Clinical Trials Register

Summary
EudraCT Number:	2008-004177-17
Sponsor's Protocol Code Number:	OMB110918
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2010-03-09
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

Germany - PEI

A.2

EudraCT number

2008-004177-17

A.3

Full title of the trial

A Randomized, Open Label Study of Ofatumumab and Bendamustine Combination Therapy Compared with Bendamustine Monotherapy in Indolent B-cell Non-Hodgkin’s Lymphoma Unresponsive to Rituximab or a Rituximab-Containing Regimen During or Within Six Months of Treatment

A.3.1

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

Study of a new drug combination for the treatment of Non Hodgkin’s Lymphoma

A.3.2

Name or abbreviated title of the trial where available

COMPLEMENT A+B

A.4.1

Sponsor's protocol code number

OMB110918

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1145-5175

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 Pharma Services AG
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 Services 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(0)613241111
B.5.5	Fax number	+41(0)613248001
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 Frimley Business Park Camberley GU16 7SR United Kingdom
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	ofatumumab
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.3.9.3	Other descriptive name	HuMax-CD20
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)	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)	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	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.2.5	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	Bendamustine
D.3.4	Pharmaceutical form	Powder 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	Bendamustine
D.3.9.1	CAS number	16506-27-7
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	25
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)	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	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

Indolent B-cell Non-Hodgkin’s Lymphoma

E.1.1.1

Medical condition in easily understood language

Cancer in the blood or 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	20.0
E.1.2	Level	HLGT
E.1.2	Classification code	10025320
E.1.2	Term	Lymphomas non-Hodgkin's B-cell
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 establish effectiveness of ofatumumab in combination with bendamustine in patients with indolent B-cell NHL disease relapsed after rituximab therapy

E.2.2

Secondary objectives of the trial

· To establish effectiveness of ofatumumab in combination with bendamustine in subjects with follicular lymphoma refractory to rituximab-containing therapy
· To evaluate and compare ORR, OS, time toand duration of response, and time to progression (TTP) in subjects treated with ofatumumab and bendamustine combination therapy to those treated with bendamustine alone
· To evaluate and compare ORR, OS, time to and duration of response, and time to progression (TTP) in subjects with follicular lymphoma treated with ofatumumab and bendamustine combination therapy to those treated with bendamustine alone
· To evaluate and compare the safety and tolerability in subjects treated with ofatumumab and bendamustine combination therapy to those treated with bendamustine alone
· To evaluate and compare the two treatment arms with respect to changes in subjects’ health-related quality of life

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma, marginal zone lymphoma, and follicular lymphoma; grades 1, 2 and 3A, defined according to World Health Organization guidelines. Subjects with a diagnosis of SLL who have a peripheral blood monoclonal B lymphocyte count of ≥5,000/µL are considered to have CLL and are not eligible for this study.
• Tumor verified to be CD20+ positive from a previous or current tissue biopsy.
•CT imaging in screening phase (based on local evaluation) showing 2 or more clearly demarcated lesions/nodes with a long axis >1.5 cm and short axis ≥ 1.0 cm or 1 clearly demarcated lesion/node with a long axis >2.0 cm and short axis ≥1.0 cm (Section 6.2.5 of Study Protocol). CT imaging performed at screening as baseline image.
2. Indolent B-cell NHL with failure to achieve at least a partial response lasting 6 months beyond the end of treatment with rituximab or a rituximab-containing regimen (See Section 6.2.5.4– Section 6.2.5.5 of study protocol for details on response criteria), i.e.:
•Stable disease (SD) after rituximab or a rituximab-containing regimen (imaging will support this finding. NOTE: in cases of SD after rituximab monotherapy as induction treatment, the minimum time to confirm SD by imaging is 60 days from start of first rituximab infusion) or,
• Disease progression during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Imaging must support this finding and will be done ≤ 6 months after the last infusion of rituximab. Note: Subjects must have received a minimum of 4 rituximab infusions as monotherapy or 3 infusions as part of rituximab-containing combination regimens
3. ECOG Performance Status of 0, 1, or 2
4. Age ≥ 18 years
5. Life expectancy of at least 6 months
6. 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

