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

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ClinicalTrials.gov Identifier: NCT01843374
Recruitment Status : Active, not recruiting
First Posted : April 30, 2013
Results First Posted : August 17, 2017
Last Update Posted : March 27, 2019
Sponsor:
Information provided by (Responsible Party):
MedImmune LLC

Tracking Information
First Submitted Date  ICMJE April 22, 2013
First Posted Date  ICMJE April 30, 2013
Results First Submitted Date  ICMJE April 10, 2017
Results First Posted Date  ICMJE August 17, 2017
Last Update Posted Date March 27, 2019
Actual Study Start Date  ICMJE May 17, 2013
Actual Primary Completion Date January 24, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 15, 2017)
Overall Survival (OS) [ Time Frame: 3 years. ]
Overall survival (OS) by treatment arm
Original Primary Outcome Measures  ICMJE
 (submitted: April 25, 2013)
Overall survival (OS) time by treatment arm [ Time Frame: Time from randomization until death due to any cause, assessed up to 3 years. ]
The primary analysis of OS will be performed after a number of deaths have occurred among the approximately 180 participants randomized. For participants who are alive at the time of the primary analysis or lost to follow-up, OS will be censored on the last date when participants are known to be alive.
Change History Complete list of historical versions of study NCT01843374 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 15, 2017)
  • OS Rate at 18 Months by Treatment Arm [ Time Frame: 18 months ]
    The percentage of patients still alive at 18 months
  • Progression-free Survival by Treatment Arm [ Time Frame: Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years. ]
    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.
  • Overall Response Rate by Treatment Arm [ Time Frame: Time from randomization to best response to treatment, assessed up to 3 years. ]
    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.
  • Duration of Response by Treatment Arm [ Time Frame: 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. ]
    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.
  • Disease Control Rate by Treatment Arm [ Time Frame: Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years. ]
    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
  • Durable Disease Control Rate by Treatment Arm [ Time Frame: Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years. ]
    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
  • Number of Participants Reporting Any Adverse Event [ Time Frame: Day 1- 90 days post dose ]
    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.
  • Number of Participants Reporting Any Serious Adverse Events [ Time Frame: Day 1 to 90 days post dose ]
  • Number of Participants With Positive Anti-drug Antibodies [ Time Frame: Week 5 ]
    The immunogenicity titer is reported for samples confirmed positive for the presence of anti tremelimumab antibodies.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 25, 2013)
  • Durable Disease Control Rate by Treatment Arm [ Time Frame: Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years. ]
    Durable DCR is defined as the proportion of participants with best response of complete response (CR), partial response (PR), or stable disease (SD) of ≥ 6 months duration
  • Length of progression-free survival by treatment arm [ Time Frame: Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years. ]
    Progression-free survival will be measured from randomization to the first documentation of disease progression or death due to any cause, whichever occurs first.
  • Overall response rate by treatment arm [ Time Frame: Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years. ]
    Overall response rate is defined as the proportion of participants with confirmed CR or PR.
  • Duration of Response by Treatment Arm [ Time Frame: Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years. ]
    Duration of response will be defined as the duration from the first documentation of objective response (CR or PR) to the first documented disease progression.
  • Number of Participants Reporting Any Adverse Event [ Time Frame: Day 1- 90 days post dose ]
    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.
  • Number of participants with changes in patient-reported outcomes [ Time Frame: Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years. ]
    Patient-reported outcomes as measured by the LCSS-Meso (for disease-related symptoms and health-related QoL), EQ-5D-3L (for health status), and BPI-sf (for pain) will be summarized descriptively; the change from baseline for total score and individual domain scores by treatment arm at each time point will be explored.
  • Number of Participants Reporting Any Serious Adverse Events [ Time Frame: Day 1 to 90 days post dose ]
  • Number of participants with anti-drug antibodies [ Time Frame: Week 5 ]
    The immunogenicity titer will be reported for samples confirmed positive for the presence of anti tremelimumab antibodies.
  • Tremelimumab blood concentration [ Time Frame: Week 5 ]
    Tremelimumab concentration data and summary statistics will be tabulated.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Randomized, Double-blind Study Comparing Tremelimumab to Placebo in Subjects With Unresectable Malignant Mesothelioma
Official Title  ICMJE 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
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, and a 90-day follow-up period.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Unresectable Pleural or Peritoneal Malignant Mesothelioma
Intervention  ICMJE
  • Drug: Tremelimumab
    Tremelimumab is to be administered as an IV solution, followed by observation.
  • Drug: Placebo
    Placebo is to be administered as an IV solution, followed by observation.
Study Arms  ICMJE
  • Experimental: Tremelimumab
    Tremelimumab
    Intervention: Drug: Tremelimumab
  • Placebo Comparator: Placebo
    Placebo
    Intervention: Drug: Placebo
Publications * Maio M, Scherpereel A, Calabrò L, Aerts J, Cedres Perez S, 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: August 15, 2017)
571
Original Estimated Enrollment  ICMJE
 (submitted: April 25, 2013)
180
Estimated Study Completion Date  ICMJE December 31, 2019
Actual Primary Completion Date January 24, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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. 2. 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 erythematosis or Wegener's granulomatosis;
  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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belgium,   Canada,   Denmark,   France,   Germany,   Hungary,   Israel,   Italy,   Korea, Republic of,   Netherlands,   Poland,   Romania,   Russian Federation,   South Africa,   Spain,   Sweden,   United Kingdom,   United States
Removed Location Countries Brazil
 
Administrative Information
NCT Number  ICMJE NCT01843374
Other Study ID Numbers  ICMJE D4880C00003
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party MedImmune LLC
Study Sponsor  ICMJE MedImmune LLC
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account MedImmune LLC
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP