Clinical Trials Register

Summary
EudraCT Number:	2011-002041-36
Sponsor's Protocol Code Number:	POLARIS2009-001
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-06-02
Trial results	View 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

2011-002041-36

A.3

Full title of the trial

A Randomized, Double-Blind, Multi-Center Phase 3 Study of ADI-PEG
20 Plus Best Supportive Care (BSC) Versus Placebo Plus BSC in
Subjects With Advanced Hepatocellular Carcinoma (HCC) Who Have
Failed Prior Systemic Therapy

A.3.1

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

A study to test new drug ADI-PEG 20 against standard medication and placebo in patients with advanced liver cancer

A.4.1

Sponsor's protocol code number

POLARIS2009-001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Polaris Group
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 Group
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 Group
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	6370 Nancy Ridge Drive, Suite 106
B.5.3.2	Town/ city	San Diego
B.5.3.3	Post code	CA 92121
B.5.3.4	Country	United States
B.5.4	Telephone number	1858452 6688
B.5.5	Fax number	1858452 3199
B.5.6	E-mail	HCCStudy@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	Yes
D.2.5.1	Orphan drug designation number	EU/3/05/289
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.3.8	INN - Proposed INN	PEGylated Arginine Deiminase
D.3.9.2	Current sponsor code	ADI-PEG 20
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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	Solution 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 Hepatocellular Carcinoma

E.1.1.1

Medical condition in easily understood language

Advanced Liver Cancer

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10019829
E.1.2	Term	Hepatocellular carcinoma recurrent
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

To assess overall survival

E.2.2

Secondary objectives of the trial

- Assessment of safety and tolerability
- Assessment of progression-free survival (PFS), tumor response rate by RECIST (1.1) criteria and time to progression (TTP)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Prior diagnosis of HCC confirmed histologically or cytologically.
2. Prior treatment with at least 1 systemic agent, with documented PD after systemic agent(s), or AEs associated with prior systemic agent(s) that resulted in discontinuance of that agent(s). Failure is defined as having progressed radiographically on, or been intolerant to prior systemic therapy. Intolerance is defined as discontinuation due to an AE(s) on prior systemic therapy that was unacceptable to the treating physician and / or patient, with or without dose interruption and modification. For sorafenib or any other systemic antineoplastic agent, failure requires at least 14 days of treatment for the agent that defines failure, except for a subject that has a severe allergic reaction to the prior systemic agent at any time, even less than 14 days of treatment of that agent and thus it would be imprudent to re-challenge them with that agent.
3. Measurable disease using RECIST 1.1 criteria (Appendix A). At least 1 measurable lesion must be present. Subjects who have received local-regional therapy such as (but not limited to) chemoembolization, embolization, cryoablation, hepatic artery therapy, percutaneous ethanol injection, radiation therapy, radiofrequency ablation or surgery are eligible, provided that they have either a target lesion which has not been treated with local therapy and/or the target lesion(s) within the field of the local regional therapy has shown an increase of ≥ 20% in size. Local-regional therapy must be completed at least 4 weeks prior to the baseline CT scan. Local therapies including chemoembolization do not count as prior systemic therapy.
4. Cirrhotic status of Child-Pugh grade A and B7. Child-Pugh status should be determined based on clinical findings and laboratory data during the screening period (Appendix C). Subjects on anti-coagulants are to receive only 1 point for their INR status.
5. Expected survival of at least 3 months.
6. Age ≥ 18 years.
7. No prior systemic treatment for HCC in the last 2 weeks prior to first dose of study drug or placebo.
8. Fully recovered from any prior major surgery and none within 2 weeks prior to first dose of study drug or placebo. Liver biopsy for HCC confirmation is allowed.
9. Female subjects of childbearing age and male subjects must be asked to use appropriate contraception for both the male and female for the duration of the study. Subjects must agree to use two forms of contraception or agree to refrain from intercourse for the duration of the study. 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.
10. Informed consent must be obtained prior to study initiation.
11. No concurrent investigational studies are allowed.
12. Total bilirubin <3.0 mg/dL and no evidence of bile obstruction.
13. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 x upper limit of normal range.
14. Absolute neutrophil count (ANC) >1,500/µL.
15. Platelets >50,000/µL.
16. Serum uric acid ≤ 8 mg/dL (with or without medication control).
17. Serum creatinine ≤ 1.5 x the upper limit of normal range, or, if serum creatinine >1.5 x the upper limit of normal range, then the creatinine clearance must be ≥ 60 mL/min.
18. Serum albumin level ≥ 2.8 g/dl.
19. Prothrombin time (PT)-international normalized ratio (INR): PT <6 seconds above control or INR <1.7.
20. Subjects with active hepatitis B or C on anti-viremic compounds may remain on such treatment, except for interferon.
21. Brain metastases are allowed if well controlled and without seizures.
22. Encephalopathy – none or mild (grade 1 or 2, by Child-Pugh classification); lactulose of other supportive care allowed.
23. Ascites – absent or slight (by Child-Pugh classification); diuretic therapy allowed.

