Clinical Trials Register

Summary
EudraCT Number:	2012-001597-29
Sponsor's Protocol Code Number:	HEM2012ZrOR001
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-05-15
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

Netherlands - Competent Authority

A.2

EudraCT number

2012-001597-29

A.3

Full title of the trial

Tumor uptake of 89Zirconium-ofatumumab and 89Zirconium-rituximab in diffuse large B cell lymphoma patients

Tumor opname van 89Zirconium-ofatumumab en 89Zirconium-rituximab bij patienten met een diffuus grootcellig B cel lymfoom

A.3.1

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

Tumor uptake of ofatumumab and rituximab, labeled with 89Zirconium, in patients with malignant lymphoma.

Tumor opname van ofatumumab en rituximab, gelabeld met 89Zirconium bij patienten met lymfeklierkanker

A.3.2

Name or abbreviated title of the trial where available

Tumor uptake of 89Zr-ofatumumab and 89Zr-rituximab

A.4.1

Sponsor's protocol code number

HEM2012ZrOR001

A.5.4

Other Identifiers

Name:

Nederlands Trial Register (NTR)

Number:

NTR3392

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	VU University Medical Center
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	VU University Medical Center
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	GlaxoSmithKline
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	VU University Medical Center
B.5.2	Functional name of contact point	department of Hematology
B.5.3	Address:
B.5.3.1	Street Address	De Boelelaan 1118
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1081 HV
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31204442604
B.5.5	Fax number	31204442601
B.5.6	E-mail	yws.jauw@vumc.nl

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	rituximab-N-succinyl-desferal-zirconium-89
D.3.2	Product code	89Zr-rituximab
D.3.4	Pharmaceutical form	Solution for injection/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	Yes
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
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	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	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	ofatumumab-N-succinyl-desferal-zirconium-89
D.3.2	Product code	89Zr-ofatumumab
D.3.4	Pharmaceutical form	Solution for injection/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	OFATUMUMAB
D.3.9.1	CAS number	679818-59-8
D.3.9.4	EV Substance Code	SUB25221
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	20
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)	Yes
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	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 (DLBCL)

E.1.1.1

Medical condition in easily understood language

lymphoma

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	HLT
E.1.2	Classification code	10012819
E.1.2	Term	Diffuse large B-cell lymphomas
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

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 compare the biodistribution and uptake in DLBCL of 89Zirconium (89Zr)-ofatumumab and 89Zr-rituximab (visual and quantitative).

E.2.2

Secondary objectives of the trial

1. to compare the biodistribution and uptake in DLBCL of 89Zr-ofatumumab and 89Zr-rituximab with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) (visual and quantitative).
2. to quantify biodistribution and dosimetry in normal tissue of 89Zr-ofatumumab and 89Zr-rituximab.
3. to investigate whether increased uptake in DLBCL on immuno-positron emission tomography (immuno-PET) is associated with clinical efficacy.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients to be included must be before initiation of second-line treatment in or conform OMB 110928 study, meeting the following criteria (conform the inclusion criteria of OMB 110928 study protocol):
Patients have refractory or relapsed (see protocol for definition) CD20 positive DLBCL during or after first line treatment with rituximab combined with anthracycline-based chemotherapy, confirmed by biopsy after first line treatment.
Age 18 years or older. Baseline 18F-FDG PET scan with positive lesions, compatible with CT defined anatomical tumor sites. CT-scan showing at least one or more clearly demarcated lesions with a largest diameter ≥ 1.5 cm or 1 clearly demarcated lesion with a largest diameter ≥ 2.0 cm (not previously irradiated). ECOG performance status 0,1 or 2. Patients must be eligible for high dose chemotherapy and autologous stem cell transplantation. Resolution of toxicities from first-line therapy to grade ≤ 1. Patients must be able to adhere to the study appointments and other protocol requirements. Patients must be capable of giving written informed consent and the consent must have been obtained prior to the study related procedures.

