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

Phase 1

• Conditions: Chronic Lymphocytic Leukaemia

• Registration Number: EUCTR2008-004932-19-FR
• Lead Sponsor: GlaxoSmithKline Research & Development Limited

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2008-11-14
• Last Update Posted: 23 July 2018

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 522

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. at least 6cm below the left costal margin) or progressive or
symptomatic splenomegaly

• Massive nodes (i.e. at least 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 > 100.5°F (38.0°C) for = 2 weeks without evidence of infection;
or

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, in the opinion of the investigator

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.
Are the trial subjects under 18? no
Number of subjects for this age range:
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

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/day equivalent to hydrocortisone, or chemotherapy*

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

5. Known CNS involvement of CLL

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 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 screening (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 or due to Gilbert’s syndrome)

• 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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: 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.;Secondary Objective: 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.<br>;Primary end point(s): •Progression free survival (PFS), defined as the interval between randomization until disease progression or death.