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

NCT02709512 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: POLARIS2015-003
• Study Type: interventional
• Target: 249
• Locations: 5 countries
• Sites: 45

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.

Conditions

Mesothelioma

Keywords

Malignant Pleural Mesothelioma

Outcome Measures

Primary Outcomes (3)

• 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).

  approximately 18 months

• 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).

  Approximately 18 months

• 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).

  18 months

Secondary Outcomes (1)

• Progression Free Survival

  approximately 18 months

Study Arms (2)

Drug: ADI-PEG 20 plus Pem Platinum

EXPERIMENTAL

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: ADI-PEG 20 plus Pem Platinum

Drug: Placebo plus Pem Platinum

PLACEBO COMPARATOR

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

Other: Placebo plus Pem Platinum

Interventions

ADI-PEG 20 plus Pem Platinum DRUG

Investigational Drug in combination approved standard of care treatment for this indication

Also known as: Pemetrexed, Cisplatin, Carboplatin

Drug: ADI-PEG 20 plus Pem Platinum

Placebo plus Pem Platinum OTHER

Placebo in combination approved standard of care treatment for this indication

Also known as: Pemetrexed, Cisplatin, Carboplatin

Drug: Placebo plus Pem Platinum

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Polaris Group: lead

Study Sites (45)

Mayo Clinic

Phoenix, Arizona, 85054, United States

Location

UCLA Hematology & Oncology - Santa Monica

Los Angeles, California, 90095, United States

Location

University of California San Francisco Helen Diller Comprehensive Cancer Center

San Francisco, California, 94115, United States

Location

H. Lee Moffitt Cancer Center & Research Institute

Tampa, Florida, 33612, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

University of Maryland, Marlene & Stewart Greenebaum Comprehensive Cancer Center

Baltimore, Maryland, 21201, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Chris O'Brien Lifehouse

Camperdown, New South Wales, 2050, Australia

Location

Tweed Hospital (NNSW LHD)

Tweed Heads, New South Wales, 2486, Australia

Location

Princess Alexandria Hospital and Health Services

Woolloongabba, Queensland, 4102, Australia

Location

Southern Adelaide Local Health Network, Inc.

Bedford Park, South Australia, 5042, Australia

Location

Austin Health

Heidelberg, Victoria, 3084, Australia

Location

Sir Charles Gairdner Hospital

Perth, Western Australia, 6009, Australia

Location

SS. Antonio e Biagio e Cesare Arrigo Hospital

Alessandria, AL, 15121, Italy

Location

Humanitas Gavazzeni

Bergamo, BG, 24125, Italy

Location

Ospedale Villa Scassi

Genova, GE, 16149, Italy

Location

Azienda Ospedaliera San Gerardo - Monza, Chirurgia Toracica

Monza, MB, 20900, Italy

Location

European Institute of Oncology

Milan, MI, 20141, Italy

Location

Fondazione IRCCS Policlinico San Matteo

Pavia, PV, 27100, Italy

Location

Fondazione IRCCS - Istituto Nazionale dei Tumori Milano

Milan, 20133, Italy

Location

Azienda Ospedaliero Universitaria di Parma

Parma, 43126, Italy

Location

Azienda Ospedaliero Universitaria Pisana

Pisa, 56124, Italy

Location

Kaohsiung Medical University Chung-Ho Memorial Hospital

Kaohsiung City, 807, Taiwan

Location

Chang Gung Medical Foundation Kaohsiung

Kaohsiung City, 83301, Taiwan

Location

Taichung Veterans General Hospital

Taichung, 407, Taiwan

Location

National Taiwan University Hospital

Taipei, 10002, Taiwan

Location

Taipei Veterans General Hospital

Taipei, 112, Taiwan

Location

Chang Gung Memorial Foundation LinKou Branch

Taoyuan District, 33305, Taiwan

Location

Addenbrooke's Hospital

Cambridge, Cambridgeshire, CB20QQ, United Kingdom

Location

Plymouth Hospitals (Derriford Hospital)

