Clinical Trials Register

Summary
EudraCT Number:	2009-012518-39
Sponsor's Protocol Code Number:	OMB112517
National Competent Authority:	Finland - Fimea
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2010-02-16
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

Finland - Fimea

A.2

EudraCT number

2009-012518-39

A.3

Full title of the trial

A phase III, open label, randomized, multicenter trial of ofatumumab maintenance treatment versus no further treatment in subjects with relapsed chronic lymphocytic leukemia (CLL) who have responded to induction therapy

A.3.1

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

A study to see if ofatumumab helps response last longer after treatment for relapsed CLL compared to watching and re-treating CLL

A.4.1

Sponsor's protocol code number

OMB112517

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1148-0253

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 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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/08/581
D.3 Description of the IMP
D.3.1	Product name	ofatumumab
D.3.2	Product code	GSK1841157
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	Ofatumumab
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	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	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.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

Chronic lymphocytic leukemia is a cancer of the B-cells (a type of blood cell)

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10068919
E.1.2	Term	B-cell chronic lymphocytic leukemia
E.1.2	System Organ Class	100000004864

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 (PFS) of ofatumumab maintenance treatment versus no further treatment after remission induction in subjects with relapsed Chronic Lymphocytic Leukaemia (CLL).

E.2.2

Secondary objectives of the trial

● To evaluate the improvement in response, improvement in response time to next CLL treatment and overall survival in subjects receiving ofatumumab maintenance compared to no further treatment
● To evaluate the PFS after next-line therapy and the time to progression after nextline therapy
● To evaluate the safety and tolerability in subjects with CLL receiving ofatumumab maintenance compared to no further treatment
● To evaluate the health-related quality of life in subjects with CLL receiving ofatumumab maintenance compared to no further treatment as assessed by changes in patient reported outcome (PRO) measures relative to baseline
● To evaluate prognostic marker correlation with clinical response in subjects with CLL receiving ofatumumab maintenance compared to no further treatment
● To evaluate ofatumumab pharmacokinetic parameters in subjects with CLL receiving maintenance ofatumumab every 2 months

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:
Adults with documented diagnosis of CLL based on the modified IWCLL updated NCIWG guidelines
1. At least PR according to the revised 2008 NCI-WG CLL criteria within 3 months of the response assessment after the last dose of 2nd/3rd line treatment
2. The anti-leukemic treatment before study entry should have been for at least 3 months or 3 cycles
3. ECOG Performance Status of 0-2
4. 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. Known primary or secondary fludarabine-refractory subjects, defined as treatment failure (failure to achieve a CR or PR) or disease progression within 6 months
2. Prior maintenance therapy
3. Known transformation of CLL (e.g. Richter’s transformation), prolymphocytic leukemia (PLL), or CNS involvement of CLL
4. Active Autoimmune Hemolytic Anemia (AIHA) requiring treatment except if in the opinion of the investigator it is thought not to affect the subject’s safety, the conduct of the study or the interpretation of the data
5. Previous autologous or allogeneic stem cell transplantation
6. 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 B or C (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 HBV DNA test will be performed and if positive the subject will be excluded*.)
7. Other past or current malignancy (with the exception of basal cell carcinoma of the skin or in situ carcinoma of the cervix or breast) unless the tumor was successfully treated with curative intent at least 2 years prior to trial entry except if in the opinion of the investigator it is thought not to affect the subject’s safety, the conduct of the study or the interpretation of the data
8. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months prior to screening, congestive heart failure, and arrhythmia requiring therapy, with the exception of extra systoles or minor conduction abnormalities except if in the opinion of the investigator it is thought not to affect the subject’s safety, the conduct of the study or the interpretation of the data
9. History of significant cerebrovascular disease or event with symptoms or sequelae
10. Significant concurrent, uncontrolled medical condition that in the opinion of the investigator contraindicates participation in this study
11. Other anti-leukemic use of medications including glucocorticoids
12. Known HIV positive
13. Screening laboratory values:
• Platelets<50 x 10^9/L
• Neutrophils<1.0 x 10^9/L
• Creatinine > 1.5 times upper normal limit (unless normal creatinine clearance)
• Total bilirubin > 1.5 times upper normal limit (unless due to liver involvement of CLL or Gilbert’s syndrome)
• Alanine Aminotransferase (ALT) > 2.5 times upper normal limit (unless due to liver involvement of CLL)
• Alkaline phosphatase > 2.5 times upper normal limit
14. Known or suspected hypersensitivity to ofatumumab that in the opinion of the investigator or medical monitor contraindicates study participation
15. Subjects who have received treatment with any non-marketed drug substance or experimental therapy within 5-terminal half-lives or 4 weeks whichever is longer prior to first dose of study medication or currently participating in any other interventional clinical study
Note: Participation in any other interventional clinical study after disease progression during post PD follow-up is permitted.
16. 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 ofatumumab dose. Adequate contraception is defined as abstinence, oral hormonal birth control, implants of levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive patches, intrauterine device, and male partner sterilization if male partner is sole partner for that subject. For females in the USA, the use of a double barrier method is also considered adequate (condom or occlusive cap plus spermicidal agent).

