Clinical Trials Register

Summary
EudraCT Number:	2010-019522-13
Sponsor's Protocol Code Number:	GP13-301
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-08-01
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

Portugal - INFARMED

A.2

EudraCT number

2010-019522-13

A.3

Full title of the trial

A randomized, controlled, double-blind Phase III trial to compare the efficacy, safety and pharmacokinetics of GP2013 plus Cyclophosphamide, Vincristine, Prednisone vs. MabThera® plus Cyclophosphamide, Vincristine, Prednisone, followed by GP2013 or MabThera® maintenance therapy in patients with previously untreated, advanced stage 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 GP2013 in combination with a standard chemotherapy (CVP) or rituximab MabThera in combination with a standard chemotherapy (CVP), including GP2013/MabThera maintenance therapy in patient with previously untreated advanced stage follicular lymphoma.

A.4.1

Sponsor's protocol code number

GP13-301

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	HEXAL AG (a Sandoz company)
B.1.3.4	Country	Germany
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	HEXAL AG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	HEXAL AG (a Sandoz company)
B.5.2	Functional name of contact point	Sanjay Akhani
B.5.3	Address:
B.5.3.1	Street Address	Industriestrasse 25
B.5.3.2	Town/ city	Holzkirchen
B.5.3.3	Post code	D-83607
B.5.3.4	Country	Germany
B.5.4	Telephone number	00498024 476 4630
B.5.5	Fax number	00498024 476 2979
B.5.6	E-mail	sanjaykumar.akhani@sandoz.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	GP2013 IV Solution for Infusion
D.3.2	Product code	GP2013
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.3.9.2	Current sponsor code	GP2013
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.3.4	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.3.9.4	EV Substance Code	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 stage 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	20.0
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	20.0
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 comparability of the overall response rate in patients with previously untreated, advanced stage follicular lymphoma who receive GP2013-CVP combination treatment to patients who receive MabThera®-CVP treatment. ORR will be determined during the combination treatment period using Modified Response Criteria for Malignant Lymphoma.

E.2.2

Secondary objectives of the trial

Other efficacy
• To evaluate CR rate at the end of combination treatment period;
• To evaluate PR rate at the end of combination treatment period;
• To evaluate PFS, which is defined as time from date of randomization
to date of first documented progression of disease, or death due to any
cause;
• To evaluate OS, which is defined as: time from date of randomization
to date of death due to any cause.
Safety
• To describe safety of GP2013-CVP in comparison to MabThera®-CVP;
• To evaluate the incidence of ADA formation against GP2013 and
MabThera®.
Pharmacokinetics/Pharmacodynamics
• To evaluate the pharmacokinetics of GP2013 and MabThera®. To
evaluate peripheral CD19+ Bcell count as a pharmacodynamic marker
following treatment with GP2013-CVP and MabThera®- CVP.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Patient with previously untreated advanced stage, CD20-positive FL:
a. Ann Arbor classification stage III/IV;
b. WHO histologic grade 1, 2 or 3a, as confirmed by central pathological testing; and
c. Require therapy for FL as per local guidelines or in the opinion of the treating physician.
2. Patient age ≥ 18 years.
3. Patient with at least one measurable lesion (accurately measurable in at least 2 perpendicular dimensions);
a. at least 1 measurable nodal lesion > 20 mm in the long axis; OR
b. at least 1 measurable extranodal lesion with both long and short axes ≥ 10 mm.
4. Patient with ECOG performance status 0, 1 or 2.
5. Patient with adequate cardiac function defined as cardiac ejection fraction ≥ 45% as measured by 2D-ECHO or MUGA, without clinically significant abnormalities.
6. Patient with the following laboratory values obtained during Screening (up to 28 days before randomization):
a. hemoglobin ≥ 10g/dL (unless abnormalities are due to histologically proven bone marrow involvement by lymphoma);
b. absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (unless abnormalities are due to histologically proven bone marrow involvement by lymphoma);
c. platelet count ≥ 100 x 10^9/L (unless abnormalities are due to histologically proven bone marrow involvement by lymphoma);
d. total bilirubin < 1.5 x ULN (upper limit of normal) (if Gilbert-Meulengracht syndrome is present, up to 2.0 x ULN is allowed);
e. transaminases < 2.5 x ULN;
f. serum creatinine level < 2 x ULN or calculated creatinine clearance > 50 mL/min;
g. negative serologic or virologic markers for active or latent hepatitis B and hepatitis C infections.
7. Sexually active males who accept to use a condom during intercourse while taking the drug and for 12 months after stopping treatment as they should not father a child in this period. A condom is required to be used also by vasectomised men (as well as during intercourse with a male partner) in order to prevent delivery of the drug via seminal fluid.
8. a) Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partner have been sterilized by vasectomy or other means, who accept to use a highly effective method of birth control while taking study drug and for 12 months after stopping treatment.
OR
b) Women who are considered post-menopausal and not of child bearing potential i.e. if they have had 6 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago (in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment).
9. Patient has signed and dated informed consent documents according to local guidelines.

