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

Primary Purpose

Mesothelioma

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
ADI-PEG 20 plus Pem Platinum
Placebo plus Pem Platinum
Sponsored by
Polaris Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Mesothelioma focused on measuring Malignant Pleural Mesothelioma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Mayo Clinic
  • UCLA Hematology & Oncology - Santa Monica
  • University of California San Francisco Helen Diller Comprehensive Cancer Center
  • H. Lee Moffitt Cancer Center & Research Institute
  • University of Chicago
  • University of Maryland, Marlene & Stewart Greenebaum Comprehensive Cancer Center
  • Henry Ford Hospital
  • Mayo Clinic
  • Memorial Sloan Kettering Cancer Center
  • MD Anderson Cancer Center
  • Chris O'Brien Lifehouse
  • Tweed Hospital (NNSW LHD)
  • Princess Alexandria Hospital and Health Services
  • Southern Adelaide Local Health Network, Inc.
  • Austin Health
  • Sir Charles Gairdner Hospital
  • SS. Antonio e Biagio e Cesare Arrigo Hospital
  • Humanitas Gavazzeni
  • Ospedale Villa Scassi
  • Azienda Ospedaliera San Gerardo - Monza, Chirurgia Toracica
  • European Institute of Oncology
  • Fondazione IRCCS Policlinico San Matteo
  • Fondazione IRCCS - Istituto Nazionale dei Tumori Milano
  • Azienda Ospedaliero Universitaria di Parma
  • Azienda Ospedaliero Universitaria Pisana
  • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Chang Gung Medical Foundation Kaohsiung
  • Taichung Veterans General Hospital
  • National Taiwan University Hospital
  • Taipei Veterans General Hospital
  • Chang Gung Memorial Foundation LinKou Branch
  • Addenbrooke's Hospital
  • Plymouth Hospitals (Derriford Hospital)
  • Centre for Experimental Cancer Medicine (CECM)
  • Southampton General Hospital
  • University Hospitals Leicester
  • Scunthorpe General Hospital
  • Wansbeck General Hospital
  • Oxford Cancer and Haematology Centre, The Churchill Hospital
  • Velindre Cancer Centre
  • Edinburgh Cancer Centre
  • Beatson West of Scotland Cancer Centre
  • St James's University Hospital
  • St Bartholomew's Hospital
  • University Hospital of South Manchester

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Drug: ADI-PEG 20 plus Pem Platinum

Drug: Placebo plus Pem Platinum

Arm Description

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

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

Outcomes

Primary Outcome Measures

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).
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).
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).

Secondary Outcome Measures

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.

Full Information

First Posted
March 5, 2016
Last Updated
September 9, 2023
Sponsor
Polaris Group
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1. Study Identification

Unique Protocol Identification Number
NCT02709512
Brief Title
Ph 2/3 Study in Subjects With MPM to Assess ADI-PEG 20 With Pemetrexed and Cisplatin
Acronym
ATOMIC
Official Title
Randomized, Double-Blind, Phase 2/3 Study in Subjects With Malignant Pleural Mesotheliomato Assess ADI-PEG 20 With Pemetrexed and Cisplatin (ATOMIC-Meso Phase 2/3 Study)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Completed
Study Start Date
August 1, 2017 (Actual)
Primary Completion Date
August 15, 2022 (Actual)
Study Completion Date
August 15, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Polaris Group

