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Clinical Trial Results:
A Randomised Stratified Multicentre Phase II Clinical Trial of Single-Agent ADI-PEG 20 (Pegylated Arginine Deiminase) in Patients with Malignant Pleural Mesothelioma.

Summary
EudraCT number	2006-004592-35
Trial protocol	GB
Global end of trial date	30 Apr 2015

Results information
Results version number	v2(current)
This version publication date	19 Dec 2021
First version publication date	16 Sep 2017
Other versions	v1
Version creation reason	Correction of full data set A p value anomaly has been identified that needs correcting
Summary report(s)	ADAM Publication_Sep2016

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

6836

ISRCTN number

US NCT number

NCT01279967

WHO universal trial number (UTN)

Sponsor organisation name

Barts Health NHS Trust

Sponsor organisation address

5 Walden Street, London, United Kingdom, E1 2EF

Public contact

CECM Trials Team, Queen Mary University London, 0044 02078828197, bci-cecmmonitoring@qmul.ac.uk

Scientific contact

CECM Trials Team, Queen Mary University London, 0044 02078828197, bci-cecmmonitoring@qmul.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

01 Sep 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Apr 2015

Global end of trial reached?

Yes

Global end of trial date

30 Apr 2015

Was the trial ended prematurely?

Main objective of the trial

To assess the time to disease progression between the control group receiving best supportive care and the group receiving ADI-PEG 20 and best supportive care.

Protection of trial subjects

The Trial Management Group consisted of an independent chairperson, the Chief Investigator, trial co-ordination team, collaborators, and the trial statistician and provided review of cumulative reports of all Serious Adverse Events (SAEs) on a minimum 6 monthly basis to identify patterns or trends of events or identify safety issues, which would not be apparent on an individual basis.

Background therapy

Evidence for comparator

Actual start date of recruitment

14 Jan 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 68

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

From March 2, 2011 to March 21, 2013 201 patients were screened to take part in ADAM.

Screening details

From March 2, 2011 to March 21, 2013 201 patients were screened to take part in ADAM. Of these 97 were found to be ASS1 negative and 70 were randomised into the trial. 2 patients were subsequently found to be ineligible so that the total number of patients randomised into the trial is 68.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Not applicable

Are arms mutually exclusive

Yes

ADI-PEG20 + BSC

Arm description

Patients randomised into this arm received a weekly intramuscular injection of ADI-PEG20 (36.8mg/m2) for up to 6 months (cycles) plus best supportive care (BSC). Patients continued to receive study treatment, with regular blood sampling, until disease progression, withdrawal of consent, or unacceptable toxic effects. ADI-PEG20–treated patients with disease control were allowed to exceed 6 cycles. Chemotherapy-naive patients were offered chemotherapy on progression.

Arm type

Experimental

Investigational medicinal product name

Pegylated arginine deiminase (ADI-PEG 20)

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Weekly intramuscular injection of ADI-PEG20 dose of 36.8mg/m2 (equivalent to 320IU/m2) for up to 6 months.

BSC alone

Arm description

Best supportive care

Arm type

Control

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	ADI-PEG20 + BSC	BSC alone
Started	44	24
Completed	44	24

Baseline characteristics

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Reporting group title

ADI-PEG20 + BSC

Reporting group description

Reporting group title

BSC alone

Reporting group description

Best supportive care

Reporting group values	ADI-PEG20 + BSC	BSC alone	Total
Number of subjects	44	24	68
Age categorical
Units: Subjects
Adults (18-64 years)	17	13	30
From 65-84 years	27	11	38
Gender categorical
Units: Subjects
Female	8	5	13
Male	36	19	55
ECOG
Units: Subjects
PS 0	9	7	16
PS 1	35	17	52
Smoking history
Units: Subjects
Never smoker	18	7	25
Current smoker	1	1	2
Ex-smoker	25	16	41
Histological sub-type
Units: Subjects
Sarcomatoid	1	1	2
Non-sarcomatoid	43	23	66
Prior Chemotherapy
Units: Subjects
None	17	11	28
Platinum based	27	13	40

Subject analysis set title

All analyses

Subject analysis set type

Intention-to-treat

Subject analysis set description

All eligible patients that had been randomised (excludes 2 patients who were randomised but not eligible, as ascertained after randomisation)

Subject analysis sets values	All analyses
Number of subjects	68
Age categorical
Units: Subjects
Adults (18-64 years)	30
From 65-84 years	38
Age continuous
Units:
	±
Gender categorical
Units: Subjects
Female
Male
ECOG
Units: Subjects
PS 0
PS 1
Smoking history
Units: Subjects
Never smoker
Current smoker
Ex-smoker
Histological sub-type
Units: Subjects
Sarcomatoid
Non-sarcomatoid
Prior Chemotherapy
Units: Subjects
None
Platinum based

