BIFROST: Ofatumumab With Fludarabine and Cyclophosphamide in B-CLL Patients

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00410163
• Collaborator: (none)
• Enrollment: 61
• Locations: 2
• Arms: 2
• Duration (Months): 76
• Patients Per Site: 30.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

To investigate the safety and efficacy of two dose regimes of ofatumumab in combination with chemotherapy in previously untreated patients with B-CLL

Condition or Disease	Intervention/Treatment	Phase
Leukaemia, Lymphocytic, Chronic	Drug: Ofatumumab 500mg; Drug: Ofatumumab 1000mg; Drug: Fludarabine; Drug: Cyclophosphamide	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-labeled, Randomized, Two-dose, Parallel Group Trial of Ofatumumab, a Fully Human Monoclonal Anti-CD20 Antibody, in Combination With Fludarabine and Cyclophosphamide, in Patients With Previously Untreated B-cell CLL
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Mar 1, 2009
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Active Comparator 1 Each patient will receive a total of 6 infusions with ofatumumab every 4 weeks in combination with fludarabine and cyclophosphamide. The first infusion will be 300mg followed by 5 infusions of 500mg	Drug: Ofatumumab 500mg; Ofatumumab 500mg or should be diluted into 1000mL pyrogenefree saline and administered as an IV infusion.Duration of infusion will be approximately 6½ hours.Infusions should be given every 4 weeks until a total of 6 infusions has been given.; Drug: Fludarabine; Fludarabine (25 mg/m2) should be administered as an IV infusion daily, Days 2 through 4 of Course 1, and Days 1 through 3 of Courses 2 through 6, every 4 weeks for 6 courses; Drug: Cyclophosphamide; Cyclophosphamide (250 mg/m2) should be administered as an IV infusion daily, Days 2 through 4 of Course 1, and Days 1 through 3 of Courses 2 through 6, every 4 weeks for 6 courses.
Active Comparator: Active Comparator 2 Each patient will receive a total of 6 monthly infusions with ofatumumab in combination with fludarabine and cyclophosphamide. The first infusion will be 300mg followed by 5 infusions of 1000mg	Drug: Ofatumumab 1000mg; Ofatumumab 1000mg or should be diluted into 1000mL pyrogenefree saline and administered as an IV infusion.Duration of infusion will be approximately 6½ hours.Infusions should be given every 4 weeks until a total of 6 infusions has been given.; Drug: Fludarabine; Fludarabine (25 mg/m2) should be administered as an IV infusion daily, Days 2 through 4 of Course 1, and Days 1 through 3 of Courses 2 through 6, every 4 weeks for 6 courses; Drug: Cyclophosphamide; Cyclophosphamide (250 mg/m2) should be administered as an IV infusion daily, Days 2 through 4 of Course 1, and Days 1 through 3 of Courses 2 through 6, every 4 weeks for 6 courses.

Outcome Measures

Primary Outcome Measures

1. Number of Participants (Par.) With Complete Remission (CR), Measured From Start of Treatment Until 3 Months After Last Infusion [Start of treatment (Day 1 of Week 0) until 3 months after start of last infusion (up to Week 32)]

   Par. were evaluated for response by an Independent Endpoint Review Committee (IRC) in accordance with the National Cancer Institute-sponsored Working Group (NCI-WG) 1996 guideline. Par. with Complete Remission (CR) were classified as "complete responders". As per NCI-WG, CR requires all of the following criteria for a period of >=2 months: absence of lymphadenopathy (all lymph nodes <1.0 centimeters), no hepatomegaly/splenomegaly, absence of constitutional symptoms, lymphocytes <=4.0*10^9/liter (L), neutrophil leukocytes >=1.5*10^9/L, platelets >100*10^9/L, and hemoglobin >11 grams/deciliter.

2. Number of Participants (Par.) Who Were Classified as Responders and Non-responders [From start of treatment (Day 1 of Week 0) until 3 months after start of last infusion (up to Week 32)]

   Par. were evaluated by an IRC in accordance with NCI-WG 1996 guideline. Responders: CR, Nodular Partial Remission (nPR, same as CR, but persistent bone marrow nodules), and Partial Remission (PR, >=50% decrease in lymphocytes from pretreatment baseline (BL) value, >=50% reduction in lymphadenopathy, >=50% reduction of liver/spleen and neutrophils >= 1.5*10^9/L or platelets >100*10^9/L or hemoglobin >11 g/dL (or 50% improvement over BL for neutrophils, platelets, hemoglobin); non-responders: Stable Disease (SD, did not achieve CR/PR, and no PD), Progressive Disease (PD), or Not Evaluable (NE).

