Clinical Trials Register

Summary
EudraCT Number:	2011-002813-12
Sponsor's Protocol Code Number:	CT-P103.1
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2011-10-10
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2011-002813-12

A.3

Full title of the trial

A Phase 3, Randomized, Parallel-Group, Active-Controlled, Double-Blind Study to Compare the Efficacy and Safety of CT-P10 With MabThera, Each Administered in Combination With Cyclophosphamide, Vincristine, and Prednisone (CVP) in Patients With Advanced Follicular Lymphoma.

A.3.1

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

A randomized Phase III clinical trial to compare the efficacy and safety of the biosimilar rituximab CT-P10 in combination with a standard chemotherapy (CVP) or rituximab MabThera in combination with a standard chemotherapy (CVP),in patient with previously untreated advanced stage follicular lymphoma.

A.4.1

Sponsor's protocol code number

CT-P103.1

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	CELLTRION, Inc
B.1.3.4	Country	Korea, Republic of
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	CELLTRION, Inc
B.4.2	Country	Korea, Republic of
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Regulatory Affairs & Clinical Operation
B.5.2	Functional name of contact point	Reg Affairs & Clinical Operation
B.5.3	Address:
B.5.3.1	Street Address	13-6, Songdo-dong, Yeonsu-gu
B.5.3.2	Town/ city	Incheon
B.5.3.3	Post code	406-840
B.5.3.4	Country	Korea, Republic of
B.5.4	Telephone number	8232850-5394/6551
B.5.5	Fax number	8232850-5060
B.5.6	E-mail	hyukjae.lee@celltrion.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	CT-P10
D.3.2	Product code	CT-P10
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Rituximab
D.3.9.1	CAS number	174722-31-7
D.3.9.2	Current sponsor code	CTP10
D.3.9.3	Other descriptive name	SUB12570MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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	No
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	Yes
D.3.11.13.1	Other medicinal product type	monoclonal antibody
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.1.1.1	Trade name	MabThera®
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	MabThera
D.3.2	Product code	L01XC02
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
D.3.9.3	Other descriptive name	SUB12570MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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	No
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	Yes
D.3.11.13.1	Other medicinal product type	monoclonal antibody

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Advanced Follicular Lymphoma

E.1.1.1

Medical condition in easily understood language

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	14.0
E.1.2	Level	PT
E.1.2	Classification code	10016910
E.1.2	Term	Follicle centre lymphoma, follicular grade I, II, III stage IV
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	PT
E.1.2	Classification code	10016909
E.1.2	Term	Follicle centre lymphoma, follicular grade I, II, III stage III
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To demonstrate that CT-P10 is equivalent to MabThera in terms of efficacy as determined by the complete response (CR) rate (CR plus unconfirmed CR) according to the 1999 International Working Group (IWG) criteria in previously untreated patients with advanced (stage III-IV), CD20+, FL.

E.2.2

Secondary objectives of the trial

To evaluate additional efficacy parameters, pharmacokinetics, pharmacodynamics, and overall safety of CT-P10 in comparison with MabThera for up to 81 weeks of treatment.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Each patient must meet all of the following criteria to be enrolled in this study:
1. Patient is male or female between 18 and 75 years old, inclusive.
2. Patient has histologically confirmed FL according to the Revised European-American Lymphoma/World Health Organization classification; grades 1 to 3 based on local practice.
3. Patient has at least 1 measurable tumor mass (greater than 1.5 cm in the longest dimension or 1.1 to 1.5 cm in the longest dimension and greater than 1.0 cm in the shortest axis) that has not previously been irradiated.
4. Patient has confirmed CD20+ lymphoma, as assessed by central laboratory review. (Tissue obtained within 6 months before Day 1 of Cycle 1 will be reviewed by a central independent reviewer to detect pathological type.)
5. Patient has Ann Arbor stage III or IV disease.
6. Patient has an Eastern Cooperative Oncology Group performance status of 0 to 2.
7. Patient has a life expectancy of more than 6 months.
8. Patient needs treatment for FL in the opinion of the participating clinician.
9. For both male and female patients and their partners of childbearing potential, patient agrees to use one of the following medically acceptable methods of contraception during the course of the study and for 6 months following discontinuation of study treatment (excluding women who are not of childbearing potential and men who have been sterilized):
• Barrier contraceptives (male condom, female condom or diaphragm with a spermicidal gel)
• Hormonal contraceptives (implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings)
• Intrauterine devices.
Male and female patients and their partners who have been surgically sterilized for less than 6 months prior to study entry must agree to use 1 medically acceptable method of contraception.
Menopausal females must have experienced their last period more than 12 months prior to study entry (ie, when the informed consent form [ICF] is signed) to be classified as not of childbearing potential.
10. For both premenopausal women and women who are less than 2 years after the onset of menopause, patient has a negative serum pregnancy test during the Screening Period or within 2 weeks before Day 1 of Cycle 1 of study treatment.
11. Patient has adequate bone marrow, hepatic, and renal function reserve as evidenced by:
• hemoglobin level of ≥10 g/dL
• absolute neutrophil count of ≥1500/μL
• platelet count of ≥100 000/μL
• total bilirubin level of ≤2.0 mg/dL
• aspartate aminotransferase and alanine aminotransferase levels of ≤3 times the upper limit of normal (ULN) for the reference laboratory (≤5 × ULN for the reference laboratory with known hepatic involvement by lymphoma)
• A serum creatinine level of ≤1.5 × ULN for the reference laboratory, or a calculated creatinine clearance by the Cockroft-Gault equation (Rostoker et al 2007) of ≥50 mL/min.
12. Patient is able to understand verbal and written instructions and can comply with all study requirements.
13. Patient is informed, given ample time and opportunity to read and understand about participation in the study, and has signed and dated the written ICF.

