Clinical trial NCT01843374: Randomized, Double-blind Study Comparing Tremelimumab to Placebo in Subjects With Unresectable Malignant Mesothelioma
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Unresectable Pleural or Peritoneal Malignant Mesothelioma
Keywords: tremelimumab
pleural, peritoneal
malignant mesothelioma
CTLA-4
Lead sponsor: MedImmune LLC
Sponsor class: INDUSTRY
First posted: 2013-04-30
Enrollment: 571
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: 3 years.
Secondary outcomes:
measure: OS Rate at 18 Months by Treatment Arm
timeFrame: 18 months
measure: Progression-free Survival by Treatment Arm
timeFrame: Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years.
measure: Overall Response Rate by Treatment Arm
timeFrame: Time from randomization to best response to treatment, assessed up to 3 years.
measure: Duration of Response by Treatment Arm
timeFrame: 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.
measure: Disease Control Rate by Treatment Arm
timeFrame: Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years.
measure: Durable Disease Control Rate by Treatment Arm
timeFrame: Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years.
measure: Number of Participants Reporting Any Adverse Event
timeFrame: Day 1- 90 days post dose
measure: Number of Participants Reporting Any Serious Adverse Events
timeFrame: Day 1 to 90 days post dose
measure: Number of Participants With Positive Anti-drug Antibodies
timeFrame: Week 5
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Research Site
state: Arizona
city: La Jolla
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: San Francisco
country: United States
facility: Research Site
state: California
city: Santa Monica
country: United States
facility: Research Site
state: California
city: New Haven
country: United States
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state: Connecticut
city: Newark
country: United States
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state: Delaware
city: Tampa
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state: Florida
city: Augusta
country: United States
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state: Georgia
city: Chicago
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state: Illinois
city: Peoria
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state: Illinois
city: Baltimore
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state: Maryland
city: Baltimore
country: United States
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state: Maryland
city: Minneapolis
country: United States
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state: Minnesota
city: New York
country: United States
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state: New York
city: Rochester
country: United States
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state: New York
city: Durham
country: United States
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state: North Carolina
city: Canton
country: United States
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state: Ohio
city: Philadelphia
country: United States
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state: Pennsylvania
city: Dallas
country: United States
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state: Texas
city: Houston
country: United States
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state: Texas
city: Adelaide
country: Australia
facility: Research Site
city: Auchenflower
country: Australia
facility: Research Site
city: Box Hill
country: Australia
facility: Research Site
city: Chermside
country: Australia
facility: Research Site
city: East Bentleigh
country: Australia
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city: Gosford
country: Australia
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city: Heidelberg
country: Australia
facility: Research Site
city: Nedlands
country: Australia
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city: Saint Leonards
country: Australia
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city: Waratah
country: Australia
facility: Research Site
city: Edegem
country: Belgium
facility: Research Site
city: Gent
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
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city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Sainte Foy
country: Canada
facility: Research Site
state: Quebec
city: Copenhagen
country: Denmark
facility: Research Site
city: Caen Cedex
country: France
facility: Research Site
city: Le Mans Cedex
country: France
facility: Research Site
city: Lille Cedex
country: France
facility: Research Site
city: Nice
country: France
facility: Research Site
city: Rennes Cedex 9
country: France
facility: Research Site
city: Toulouse
country: France
facility: Research Site
city: Villejuif Cedex
country: France
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Esslingen a.N.
country: Germany
facility: Research Site
city: Freiburg
country: Germany
facility: Research Site
city: Gauting
country: Germany
facility: Research Site
city: Grosshansdorf
country: Germany
facility: Research Site
city: Hamburg
country: Germany
facility: Research Site
city: Hemer
country: Germany
facility: Research Site
city: Karlsruhe
country: Germany
facility: Research Site
city: Lubeck
country: Germany
facility: Research Site
city: Löwenstein
country: Germany
facility: Research Site
city: Gyöngyös - Mátraháza
country: Hungary
facility: Research Site
city: Törökbálint
country: Hungary
facility: Research Site
city: Beer Sheva
country: Israel
facility: Research Site
city: Alessandria
country: Italy
facility: Research Site
city: Aviano
country: Italy
facility: Research Site
city: Bergamo
country: Italy
facility: Research Site
city: Bologna
country: Italy
facility: Research Site
city: Candiolo
country: Italy
facility: Research Site
city: Genova
country: Italy
facility: Research Site
city: Meldola
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Orbassano
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Rozzano
country: Italy
facility: Research Site
city: Siena
country: Italy
facility: Research Site
city: Jeonnam
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Breda
country: Netherlands
facility: Research Site
city: Eindhoven
country: Netherlands
facility: Research Site
city: Rotterdam
country: Netherlands
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city: Gdansk
country: Poland
facility: Research Site
city: Poznan
country: Poland
facility: Research Site
city: Szczecin
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Craiova
country: Romania
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Nizhny Novgorod
country: Russian Federation
facility: Research Site
city: Saint-Petersburg
country: Russian Federation
facility: Research Site
city: Kraaifontein
country: South Africa
facility: Research Site
city: Pretoria
country: South Africa
facility: Research Site
city: Pretoria
country: South Africa
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Sabadell (Barcelona)
country: Spain
facility: Research Site
city: San Sebastian
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Linkoping
country: Sweden
facility: Research Site
city: Lund
country: Sweden
facility: Research Site
city: Umea
country: Sweden
facility: Research Site
city: Leeds
country: United Kingdom
facility: Research Site
city: Leicester
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Maidstone
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Plymouth
country: United Kingdom
facility: Research Site
city: Southampton
country: United Kingdom
facility: Research Site
city: Wirral
country: United Kingdom
facility: Research Site
Study officials:
References:
citation: 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.
citation: 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.