Tremelimumab to Placebo in Subjects With Unresectable Malignant Mesothelioma

Study Overview
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Brief Summary
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This is a Phase 2b, randomized, double-blind, parallel-group study. Subjects with unresectable pleural or peritoneal malignant mesothelioma will be randomized in a 2:1 ratio to receive either tremelimumab or placebo. Approximately 564 subjects will be enrolled at study centers in multiple countries. The study consists of a screening period, a treatment period, a 90-day follow-up period for safety, and a long-term survival follow-up period.

Detailed Description
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This is a Phase 2b, randomized, double-blind, parallel-group study. Subjects with unresectable pleural or peritoneal malignant mesothelioma will be randomized in a 2:1 ratio to receive either tremelimumab or placebo. Randomization will be stratified by EORTC status (low-risk vs high-risk), line of therapy (second vs third), and anatomical site (pleural vs peritoneal). This study plans to use the EORTC to stratify subjects into high or low risk groups in order to ensure balanced randomization to the different treatment groups. For subjects in whom pemetrexed was contraindicated or not tolerated or not an approved therapy (eg, peritoneal mesothelioma), prior therapy with a first-line platinum-based regimen is required. Approximately 564 subjects will be enrolled at study centers in multiple countries. The study consists of a screening period, a treatment period, a 90-day follow-up period for safety, and a long-term survival follow-up period.

Official Title
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A Phase 2b, Randomized, Double-blind Study Comparing Tremelimumab to Placebo in Second- or Third-line Treatment of Subjects With Unresectable Pleural or Peritoneal Malignant Mesothelioma

Conditions
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Unresectable Pleural or Peritoneal Malignant Mesothelioma

Intervention / Treatment
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* Drug: Tremelimumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically and/or cytologically confirmed pleural or peritoneal malignant mesothelioma; Disease not amenable to curative surgery; Age 18 and over at the time of consent; ECOG Performance status 0-1; Progressed after previous receipt of 1-2 prior systemic treatments for advanced disease that included a first-line pemetrexed (or anti-folate)-based regimen in combination with platinum agent. Recovered from all toxicities associated with prior treatment, to acceptable baseline status, or a NCI CTCAE Grade of 0 or 1, except for toxicities not considered a safety risk, Measurable diseaseby modified RECIST for pleural mesothelioma or RECIST v1.1 for peritoneal mesothelioma; Adequate bone marrow, hepatic, and renal function determined within 14 days prior to randomization defined as: Negative screening test results for human immunodeficiency virus (HIV), hepatitis A, B and C. Written informed consent and any locally required authorization (eg, HIPAA in the USA, EU Data Privacy Directive authorization in the EU) obtained from the subject/legal representative prior to performing any protocol- related procedures, including screening evaluations; Females of childbearing potential who are sexually active with a nonsterilized male partner must use a highly effective method of contraception for 28 days prior to the first dose of investigational product, and must agree to continue using such precautions for 6 months after the final dose of investigational product; cessation of contraception after this point should be discussed with a responsible physician. Nonsterilized males who are sexually active with a female partner of childbearing potential must use a highly effective method of contraception from Days 1 through 90 post last dose. In addition, they must refrain from sperm donation for 90 days after the final dose of investigational product. Exclusion Criteria: Subjects who failed more than 2 prior systemic treatment regimens for advanced malignant mesothelioma; Received any prior mAb against CTLA-4, programmed cell death 1 (PD1) or programmed cell death 1 ligand 1 (PD-L1); History of chronic inflammatory or autoimmune disease with symptomatic disease within the last 3 years prior to randomization. Active, untreated central nervous system (CNS) metastasis Any serious uncontrolled medical disorder or active infection that would impair the subject's ability to receive investigational product; History of other malignancy unless the subject has been disease-free for at least 3 years; Pregnant or breast feeding at time of consent; Any condition that would prohibit the understanding or rendering of information and consent and compliance with the requirements of this protocol; Active or history of diverticulitis; Active or history of inflammatory bowel disease, irritable bowel disease, celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea. Active or history of systemic lupus erythematosus or granulomatosis with polyangiitis; History of sarcoidosis syndrome; Currently receiving systemic corticosteroids or other immunosuppressive medications or has a medical condition that requires the chronic use of corticosteroids. Subjects should not be vaccinated with live attenuated vaccines within one month prior to starting tremelimumab treatment; The last dose of prior chemotherapy or radiation therapy was received less than 2 weeks prior to randomization; Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of vitiligo and alopecia; Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results; Concurrent enrollment in another clinical study or receipt of an investigational product within the last 4 weeks Employees of the study site directly involved with the conduct of the study, or immediate family members of any such individuals; Subjects with a history of hypersensitivity to compounds of similar biologic composition to tremelimumab or any constituent of the product.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tremelimumab<br>Tremelimumab | Drug: Tremelimumab<br>* Tremelimumab is to be administered as an IV solution, followed by observation.<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo is to be administered as an IV solution, followed by observation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival (OS) by treatment arm | 3 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS Rate at 18 Months by Treatment Arm | The percentage of patients still alive at 18 months | 18 months | 
| Progression-free Survival by Treatment Arm | Progression-free survival will be measured from randomization to the first documentation of disease progression or death due to any cause, whichever occurs first. Progression is defined using the modified Response Evaluation Criteria in Solid Tumours (RECIST) for pleural mesothelioma or RECIST v1.1 for peritoneal mesothelioma and assessed by computed tomography (CT) or magnetic resonance imaging (MRI), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years. | 
| Overall Response Rate by Treatment Arm | Overall response rate is defined as the proportion of participants with confirmed CR or PR per the modified Response Evaluation Criteria in Solid Tumours (RECIST) for pleural mesothelioma or RECIST v1.1 for peritoneal mesothelioma and assessed by computed tomography (CT) or magnetic resonance imaging (MRI). Complete Response (CR) corresponds to disappearance of all target lesions, and Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. Overall Response (OR) = CR + PR. | Time from randomization to best response to treatment, assessed up to 3 years. | 
| Duration of Response by Treatment Arm | Duration of response will be defined as the duration from the first documentation of complete response (CR), partial response (PR) to the first documented disease progression. | Duration of response from the first documentation of objcetive response (confirmed CR or PR) to the first documented disease progression, assessed up to 14 weeks after the initial response. | 
| Disease Control Rate by Treatment Arm | Disease control rate (DCR) is defined as the proportion of participants with best response of complete response (CR), partial response (PR), or stable disease (SD) of ≥ 12 weeks duration | Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years. | 
| Durable Disease Control Rate by Treatment Arm | Durable disease control rate (DDCR) is defined as the percentage of participants with best response of complete response (CR), partial response (PR), or stable disease (SD) of ≥ 6 months duration | Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years. | 
| Number of Participants Reporting Any Adverse Event | Any untoward medical occurrence in a patient or clinical investigation participants administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. | Day 1- 90 days post dose | 
| Number of Participants Reporting Any Serious Adverse Events |  | Day 1 to 90 days post dose | 
| Number of Participants With Positive Anti-drug Antibodies | The immunogenicity titer is reported for samples confirmed positive for the presence of anti tremelimumab antibodies. | Week 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tremelimumab, pleural, peritoneal, malignant mesothelioma, CTLA-4