E.4

Principal exclusion criteria

1. Patient has allergies or hypersensitivity to murine, chimeric, human or humanized proteins, cyclophosphamide, vincristine, or prednisone.
2. Patient has evidence of histologically transformation to high-grade or diffuse large B cell lymphoma.
3. Patient has known central nervous system involvement.
4. Patient has received previous treatment for non-Hodgkin’s lymphoma.
5. Patient has had recent radiotherapy or major surgery within 4 weeks before Day 1 of Cycle 1, except lymph node biopsy.
6. Patient has a current diagnosis of tuberculosis (TB) defined by chest x-ray or other severe infections, such as sepsis, abscesses, or opportunistic infections.
7. Patient has a known infection with human immunodeficiency virus, hepatitis B, or hepatitis C infection. (carriers of hepatitis B are not permitted to enroll into the study).
8. Patient has New York Heart Association class III or IV heart failure, severe uncontrolled cardiac disease (unstable angina, arrhythmias, clinically significant electrocardiogram [ECG] abnormalities), or myocardial infarction within the previous 6 months prior to the date of consent.
9. Patient has any malignancy other than non-Hodgkin’s lymphoma, except adequately treated squamous or basal cell carcinoma of the skin or cervical carcinoma in situ, within the previous 3 years before the ICF is signed.
10. Patient has a current or recent (within 30 days before the ICF is signed) treatment with any other investigational medicinal product or device.
11. Patient has diabetes mellitus, except well-controlled type 2 diabetes mellitus. Well-controlled type 2 diabetes mellitus will be judged by each investigator.
12. Patient is pregnant or lactating. Patients who are planning to be pregnant or to breastfeed before, during, or within 12 months after the last infusion of study treatment are not permitted to enroll into the study.
13. Patient is taking a live or live-attenuated vaccine within 8 weeks before Day 1 of Cycle 1 of study treatment or a killed vaccine within 4 weeks before Day 1 of Cycle 1 of study treatment. Live or live-attenuated vaccines are not permitted during the study.
14. Patient has evidence of any other coexisting disease or medical or psychological condition, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational product, or patient is a high risk for treatment complications.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint will be the CR rate (CR plus CRu) according to the 1999 IWG

E.5.1.1

Timepoint(s) of evaluation of this end point

8 cycles in the Core Study Period (24 weeks) of study treatment.

E.5.2

Secondary end point(s)

• Overall response rates (according to the 1999 IWG criteria [Appendix 6.5] and the 2007 IWG criteria [Appendix 6.6])
• PFS, defined as the interval between randomization and disease progression, or death from any cause (Cheson et al 2007)
• TTP, defined as the interval between randomization and progression, relapse after complete remission, or death as a result of lymphoma (Cheson et al 2007)
• Time to treatment failure (TTF), defined as the time between randomization and discontinuation of treatment for any reason: progressive disease, toxicity, patient preference, institution of a new anti lymphoma treatment without documented progression, or death from any cause (Cheson et al 2007)
• Response duration, measured from the time when criteria for response (ie, CR or PR) is met, for which the event is the first documentation of relapse or progression (Cheson et al 2007)
• Disease-free survival (DFS), measured from the time of occurrence of attained CR to disease recurrence or death as a result of lymphoma or acute toxicity of treatment (Cheson et al 2007)
• OS, defined as the interval between randomization and death from any cause (Cheson et al 2007).

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary efficacy endpoints include overall response rate during the Core Study Period, Maintenance Study Period, and Follow-up Period

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

Yes

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

MabThera

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

100

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

Argentina

Belarus

Brazil

Bulgaria

Croatia

Georgia

Greece

Hungary

Iceland

India

Israel

Japan

Korea, Republic of

Latvia

Lithuania

Mexico

Netherlands

Peru

Poland

Romania

Russian Federation

Serbia

South Africa

Spain

Ukraine

United Kingdom

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

The end of the study is defined as the date on which the last patient completes the last visit.

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.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

370

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

370

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

740

F.4.2.2

In the whole clinical trial

740

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Standard of Care

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2011-12-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-11-15

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2013-03-19

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