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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Unresectable Pleural or Peritoneal Malignant Mesothelioma
• Intervention / Treatment: Drug: Tremelimumab; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 571
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, 5000
    • Research Site
  • Auchenflower, Australia, 4066
    • Research Site
  • Box Hill, Australia, 3128
    • Research Site
  • Chermside, Australia, 4032
    • Research Site
  • East Bentleigh, Australia, 3165
    • Research Site
  • Gosford, Australia, 2250
    • Research Site
  • Heidelberg, Australia, 3084
    • Research Site
  • Nedlands, Australia, 6009
    • Research Site
  • Saint Leonards, Australia, 2065
    • Research Site
  • Waratah, Australia, 2298
    • Research Site
• Belgium
  • Edegem, Belgium, 2650
    • Research Site
  • Gent, Belgium, 9000
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Research Site
  • Quebec
    • Sainte Foy, Quebec, Canada, G1V 4G5
      • Research Site
• Denmark
  • Copenhagen, Denmark, 2100
    • Research Site
• France
  • Caen Cedex, France, 14076
    • Research Site
  • Le Mans Cedex, France, 72037
    • Research Site
  • Lille Cedex, France, 59037
    • Research Site
  • Nice, France, 06189
    • Research Site
  • Rennes Cedex 9, France, 35033
    • Research Site
  • Toulouse, France, 31059
    • Research Site
  • Villejuif Cedex, France, 94805
    • Research Site
• Germany
  • Berlin, Germany, 13125
    • Research Site
  • Esslingen a.N., Germany, 73730
    • Research Site
  • Freiburg, Germany, 79106
    • Research Site
  • Gauting, Germany, 82131
    • Research Site
  • Grosshansdorf, Germany, 22927
    • Research Site
  • Hamburg, Germany, 21075
    • Research Site
  • Hemer, Germany, 58675
    • Research Site
  • Karlsruhe, Germany, 76137
    • Research Site
  • Lubeck, Germany, 23538
    • Research Site
  • Löwenstein, Germany, 74245
    • Research Site
• Hungary
  • Gyöngyös - Mátraháza, Hungary, 3200
    • Research Site
  • Törökbálint, Hungary, 2045
    • Research Site
• Israel
  • Beer Sheva, Israel, 84101
    • Research Site
• Italy
  • Alessandria, Italy, 15100
    • Research Site
  • Aviano, Italy, 33081
    • Research Site
  • Bergamo, Italy, 24125
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  • Bologna, Italy, 40138
    • Research Site
  • Candiolo, Italy, 10060
    • Research Site
  • Genova, Italy, 16132
    • Research Site
  • Meldola, Italy, 47014
    • Research Site
  • Milano, Italy, 20133
    • Research Site
  • Orbassano, Italy, 10043
    • Research Site
  • Padova, Italy, 35128
    • Research Site
  • Rozzano, Italy, 20089
    • Research Site
  • Siena, Italy, 53100
    • Research Site
• Korea, Republic of
  • Jeonnam, Korea, Republic of, 58128
    • Research Site
  • Seoul, Korea, Republic of, 03722
    • Research Site
  • Seoul, Korea, Republic of, 05505
    • Research Site
  • Seoul, Korea, Republic of, 06351
    • Research Site
• Netherlands
  • Breda, Netherlands, 4818 CK
    • Research Site
  • Eindhoven, Netherlands, 5623EJ
    • Research Site
  • Rotterdam, Netherlands, 3015 GD
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• Poland
  • Gdansk, Poland, 80-952
    • Research Site
  • Poznan, Poland, 60-693
    • Research Site
  • Szczecin, Poland, 70-891
    • Research Site
  • Warszawa, Poland, 02-781
    • Research Site
• Romania
  • Craiova, Romania, 200385
    • Research Site
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Research Site
  • Nizhny Novgorod, Russian Federation, 603006
    • Research Site
  • Saint-Petersburg, Russian Federation, 197022
    • Research Site
• South Africa
  • Kraaifontein, South Africa, 7570
    • Research Site
  • Pretoria, South Africa, 0081
    • Research Site
  • Pretoria, South Africa, 0181
    • Research Site
• Spain
  • Barcelona, Spain, 08035
    • Research Site
  • Madrid, Spain, 28040
    • Research Site
  • Sabadell (Barcelona), Spain, 08208
    • Research Site
  • San Sebastian, Spain, 20014
    • Research Site
  • Sevilla, Spain, 41013
    • Research Site
• Sweden
  • Linkoping, Sweden, 58185
    • Research Site
  • Lund, Sweden, 22185
    • Research Site
  • Umea, Sweden, SE90185
    • Research Site
• United Kingdom
  • Leeds, United Kingdom, LS9 7TF
    • Research Site
  • Leicester, United Kingdom, LE1 5WW
    • Research Site
  • London, United Kingdom, EC1A 7BE
    • Research Site
  • London, United Kingdom, SE1 9RT
    • Research Site
  • Maidstone, United Kingdom, ME16 9QQ
    • Research Site
  • Manchester, United Kingdom, M23 9LT
    • Research Site
  • Plymouth, United Kingdom, PL6 8DH
    • Research Site
  • Southampton, United Kingdom, SO16 6YD
    • Research Site
  • Wirral, United Kingdom, CH63 4JY
    • Research Site
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Research Site
  • California
    • La Jolla, California, United States, 92093
      • Research Site
    • Los Angeles, California, United States, 90025
      • Research Site
    • San Francisco, California, United States, 94143
      • Research Site
    • Santa Monica, California, United States, 90404
      • Research Site
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Research Site
  • Delaware
    • Newark, Delaware, United States, 19718
      • Research Site
  • Florida
    • Tampa, Florida, United States, 33612
      • Research Site
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Research Site
    • Peoria, Illinois, United States, 61615
      • Research Site
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Research Site
    • Baltimore, Maryland, United States, 21231
      • Research Site
  • Minnesota
    • Minneapolis, Minnesota, United States, 55445
      • Research Site
  • New York
    • New York, New York, United States, 10065
      • Research Site
    • Rochester, New York, United States, 14642
      • Research Site
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Research Site
  • Ohio
    • Canton, Ohio, United States, 44710
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75390
      • Research Site
    • Houston, Texas, United States, 77030
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histologically and/or cytologically confirmed pleural or peritoneal malignant mesothelioma;
2. Disease not amenable to curative surgery;
3. Age 18 and over at the time of consent;
4. ECOG Performance status 0-1;
5. 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.
6. 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,
7. Measurable diseaseby modified RECIST for pleural mesothelioma or RECIST v1.1 for peritoneal mesothelioma;
8. Adequate bone marrow, hepatic, and renal function determined within 14 days prior to randomization defined as:
9. Negative screening test results for human immunodeficiency virus (HIV), hepatitis A, B and C.
10. 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;
11. 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.
12. 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:

1. Subjects who failed more than 2 prior systemic treatment regimens for advanced malignant mesothelioma;
2. Received any prior mAb against CTLA-4, programmed cell death 1 (PD1) or programmed cell death 1 ligand 1 (PD-L1);
3. History of chronic inflammatory or autoimmune disease with symptomatic disease within the last 3 years prior to randomization.
4. Active, untreated central nervous system (CNS) metastasis
5. Any serious uncontrolled medical disorder or active infection that would impair the subject's ability to receive investigational product;
6. History of other malignancy unless the subject has been disease-free for at least 3 years;
7. Pregnant or breast feeding at time of consent;
8. Any condition that would prohibit the understanding or rendering of information and consent and compliance with the requirements of this protocol;
9. Active or history of diverticulitis;
10. 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;
11. History of sarcoidosis syndrome;
12. Currently receiving systemic corticosteroids or other immunosuppressive medications or has a medical condition that requires the chronic use of corticosteroids.
13. Subjects should not be vaccinated with live attenuated vaccines within one month prior to starting tremelimumab treatment;
14. The last dose of prior chemotherapy or radiation therapy was received less than 2 weeks prior to randomization;
15. Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of vitiligo and alopecia;
16. 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;
17. Concurrent enrollment in another clinical study or receipt of an investigational product within the last 4 weeks
18. Employees of the study site directly involved with the conduct of the study, or immediate family members of any such individuals;
19. Subjects with a history of hypersensitivity to compounds of similar biologic composition to tremelimumab or any constituent of the product.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo is to be administered as an IV solution, followed by observation.
Experimental: Tremelimumab	Drug: Tremelimumab; Tremelimumab is to be administered as an IV solution, followed by observation.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: MedImmune LLC

Publications and helpful links

General Publications

• Baverel P, Roskos L, Tatipalli M, Lee N, Stockman P, Taboada M, Vicini P, Horgan K, Narwal R. Exposure-Response Analysis of Overall Survival for Tremelimumab in Unresectable Malignant Mesothelioma: The Confounding Effect of Disease Status. Clin Transl Sci. 2019 Sep;12(5):450-458. doi: 10.1111/cts.12633. Epub 2019 Apr 12.
• Maio M, Scherpereel A, Calabro L, Aerts J, Perez SC, Bearz A, Nackaerts K, Fennell DA, Kowalski D, Tsao AS, Taylor P, Grosso F, Antonia SJ, Nowak AK, Taboada M, Puglisi M, Stockman PK, Kindler HL. Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Lancet Oncol. 2017 Sep;18(9):1261-1273. doi: 10.1016/S1470-2045(17)30446-1. Epub 2017 Jul 17.

Helpful Links

• FINAL Redacted PROTOCOL_ 03Jan2017

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2013
• Primary Completion (Actual): January 24, 2016
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: April 22, 2013
• First Submitted That Met QC Criteria: April 25, 2013
• First Posted (Estimated): April 30, 2013

Study Record Updates

• Last Update Posted (Estimated): January 19, 2024
• Last Update Submitted That Met QC Criteria: January 17, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: tremelimumab; CTLA-4; malignant mesothelioma; pleural, peritoneal
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Antineoplastic Agents; Tremelimumab
• Other Study ID Numbers: D4880C00003; 2012-003524-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP