Clinical Trials Register

Summary
EudraCT Number:	2011-004916-51
Sponsor's Protocol Code Number:	SPI-ZEV-11-301
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-06-07
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

Ireland - HPRA

A.2

EudraCT number

2011-004916-51

A.3

Full title of the trial

A Phase 3, Open-label, Multicenter, Randomized Study of Sequential Zevalin (ibritumomab tiuxetan) versus Observation in Patients at Least 60 Years of Age with Newly Diagnosed Diffuse Large B-cell Lymphoma in PET-negative Complete Remission After R-CHOP or R-CHOP-like Therapy

A.3.1

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

Zevalin in patients with Diffuse Large B-cell Lymphoma

A.3.2

Name or abbreviated title of the trial where available

Zevalin in patients with Diffuse Large B-cell Lymphoma

A.4.1

Sponsor's protocol code number

SPI-ZEV-11-301

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01510184

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	Spectrum 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	Spectrum 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	European Medical Advisory Services Ltd (Emas)
B.5.2	Functional name of contact point	N/A
B.5.3	Address:
B.5.3.1	Street Address	71 Knowl Piece, Wilbury way
B.5.3.2	Town/ city	Hitchin
B.5.3.3	Post code	SG4 0TY
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+441462424400
B.5.5	Fax number	+441462600453
B.5.6	E-mail	ClinicalTrials@emaspharma.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	Yes
D.2.1.1.1	Trade name	Zevalin
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG
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	Zevalin
D.3.4	Pharmaceutical form	Kit for radiopharmaceutical preparation
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	IBRITUMOMAB TIUXETAN
D.3.9.1	CAS number	206181-63-7
D.3.9.3	Other descriptive name	IBRITUMOMAB TIUXETAN
D.3.9.4	EV Substance Code	SUB20031
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.6
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	YTTRIUM (90Y) IBRITUMOMAB TIUXETAN
D.3.9.3	Other descriptive name	YTTRIUM (90Y) IBRITUMOMAB TIUXETAN
D.3.9.4	EV Substance Code	SUB30555
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.208
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	Yes
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.IMP: 2
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	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	Rituximab
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/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Diffuse large B-cell lymphoma

E.1.1.1

Medical condition in easily understood language

Diffuse large B-cell lymphoma

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	17.0
E.1.2	Level	PT
E.1.2	Classification code	10012818
E.1.2	Term	Diffuse large B-cell lymphoma
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

Evaluate the efficacy and safety of the Zevalin Regimen compared with observation alone in patients who are in PET-negative complete response per Revised Response Criteria for Mlignant Lymphoma, after first line CHOP.

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patient is 60-years of age or older at time of randomization
2. Histologically confirmed Ann Arbor stage II, III, or IV DLBCL; or FL
Grade 3B according to the REAL/WHO classification (from initialdiagnosis made prior to starting R-chemotherapy).
3. An H&E stained slide and unstained slides must be available for
confirmatory pathology review, as per the separate Pathology Guidance
document. Patients may be randomized based on the local diagnosis.
4. Presence of at least one IPI risk factor. The aaIPI is defined by one
point for each factor:
a. LDH > upper limit of normal (ULN);
b. Stage III or IV; and
c. WHO/ECOG performance status >1.
5. First-line treatment must have been 6 cycles of standard R-CHOP or RCHOP-
like chemotherapy (e.g. R-CHOP21, R-CHOP14, or DA-EPOCH-R).
Patients who received pre-phase therapy for the purpose of improving
performance status prior to initiating R-CHOP are eligible.
Standard dose reductions for toxicity are allowed.
6. Complete remission (CR) according to the Revised Response Criteria
for Malignant Lymphoma [22] (Appendix 2) after first-line treatment.
a. Diagnostic CT scans with contrast of chest, abdomen, and pelvis must have been performed within 6 weeks after the last dose of the last cycle of R-chemotherapy. A neck CT will be applicable if the patient had
involvement of the neck region by palpation / physical examination at
initial diagnosis. The CT portion of an FDG PET that includes the neck will
be acceptable if the neck had involvement.
b. A negative FDG-PET scan performed within 8 weeks after the first
dose
of the last cycle of R-chemotherapy and confirming CR, with negative
defined as a score of 1-3 on the Deauville 5-point scale (Appendix 3)
used to quantify radionucleotide density in PET scans as determined
locally [23]. PET positive/indeterminate lesions which are confirmed on
biopsy to harbor no active lymphoma will be considered negative for
determination of CR status.
c. If positive bone marrow involvement at initial diagnosis the patient
must have a negative bone marrow biopsy following R-chemotherapy to
confirm the CR.
7. WHO/ECOG performance status of 0, 1 or 2.
8. Adequate hematopoietic functions unsupported by transfusion within
the last 2 weeks: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L,
Hemoglobin (Hgb) ≥ 9 g/dL, Platelets ≥ 100 x 109/L. Patients with
blood counts close to recovery towards these values after R-CHOP
should be discussed with the study Medical Monitor prior to
randomization, but blood counts must have met these thresholds prior to
treatment with Y-90 Zevalin.
9. In patients who had a post R-chemotherapy bone marrow biopsy
performed, the marrow must show cellularity > 15%. For patients
without a post R-chemotherapy bone marrow biopsy (i.e. those patients
with negative marrow at diagnosis), a repeat biopsy to assess bone
marrow cellularity of > 15% will be required only for patients
randomized to the Zevalin Regimen.
10. Life expectancy of 6 months or longer.
11. Written informed consent obtained according to local guidelines.

E.4

Principal exclusion criteria

1. Presence of any other malignancy or history of prior malignancy
within 5 years of study entry. Within 5 years, patients treated with
curative intent for Stage I or II cancers are eligible provided they have
a life expectancy of > 5 years. The 5-year exclusion rule does not apply
to-non melanoma skin tumors and in situ cervical cancer.
2. Prior radioimmunotherapy, including radiation therapy for NHL, or
any other NHL therapy.
3. Presence of central nervous system (CNS) involvement, or testicular
lymphoma at first diagnosis.
4. DLBCL as histological transformation of previously diagnosed indolent
B-cell lymphoma. Patients with De Novo Transformed DLBCL, defined as
DLBCL on lymph node biopsy and a "discordant marrow" with small cells
at initial diagnosis, are eligible.
5. Known seropositivity for hepatitis C virus (HCV) or hepatitis B
surface antigen (HbsAg). Patients who are positive for HbsAg but
without active disease (Hep B PCR below the limits of detection) and
who receive adequate prophylaxis may be enrolled, but should continue
prophylaxis for at least 6 months after the last dose of rituximab or
Zevalin.
6. Known history of HIV infection.
7. Abnormal liver function: total bilirubin > 2 × ULN unless secondary
to Gilbert disease.
8. Abnormal renal function: serum creatinine > 2.0 × ULN.
9. Ongoing toxic effects of chemotherapy > grade 2 and expected to
interfere with Zevalin treatment.
10. Known hypersensitivity to murine or chimeric antibodies or proteins.
11. Colony stimulating factor therapy administered more than 8 weeks
after last dose of R-chemotherapy or within 4 weeks prior to planned
administration of Zevalin.
12. Concurrent severe and/or medically uncontrolled disease (e.g.
uncontrolled diabetes, congestive heart failure, myocardial infarction
within 6 months of study, unstable and uncontrolled hypertension,
chronic renal disease, or active uncontrolled infection) which could
compromise participation in the study.
13. Treatment with investigational drugs less than 4 weeks prior to
randomization.
14. Major surgery less than 4 weeks prior to randomization.
15. Concurrent systemic corticosteroid use or any reason except as
premedication in case of known or suspected allergies to contrast media
or as premedication for potential side effects of rituximab
treatment. Patients on a chronic dose of prednisone for a medical
condition (e.g. Asthma or autoimmune disease) less than or equal to
20mg daily, stable for 4 weeks, are permissible.
16. Unwillingness or inability to comply with the protocol.
17. Pregnant women or women who are breastfeeding

E.5 End points

E.5.1

Primary end point(s)

Overall survival

E.5.1.1

Timepoint(s) of evaluation of this end point

Overall survival - assessed throughout the period of the study.

E.5.2

Secondary end point(s)

24-month overall-survival rate post-randomisation

Progression-free survival

E.5.2.1

Timepoint(s) of evaluation of this end point

24-month overall-survival rate post-randomisation - proportion of all randomised patients who die within 24 months of randomisation.

Progression-free survival - assessed throughout the period of the study.

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Observation, no Zevalin administered

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

Austria

Belgium

Canada

France

Germany

Ireland

Israel

Italy

Netherlands

Portugal

Spain

United Kingdom

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

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.1.1.1

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

440

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

300

F.4.2.2

In the whole clinical trial

490

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)

Patient will continue receive standard of care at the institution at which they are treated.

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

2012-07-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-09-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-10-28

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