E.4

Principal exclusion criteria

Patients are excluded if they meet the following criteria (conform the exclusion criteria of OMB 110928 study protocol):
- any previous therapy for DLBCL, with the exception of first-line treatment with rituximab in combination with anthracycline-based chemotherapy, or radiotherapy as part of the first-line treatment plan or to a limited field at a aximum dose of ≤10Gy to control life-threatening symptoms.
- received any of the following treatments within 4 weeks prior to start of trial therapy (unless otherwise stated): anti-cancer therapy, radiotherapy (unless limited field at a maximum dose of ≤ 10Gy to control life-threatening symptoms), treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrolment (whichever is longer) or currently participating in any other interventional clinical study, glucocorticoid use, unless given in doses ≤100 mg/day hydrocortisone (or equivalent dose of other glucocorticoids) for < 7 days for exacerbations other than lymphoma (e.g. asthma).
- Significant cerebrovascular disease.
- Chronic or active infections with systemic treatment with antibiotics, antifungal or antiviral medication.
- Other malignancy.
- Prior treatment with monoclonal antibodies, with the exception of rituximab, within 3 months prior to start of the study.
- Pregnancy or lactation
- Women of childbearing potential or male subjects, unable or unwilling to adhere to the adequate contraception conform study protocol.

E.5 End points

E.5.1

Primary end point(s)

1.The detection of 89Zr-ofatumumab and 89Zr-rituximab in DLBCL tumor lesions:
• visual (present/absent).
• quantitative (measured in peak Standardized Uptake Value (SUVpeak)).

E.5.1.1

Timepoint(s) of evaluation of this end point

Immuno-PET scans obtained 1 hour, 72 hours and 144 hours post injection of 89Zirconium-ofatumumab or 89Zirconium-rituximab.

E.5.2

Secondary end point(s)

1. The detection of 18F-FDG in DLBCL tumor lesions:
• visual (present/absent)
• quantitative (in SUVpreak).
2. The detection of 89Zr-ofatumumab and 89Zr-rituximab in normal tissue:
• visual: description of biodistribution
• quantitative (% uptake (of total injected) 89Zr-ofatumumab and 89Zr-rituximab, calculated residence times and calculated organ absorbed doses for 89Zr-ofatumumab and 89Zr-rituximab)
3. Clinical outcome:
• in categories: complete remission, partial remission, stable disease or relapsed/progressive disease, using the Revised Response Criteria for Malignant Lymphoma (RRMCML) for disease assessment, assessed by CT after the second cycle of therapy / by PET performed after the third cycle of therapy, conform OMB110928 study protocol.

E.5.2.1

Timepoint(s) of evaluation of this end point

Immuno-PET scans obtained 1 hour, 72 hours and 144 hours post injection of 89Zirconium-ofatumumab or 89Zirconium-rituximab.

CT after the second cycle of therapy / by PET performed after the third cycle of therapy, conform OMB110928 study protocol.

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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

Information not present in EudraCT

E.8.1.2

Open

Information not present in EudraCT

E.8.1.3

Single blind

Information not present in EudraCT

E.8.1.4

Double blind

Information not present in EudraCT

E.8.1.5

Parallel group

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

E.8.1.7

Other

Information not present in EudraCT

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

The end of the study is defined as the last patients clinical follow-up parameter as used in this pilot study (CT scan after the second cycle of salvage therapy / 18F-FDG PET after the third cycle of salvage therapy).

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

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)

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

Information not present in EudraCT

F.3.3.2

Women of child-bearing potential using contraception

Information not present in EudraCT

F.3.3.3

Pregnant women

Information not present in EudraCT

F.3.3.4

Nursing women

Information not present in EudraCT

F.3.3.5

Emergency situation

Information not present in EudraCT

F.3.3.6

Subjects incapable of giving consent personally

Information not present in EudraCT

F.3.3.7

Others

Information not present in EudraCT

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

Patients will be treated according to the OMB 110928 study protocol.

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

2012-05-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-07-10

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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