Mesothelioma
Conditions
Keywords
Malignant Pleural Mesothelioma
Brief summary
This is a study of ADI-PEG 20 (pegylated arginine deiminase), an arginine degrading enzyme versus placebo in patients with malignant pleural mesothelioma. Malignant pleural mesothelioma have been found to require arginine, an amino acid. Thus the hypothesis is that by restricting arginine with ADI-PEG 20, the malignant pleural mesothelioma cells will starve and die.
Interventions
DRUGADI-PEG 20 plus Pem Platinum
Investigational Drug in combination approved standard of care treatment for this indication
OTHERPlacebo plus Pem Platinum
Placebo in combination approved standard of care treatment for this indication
Sponsors
Polaris Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically proven unresectable MPM of biphasic or sarcomatoid histology * Naïve to chemotherapy or immunotherapy * ECOG PS 0-1 * Expected survival of at least 3 months * Age 18 years or over (there is no upper age limit) * Measurable disease by modified RECIST criteria for MPM for local pleural disease and RECIST 1.1 criteria for metastatic lesions * Written (signed and dated) informed consent and must be capable of co-operating with treatment and follow up * Adequate hematologic, hepatic, and renal function
Exclusion criteria
* Radiotherapy (except for palliative reasons) in the previous two weeks before study treatment * History of unstable cardiac disease * Ongoing toxic manifestations of previous treatments * Symptomatic brain or spinal cord metastases (patients must be stable for \> 1 month post radiotherapy or surgery) * Major thoracic or abdominal surgery from which the patient has not yet recovered.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate | approximately 18 months | Objective Response Rate is calculated as the proportion of subjects whose best tumor response from all post-baseline tumor assessments is complete response (CR) or partial response (PR). The best tumor response is the best response recorded from the start of the treatment until the end of treatment taking into account any requirement for confirmation. To test Objective Response Rate significance, a Relative Risk Ratio (ADI-PEG 20 / Placebo) was calculated as the common relative risk of having a response (CR or PR) based on the Mantel-Haenszel estimator controlling for tumor histology (biphasic versus sarcomatoid). |
| Overall Survival Phase 3 Interim Analysis | Approximately 18 months | The primary analysis of OS Phase 3 was performed at the interim analysis. This was performed once 50% of the planned OS events for phase 3 have occurred (ie, 169 of the 338 planned OS events). This interim analysis will evaluate OS in the ITT population in an unblinded manner. The OS data at the second interim analysis will be analyzed to support the following decisions: Futility stopping: Terminate the study due to futility at the interim analysis. Sample size re-estimation: Increase the target number of OS events after the second interim analysis.. The treatment effect on OS will be evaluated using the stratified log-rank test (stratified by tumor histology). |
| Overall Survival | 18 months | Overall survival is defined as the time from randomization until death. In the event that no death was documented prior to study termination or analysis cutoff, OS was censored at the last known date the subject was known to be alive, either through completion of on-study visits or through survival follow-up contact. The treatment effect on OS was evaluated using the stratified log-rank test (stratified by tumor histology). The Kaplan-Meier curves were also plotted. A Cox proportional hazard model with an adjustment for tumor histology (biphasic vs sarcomatoid) was used to compute the estimated hazard ratio and two-sided 95% CI. The treatment effect on OS was evaluated using the stratified log-rank test (stratified by tumor histology). The significance level to be used in the OS analysis at the final analysis was based on α = 0.04999 (two-sided). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | approximately 18 months | The key secondary endpoint for the phase 3 portion is PFS, which will be analyzed only if the analysis of OS is statistically significant at the final analysis, with alpha level of 0.05 (two-sided) using the same statistical methodologies as applied to OS. |
Countries
Australia, Italy, Taiwan, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Drug: ADI-PEG 20 Plus Pem Platinum Dose: 36 mg/m2 given weekly Route of Administration: Intramuscular (IM) Duration : Course of Study
In Combination With:
Pemetrexed Dose: 500 mg/m2 every 3 weeks Route of Administration: Intravenous Cisplatin Dose: 75 mg/m2 every 3 weeks Route of Administration: Intravenous Carboplatin Dose: AUC 5 mg/mL/min every 3 weeks Route of Administration: Intravenous
ADI-PEG 20 plus Pem Platinum: Investigational Drug in combination approved standard of care treatment for this indication | 125 |
| Drug: Placebo Plus Pem Platinum Dose: 36 mg/m2 given weekly Route of Administration: Intramuscular (IM) Duration : Course of Study