E.4

Principal exclusion criteria

1. Candidate for potential curative therapies (i.e., resection or transplantation) or loco-regional approaches (i.e., ablation, embolization).
2. Prior allograft transplantation including liver transplantation.
3. Significant cardiac disease (New York Heart Association Class III or IV; Appendix D).
4. Serious infection requiring treatment with systemically administered antibiotics.
5. Pregnancy or lactation.
6. Expected non-compliance.
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), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness or social situations that would limit compliance with study requirements.
8. Subjects who have had any anticancer treatment within 2 weeks prior to first dose of study drug or placebo.
9. Subjects who have not fully recovered from toxicities associated with previous HCC loco-regional or systemic therapies.
10. Subjects with history of another primary cancer, with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid tumor with no known active disease present in the opinion of the investigator will not affect patient outcome in the setting of current HCC diagnosis.
11. Subjects who had been treated with ADI-PEG 20 previously.
12. Allergy to pegylated products.
13. History of seizure disorder.
14. Bleeding esophageal or gastric varices within the prior three months, except if banded or treated.
15. Subjects known to be HIV positive.
16. Uncontrolled ascites (defined as not easily controlled with diuretic treatment).
17. Having received any blood transfusion, blood component preparation, erythropoietin, albumin preparation, or granulocyte colony stimulating factors (G-CSF) within 7 days prior to screening laboratories or after screening laboratories have been obtained until first dose of study drug or placebo.
18. Use of traditional medicines approved by local authorities, including but not limited to Chinese herbs within 2 weeks prior to the first dose of study drug or placebo.
19. Eastern Cooperative Oncology Group (ECOG) performance status > 2.

E.5 End points

E.5.1

Primary end point(s)

Overall survival will be summarized using the Kaplan-Meier method. Point estimates (25th, 50th, and 75th percentiles) along with 95% confidence intervals will be provided by treatment group. Survival estimates will also be shown graphically for each treatment group.
Treatments will be compared using a stratified log-rank test (stratified by the four levels of the region – sorafenib treatment status variable).

E.5.1.1

Timepoint(s) of evaluation of this end point

OS is assessed weekly while patients are receiving treatment and then monthly thereafter.

E.5.2

Secondary end point(s)

The secondary efficacy variables are PFS, objective response rate, duration of objective response, tumor response at each visit, time to tumor progression, disease control rate at each visit, and the occurrence of surgical resections.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoints are assessed every 8 weeks based on CT/MRI scans. Surgical resection will be assessed whenever it occurs.

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

E.6.7

Pharmacodynamic

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

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)

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

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

China

Korea, Republic of

Taiwan

United States

E.8.7

Trial has a data monitoring committee

Yes

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

Subjects may continue to receive treatments unless 1 of the following occurs at anytime during the course of therapy: (1) unacceptable AEs, or (2) death, or (3) PD. Subjects with a complete response (CR) may receive one more cycle (4 weekly treatments).

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