Clinical Trials Register

Summary
EudraCT Number:	2015-004281-28
Sponsor's Protocol Code Number:	POLARIS2015-003
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-11-13
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2015-004281-28

A.3

Full title of the trial

Randomized, Double-Blind, Phase 2/3 Study in Subjects with Malignant Pleural Mesothelioma to Assess ADI-PEG 20 with Pemetrexed and Cisplatin (ATOMIC-Meso Phase 2/3 Study)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Phase 2/3 Study in Subjects with Malignant Pleural Mesothelioma to determine the treatment effect of ADI-PEG 20 or Placebo given in combination with Pemetrexed and Cisplatin.

A.3.2

Name or abbreviated title of the trial where available

Phase 2/3 ATOMIC Study of MPM to Assess ADI-PEG 20 with PemCis v5

A.4.1

Sponsor's protocol code number

POLARIS2015-003

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02709512

A.5.4

Other Identifiers

Name:

US FDA IND

Number:

128604

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Polaris Pharmaceuticals, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Polaris Pharmaceuticals, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Polaris Pharmaceuticals Inc
B.5.2	Functional name of contact point	Lisa Chang
B.5.3	Address:
B.5.3.1	Street Address	9373 Towne Centre Drive Suite 150
B.5.3.2	Town/ city	San Diego
B.5.3.3	Post code	92121
B.5.3.4	Country	United States
B.5.4	Telephone number	8584526688
B.5.5	Fax number	8584523199
B.5.6	E-mail	lchang@polarispharma.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ADI-PEG 20
D.3.2	Product code	ADI-PEG 20
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	ADI-PEG 20
D.3.9.3	Other descriptive name	Pegargiminase [USAN Council Name]
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 12
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Suspension for injection
D.8.4	Route of administration of the placebo	Intramuscular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Advanced malignant pleural mesothelioma (MPM)

E.1.1.1

Medical condition in easily understood language

Malignant pleural mesothelioma is a rare form of cancer that affects the thin cell wall lining (or mesothelium) of lungs and chest wall, often diagnosed in people exposed to high levels of asbestos.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10035605
E.1.2	Term	Pleural mesothelioma malignant advanced
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Determine effectiveness of study treatment by looking at response rate (RR), as measured by modified RECIST and RECIST 1.1 criteria (phase 2 portion), and overall survival (phase 3 portion).

Modified RECIST and RECIST 1.1 criteria were developed as standards to assess the response in patients with cancer, based on measurement of viable tumor on scans [computed tomography (CT) and magnetic resonance imaging (MRI)].

Overall survival is the percentage of people in a study or treatment group who are still alive for a certain period of time after they started treatment for a disease, such as cancer.

E.2.2

Secondary objectives of the trial

Key Secondary objective - Phase 2:
- Determine the duration of response

Key Secondary objectives for Phase 3:
- Assess progression free survival (the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse. In a clinical trial, measuring the progression-free survival is one way to see how well a new treatment works)

Other Secondary objectives:
- Assessment of safety and tolerability of ADI-PEG 20 in combination with pemetrexed and cisplatin (standard-of-care)
- Determine the pharmacokinetics (how the body affects the drug) of ADI-PEG 20.
- Determine the pharmacodynamics (how the drug affects the body) of ADI-PEG 20 in combination with pemetrexed and cisplatin
- Determine the immunogenicity (ability to cause an immune response) of ADI-PEG 20 in combination with pemetrexed and cisplatin

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histologically proven unresectable MPM of biphasic or sarcomatoid histology. Biphasic MPM is defined using the World Health Organization’s international histological classification of tumors as containing an epithelial and a sarcomatoid component with each component comprising at least 10% of the tumor (Corson 2004, Allen 2005).
2. Naïve to prior chemotherapy or immunotherapy (i.e., this is a first-line systemic therapy study).
3. Measurable disease as assessed by modified RECIST for MPM local pleural disease (Appendix A) and RECIST 1.1 for metastatic lesions (Appendix B).
4. ECOG performance status of 0 – 1 (Appendix C).
5. Predicted life expectancy of at least 12 weeks.
6. Age ≥ 18 years (there is no upper age limit).
7. Fully recovered from any prior surgery and no major surgery within 4 weeks. Surgery for placement of vascular access devices is acceptable.
8. Subjects and their partners must be asked to use appropriate contraception. They must agree to use two forms of contraception or agree to refrain from intercourse for the duration of the study and for 35 days after last dose of ADI-PEG 20 or for at least six months after treatment with pemetrexed and cisplatin whichever is the longer duration. Females must not be pregnant at the start of the study, and a serum human chorionic gonadotropin (HCG) pregnancy test must be negative before entry into the study. If positive HCG pregnancy test, further evaluation to rule out pregnancy must be performed according to GCP before this patient is claimed eligible.
9. Informed consent must be obtained prior to study initiation.
10. Hemoglobin (HB) > 9.0 g/dL.
11. Absolute neutrophil count (ANC) > 1,500/µL.
12. Platelets > 75,000/µL.
13. Either: (i) serum bilirubin ≤ 1.5 x upper limit of normal (ULN) or
(ii) alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or alkaline phosphatase (ALP) ≤ 3 x (ULN) unless raised due to tumor in which case up to 5 x ULN is permissible
14. Serum uric acid ≤ 10 mg/dL (595 µmol/L) (with or without medication control).
15. Creatinine clearance ≥ 45 mL/min (estimated, using Cockcroft and Gault formula). Cisplatin dose adjustment is recommended for subjects with a creatinine clearance between 45 and 59 mL/min (Bennis 2014) as follows: reduce cisplatin dose by 25% for clearance between 50 59.9 mL/min and by 50% for clearance between 45 – 49.9 mL/min.