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mesothelioma
Keywords
Malignant Pleural Mesothelioma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
249 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Drug: ADI-PEG 20 plus Pem Platinum
Arm Type
Experimental
Arm Description
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
Arm Title
Drug: Placebo plus Pem Platinum
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
ADI-PEG 20 plus Pem Platinum
Other Intervention Name(s)
Pemetrexed, Cisplatin, Carboplatin
Intervention Description
Investigational Drug in combination approved standard of care treatment for this indication
Intervention Type
Other
Intervention Name(s)
Placebo plus Pem Platinum
Other Intervention Name(s)
Pemetrexed, Cisplatin, Carboplatin
Intervention Description
Placebo in combination approved standard of care treatment for this indication
Primary Outcome Measure Information:
Title
Response Rate
Description
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
Title
Overall Survival Phase 3 Interim Analysis
Description
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
Title
Overall Survival
Description
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
Secondary Outcome Measure Information:
Title
Progression Free Survival
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John S Bomalaski, MD
Organizational Affiliation
Polaris Group
Official's Role
Study Director
Facility Information:
Facility Name
Mayo Clinic
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85054
Country
United States
Facility Name
UCLA Hematology & Oncology - Santa Monica
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
University of California San Francisco Helen Diller Comprehensive Cancer Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
H. Lee Moffitt Cancer Center & Research Institute
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
University of Maryland, Marlene & Stewart Greenebaum Comprehensive Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Henry Ford Hospital
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Chris O'Brien Lifehouse
City
Camperdown
State/Province
New South Wales
ZIP/Postal Code
2050
Country
Australia
Facility Name
Tweed Hospital (NNSW LHD)
City
Tweed Heads
State/Province
New South Wales
ZIP/Postal Code
2486
Country
Australia
Facility Name
Princess Alexandria Hospital and Health Services
City
Woolloongabba
State/Province
Queensland
ZIP/Postal Code
4102
Country
Australia
Facility Name
Southern Adelaide Local Health Network, Inc.
City
Bedford Park
State/Province
South Australia
ZIP/Postal Code
5042
Country
Australia
Facility Name
Austin Health
City
Heidelberg
State/Province
Victoria
ZIP/Postal Code
3084
Country
Australia
Facility Name
Sir Charles Gairdner Hospital
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6009
Country
Australia
Facility Name
SS. Antonio e Biagio e Cesare Arrigo Hospital
City
Alessandria
State/Province
AL
ZIP/Postal Code
15121
Country
Italy
Facility Name
Humanitas Gavazzeni
City
Bergamo
State/Province
BG
ZIP/Postal Code
24125
Country
Italy
Facility Name
Ospedale Villa Scassi
City
Genova
State/Province
GE
ZIP/Postal Code
16149
Country
Italy
Facility Name
Azienda Ospedaliera San Gerardo - Monza, Chirurgia Toracica
City
Monza
State/Province
MB
ZIP/Postal Code
20900
Country
Italy
Facility Name
European Institute of Oncology
City
Milano
State/Province
MI
ZIP/Postal Code
20141
Country
Italy
Facility Name
Fondazione IRCCS Policlinico San Matteo
City
Pavia
State/Province
PV
ZIP/Postal Code
27100
Country
Italy
Facility Name
Fondazione IRCCS - Istituto Nazionale dei Tumori Milano
City
Milan
ZIP/Postal Code
20133
Country
Italy
Facility Name
Azienda Ospedaliero Universitaria di Parma
City
Parma
ZIP/Postal Code
43126
Country
Italy
Facility Name
Azienda Ospedaliero Universitaria Pisana
City
Pisa
ZIP/Postal Code
56124
Country
Italy
Facility Name
Kaohsiung Medical University Chung-Ho Memorial Hospital
City
Kaohsiung
ZIP/Postal Code
807
Country
Taiwan
Facility Name
Chang Gung Medical Foundation Kaohsiung
City
Kaohsiung
ZIP/Postal Code
83301
Country
Taiwan
Facility Name
Taichung Veterans General Hospital
City
Taichung
ZIP/Postal Code
407
Country
Taiwan
Facility Name
National Taiwan University Hospital
City
Taipei
ZIP/Postal Code
10002
Country
Taiwan
Facility Name
Taipei Veterans General Hospital
City
Taipei
ZIP/Postal Code
112
Country
Taiwan
Facility Name
Chang Gung Memorial Foundation LinKou Branch
City
Taoyuan
ZIP/Postal Code
33305
Country
Taiwan
Facility Name
Addenbrooke's Hospital
City
Cambridge
State/Province
Cambridgeshire
ZIP/Postal Code
CB20QQ
Country
United Kingdom
Facility Name
Plymouth Hospitals (Derriford Hospital)
City
Plymouth
State/Province
Devon
ZIP/Postal Code
PL6 8DH
Country
United Kingdom
Facility Name
Centre for Experimental Cancer Medicine (CECM)
City
London
State/Province
England
ZIP/Postal Code
EC1M 6BQ
Country
United Kingdom
Facility Name
Southampton General Hospital
City
Southampton
State/Province
Hampshire
ZIP/Postal Code
SO16 6YD
Country
United Kingdom
Facility Name
University Hospitals Leicester
City
Leicester
State/Province
Leicestershire
ZIP/Postal Code
LE1 5WW
Country
United Kingdom
Facility Name
Scunthorpe General Hospital
City
Scunthorpe
State/Province
North Lincolnshire
ZIP/Postal Code
DN15 7BH
Country
United Kingdom
Facility Name
Wansbeck General Hospital
City
Ashington
State/Province
Northumberland
ZIP/Postal Code
NE63 9JJ
Country
United Kingdom
Facility Name
Oxford Cancer and Haematology Centre, The Churchill Hospital
City
Oxford
State/Province
Oxfordshire
ZIP/Postal Code
OX3 7LE
Country
United Kingdom
Facility Name
Velindre Cancer Centre
City
Cardiff
ZIP/Postal Code
CF14 2TL
Country
United Kingdom
Facility Name
Edinburgh Cancer Centre
City
Edinburgh
ZIP/Postal Code
EH4 2XU
Country
United Kingdom
Facility Name
Beatson West of Scotland Cancer Centre
City
Glasgow
ZIP/Postal Code
G12 0YN
Country
United Kingdom
Facility Name
St James's University Hospital
City
Leeds
ZIP/Postal Code
LS9 7TF
Country
United Kingdom
Facility Name
St Bartholomew's Hospital
City
London
ZIP/Postal Code
EC1A 7BE
Country
United Kingdom
Facility Name
University Hospital of South Manchester
City
Manchester
ZIP/Postal Code
M23 9LT
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
34589965
Citation
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.
Results Reference
derived
PubMed Identifier
33358660
Citation
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.
Results Reference
derived

Learn more about this trial

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

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