Clinical Trials Register

Summary
EudraCT Number:	2008-004932-19
Sponsor's Protocol Code Number:	OMB110911
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-11-03
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

Sweden - MPA

A.2

EudraCT number

2008-004932-19

A.3

Full title of the trial

A phase III, open label, randomized, multicenter trial of Ofatumumab added to Chlorambucil vs. Chlorambucil Monotherapy in previously untreated patients with Chronic Lymphocytic Leukemia

A.3.1

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

Study of a new drug combination to treat Leukemia

A.4.1

Sponsor's protocol code number

OMB110911

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00748189

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	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
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	Novartis
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma AG
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Forum 1 Novartis Campus
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4056
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41 61 324 1111
B.5.5	Fax number	+41 61 324 8001
B.5.6	E-mail	clinicaltrial.enquiries@novartis.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	ARZERRA™
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm 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	ofatumumab
D.3.2	Product code	GSK1841157
D.3.4	Pharmaceutical form	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	Ofatumumab
D.3.9.1	CAS number	679818-59-8
D.3.9.2	Current sponsor code	GSK1841157
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	100
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
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	Information not present in EudraCT
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	Information not present in EudraCT
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	Leukeran
D.2.1.1.2	Name of the Marketing Authorisation holder	ALKOPHARMA SARL
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	Leukeran
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Chlorambucil
D.3.9.3	Other descriptive name	Chlorambucil
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	2
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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

Chronic Lymphocytic Leukaemia

E.1.1.1

Medical condition in easily understood language

Leukemia, Cancer of white blood cells

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	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10008976
E.1.2	Term	Chronic lymphocytic leukemia
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	18.1
E.1.2	Level	SOC
E.1.2	Classification code	10029104
E.1.2	Term	Neoplasms benign, malignant and unspecified (incl cysts and polyps)
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	18.1
E.1.2	Level	HLGT
E.1.2	Classification code	10024324
E.1.2	Term	Leukaemias
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	SOC
E.1.2	Classification code	10005329
E.1.2	Term	Blood and lymphatic system disorders
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	HLT
E.1.2	Classification code	10024295
E.1.2	Term	Leukaemias chronic lymphocytic
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	PT
E.1.2	Classification code	10008959
E.1.2	Term	Chronic lymphocytic leukaemia (in remission)
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to evaluate progression-free-survival of ofatumumab added to chlorambucil therapy vs. chlorambucil therapy for the treatment of previously untreated (frontline) CLL.

E.2.2

Secondary objectives of the trial

Secondary objectives are to evaluate clinical benefit, safety, tolerability, changes in patient reported outcome measures (PRO) and pharmacokinetics of subjects treated with ofatumumab added to chlorambucil.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Drug-Drug Interaction and Electrocardiogram Sub-Study Protocol

A sub-study will be conducted in order to determine whether ofatumumab has an effect on the corrected QT interval (QTc) or on chlorambucil pharmacokinetics. All patients enrolled at participating sites are encouraged to enroll in the ECG and drug-drug interaction sub-study in order to avoid patient selection bias. A minimum of 50 subjects (25 per treatment arm) will participate in the sub-study. Subject participating in the sub-study will not require any additional study visits to the visits required for the main study. Objectives: • To evaluate the potential effect of ofatumumab on QTc interval • To evaluate the potential effect of ofatumumab on chlorambucil pharmacokinetics Study Endpoints/Assessments: • QTcF (Fridericia-Corrected QT Interval) • Plasma ofatumumab concentrations • Plasma chlorambucil and phenylacetic acid mustard concentrations Full details are available in Appendix 5 of the amended protocol for OMB110911, dated 25th November 2009.

E.3

Principal inclusion criteria

1. Diagnosis of CLL defined by:
• Circulating lymphocytes ≥5,000/μL
AND
• Flow cytometry confirmation of immunophenotype with CD5, CD19, CD20,
CD23, CD79b, and surface Ig prior to Visit 2
Lymphocytosis with less than 5,000/μL B lymphocytes displaying the CLLimmunophenotype but in the absence of other features of a B-cell
lymphoproliferate disorder (lymphadenopathy, organomegaly, cytopenias,
disease-related symptoms) is defined as monoclonal B-lymphocytosis (MBL), not
CLL.