E.4

Principal exclusion criteria

1. Radiotherapy (except for palliative reasons) the previous two weeks before.
2. Ongoing toxic manifestations of previous treatments.
3. Symptomatic brain or spinal cord metastases (patients must be stable for > 1 month post radiotherapy or surgery).
4. Major thoracic or abdominal surgery from which the patient has not yet recovered.
5. Serious infection requiring treatment with intravenous antibiotics at the time of study entrance, or an infection requiring intravenous therapy within 7 days prior.
6. Known to be serologically positive for human immunodeficiency virus (HIV). Testing to determine possible infection status is not required.
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association Class III or IV), symptomatic cardiac arrhythmia, previous history of myocardial infarction (unless stable and good ejection fraction on echocardiogram) or psychiatric illness and social situations that would limit compliance with study requirements.
8. Is a participant of, or plans to participate in, another interventional clinical study whilst taking part in this study. Participation in an observational or biomarker study would be acceptable, with prior Sponsor approval.
9. Subjects with history of another primary cancer, including co-existent second malignancy, with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary malignancy with no known active disease present in the opinion of the Investigator will not affect patient outcome.
10. Allergy to cisplatin or other platinum-containing compounds.
11. Pregnancy or lactation.
12. Expected non-compliance.
13. Subjects who had been treated with ADI-PEG 20 previously.
14. History of uncontrolled seizure disorder not related to underlying cancer.
15. ECOG performance status > 2.
16. Allergy to pegylated compounds.
17. Allergy to E. coli drug products (such as GMCSF).
18. Allergy to pemetrexed or to any other ingredient used in the formulation.

E.5 End points

E.5.1

Primary end point(s)

The primary objective of this study is:
• Determine efficacy as determined by the objective response rate (RR), measured by modified RECIST and RECIST 1.1 criteria (phase 2 portion), and OS (phase 3 portion).

The goal of the phase 2 portion of the trial is to provide data to support accelerated approval by the United States Food & Drug Administration, and the goal of the phase 3 portion of the trial is to provide a confirmatory study that would be ongoing at the time of the marketing application.

E.5.1.1

Timepoint(s) of evaluation of this end point

Scans are to be performed every 6 weeks and after every 8th weekly dose of ADI-PEG 20 or placebo during ADI-PEG 20 or placebo only treatment. Confirmatory scans are no longer required in Phase 3 (Protocol V5).

This study will include two separate interim analyses:
• The first interim analysis will be conducted at the end of the phase 2 portion, after adequate response assessment of the first 176 subjects enrolled. This interim analysis will evaluate the treatment effect on RR in the ITT population.
• The second interim analysis will be 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.

E.5.2

Secondary end point(s)

The key secondary objective of the phase 2 portion is:
• Determine the duration of response

The key secondary objectives of the phase 3 portion are:
• Assess progression free survival (PFS)

Other secondary objectives of this study include:
• Assessment of safety and tolerability of ADI-PEG 20 in combination with pemetrexed and cisplatin
• Determine the pharmacodynamics of ADI-PEG 20 in combination with pemetrexed and cisplatin
• Determine the immunogenicity of ADI-PEG 20 in combination with pemetrexed and cisplatin
• Determine the pharmacokinetics of ADI-PEG 20 in combination with pemetrexed and cisplatin

E.5.2.1

Timepoint(s) of evaluation of this end point

The key secondary objective of the phase 2 portion (DOR) will be analyzed at the end of the phase 2 portion.

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.

Safety and tolerability will be monitored throughout the study by lead investigators, sponsor, and DSMB (as outlined in Charter). A complete evaluation of these and other secondary objectives will be conducted at the interim analysis and/or final analysis.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

immunologic

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Italy

United States

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1