HuMax-CD20 in B-Cell Chronic Lymphocytic Leukemia (B-CLL) Patients Failing Fludarabine and Alemtuzumab

Study Overview
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Brief Summary
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The purpose of this study is to determine whether HuMax-CD20 (ofatumumab) is effective in the treatment of patients failing both fludarabine and alemtuzumab.

Official Title
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A Single-arm, International, Multi-center Trial of HuMax-CD20, a Fully Human Monoclonal Anti-CD20 Antibody, in Patients With B-cell Chronic Lymphocytic Leukemia Who Have Failed Fludarabine and Alemtuzumab

Conditions
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Leukaemia, Lymphocytic, Chronic

Intervention / Treatment
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* Drug: ofatumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Tumor cell phenotype consistent with B-CLL Patients with active B-CLL and with an indication for treatment Failing at least one fludarabine-containing treatment regimen Failing at least one alemtuzumab-containing treatment regimen ECOG Performance Status of 0, 1, or 2 Life expectancy of at least 4 months Exclusion Criteria: Previous treatment with alemtuzumab within 6 weeks prior to Visit 2 Previous autologous stem cell transplantation within 6 months prior to Visit 2 Allogeneic stem cell transplantation Radioimmunotherapy

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ofatumumab<br>Anti-CD20 antibody therapy | Drug: ofatumumab<br>* Intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants (Par.) Classified as Responders and Non-responders for Objective Response as Assessed by an Independent Endpoint Review Committee (IRC) in Accordance With the National Cancer Institute Working Group (NCIWG) 1996 Guidelines | Par. with complete remission (CR), nodular partial remission (nPR), and partial remission (PR) were classified as responders, while those with stable disease (SD) and progressive disease (PD) were classified as non-responders. Per the NCIWG guideline (1996): CR; no lymphadenopathy/hepatomegaly/splenomegaly/constitutional symptoms, normal hematology, bone marrow sample as normocellular for age, <30% lymphocytes (LC), no lymphoid nodule; PR: a >=50% decrease in LC/lymphadenopathy; nPR: persistent nodules in bone marrow; PD: new lesion or increase by >=50% from baseline; SD: no CR, PR, or PD. | Start of treatment (Week 0 of Visit 2) until Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | Duration of response is defined as the time from the initial response (first visit at which response is observed) to progression or death. If the participant had progression between scheduled visits, no progression at the end of the trial, treatment discontinuation for undocumented progression, treatment discontinuation for toxicity or other reason, new anti-cancer treatment, and experienced death or progression after two or more missed visits in a row the endpoint was censored. | Start of treatment (Week 0 of Visit 2) until Week 24 | 
| Progression-Free Survival (PFS) | PFS is defined as the time from randomization until progression/death. Per the IRC, if the participant had progression between scheduled visits, died before the first assessment, or died between adequate visits, the endpoint was considered progressed. If there was no progression at the end of the trial, treatment discontinuation for undocumented progression, treatment discontinuation for toxicity/other reason, new anti-cancer treatment, and death/progression after 2 or more missed visits in a row, the endpoint was censored. Clinical progression is not considered as progression endpoint. | Start of treatment (Week 0 of Visit 2) until Week 24 | 
| Time to Next Chronic Lymphocytic Leukemia (CLL) Treatment | Time to next chronic lymphocytic leukemia (CLL) treatment is defined as the time from treatment allocation/randomization (Visit 2) until the time of the first administration of the next CLL treatment other than ofatumumab (or HuMaxCD20, a fully human monoclonal antibody to CD20 that is expressed on the surface of B-cells). | Time from randomization (Week 0 of Visit 2) until the time of first administration of a CLL treatment other than ofatumumab (assessed for a median of 8.7 weeks currently [or up to 13.3 months]) | 