E.4

Principal exclusion criteria

Patients eligible for this study must not meet any of the following criteria:
1. Patient with Grade 3b (aggressive) FL or any histology other than FL grade 1, 2 or 3a.
2. Patient with histological evidence of transformation to high grade or diffuse large B-cell lymphoma.
3. Patient who has previously received any prior therapy for lymphoma,
e.g. cytostatic or cytotoxic agents, antibodies, anti-lymphoma
vaccination, experimental treatments and radiotherapy, except who
received involved field radiation 4 weeks prior to Cycle 1 Day 1, of up to
two lesions that will not be used to evaluate disease progression.
4. Evidence of significant leukemic disease defined as >10 x 109 /L
circulating CD20+ lymphoma cells.
5. Patient with clinical evidence of central nervous system (CNS)
involvement by lymphoma or any evidence of spinal cord compression by
lymphoma.
6. Patient with evidence of any uncontrolled, chronic active infection
(viral, bacterial, including tuberculosis or fungal).
7. Patient receiving (>3 months), high dose (> 20 mg of
prednisone or > approximately 3 mg of dexamethasone per day or
equivalent doses of other steroid medications) of systemic corticosteroids.
8. Patient with any malignancy within 5 years prior to date of randomization, with the exception of adequately treated in situ carcinoma of the cervix uteri, basal or squamous cell carcinoma or nonmelanomatous skin cancer.
9. Patient with a known hypersensitivity to any of the study treatment ingredients e.g. to recombinant human antibodies.
10. Patient with concurrent serious illnesses, uncontrolled medical conditions, or other medical history including clinically relevant abnormal laboratory results, which in the investigator's opinion would be interfere with a patient's participation in the study, or with the interpretation of study results:
a. uncontrolled neurological disease (e.g. recurrent seizures despite existing anticonvulsant therapy);
b. neuropathy ≥ grade 1, neuromuscular disease;
c. severe disturbance of liver function;
d. severe constipation;
e. cystitis or other ongoing infections;
f. disturbance of micturition;
g. severe chronic obstructive pulmonary disease with clinically manifest hypoxemia (dyspnea > grade 1);
h. uncontrolled hypertension(defined as systolic BP > 160 mm Hg or diastolic > 100 mm Hg);
i. history of stroke or cerebral ischemia (within 6 months prior to randomization);
j. history of myocardial infarction or other clinically significant myocardial disease (within 6 months prior to screening) or unstable angina (≥ NYHA Grade II);
k. known infection with HIV or any other severe immunecompromised state according to patient history (if required by local regulations or clinical practice guidelines, patient may be tested during the screening period to confirm HIV status);
l. evidence of ongoing drug or alcohol abuse within the last 6 months before screening;
m . active tuberculosis. Patients with evidence of latent tuberculosis as per results of the tuberculosis screening test and further follow-up may enter the study after evaluation by an appropriate specialist and after sufficient treatment has been initiated according to local medical practice.
11. Patient has had major surgery, open biopsy or trauma within 4 weeks prior to date of screening (lymph node biopsy is not regarded as major surgery), or expects the need for major surgery during the course of study treatment.
12. Female patient who is nursing (lactating/breast-feeding), pregnant or planning a pregnancy within 12 months after the last infusion of study drug; where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).
13. Patient has received therapy with any other investigational medicinal product within the last 30 days or 5 times the half-life, whichever is longer, prior to screening.
14. Patient plans to receive live vaccines during the study or has received live vaccines 4 weeks prior to date of screening. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
15. Patient is using growth factors or transfusions to meet study eligibility requirements during Screening period. (The use of growth factors and transfusions during screening is permissible, if there is suspicion of bone marrow involvement by lymphoma and patient is deemed not to be growth factor-dependent or transfusion-dependent

E.5 End points

E.5.1

Primary end point(s)

Overall response rate at the end of combination treatment period using modified response criteria for lymphoma. Overall response rate is defined as the proportion of patients whose best overall disease response is either complete response or partial response at the end of the combination treatment period based on independent central radiology review.

E.5.1.1

Timepoint(s) of evaluation of this end point

month 6

E.5.2

Secondary end point(s)

Other efficacy
* Complete response
* Partial response
* Progressive free survival (from date of randomization to date of first
documented progression of disease, or death due to any cause.)
* Overall survival (from date of randomization to date of death due to
any cause)
Safety:
* Incidence, severity, type and relationship of AEs to the study
treatments
* Percentage of patients with anti-drug antibodies formation
Pharmacokinetics/Pharmacodynamics:
* Pharmacokinetic variables (Cmax, Cmin)
* CD19+ B-cell count (AUEC0-21 days)

E.5.2.1

Timepoint(s) of evaluation of this end point

Other efficacy
* CR: after 6 months and at the end of maintenance
* PR: after 6 months and at the end of maintenance
* PFS: end of 3-year follow-up period
* OS: at the end of maintenance
Safety:after 6 months and at the end of maintenance
Pharmacokinetics/Pharmacodynamics: after 6 months and at the end of maintenance
Exploratory: after 6 months and at the end of maintenance

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

Comparability

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

Yes

E.8.1.7.1

Other trial design description

Due to implementation of USM, all the subjects assigned to GP2013 were shifted to MabThera (blinded)

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

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

Argentina

Australia

Austria

Brazil

Bulgaria

Colombia

France

Germany

Hungary

India

Israel

Malaysia

Netherlands

Peru

Poland

Portugal

Romania

Russian Federation

South Africa

Spain

Ukraine

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

Last visit, last subject

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1