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

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.

Time frame: Start of treatment (Week 0 of Visit 2) until Week 24

Population: Full Analysis Set (FAS): all participants who had been exposed to study drug irrespective of their compliance to the planned course of treatment. Participants not evaluable (NE) were due to patient withdraw, refusal, non-trial drug related AEs, and death

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.

Time frame: Visit 9 (Week 7) and Visit 14 (Week 24)

Population: FAS. Data were provided for the number of participants attending each visit for whom the parameter could be calculated. Participants withdrawn during the study were not analyzed.

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.

Time frame: Visit 9 (Week 7) and Visit 14 (Week 24)

Population: FAS. Data were provided for the number of participants attending each visit for whom the parameter could be calculated. Participants withdrawn during the study were not analyzed.

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

Time frame: Visit 2 (Week 0), Visit 9 (Week 7), and Visit 14 (Week 24)

Population: FAS. Data were provided for the number of participants attending each visit. Participants withdrawn during the study were not analyzed.

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.

Time frame: Start of treatment (Week 0 of Visit 2) until Week 24

Population: FAS

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.

Time frame: Visit 9 (Week 7) and Visit14 (Week 24)

Population: FAS. Data were provided for the number of participants attending each visit for whom the parameter could be calculated. Participants withdrawn during the study were not analyzed.

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.

Time frame: Baseline (Visit 2) until Week 24 (Visit 14)

Population: FAS

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.

Time frame: 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)

Population: FAS

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.

Time frame: Screening (Visit 1, <=14 days prior to Visit 2)

Population: FAS. Par. were categorized hierarchically (by severity of abnormality): par. with a 17 p deletion (D); par. with an 11q D, but not a 17 p D; par. with 12q trisomy, but not a 17p or 11q D; par. with no aberrations found; par. with a 13q D as the sole aberration; and par. with 6q D (and not any of the above categories). Some par. had missing data.

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.

Time frame: Baseline (Visit 2) and Week 24

Population: FAS. Data were provided for the number of participants with constitutional symptoms at baseline attending each visit. Participants withdrawn during the study were not analyzed. (Participants without baseline constitutional symptoms did not experience new constitutional symptoms during the trial period.)

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).

Time frame: Baseline (Visit 2) until Week 24

Population: FAS. Data were provided for the number of participants with hepatomegaly from baseline attending each visit. Participants withdrawn during the study were not analyzed. Only participants with baseline hepatomegaly and a post-baseline assessment are included.

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.

Time frame: Baseline (Visit 2) to end of study (up to Week 24)

Population: FAS. Data were provided for the number of participants with lymphadenopathy at baseline attending each visit. Participants withdrawn during the study were not analyzed. (Participants without baseline lymphadenopathy remained free of lymphadenopathy during the trial.)

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).

Time frame: Baseline (Visit 2) until Week 24

Population: FAS. Data were provided for the number of participants with splenomegaly at baseline attending each visit. Participants withdrawn during the study were not analyzed. Only participants with baseline splenomegaly and a post-baseline assessment are included.

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.

Time frame: Baseline (Visit 2) to Week 28

Population: FAS. Par. were excluded from analysis if they received treatment of red blood cells (RBCs), received transfusions or a RBC growth factor (erythropoietin), died, withdrew from the trial, or began next CLL treatment. Only those par. remaining in the study at Week 28 were analyzed. No par. in the Other treatment arm met the criteria for analysis.

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.

Time frame: Baseline (Visit 2) to Week 28

Population: FAS. Only those par. remaining in the study at Week 28 were analyzed. No par. in the Other treatment arm met the criteria for analysis.

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.

Time frame: Baseline (Visit 2) to Week 28

Population: FAS. Only those participants remaining in the study at Week 28 were analyzed. No par. in the Other treatment arm met the criteria for analysis.

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.

Time frame: Baseline (Visit 2) and Week 24

Population: FAS. Data were provided for participants (par.) with an ECOG score \>0 at baseline attending each visit. Par. withdrawn from the study were not analyzed. (55 par. had an ECOG performance status of 0 at baseline and therefore did not have the opportunity to improve. No par. with an ECOG score of 0 at baseline worsened during the trial.)

OS is defined as the time from allocation to death. OS will also be subgrouped for responders and non-responders.

Time frame: Start of randomization (Week 0 of Visit 2) until death (up to a median of 17.1 weeks)

Population: FAS

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.

Time frame: Baseline (Visit 2) until Week 7 (Visit 9)

Population: FAS

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.

Time frame: Baseline (Visit 2) until Week 7 (Visit 9)

Population: FAS

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.

Time frame: Start of treatment (Week 0 of Visit 2) until Week 24

Population: FAS

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 frame: 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])

Population: FAS

Vss is defined as the volume of distribution at steady state of ofatumumab.

Time frame: Visit 9 (Week 7) and Visit 14 (Week 24)

Population: FAS. Data were provided for the number of participants attending each visit for whom the parameter could be calculated. Participants withdrawn during the study were not analyzed.