Secondary Outcome Measures

1. Duration of Response [From time of initial response to disease progression or death, whichever came first, assessed over 2 years]

   The duration of response was defined as the time from the initial response (the first visit at which response was observed) to progression or death. For participants who were lost to follow-up, duration of response was censored at the date of the last attended visit at which the endpoint was assessed.

2. Progression-Free Survival [From time of randomization to first documented evidence of disease progression or death due to any cause, whichever came first, assessed over 2 years]

   Progression-free survival (PFS) was defined as the time from randomization until the first radiologically or clinically documented evidence of progression or death due to any cause, if sooner. For participants who were lost to follow-up, PFS was censored at the date of the last attended visit at which the endpoint was assessed. The Kaplan-Meier method was used to estimate PFS.

3. Time to Next Anti-chronic Lymphocytic Leukemia (CLL) Therapy or Death [From time of randomization to first administration of next anti-CLL therapy other than ofatumumab or death, assessed over 5 years]

   Time to next anti-CLL (anti-lymphoma) therapy was defined as the time from randomization until the time of first administration of the next anti-lymphoma therapy other than ofatumumab or death. For participants who were lost to follow-up, the time was censored at the date of the last attended visit at which the endpoint was assessed.

4. Median Percent Change in Tumor Size From Baseline (Visit 2, Wk 0) at Visits 9, 21, 25, 29, 33, 34, 35, and 37 [Baseline Visit 2 (Week [Wk] 0); Visits 9 (Wk 4), 21 (Wk 12), 25 (Wk 16), 29 (Wk 20), 33 (Month [M] 1 after start of last infusion [LI]), 34 (M 3 after start of LI), 35 (M 6 after start of LI), 36 (M 9 after start of LI), and 37 (M 12 after start of L]

   Tumor size was measured by physical examination of palpable abnormal lymph nodes. Percent change from Baseline (Visit 2, Week 0) = (value at indicated visits minus value at Visit 2 divided by value at Visit 2) * 100. Visits 33, 34, 35, 36, and 37 are measured in the number of months from the start of the last infusion. The start of the last infusion could have occurred up to Week 20.

5. Median Percent Change in CD5+CD19+ and CD5+CD20+ Cells in Peripheral Blood From Onset of Course 3 Throughout Follow-up (FU) Compared to Screening [Baseline Visit 2 (Week [Wk] 0); Visits 15 (Wk 8), 21 (Wk 12), 25 (Wk 16), 29 (Wk 20), 33 (Month [M] 1 after start of last infusion [LI]), 34 (M 3 after start of LI)]

   Malignant B cells (CD5+CD19+ and CD5+CD20+) were measured in peripheral blood samples by flow cytometry. Percent change from Screening (Visit 1, Week -2) = (value at indicated visits minus value at Visit 1 divided by value at Visit 1) * 100. Visits 33 and 34 are measured in the number of months from the start of the last infusion. The start of the last infusion could have occurred up to Week 20.

6. Number of Participants Who Experienced Any Adverse Event From First Treatment (Visit 2) to Visit 43 (Month 60) [From first treatment (Visit 2) up to Visit 43 (Month 60)]

   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 this treatment. A list of AEs experienced in the study at a frequency threshold of 5% can be found in the AE section.

7. Number of Participants With Positive Human Anti-human Anti Bodies (HAHA) at Visits 1, 21, 35, and 39 [Visits 1 (Screening, Visit -2), 21 (Week 12), 35 (Month 6), and 39 (Month 18)]

   HAHA are indicators of immunogenicity to ofatumumab. Blood samples were drawn from participants at Visits 1, 21, 35, and 39 for analysis of HAHA. Analysis of HAHA was done in batches.

8. Number of Participants Who Reported Myelosuppression (Anemia, Leukopenia, Neutropenia, and Thrombocytopenia) [From first treatment (Visit 2) up to Visit 43 (Month 60)]

   Myelosuppression is one of the expected AEs for FC treatment and is defined as the decrease in the ability of the bone marrow to produce blood cells. The number of participants with myelosuppression was assessed from laboratory measurements with Grades 3(severe)-4 (life-threatening/disabling) (1, mild; 2, moderate; 5, death) according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. The CTCAE is issued by the National Cancer Institute (NCI) and is the standard classification used for the severity grading scale for AEs in cancer therapy clinical studies.

9. Percent Change From Screening (Visit 1) in Complement (CH50) Levels at Visit 9 (Week 4) [Visit 1 (Week -2) and Visit 9 (Week 4)]

   Blood samples were drawn from participants at Visits 1 and 9 for analysis of complement (CH50) levels. Analysis of CH50 was done in batches, and CH50 levels were measured two hours after the end of study medication infusion. Percent change from Screening (Visit 1, Week -2) = (value at Visit 9 minus value at Visit 1 divided by value at Visit 1) * 100.

