Ofatumumab Cardiac Repolarization (QTc) Study in Fludarabine-Refractory Chronic Lymphocytic Leukemia Subjects

Study Overview
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Brief Summary
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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
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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).

Official Title
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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

Conditions
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Leukaemia, Lymphocytic, Chronic

Intervention / Treatment
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* Biological: Ofatumumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Six months treatmet with ofatumumab will be given to subjects with chronic lymphocytic leukemia. | Biological: Ofatumumab<br>* Anti-CD20 monoclonal antibody<br>* Other names: Arzerra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac Repolarization (Fredericia's QTc) | ECGs are collected in triplicate during the study to assess QTc effect. | 25-week ofatumumab treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentrations of ofatumumab and electrocardiogram (ECG) parameters | The pharmacokinetic results will be correlated to ECG findings to determine if drug concentrations relate to any ECG effects. | 25-week ofatumumab treatment period | 
| Vital signs, weight, adverse events | Safety and tolerability of ofatumumab therapy will be determined by analysing changes in vital signs, weight, or development of adverse events. | 25-week ofatumumab treatment period plus 6-month follow-up after final ofatumumab infusion | 
| Flow cytometry | Efficacy of ofatumumab therapy will be measured by the number of CD20 positive cells in the blood | 25-week ofatumumab treatment period plus 6-month follow-up after final ofatumumab infusion | 
| Cytokine, chemokine, human anti-human antibodies | Effect of ofatumumab on circulating biomarkers in refractory Chronic Lymphocytic Leukemia (CLL) subjects will be determined by measuring changes in the cytokine, chemokine, human anti-human antibody levels. | 25-week ofatumumab treatment period plus 6-month follow-up after final ofatumumab infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic lymphocytic leukemia, Cardiac Repolarization (QTc)