Clinical trial NCT01110031: Ofatumumab Cardiac Repolarization (QTc) Study in Fludarabine-Refractory Chronic Lymphocytic Leukemia Subjects
Official title: An Open-Label, Single-Arm, Phase I Study to Evaluate the Effect of Ofatumumab on Cardiac Repolarization (QTc Duration) in Patients With Fludarabine-Refractory B-cell Chronic Lymphocytic Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Leukaemia, Lymphocytic, Chronic
Keywords: Chronic lymphocytic leukemia
Cardiac Repolarization (QTc)
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2010-04-23
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: Ofatumumab is a fully-human monoclonal antibody that exhibits high binding affinity to an antigen on the surface of B lymphocytes. Antigen engagement by ofatumumab results in maximal B-cell killing through complement-dependent cytotoxicity and antigen-dependent cellular cytotoxicity in both antigen high- and low-expressing cells. Recent research has shown that ofatumumab-dependent B-cell depletion provides clinical benefit to subjects with CD20-positive cancers such as chronic lymphocytic leukemia (CLL). The purpose of the current study is to assess the impact of ofatumumab on electrocardiographic parameters with particular focus on cardiac repolarization (QTc interval duration) in subjects with refractory CLL. Subjects enrolled in this open-label, single-arm trial will receive ofatumumab at the highest clinical dose (2000 mg) studied or planned for study. Ofatumumab will be administered as eight weekly intravenous (IV) infusions followed by four monthly infusions, beginning in Week 13, across a 25-week treatment period. Cardiovascular effects will be evaluated during treatment through routine 12-lead electrocardiographic (ECG) monitoring. The pharmacokinetic relationship between plasma concentration of ofatumumab and its effect on QTc interval duration will be examined. Specifically, ECG assessments will be collected in triplicate at baseline, at the time of maximum ofatumumab concentrations periodically on-therapy, and at the end of treatment. After completion of the final ofatumumab infusion, subjects will continue to be followed for safety and efficacy for six months relative to the last ofatumumab dose.

Detailed description: The purpose of this trial is to assess the impact of ofatumumab on electrocardiographic parameters with particular focus on cardiac repolarization (QTc interval duration) in subjects with refractory Chronic Lymphocytic Leukemia (CLL).

Eligibility criteria: Inclusion Criteria:

* Confirmed diagnosis of Chronic Lymphocytic Leukemia (CLL).
* Active CLL disease and indication for treatment.
* Previous treatment with fludarabine-containing treatment that did not achieve at least a partial response or, disease progression occurred in responders within six months of the last dose of a fludarabine-containing treatment regimen.
* Fully active at a minimum, or fully capable of self-care and up and about more than 50% of waking hours.
* Age 18 years or older.
* Signed written informed consent.
* Acceptable levels of laboratory chemistry tests of potassium and magnesium.
* Males and female subjects must agree to use contraception (if fertile) from the time of the first dose of study medication until one year following last dose of ofatumumab.

Exclusion Criteria:

* Any abnormal electrocardiogram (ECG) or cardiac conduction findings .
* Certain heart problems, chronic infections, or serious significant diseases.
* Known transformation of CLL.
* CLL central nervous sytem involvement.
* Abnormal/inadequate blood values, liver, or kidney function.
* Past or current malignancy besides CLL, unless you have been free of malignancy for at least two years, have a history of completely resected non-melanoma skin cancer, or have been successfully treated.
* Lactating women or women with a positive pregnancy test.
* Use of medications known to prolong the heart rhythm.

Primary outcomes:
measure: Cardiac Repolarization (Fredericia's QTc)
timeFrame: 25-week ofatumumab treatment period
Secondary outcomes:
measure: Plasma concentrations of ofatumumab and electrocardiogram (ECG) parameters
timeFrame: 25-week ofatumumab treatment period
measure: Vital signs, weight, adverse events
timeFrame: 25-week ofatumumab treatment period plus 6-month follow-up after final ofatumumab infusion
measure: Flow cytometry
timeFrame: 25-week ofatumumab treatment period plus 6-month follow-up after final ofatumumab infusion
measure: Cytokine, chemokine, human anti-human antibodies
timeFrame: 25-week ofatumumab treatment period plus 6-month follow-up after final ofatumumab infusion
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: GSK Investigational Site
state: California
city: Randwick
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Auckland
country: New Zealand
facility: GSK Investigational Site
city: Christchurch
country: New Zealand
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Jewell RC, Laubscher K, Lewis E, Fang L, Gafoor Z, Carey J, McKeown A, West S, Wright O, Sedoti D, Dixon I, Hottenstein CS, Chan G. Assessment of the effect of ofatumumab on cardiac repolarization. J Clin Pharmacol. 2015 Jan;55(1):114-21. doi: 10.1002/jcph.376. Epub 2014 Aug 21.