* If HBV DNA is negative, subject may be included but must undergo HBV DNA monitoring (see Section 6.3.4 of study protocol). Prophylactic antiviral therapy may be initiated at the discretion of the investigator. Consult with a physician experienced in the care and management of subjects with hepatitis B to manage/treat subjects who are anti-HBc positive.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is progression-free-survival which is defined as the time from randomization to the date of disease progression or death due to any cause.

E.5.1.1

Timepoint(s) of evaluation of this end point

Calculated from entry into the study until the time of disease progression (or death due to any cause). To be evaluated at interim efficacy analysis (events =187 events) and at the time the full number of events are reached (280 events)

E.5.2

Secondary end point(s)

Secondary Endpoints:
Clinical:
● Improvement in response
● Time to next treatment
● Overall survival
● Progression-free survival after next-line therapy
● Time to progression after next-line therapy
● Changes in patient reported outcome (PRO) measures
● Changes in patient reported outcome (PRO) scores
● Improvement of ECOG performance status
● B-symptoms/Constitutional symptoms/fatigue
● Incidences of and number of subjects with grade 3 and 4 infections
● Incidence, severity of adverse events, serious adverse events and other safety parameters
● Evaluation of myelosuppression (anemia, neutropenia, thrombocytopenia)
● Frequency of transfusions
● Incidence of Autoimmune Hemolytic Anemia (AIHA)
● Human Anti Human Antibodies (HAHA)
● IgG, IgA, IgM serum levels
Disease markers:
● Minimal Residual Disease (MRD)
● B-cell monitoring
● Prognostic markers correlating with clinical response:
● Cytogenetics by fluorescent in situ hybridization (FISH)
● IgVH mutational status
● β2 microglobulin
● Changes in complement levels
Pharmacokinetics:
● Plasma ofatumumab concentrations

E.5.2.1

Timepoint(s) of evaluation of this end point

•Improvement in response--- assessed at each visit (every 2 months during study, every 3 months in follow-up)
•Time to next treatment—following progressive disease, assessed ~ every 3 months in survival follow-up (at minimum- yearly)
•Overall survival-assessed at each visit (e every 2 months during study, every 3 months in follow-up, ~ every 3 months in survival follow-up) until time of death
•PFS after next-line treatment- assessed after next CLL treatment at every survival follow-up visit (~ every 3 months)
•Changes in PRO measures –assessed at baseline, study visits and follow-up
•Changes in PRO scores- assessed at baseline, study visits and follow-up
•Improvement of ECOG performance- assessed at baseline, study visits and follow-up

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

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Observation only

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

Brazil

Canada

India

Israel

Korea, Republic of

Russian Federation

Turkey

Ukraine

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

Last Patient Last Visit

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:

155

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

377

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

372

F.4.2.2

In the whole clinical trial

532

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)

None.

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

2010-04-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-03-15

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2018-06-26

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