| Overall Survival | OS is defined as the time from allocation to death. OS will also be subgrouped for responders and non-responders. | Start of randomization (Week 0 of Visit 2) until death (up to a median of 17.1 weeks) | 
| Percent Change From Baseline to Week 7 in Peripheral CD5+CD19+ Cell Counts | The peripheral blood for each participant was collected and analyzed for CD5+CD19+ cell counts. CD is cluster of differentiation, is a cell surface marker for immunophenotyping, and, in this case, is a surrogate for B cell malignancy (indicates malignant B cells). Percent change from Visit 2 (Week 0, Baseline) = (value at Week 7 minus value at Week 0 divided by value at Week 0) x 100. | Baseline (Visit 2) until Week 7 (Visit 9) | 
| Percent Change From Baseline to Week 7 in Peripheral CD5+CD20+ Cell Counts | The peripheral blood for each participant was collected and analyzed for CD5+CD20+ cell counts. CD is cluster of differentiation, is a cell surface marker for immunophenotyping, and, in this case, is a surrogate for B cell malignancy (indicates malignant B cells). Percent change from Visit 2 (Week 0, Baseline) = (value at Week 7 minus value at Week 0 divided by value at Week 0) x 100. | Baseline (Visit 2) until Week 7 (Visit 9) | 
| Median Percent Change of Tumor Size (Sum of Products Dimensions [SPD]) From Baseline (Visit 2) to Week 24 (Visit 14) | Tumor size and change in tumor size will be measured by the absolute value of and the percent change in the sum of products of the diameters of the largest abnormal lymph nodes from Baseline to Week 24 (Visit 14). Percent change from Visit 2 (Baseline, Week 0) = (value at Week 24 minus value at Week 0 divided by value at Week 0) x 100. | Baseline (Visit 2) until Week 24 (Visit 14) | 
| Number of Participants With Complete Resolution of Constitutional Symptoms at Week 24 | Participants with complete resolution of constitutional symptoms were those in whom no constitutional symptoms, such as night sweats, weight loss, and fever or extreme fatigue, were observed. | Baseline (Visit 2) and Week 24 | 
| Number of Participants With Complete Resolution of Lymphadenopathy | Participants with complete resolution of lymphadenopathy (disease involving the lymph nodes) were defined as those in whom all observed lymph nodes were of normal size (all nodes <1 centimeters) as determined by physical examination assessed by the investigator. All palpable lymph node sizes were recorded. | Baseline (Visit 2) to end of study (up to Week 24) | 
| Number of Participants With Improvement on the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale at Week 24 | ECOG performance status is a measure of the participant's ability to carry out activities of daily living on 6-point scale (0=fully active, 1=restricted in physically activity, ambulatory, 2=ambulatory [>50% of waking hours], 3=capable of only limited self care, 4=completely disabled, 5=Dead). Improvement in ECOG performance status is defined as a decrease from baseline by at least one score on the ECOG scale. | Baseline (Visit 2) and Week 24 | 
| Number of Participants Who Were Positive, Negative, or Had Missing Data for the Indicated Fluorescence in Situ Hybridization (FISH) Prognostic Factors at Screening | The number of participants (par.) who were positive, negative, or had missing data for the following prognostic factors indicative of altered responsiveness to treatment and/or survival was measured: 17p-, 11q-, +12q, 6q-, 13q-. Par. were assessed by FISH for these chromosomal abnormalities known tobe prognostic for time to treatment and survival when detected at diagnosis. Par. were categorized by the chromosomal abnormality detected: 17 p deletion, 11q deletion (but not 17 p deletion), 12 q trisomy (but not 17 p or 111q deletion), 13q deletion only, and no chromosomal abnormalities found. | Screening (Visit 1, <=14 days prior to Visit 2) | 
| Number of Participants With Improvement in Hemoglobin | The number of participants (par.) who had improvement in hemoglobin levels >=11 grams (g)/deciliter (dl) (6.8 millimoles/liter) or 50% improvement over baseline was measured. | Baseline (Visit 2) to Week 28 | 
| Number of Participants With Improvement in Thrombocytopenia (Thromb.) | Improvement in thromb. is defined as a decrease from Visit 2 by >=1 National Cancer Institute Common Terminology Criteria (NCI CTC) grade. Thromb. is defined as low platelet counts resulting from refractory CLL, damage from prior treatment, advanced age, or reduced bone marrow function and can be considered as an adverse condition. Adverse events (AEs) such as thromb. in a cancer indication are graded on a scale determined by the NCI called the NCI CTC: lowest, grade 1; highest, grade 5 (death). Changes in this grading can assess improvements or declines in the severity of the AE. | Baseline (Visit 2) to Week 28 | 
| Number of Participants With Complete Resolution of Hepatomegaly | Participants with complete resolution of enlarged liver (hepatomegaly) were defined as those with an enlarged palpable liver at baseline followed by the absence of hepatomegaly post- baseline (i.e., the liver was of normal size). Liver size was assessed by physical examination and documented as centimeters under the costal margin with relative changes in spleen size in 1 dimension calculated based on palpated numeric measurements (as per the 1996 NCIWG guidelines). | Baseline (Visit 2) until Week 24 | 
| Number of Participants With Improvement in Neutropenia | Low levels of neutrophils (neutropenia) may increase the risk of developing serious infections and may be considered an adverse condition and evaluated on the NCI CTC with a grade. Improvement in neutropenia is defined as a decrease from Visit 2 (baseline) by at least one NCI CTC grade. Improvement is defined as a decrease from Visit 2 by at least one NCI CTC grade. | Baseline (Visit 2) to Week 28 | 
| Number of Participants With Complete Resolution of Splenomegaly | Participants with complete resolution of enlarged spleen (splenomegaly) were defined as those with an enlarged palpable spleen at baseline followed by the absence of splenomegaly post-baseline (i.e., the spleen was of normal size). Spleen size was assessed by physical examination and documented as centimeters under the costal margin with relative changes in spleen size in 1 dimension calculated based on palpated numeric measurements (as per the 1996 NCIWG guidelines). | Baseline (Visit 2) until Week 24 | 
| Number of Participants Who Experienced Any Adverse Event | An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with the treatment. A list of AEs experienced in the study with a frequency threshold of 5% can be found in the AE section of this results record. | From first infusion (Visit 2/Week 0) to Visit 21 (Month 24 of follow-up [up to Month 48]) or time of withdrawal (treatment and follow-up) | 
| Cmax and Ctrough at Dose 1 (Visit 2, Week 0), Dose 8 (Visit 9, Week 7), and Dose 12 (Visit 14, Week 24) | Cmax is defined as the maximum concentration of drug in serum samples. Ctrough is defined as the trough serum concentration (measured concentration at the end of a dosing interval [taken directly before the next administration]). No drug was present before the first infusion; therefore, there are no Ctrough results for Dose 1 | Visit 2 (Week 0), Visit 9 (Week 7), and Visit 14 (Week 24) | 
| AUC (0-inf) and AUC(0-tau) at Dose 8 (Visit 9, Week 7) and Dose 12 (Visit 14, Week 24) | AUC is defined as the area under the ofatumumab concentration-time curve as a measure of drug exposure. AUC(0-inf) is AUC from the start of infusion extrapolated to infinity. AUC(0-tau) is AUC from the start of infusion over the dosing interval. | Visit 9 (Week 7) and Visit 14 (Week 24) | 
| Half-life (t1/2) at Dose 8 (Visit 9, Week 7) and at Dose 12 (Visit 14, Week 24) | Half-life ( t1/2) is defined as the terminal half-life and is the time required for the amount of drug in the body to decrease by half. | Visit 9 (Week 7) and Visit14 (Week 24) | 
| Clearance (CL) After Dose 8 (Visit 9, Week 7) and Dose 12 (Visit 14, Week 24) | CL is the clearance of drug from serum, which is defined as the volume of serum from which the drug is cleared per unit time. | Visit 9 (Week 7) and Visit 14 (Week 24) | 
| Volume of Distribution at Steady State (Vss) at Dose 8 (Visit 9, Week 7) and at Dose 12 (Visit 14, Week 24) | Vss is defined as the volume of distribution at steady state of ofatumumab. | Visit 9 (Week 7) and Visit 14 (Week 24) |