Trial Outcomes & Findings for Ph 2/3 Study in Subjects With MPM to Assess ADI-PEG 20 With Pemetrexed and Cisplatin (NCT NCT02709512)

Last Updated: 2023-10-04

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

249 participants

Primary outcome timeframe

approximately 18 months

Results posted on

2023-10-04

Participant Flow

Participant milestones

Participant milestones
Measure	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	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
Phase 2 STARTED	87	89
Phase 2 COMPLETED	87	89
Phase 2 NOT COMPLETED	0	0
Phase 3 STARTED	125	124
Phase 3 COMPLETED	125	124
Phase 3 NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Ph 2/3 Study in Subjects With MPM to Assess ADI-PEG 20 With Pemetrexed and Cisplatin

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Drug: ADI-PEG 20 Plus Pem Platinum n=125 Participants 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	Drug: Placebo Plus Pem Platinum n=124 Participants 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	Total n=249 Participants Total of all reporting groups
Age, Continuous	69.5 years STANDARD_DEVIATION 7.98 • n=5 Participants	69.4 years STANDARD_DEVIATION 7.91 • n=7 Participants	69.4 years STANDARD_DEVIATION 7.93 • n=5 Participants
Sex: Female, Male Female	23 Participants n=5 Participants	20 Participants n=7 Participants	43 Participants n=5 Participants
Sex: Female, Male Male	102 Participants n=5 Participants	104 Participants n=7 Participants	206 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	119 Participants n=5 Participants	117 Participants n=7 Participants	236 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	5 Participants n=7 Participants	9 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) White	116 Participants n=5 Participants	116 Participants n=7 Participants	232 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: approximately 18 months

Outcome measures

Outcome measures
Measure	Drug: ADI-PEG 20 Plus Pem Platinum n=87 Participants 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	Drug: Placebo Plus Pem Platinum n=89 Participants 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
Response Rate	12 Participants	12 Participants

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Drug: ADI-PEG 20 Plus Pem Platinum n=78 Participants 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	Drug: Placebo Plus Pem Platinum n=91 Participants 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
Overall Survival Phase 3 Interim Analysis	9.82 months Interval 7.85 to 12.91	7.49 months Interval 5.88 to 9.46

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Drug: ADI-PEG 20 Plus Pem Platinum n=108 Participants 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	Drug: Placebo Plus Pem Platinum n=116 Participants 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
Overall Survival	9.30 months Interval 7.85 to 11.79	7.66 months Interval 6.14 to 9.53

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Drug: ADI-PEG 20 Plus Pem Platinum n=74 Participants 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	Drug: Placebo Plus Pem Platinum n=71 Participants 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
Progression Free Survival	6.24 months Interval 5.78 to 7.43	5.65 months Interval 4.14 to 5.91

Adverse Events

Drug: ADI-PEG 20 Plus Pem Platinum

Serious events: 19 serious events

Other events: 106 other events

Deaths: 62 deaths

Drug: Placebo Plus Pem Platinum

Serious events: 20 serious events

Other events: 111 other events

Deaths: 61 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Drug: ADI-PEG 20 Plus Pem Platinum n=125 participants at risk 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	Drug: Placebo Plus Pem Platinum n=124 participants at risk 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
Gastrointestinal disorders Nausea	52.0% 65/125 • Number of events 106 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	54.0% 67/124 • Number of events 111 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
General disorders Fatigue	52.8% 66/125 • Number of events 106 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	50.0% 62/124 • Number of events 111 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Gastrointestinal disorders Constipation	43.2% 54/125 • Number of events 106 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	33.1% 41/124 • Number of events 111 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Blood and lymphatic system disorders Anemia	27.2% 34/125 • Number of events 106 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	30.6% 38/124 • Number of events 111 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Metabolism and nutrition disorders Decreased Appetite	20.8% 26/125 • Number of events 106 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	35.5% 44/124 • Number of events 111 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.

Additional Information

Dr. Mirla Langlois

Polaris Pharmaceuitcals Inc

Phone: 858-452-6688

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Drug: ADI-PEG 20 Plus Pem Platinum n=125 participants at risk 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	Drug: Placebo Plus Pem Platinum n=124 participants at risk 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
Infections and infestations Pneumonia	4.0% 5/125 • Number of events 19 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	4.8% 6/124 • Number of events 20 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
General disorders Pyrexia	4.0% 5/125 • Number of events 15 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	6.5% 8/124 • Number of events 11 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Gastrointestinal disorders Nausea	0.80% 1/125 • Number of events 9 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	5.6% 7/124 • Number of events 16 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Respiratory, thoracic and mediastinal disorders Dyspnoea	4.8% 6/125 • Number of events 10 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	1.6% 2/124 • Number of events 7 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Cardiac disorders Atrial Fibrillation	3.2% 4/125 • Number of events 9 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	0.00% 0/124 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Renal and urinary disorders Acute Kidney Injury	4.8% 6/125 • Number of events 6 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	3.2% 4/124 • Number of events 4 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Blood and lymphatic system disorders Anemia	0.00% 0/125 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	4.0% 5/124 • Number of events 6 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Metabolism and nutrition disorders Dehydration	0.00% 0/125 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	2.4% 3/124 • Number of events 5 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Musculoskeletal and connective tissue disorders Musculoskeletal Testing	0.80% 1/125 • Number of events 2 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	2.4% 3/124 • Number of events 7 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Nervous system disorders Cerebrovascular Accident	0.80% 1/125 • Number of events 3 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	2.4% 3/124 • Number of events 6 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Injury, poisoning and procedural complications Fall	1.6% 2/125 • Number of events 5 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	0.81% 1/124 • Number of events 2 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Investigations Alanine aminotransferase increased	0.00% 0/125 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	1.6% 2/124 • Number of events 4 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Vascular disorders Deep Vein Thrombosis	0.00% 0/125 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	0.81% 1/124 • Number of events 2 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Immune system disorders Anaphylactic Reaction	1.6% 2/125 • Number of events 4 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	0.00% 0/124 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Psychiatric disorders Confusional State	0.00% 0/125 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	1.6% 2/124 • Number of events 2 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.
Infections and infestations Sepsis	0.80% 1/125 • Number of events 19 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.	4.8% 6/124 • Number of events 20 • Treatment-emergent AEs were collected with onset after the first dose of study drug or existing events that worsened after the first dose during the study, approximately 18 months.