Subjects meeting any of the following criteria will not be enrolled in the study:
1. Grade 3b FL or evidence that the indolent lymphoma has transformed to aggressive lymphoma as verified by biopsy confirmation
2. Previous autologous stem cell transplant in the last 6 months or previous allogeneic stem cell transplant at any time.
3. High dose steroids ≥ 25 mg prednisolone/day (or equivalent) for 7 consecutive days, given as concomitant medication, within 3 months prior to randomization. No more than 10 mg prednisone daily at the time of randomization
4. Prior bendamustine treatment within 1 year of randomization not resulting in a CR or PR for at least 6 months
5. Prior use of any monoclonal antibody (other than anti-CD20) within 3 months prior to randomization
6. Known central nervous system (CNS) involvement by indolent lymphoma
7. Other past or current malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of definitively treated non-melanoma skin cancer, or successfully treated in situ carcinoma, are eligible*
8. Chronic or current active 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
9. Clinically significant cardiac disease as judged by the investigator including unstable angina, acute myocardial infarction within 6 months of randomization, congestive heart failure, and arrhythmia requiring therapy
10. History of significant cerebrovascular disease or event with significant symptoms or sequelae
11. Significant concurrent, uncontrolled medical condition that in the opinion of the investigator or GSK medical monitor contraindicates participation this study
12. Positive serology for Hepatitis B (HB) defined as a positive test for Hepatitis B surface antigen (HbsAg). In addition, if negative for HBsAg but Hepatits B core antibody (HBcAb) positive (regardless of HBsAb status), a HBV DNA test will be performed and if positive the subject will be excluded
● Consult with a physician experienced in care and management of subjects with Hepatitis B to manage/treat subjects who are anti-HBc positive
● If HBV DNA is negative, subject may be included but must undergo HBV DNA monitoring (see Section 6.5.7.1 of study protocol). Prophylactic antiviral therapy may be initiated at the discretion of the investigator
13. Current active liver or biliary disease (subjects with Gilbert’s syndrome or asymptomatic gallstones, liver metastases related to indolent NHL or otherwise stable chronic liver disease per investigator assessment, are eligible)
14. Known human immunodeficiency virus (HIV) positive
15. Screening laboratory values:
● platelets < 100 x 109/L (unless due to indolent lymphoma involvement of the bone marrow)
● neutrophils < 1.5 x 109/L (unless due to indolent lymphoma involvement of the bone marrow)
● Serum creatinine > 1.5 times the institution’s upper limit of normal (ULN); subjects with a serum creatinine > 1.5 ULN will be eligible if the calculated creatinine clearance [Cockcroft, 1976] or creatinine clearance from a 24- hour urine collection is  40 mL/min
● Total bilirubin > 1.5 times ULN (unless due to liver involvement by FL or Gilbert’s disease)
● Transaminases > 3 times ULN
16. Known or suspected hypersensitivity to ofatumumab, bendamustine, or mannitol
17. 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 or currently participating in any other interventional clinical study
18. Known or suspected inability to comply with study protocol
19. 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 and/or occlusive cap plus spermicidal agent, as per local acceptable standards)

*Subjects can participate in the study if in the opinion of the investigator and medical monitor it is thought not to affect the subject’s safety, the conduct of the study or the interpretation of the data

E.5 End points

E.5.1

Primary end point(s)

• Progression-free survival, defined as the time interval between randomization and disease progression or death

E.5.1.1

Timepoint(s) of evaluation of this end point

Please refer to the complete list of timings that can be found in Appendices 1-3 of the study protocol.

E.5.2

Secondary end point(s)

Clinical
· Overall response rate (ORR) in all patients and patients with follicular lymphoma
· Overall survival (OS) in all patients and patients with follicular lymphoma
· Time to response and duration of response in all patients and patients with follicular lymphoma
· Time to progression and time to next therapy in all patients and patients with follicular lymphoma
· Changes in health-related quality of life (HRQL) measures in all patients and patients with follicular lymphoma
· Reduction in tumor size
· Improvement in Eastern Cooperative Oncology Group (ECOG) Performance status
· Incidence and severity of AEs, serious adverse events (SAEs) and other safety parameters including frequency of transfusions, development of Human Anti-Human Antibodies (HAHA), incidence of 3 and 4 infections, and myelosuppression (anemia, neutropenia, and thrombocytopenia)
· Overall response rate (ORR) to ofatumumab monotherapy in subjects in Arm B who progress during or following single-agent bendamustine
· Changes in clinical laboratory values
· Quantitative assessments of immunoglobulins G, A and M (IgG, IgA, IgM)
· Plasma ofatumumab concentrations
· B-cell monitoring (CD19+, CD20+)

E.5.2.1

Timepoint(s) of evaluation of this end point

Please refer to the complete list of timings that can be found in Appendices 1-3 of the 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

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

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

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.8.2.4

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

Austria

Belgium

Brazil

Canada

France

Germany

Greece

Hong Kong

Italy

Japan

Poland

Russian Federation

Slovakia

Ukraine

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

The end of the trial will be the Last Subject Last Visit after 5 year follow up

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:

137

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

130

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

125

F.4.2

For a multinational trial

F.4.2.1

In the EEA

197

F.4.2.2

In the whole clinical trial

346

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)

Subjects will be treated until disease progression or withdrawal from study treatment due to unacceptable AE(s), consent withdrawal or other reasons.

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

2010-06-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-05-04

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

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