Plymouth, Devon, PL6 8DH, United Kingdom

Location

Centre for Experimental Cancer Medicine (CECM)

London, England, EC1M 6BQ, United Kingdom

Location

Southampton General Hospital

Southampton, Hampshire, SO16 6YD, United Kingdom

Location

University Hospitals Leicester

Leicester, Leicestershire, LE1 5WW, United Kingdom

Location

Scunthorpe General Hospital

Scunthorpe, North Lincolnshire, DN15 7BH, United Kingdom

Location

Wansbeck General Hospital

Ashington, Northumberland, NE63 9JJ, United Kingdom

Location

Oxford Cancer and Haematology Centre, The Churchill Hospital

Oxford, Oxfordshire, OX3 7LE, United Kingdom

Location

Velindre Cancer Centre

Cardiff, CF14 2TL, United Kingdom

Location

Edinburgh Cancer Centre

Edinburgh, EH4 2XU, United Kingdom

Location

Beatson West of Scotland Cancer Centre

Glasgow, G12 0YN, United Kingdom

Location

St James's University Hospital

Leeds, LS9 7TF, United Kingdom

Location

St Bartholomew's Hospital

London, EC1A 7BE, United Kingdom

Location

University Hospital of South Manchester

Manchester, M23 9LT, United Kingdom

Location

Related Publications (3)

• Szlosarek PW, Creelan BC, Sarkodie T, Nolan L, Taylor P, Olevsky O, Grosso F, Cortinovis D, Chitnis M, Roy A, Gilligan D, Kindler H, Papadatos-Pastos D, Ceresoli GL, Mansfield AS, Tsao A, O'Byrne KJ, Nowak AK, Steele J, Sheaff M, Shiu CF, Kuo CL, Johnston A, Bomalaski J, Zauderer MG, Fennell DA; ATOMIC-Meso Study Group. Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial. JAMA Oncol. 2024 Apr 1;10(4):475-483. doi: 10.1001/jamaoncol.2023.6789.

  PMID: 38358753 DERIVED

• Szlosarek PW, Phillips MM, Pavlyk I, Steele J, Shamash J, Spicer J, Kumar S, Pacey S, Feng X, Johnston A, Bomalaski J, Moir G, Lau K, Ellis S, Sheaff M. Expansion Phase 1 Study of Pegargiminase Plus Pemetrexed and Cisplatin in Patients With Argininosuccinate Synthetase 1-Deficient Mesothelioma: Safety, Efficacy, and Resistance Mechanisms. JTO Clin Res Rep. 2020 Sep 3;1(4):100093. doi: 10.1016/j.jtocrr.2020.100093. eCollection 2020 Nov.

  PMID: 34589965 DERIVED

• Uprety D. CheckMate 743: A Glimmer of Hope for Malignant Pleural Mesothelioma. Clin Lung Cancer. 2021 Mar;22(2):71-73. doi: 10.1016/j.cllc.2020.11.009. Epub 2020 Dec 2. No abstract available.

  PMID: 33358660 DERIVED

MeSH Terms

Conditions

Mesothelioma; Mesothelioma, Malignant

Interventions

ADI PEG20; Pemetrexed; Cisplatin; Carboplatin

Condition Hierarchy (Ancestors)

Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Pleural Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Coordination Complexes; Organic Chemicals

Limitations and Caveats

Enrollment stopped early at the recommendation of the DSMB due to interim analysis positive results and because of slow study enrollment related to an evolving treatment landscape for MPM and the COVID-19 pandemic.

Results Point of Contact

• Title: Dr. Mirla Langlois
• Organization: Polaris Pharmaceuitcals Inc

mlanglois@polarispharma.com

858-452-6688

Study Officials

• John S Bomalaski, MD

  Polaris Group

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 5, 2016
• First Posted: March 16, 2016
• Study Start: August 1, 2017
• Primary Completion: August 15, 2022
• Study Completion: August 15, 2022
• Last Updated: October 4, 2023
• Results First Posted: October 4, 2023

Record last verified: 2023-08

Locations

IT (9); TW (6); AU (6); GB (14); US (10)