2. Considered inappropriate for fludarabine-based therapy, for reasons that include, but not limited to, advanced age or presence of co-morbidities

3. Active disease and indication for treatment based on modified NCI-WG guidelines [Hallek, 2008] defined by presenting at least any one of the following conditions:
• Evidence of progressive marrow failure as manifested by development or worsening of anemia and/or thrombocytopenia
• Massive (i.e. > 6cm below the left costal margin) or progressive or symptomatic splenomegaly
• Massive nodes (i.e. > 10cm in longest diameter) or progressive or symptomatic lymphadenopathy
• Progressive lymphocytosis with an increase of more than 50% over a two month period or an lymphocyte doubling time of less than 6 months. In patients with initial blood lymphocyte counts of less than 30x10^9/L, lymphocyte doubling time should not be used as a single parameter to define a treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded.
• A minimum of any one of the following disease-related symptoms must be present:
a) Unintentional Weight loss ≥10% within the previous six months
b) Fevers > 100.5oF (38.0oC) for ≥ 2 weeks without evidence of infection
c) Night sweats for more than 1 month without evidence of infection

4. Not been previously treated for CLL (prior autoimmune hemolytic anemia treatment permitted)

5. ECOG Performance Status of 0-2

6. Life expectancy of at least 6 months

7. Age ≥ 18 years

8. Signed written informed consent prior to performing any study-specific procedures

French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

E.4

Principal exclusion criteria

1. Prior immuno- or chemotherapy for CLL or small lymphocytic lymphoma (SLL) with any agent except corticosteroids used to treat autoimmune hemolytic anemia

2. Previous autologous or allogeneic stem cell transplantation

3. Active autoimmune hemolytic anemia (AIHA) requiring corticosteroid therapy > 100mg equivalent to hydrocortisone, or chemotherapy

4. Known transformation of CLL (e.g. Richter)

5. Known CNS involvement of CLL

6. Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active Hepatitis C.

7. Other past or current malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.

8. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months prior to Visit 1, congestive heart failure, and arrhythmia requiring therapy, with the exception of extra systoles or minor conduction abnormalities

9. History of significant cerebrovascular disease or event with significant symptoms or sequelae

10. Glucocorticoid use, unless given in doses ≤ 100mg/day hydrocortisone (or equivalent dose of other glucocorticoid) for <7 days for exacerbations other than CLL (e.g. asthma)

11. Known HIV positive

12. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded. If HBV DNA is negative, subject may be included but must undergo HBV DNA monitoring (see Section 6.3.4). Prophylactic antiviral therapy may be initiated at the discretion of the investigator.

13. Screening laboratory values:

• Creatinine > 2.0 times upper normal limit (unless normal creatinine clearance)
• Total bilirubin > 2.0 times upper normal limit (unless due to liver involvement of CLL)
• alanine transaminase (ALT) > 3.0 times upper normal limit (unless due to liver involvement of CLL)

14. Previous treatment or known or suspected hypersensitivity to ofatumumab that in the opinion of the investigator or medical monitor is a contraindication to their participation in the present study

15. Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to Visit 1, whichever is longer, treatment with any anti-CD20 monoclonal antibody within 3 months of Visit 1, or participation in any other interventional clinical study. Note: Participation in any other interventional clinical study after disease progression during post PD-followup is permitted.

16. Known or suspected inability to comply with study protocol

17. Lactating women, women with a positive pregnancy test at Visit 1 or women (of childbearing potential) as well as men with partners of childbearing potential, who are not willing to use adequate contraception from study start through one year following last treatment dose. Adequate contraception is defined as abstinence, oral hormonal birth control, hormonal birth control injections, implants of levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive patches, intrauterine device, and male partner sterilization if male partner is sole partner for that subject. The double barrier method can be used in regions where considered acceptable and adequate (condom or occlusive cap plus spermicidal agent).

E.5 End points

E.5.1

Primary end point(s)

• Progression free survival (PFS), defined as the interval between randomization until disease progression or death.

E.5.1.1

Timepoint(s) of evaluation of this end point

Anticipated: 26-May-2011

E.5.2

Secondary end point(s)

Overall response rate, Overall survival, Changes in patient reported outcome measures, Number of complete remissions, Time to response, duration of response, Time to progression, time to next therapy, Improvement of ECOG PS, Improvement in B-symptoms, Incidence and severity of AEs, SAEs and other safety parameters,Human Anti Human Antibodies (HAHA), CIRS

E.5.2.1

Timepoint(s) of evaluation of this end point

At primary endpoint analysis (26-May-2011) and at end of study (16-Jun-2022)

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

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Information not present in EudraCT

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

Information not present in EudraCT

E.7.1.2

Bioequivalence study

Information not present in EudraCT

E.7.1.3

Other

Information not present in EudraCT

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

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

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

107

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

Belgium

Brazil

Canada

Czech Republic

France

Germany

Greece

India

Ireland

Italy

Netherlands

Poland

Russian Federation

Spain

Sweden

United Kingdom

United States

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

End of trial is LSLV but there is two LSLV, one is for the primary endpoint (which is event driven) and one is for end of study (which is driven by treatment duration)

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

Information not present in EudraCT

F.1.1.2

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

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

148

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

269

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

Information not present in EudraCT

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

Information not present in EudraCT

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

319

F.4.2.2

In the whole clinical trial

444

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)

There are no plans to provide care after the 10 year follow up period.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	TFS - Trial Form Support
G.4.3.4	Network Country	Sweden

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2008-12-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-10-29

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-01-17

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