End points

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Reporting group title

ADI-PEG20 + BSC

Reporting group description

Reporting group title

BSC alone

Reporting group description

Best supportive care

Subject analysis set title

All analyses

Subject analysis set type

Intention-to-treat

Subject analysis set description

All eligible patients that had been randomised (excludes 2 patients who were randomised but not eligible, as ascertained after randomisation)

Primary: Progression free survival

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End point title

Progression free survival

End point description

End point type

Primary

End point timeframe

Until end of follow up

End point values	ADI-PEG20 + BSC	BSC alone
Number of subjects analysed	44	24
Units: Months
median (inter-quartile range (Q1-Q3))	3.2 (1.8 to 5.5)	2 (1.8 to 3.6)

ADI-PEG20 analyses

Comparison groups

ADI-PEG20 + BSC v BSC alone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.03 ^[1]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.56

Confidence interval

level

95%

sides

2-sided

lower limit

0.33

upper limit

0.96

Notes
[1] - randomised phase II trial **In v1.0 of the EudraCT report the p-value was recorded as <0.15 in error. Corrected in version 2.0 in line with the study publication**

Secondary: Overall Survival

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End point title

Overall Survival

End point description

End point type

Secondary

End point timeframe

Until end of follow up

End point values	ADI-PEG20 + BSC	BSC alone
Number of subjects analysed	44	24
Units: Months
median (inter-quartile range (Q1-Q3))	11.5 (4.2 to 22.9)	11.1 (6.9 to 14.2)

Overall survival

Comparison groups

ADI-PEG20 + BSC v BSC alone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.15 ^[3]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.68

Confidence interval

level

95%

sides

2-sided

lower limit

0.39

upper limit

1.16

Notes
[2] - The Kaplan-Meier curves did not show proportional hazards. Therefore restricted mean survival times also provided: RMST ADI-PEG20: 15.7 months BSC: 12.1 months Difference in RMST 3.6 (95% CI -1.0 to 8.1), p=0.06 (one-sided), p=0.13 (two-sided) *In v1.0 of the EudraCT report the p-value was recorded as <0.15 in error. A RMST p value of 0.6 was also recorded in error. Corrected in version 2.0 in line with the study publication**
[3] - p=0.15 (Log rank) or 0.08 (one-sided)

Secondary: Objective Response Rate

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End point title

Objective Response Rate

End point description

Proportion of evaluable subjects who achieve a confirmed SD, CR or PR per modified RECIST guidelines for plain CT and by EORTC guidelines for PET-CT. The number and percentage of subjects falling into each response category will be descriptively tabulated. At 4 months, the best response observed by patients was stable disease (SD), there were no CR or PR.

End point type

Secondary

End point timeframe

Those with evaluable disease at 4 months

End point values	ADI-PEG20 + BSC	BSC alone
Number of subjects analysed	23	9
Units: Percentage	12	2

No statistical analyses for this end point

Secondary: Adverse events

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End point title

Adverse events

End point description

Assessed from adverse event and SUSAR reporting. Based on the highest grade of toxicity (grade 1 to 4) for each patient and each event type.

End point type

Secondary

End point timeframe

Until end of follow up

End point values	ADI-PEG20 + BSC	BSC alone
Number of subjects analysed	44	24
Units: Number of patients	40	14

Attachments

Untitled (Filename: ADAM trial - Eudract toxicity table.docx)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From consent date to 30 days post last dose of IMP.

Adverse event reporting additional description

SAEs are as defined in the regulations. Non-serious adverse events are all grades 1 to 2. The uploaded table shows grade 1-2 and grade 3-4 separately.