In Combination With:
Pemetrexed Dose: 500 mg/m2 every 3 weeks Route of Administration: Intravenous Cisplatin Dose: 75 mg/m2 every 3 weeks Carboplatin Dose: AUC 5 mg/mL/min every 3 weeks Route of Administration: Intravenous
Placebo plus Pem Platinum: Placebo in combination approved standard of care treatment for this indication | 124 |
| Total | 249 |
Baseline characteristics
| Characteristic | Drug: Placebo Plus Pem Platinum | Total | Drug: ADI-PEG 20 Plus Pem Platinum |
|---|---|---|---|
| Age, Continuous | 69.4 years STANDARD_DEVIATION 7.91 | 69.4 years STANDARD_DEVIATION 7.93 | 69.5 years STANDARD_DEVIATION 7.98 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 117 Participants | 236 Participants | 119 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 9 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 10 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 116 Participants | 232 Participants | 116 Participants |
| Sex: Female, Male Female | 20 Participants | 43 Participants | 23 Participants |
| Sex: Female, Male Male | 104 Participants | 206 Participants | 102 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 62 / 125 | 61 / 124 |
| other Total, other adverse events | 106 / 125 | 111 / 124 |
| serious Total, serious adverse events | 19 / 125 | 20 / 124 |
Outcome results
Primary
Overall Survival
Overall survival is defined as the time from randomization until death. In the event that no death was documented prior to study termination or analysis cutoff, OS was censored at the last known date the subject was known to be alive, either through completion of on-study visits or through survival follow-up contact. The treatment effect on OS was evaluated using the stratified log-rank test (stratified by tumor histology). The Kaplan-Meier curves were also plotted. A Cox proportional hazard model with an adjustment for tumor histology (biphasic vs sarcomatoid) was used to compute the estimated hazard ratio and two-sided 95% CI. The treatment effect on OS was evaluated using the stratified log-rank test (stratified by tumor histology). The significance level to be used in the OS analysis at the final analysis was based on α = 0.04999 (two-sided).
Time frame: 18 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Drug: ADI-PEG 20 Plus Pem Platinum | Overall Survival | 9.30 months |
| Drug: Placebo Plus Pem Platinum | Overall Survival | 7.66 months |
p-value: 0.023495% CI: [0.55, 0.93]Log Rank
Primary
Overall Survival Phase 3 Interim Analysis
The primary analysis of OS Phase 3 was performed at the interim analysis. This was performed once 50% of the planned OS events for phase 3 have occurred (ie, 169 of the 338 planned OS events). This interim analysis will evaluate OS in the ITT population in an unblinded manner. The OS data at the second interim analysis will be analyzed to support the following decisions: Futility stopping: Terminate the study due to futility at the interim analysis. Sample size re-estimation: Increase the target number of OS events after the second interim analysis.. The treatment effect on OS will be evaluated using the stratified log-rank test (stratified by tumor histology).
Time frame: Approximately 18 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Drug: ADI-PEG 20 Plus Pem Platinum | Overall Survival Phase 3 Interim Analysis | 9.82 months |
| Drug: Placebo Plus Pem Platinum | Overall Survival Phase 3 Interim Analysis | 7.49 months |
p-value: 0.007895% CI: [0.47, 0.88]Log Rank
Primary
Response Rate
Objective Response Rate is calculated as the proportion of subjects whose best tumor response from all post-baseline tumor assessments is complete response (CR) or partial response (PR). The best tumor response is the best response recorded from the start of the treatment until the end of treatment taking into account any requirement for confirmation. To test Objective Response Rate significance, a Relative Risk Ratio (ADI-PEG 20 / Placebo) was calculated as the common relative risk of having a response (CR or PR) based on the Mantel-Haenszel estimator controlling for tumor histology (biphasic versus sarcomatoid).
Time frame: approximately 18 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Drug: ADI-PEG 20 Plus Pem Platinum | Response Rate | 12 Participants |
| Drug: Placebo Plus Pem Platinum | Response Rate | 12 Participants |
p-value: 0.948995% CI: [0.5, 2.11]Cochran-Mantel-Haenszel
Secondary
Progression Free Survival
The key secondary endpoint for the phase 3 portion is PFS, which will be analyzed only if the analysis of OS is statistically significant at the final analysis, with alpha level of 0.05 (two-sided) using the same statistical methodologies as applied to OS.
Time frame: approximately 18 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Drug: ADI-PEG 20 Plus Pem Platinum | Progression Free Survival | 6.24 months |
| Drug: Placebo Plus Pem Platinum | Progression Free Survival | 5.65 months |
p-value: 0.019395% CI: [0.46, 0.9]Log Rank