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

Phase 2

Completed

• Conditions: Mesothelioma
• Interventions: Other: Placebo plus Pem Platinum; Drug: ADI-PEG 20 plus Pem Platinum

• Registration Number: NCT02709512
• Lead Sponsor: Polaris Group

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2016-03-05
• Study First Submitted QC: 2016-03-10
• Study First Posted: 2016-03-16
• Study Start: 2017-08-01
• Primary Completion: 2022-08-15
• Study Completion: 2022-08-15
• Status Verified: 2023-08
• Results First Submitted: 2023-08-02
• Results First Submitted QC: 2023-09-09
• Last Update Submitted: 2023-09-09
• Results First Posted: 2023-10-04
• Last Update Posted: 2023-10-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 249

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Drug: Placebo plus Pem Platinum	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
Drug: ADI-PEG 20 plus Pem Platinum	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

Primary Outcome Measures

Name	Time	Method
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).
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	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 Outcome Measures

Name	Time	Method
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.

Trial Locations

Locations (44)

Wansbeck General Hospital; 🇬🇧 Ashington, Northumberland, United Kingdom

National Taiwan University Hospital; 🇨🇳 Taipei, Taiwan

UCLA Hematology & Oncology - Santa Monica; 🇺🇸 Los Angeles, California, United States

University of Chicago; 🇺🇸 Chicago, Illinois, United States

University of Maryland, Marlene & Stewart Greenebaum Comprehensive Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Chris O'Brien Lifehouse; 🇦🇺 Camperdown, New South Wales, Australia

Southampton General Hospital; 🇬🇧 Southampton, Hampshire, United Kingdom

Chang Gung Medical Foundation Kaohsiung; 🇨🇳 Kaohsiung, Taiwan

Southern Adelaide Local Health Network, Inc.; 🇦🇺 Bedford Park, South Australia, Australia

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

SS. Antonio e Biagio e Cesare Arrigo Hospital; 🇮🇹 Alessandria, AL, Italy

European Institute of Oncology; 🇮🇹 Milano, MI, Italy

Azienda Ospedaliero Universitaria di Parma; 🇮🇹 Parma, Italy

Austin Health; 🇦🇺 Heidelberg, Victoria, Australia

Tweed Hospital (NNSW LHD); 🇦🇺 Tweed Heads, New South Wales, Australia

Azienda Ospedaliera San Gerardo - Monza, Chirurgia Toracica; 🇮🇹 Monza, MB, Italy

Ospedale Villa Scassi; 🇮🇹 Genova, GE, Italy

Fondazione IRCCS Policlinico San Matteo; 🇮🇹 Pavia, PV, Italy

Azienda Ospedaliero Universitaria Pisana; 🇮🇹 Pisa, Italy

Humanitas Gavazzeni; 🇮🇹 Bergamo, BG, Italy

Taichung Veterans General Hospital; 🇨🇳 Taichung, Taiwan

Beatson West of Scotland Cancer Centre; 🇬🇧 Glasgow, United Kingdom

St Bartholomew's Hospital; 🇬🇧 London, United Kingdom

Fondazione IRCCS - Istituto Nazionale dei Tumori Milano; 🇮🇹 Milan, Italy

Velindre Cancer Centre; 🇬🇧 Cardiff, United Kingdom

University Hospital of South Manchester; 🇬🇧 Manchester, United Kingdom

University of California San Francisco Helen Diller Comprehensive Cancer Center; 🇺🇸 San Francisco, California, United States

H. Lee Moffitt Cancer Center & Research Institute; 🇺🇸 Tampa, Florida, United States

Henry Ford Hospital; 🇺🇸 Detroit, Michigan, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Princess Alexandria Hospital and Health Services; 🇦🇺 Woolloongabba, Queensland, Australia

Kaohsiung Medical University Chung-Ho Memorial Hospital; 🇨🇳 Kaohsiung, Taiwan

Chang Gung Memorial Foundation LinKou Branch; 🇨🇳 Taoyuan, Taiwan

University Hospitals Leicester; 🇬🇧 Leicester, Leicestershire, United Kingdom

Addenbrooke's Hospital; 🇬🇧 Cambridge, Cambridgeshire, United Kingdom

Scunthorpe General Hospital; 🇬🇧 Scunthorpe, North Lincolnshire, United Kingdom

St James's University Hospital; 🇬🇧 Leeds, United Kingdom

Oxford Cancer and Haematology Centre, The Churchill Hospital; 🇬🇧 Oxford, Oxfordshire, United Kingdom

Edinburgh Cancer Centre; 🇬🇧 Edinburgh, United Kingdom

Plymouth Hospitals (Derriford Hospital); 🇬🇧 Plymouth, Devon, United Kingdom

Centre for Experimental Cancer Medicine (CECM); 🇬🇧 London, England, United Kingdom

Taipei Veterans General Hospital; 🇨🇳 Taipei, Taiwan

Sir Charles Gairdner Hospital; 🇦🇺 Perth, Western Australia, Australia