Assessment type

Systematic

Dictionary name

CTCAE

Dictionary version

Reporting group title

BSC alone

Reporting group description

Best supportive care

Reporting group title

ADI-PEG20 + BSC

Reporting group description

Serious adverse events	BSC alone	ADI-PEG20 + BSC
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 24 (8.33%)	9 / 44 (20.45%)
number of deaths (all causes)	20	35
number of deaths resulting from adverse events
Investigations
Neutropenia
subjects affected / exposed	0 / 24 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Neuropathy
subjects affected / exposed	0 / 24 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	1 / 24 (4.17%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drowsiness
subjects affected / exposed	1 / 24 (4.17%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Unwell
Additional description: pale, clammy, BP low 70/35, chest pressure and rash
subjects affected / exposed	0 / 24 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
Additional description: abdominal pain due to pericardial effusion
subjects affected / exposed	0 / 24 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fever
subjects affected / exposed	0 / 24 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Pulmonary embolism
subjects affected / exposed	0 / 24 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Allergic reaction
Additional description: Allopurinol allergy with renal impairment
subjects affected / exposed	0 / 24 (0.00%)	2 / 44 (4.55%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Anaphylactoid reaction
subjects affected / exposed	0 / 24 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Difficulty swallowing
subjects affected / exposed	1 / 24 (4.17%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	0 / 24 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Adult respiratory distress syndrome
subjects affected / exposed	0 / 24 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Myositis
subjects affected / exposed	0 / 24 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Rash
subjects affected / exposed	0 / 24 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Purpuric rash legs
subjects affected / exposed	0 / 24 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	BSC alone	ADI-PEG20 + BSC
Total subjects affected by non serious adverse events
subjects affected / exposed	21 / 24 (87.50%)	43 / 44 (97.73%)
Investigations
Abnormal haematologic test result
subjects affected / exposed	2 / 24 (8.33%)	12 / 44 (27.27%)
occurrences all number	2	47
Neutropenia
subjects affected / exposed	0 / 24 (0.00%)	4 / 44 (9.09%)
occurrences all number	0	4
Vascular disorders
Hypertension
subjects affected / exposed	0 / 24 (0.00%)	2 / 44 (4.55%)
occurrences all number	0	4
Nervous system disorders
Dizzy spell
subjects affected / exposed	0 / 24 (0.00%)	6 / 44 (13.64%)
occurrences all number	0	6
General disorders and administration site conditions
Injection site reaction
subjects affected / exposed	0 / 24 (0.00%)	16 / 44 (36.36%)
occurrences all number	0	21
Chest pain and/or trouble breathing
subjects affected / exposed	8 / 24 (33.33%)	24 / 44 (54.55%)
occurrences all number	8	45
Fatigue
subjects affected / exposed	6 / 24 (25.00%)	19 / 44 (43.18%)
occurrences all number	6	36
Fever
subjects affected / exposed	1 / 24 (4.17%)	1 / 44 (2.27%)
occurrences all number	1	1
Pain
subjects affected / exposed	4 / 24 (16.67%)	22 / 44 (50.00%)
occurrences all number	5	33
Swelling in limbs
subjects affected / exposed	0 / 24 (0.00%)	3 / 44 (6.82%)
occurrences all number	0	5
Immune system disorders
Allergic reaction and/or anaphylaxis
subjects affected / exposed	0 / 24 (0.00%)	1 / 44 (2.27%)
occurrences all number	0	2
Gastrointestinal disorders
GI events
subjects affected / exposed	6 / 24 (25.00%)	23 / 44 (52.27%)
occurrences all number	14	73
Infections and infestations
Infection
subjects affected / exposed	3 / 24 (12.50%)	12 / 44 (27.27%)
occurrences all number	3	19
Rash
subjects affected / exposed	1 / 24 (4.17%)	17 / 44 (38.64%)
occurrences all number	1	24
Metabolism and nutrition disorders
Abnormal biochemical test result
subjects affected / exposed	1 / 24 (4.17%)	6 / 44 (13.64%)
occurrences all number	2	42

More information

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Were there any global substantial amendments to the protocol? Yes

25 Oct 2010

- Changes to primary endpoint (TTP to PFS) - Increased sample size - IMP dose adjustment in line with recent published data

10 Nov 2010

IMPD updates

18 Feb 2011

Inclusion of patients with prior platinum therapy

19 Sep 2011

Changes to screening timeframe

29 Mar 2012

Updates to IMP thawing process, clarification of registration, screening, withdrawal and follow-up processes

18 May 2012

Change to Sponsor name

19 Oct 2012

- Change of requirement to check serum uric acid levels on every day of dosing to Day 1 of each cycle - Inclusion of study schedule for patients who wish to extend treatment beyond 6 months - New Investigator Brochure

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/27584578

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Clinical trials

Clinical Trial Results:
A Randomised Stratified Multicentre Phase II Clinical Trial of Single-Agent ADI-PEG 20 (Pegylated Arginine Deiminase) in Patients with Malignant Pleural Mesothelioma.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression free survival

Primary: Progression free survival

Secondary: Overall Survival

Secondary: Overall Survival

Secondary: Objective Response Rate

Secondary: Objective Response Rate

Secondary: Adverse events

Secondary: Adverse events

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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Clinical trials

Clinical Trial Results: A Randomised Stratified Multicentre Phase II Clinical Trial of Single-Agent ADI-PEG 20 (Pegylated Arginine Deiminase) in Patients with Malignant Pleural Mesothelioma.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression free survival

Primary: Progression free survival

Secondary: Overall Survival

Secondary: Overall Survival

Secondary: Objective Response Rate

Secondary: Objective Response Rate

Secondary: Adverse events

Secondary: Adverse events

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A Randomised Stratified Multicentre Phase II Clinical Trial of Single-Agent ADI-PEG 20 (Pegylated Arginine Deiminase) in Patients with Malignant Pleural Mesothelioma.