10. Number of Participants Classified as Responders Having CR Who Tested Negative for Minimal Residual Disease (MRD) [From start of treatment (Day 1 of Week 0) until 3 months after start of last infusion (up to course 6 or Week 32)]

    MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment when the participant has achieved CR. For all participants who achieved CR, the follow-up bone marrow sample was tested for malignant B cells (CD5+CD19+) to determine if there was any MRD.

11. Ctrough and Cmax at the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20) [Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose)]

    Cmax is defined as the maximum concentration of drug in plasma samples. Ctrough is defined as the trough plasma concentration (measured concentration at the end of a dosing interval [taken directly before next administration]). No drug is present before the first infusion; therefore, there are no Ctrough results for the first infusion.

12. AUC(0-inf) and AUC(0-672) After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20) [Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose)]

    AUC is defined as the area under the ofatumumab concentration-time curve as a measure of drug exposure. AUC(0-672) is AUC from start of infusion to 672 hours after start of infusion; AUC(0-inf) is AUC from start of infusion extrapolated to infinity.

13. t1/2 After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20) [Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose)]

    t1/2 is defined as terminal half-life and is the time required for the amount of drug in the body to decrease by half.

14. CL After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20) [Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose)]

    CL is the clearance of drug from plasma, which is defined as the volume of plasma from which the drug is cleared per unit time.

15. Vss After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20) [Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose)]

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

16. Number of Participants With Progression or Death [From time of randomization to first documented evidence of disease progression or death due to any cause, whichever came first, assessed over 2 years]

    Disease progression is characterized by at least one of the following, per the Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia: a >=50% increase in the sum of the products of at least two lymph nodes on two consecutive determinations 2 weeks apart (at least one node must be >=2 centimeters); or the appearance of new palpable lymph nodes; or a >=50% increase in liver and/or spleen size (measurement below the costal margin); or the appearance of palpable hepatomegaly or splenomegaly not previously present; or a >=50% increase in the numbers of circulating lymphocytes to at least 5.0 * 10^9/Liter; or transformation to a more aggressive histology (e.g., Richter's syndrome or prolymphocytic leukemia with >55% prolymphocytes). For participants who were lost to follow-up, PFS was censored at the date of the last attended visit at which the endpoint was assessed. The Kaplan-Meier method was used to estimate PFS.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients with active B-CLL and with an indication for treatment

2. Age ≥ 18 years

3. Following receipt of verbal and written information about the study, the patient must provide signed informed consent before any study related activity is carried out

Exclusion Criteria:

1. Any previous treatment for B-CLL or any other treatments that can be considered active against B-CLL

2. Glucocorticoid unless given in doses ≤ 10 mg /day for other indications than B-CLL (e.g. asthma)

3. Known transformation of B-CLL

4. Known CNS involvement of B-CLL

5. Past or current malignancy, except for:

6. Cervical carcinoma Stage 1B or less

7. Non-invasive basal cell and squamous cell skin carcinoma

8. Malignant melanoma with a complete response of a duration of > 10 years

9. Other cancer diagnoses with a complete response of a duration of > 5 years

10. Chronic or current infectious disease requiring systemic treatment

11. Clinically significant cardiac disease

12. Significant concurrent, uncontrolled medical condition

13. History of significant cerebrovascular disease

14. Known HIV positive

15. Positive serology for hepatitis B, unless due to vaccination

16. Leukapheresis, except as a safety measure before chemotherapy

17. ECOG Performance Status of 3 or 4

18. Patients who at the time of inclusion are not expected to be able to complete the ofatumumab-FC regimen

19. Patients who have received treatment with any non-marketed drug substance or experimental therapy within 4 weeks prior to Visit 1

20. Current participation in any other interventional clinical study

21. Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder)

22. Breast feeding women or women with a positive pregnancy test at Visit 1

23. Women of childbearing potential not willing to use adequate contraception for up to one year after last dose of ofatumumab. Adequate contraception is defined as hormonal birth control or intrauterine device. For patients in the USA the use of a double barrier method is also considered adequate.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Houston	Texas	United States	77030
2	GSK Investigational Site	Plymouth	Devon	United Kingdom	PL68DH

