Unresectable Pleural or Peritoneal Malignant Mesothelioma
Conditions
Keywords
tremelimumab, pleural, peritoneal, malignant mesothelioma, CTLA-4
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.
Interventions
DRUGTremelimumab
Tremelimumab is to be administered as an IV solution, followed by observation.
DRUGPlacebo
Placebo is to be administered as an IV solution, followed by observation.
Sponsors
MedImmune LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 3 years. | Overall survival (OS) by treatment arm |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| OS Rate at 18 Months by Treatment Arm | 18 months | The percentage of patients still alive at 18 months |
| Progression-free Survival by Treatment Arm | 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 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 | 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 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 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 | 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 | Day 1 to 90 days post dose | — |
| Number of Participants With Positive Anti-drug Antibodies | Week 5 | The immunogenicity titer is reported for samples confirmed positive for the presence of anti tremelimumab antibodies. |
Countries
Australia, Belgium, Canada, Denmark, France, Germany, Hungary, Israel, Italy, Netherlands, Poland, Romania, Russia, South Africa, South Korea, Spain, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 658 patients were screened, 87 patients were excluded from randomisation and 571 patients were randomised: Of the 78 excluded, 66 did not meet inclusion/exclusion criteria; 19 withdrew consent and 2 were excluded for other reasons.
Participants by arm
| Arm | Count |
|---|---|
| TREMELIMUMAB TREMELIMUMAB 10 mg/kg | 382 |
| PLACEBO Placebo. | 189 |
| Total | 571 |
Baseline characteristics
| Characteristic | TREMELIMUMAB | PLACEBO | Total |
|---|---|---|---|
| Age, Continuous | 65.2 Years STANDARD_DEVIATION 9.24 | 66.3 Years STANDARD_DEVIATION 8.8 | 65.6 Years STANDARD_DEVIATION 9.1 |
| Age, Customized < 65 years | 162 Participants | 75 Participants | 237 Participants |
| Age, Customized >= 65 years | 220 Participants | 114 Participants | 334 Participants |
| Sex: Female, Male Female | 99 Participants | 38 Participants | 137 Participants |
| Sex: Female, Male Male | 283 Participants | 151 Participants | 434 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 160 / 189 | 318 / 382 |
| other Total, other adverse events | 159 / 189 | 338 / 380 |
| serious Total, serious adverse events | 85 / 189 | 218 / 380 |
Outcome results
Primary
Overall Survival (OS)
Overall survival (OS) by treatment arm
Time frame: 3 years.
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PLACEBO | Overall Survival (OS) | Number patients censored <= 2 weeks before DCO | 25 Number of Participants |
| PLACEBO | Overall Survival (OS) | Number of patients with Events (Death) | 154 Number of Participants |
| PLACEBO | Overall Survival (OS) | Number of patients censored > 2 weeks before DCO | 10 Number of Participants |
| TREMELIMUMAB | Overall Survival (OS) | Number of patients with Events (Death) | 307 Number of Participants |
| TREMELIMUMAB | Overall Survival (OS) | Number patients censored <= 2 weeks before DCO | 58 Number of Participants |
| TREMELIMUMAB | Overall Survival (OS) | Number of patients censored > 2 weeks before DCO | 17 Number of Participants |
Comparison: H0: No difference between tremelimumab and placebo H1: Difference between tremelimumab and placebop-value: 0.408195% CI: [0.76, 1.12]Log Rank
Secondary
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 frame: Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years.
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PLACEBO | Disease Control Rate by Treatment Arm | 21.7 Percentage |
| TREMELIMUMAB | Disease Control Rate by Treatment Arm | 27.7 Percentage |
Secondary
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 frame: Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years.
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PLACEBO | Durable Disease Control Rate by Treatment Arm | 16.8 Percentage |
| TREMELIMUMAB | Durable Disease Control Rate by Treatment Arm | 11.6 Percentage |
Secondary
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.
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.
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PLACEBO | Duration of Response by Treatment Arm | 4.8 Months |
| TREMELIMUMAB | Duration of Response by Treatment Arm | 5.57 Months |
Secondary
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.
Time frame: Day 1- 90 days post dose
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PLACEBO | Number of Participants Reporting Any Adverse Event | 364 Participants |
| TREMELIMUMAB | Number of Participants Reporting Any Adverse Event | 179 Participants |
Secondary
Number of Participants Reporting Any Serious Adverse Events
Time frame: Day 1 to 90 days post dose
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PLACEBO | Number of Participants Reporting Any Serious Adverse Events | 85 Participants |
| TREMELIMUMAB | Number of Participants Reporting Any Serious Adverse Events | 218 Participants |
Secondary
Number of Participants With Positive Anti-drug Antibodies
The immunogenicity titer is reported for samples confirmed positive for the presence of anti tremelimumab antibodies.
Time frame: Week 5
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PLACEBO | Number of Participants With Positive Anti-drug Antibodies | 0 Participants |
| TREMELIMUMAB | Number of Participants With Positive Anti-drug Antibodies | 15 Participants |
Secondary
OS Rate at 18 Months by Treatment Arm
The percentage of patients still alive at 18 months
Time frame: 18 months
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PLACEBO | OS Rate at 18 Months by Treatment Arm | 17.4 Percentage of Participants |
| TREMELIMUMAB | OS Rate at 18 Months by Treatment Arm | 18.2 Percentage of Participants |
p-value: 0.92695% CI: [0.793, 1.289]Log Rank
Secondary
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 frame: Time from randomization to best response to treatment, assessed up to 3 years.
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PLACEBO | Overall Response Rate by Treatment Arm | 4.5 Percentage |
| TREMELIMUMAB | Overall Response Rate by Treatment Arm | 1.1 Percentage |
Secondary
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 frame: Time from randomization to disease progression or death, whichever occurs first, assessed up to 3 years.
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PLACEBO | Progression-free Survival by Treatment Arm | 2.69 Months |
| TREMELIMUMAB | Progression-free Survival by Treatment Arm | 2.76 Months |
p-value: 0.032595% CI: [0.68, 0.98]Log Rank