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Publications

• Wierda WG, Kipps TJ, Dürig J, Griskevicius L, Stilgenbauer S, Mayer J, Smolej L, Hess G, Griniute R, Hernandez-Ilizaliturri FJ, Padmanabhan S, Gorczyca M, Chang CN, Chan G, Gupta I, Nielsen TG, Russell CA; 407 Study Investigators. Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood. 2011 Jun 16;117(24):6450-8. doi: 10.1182/blood-2010-12-323980. Epub 2011 Apr 15.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00410163
• Other Study ID Numbers: 111774; Hx-CD20-407; The BIFROST trial
• First Posted: Dec 12, 2006
• Last Update Posted: Feb 10, 2014
• Last Verified: Nov 1, 2013

• Keywords provided by GlaxoSmithKline: B-cell; cyclophosphamide; fludarabine; Chronic Lymphocytic Leukemia; Ofatumumab
• Additional relevant MeSH terms: Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Cyclophosphamide; Fludarabine; Ofatumumab; Antibodies, Monoclonal

Study Results

Participant Flow

Pre-assignment Detail	Participants received up to 6 courses (22 weeks) of treatment. After treatment, participants were evaluated for up to 18 months in a follow-up (FU) period and then entered an extended FU phase (up to Month 60). The overall study period reported is from 09 January 2007 to 05 June 2013, when all phases of the study were completed.

Arm/Group Title	Ofatumumab 500 mg + Fludarabine and Cyclophosphamide (FC)	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses. After the last infusion, the disease status of the participants was evaluated every 3 months up to 18 months during the Follow-up Period. Participants were monitored in the Extended Follow-up Phase every 6 months for survival until alternative Chronic Lymphocyte Leukemia (CLL) therapy was initiated, or until Month 60.	Ofatumumab iv infusion initiated at 300 mg for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/m^2 daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses. After the last infusion, the disease status of the participants was evaluated every 3 months up to 18 months during the Follow-up Period. Participants were monitored in the Extended Follow-up Phase every 6 months for survival until alternative CLL therapy was initiated, or until Month 60.
Period Title: Treatment and Follow-up Phase (2 Years)
STARTED	31	30
COMPLETED	19	19
NOT COMPLETED	12	11
Period Title: Treatment and Follow-up Phase (2 Years)
STARTED	20	21
COMPLETED	10	11
NOT COMPLETED	10	10

Baseline Characteristics

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC	Total
Arm/Group Description	Ofatumumab iv infusion initiated at 300 mg for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/m^2 daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab iv infusion initiated at 300 mg for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/m^2 daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Total of all reporting groups
Overall Participants	31	30	61
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	56.1 (8.4)	56.4 (8.7)	56.2 (8.5)
Sex: Female, Male (Count of Participants)
Female	11 35.5%	7 23.3%	18 29.5%
Male	20 64.5%	23 76.7%	43 70.5%
Race/Ethnicity, Customized (participants) [Number]
White	31 100%	29 96.7%	60 98.4%
Black or African American	0 0%	1 3.3%	1 1.6%

Outcome Measures

1. Primary Outcome

Title	Number of Participants (Par.) With Complete Remission (CR), Measured From Start of Treatment Until 3 Months After Last Infusion
Description	Par. were evaluated for response by an Independent Endpoint Review Committee (IRC) in accordance with the National Cancer Institute-sponsored Working Group (NCI-WG) 1996 guideline. Par. with Complete Remission (CR) were classified as "complete responders". As per NCI-WG, CR requires all of the following criteria for a period of >=2 months: absence of lymphadenopathy (all lymph nodes <1.0 centimeters), no hepatomegaly/splenomegaly, absence of constitutional symptoms, lymphocytes <=4.0*10^9/liter (L), neutrophil leukocytes >=1.5*10^9/L, platelets >100*10^9/L, and hemoglobin >11 grams/deciliter.
Time Frame	Start of treatment (Day 1 of Week 0) until 3 months after start of last infusion (up to Week 32)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all participants who had been exposed to study drug irrespective of their compliance to the planned course of treatment

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab iv infusion initiated at 300 mg for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/m^2 daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab iv infusion initiated at 300 mg for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/m^2 daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	31	30
Number [participants]	10 32.3%	15 50%

2. Secondary Outcome

Title	Duration of Response
Description	The duration of response was defined as the time from the initial response (the first visit at which response was observed) to progression or death. For participants who were lost to follow-up, duration of response was censored at the date of the last attended visit at which the endpoint was assessed.
Time Frame	From time of initial response to disease progression or death, whichever came first, assessed over 2 years

Outcome Measure Data

Analysis Population Description

FAS. Only those participants classified as responders were analyzed.

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	24	22
Median (95% Confidence Interval) [months]	NA	NA

3. Secondary Outcome

Title	Progression-Free Survival
Description	Progression-free survival (PFS) was defined as the time from randomization until the first radiologically or clinically documented evidence of progression or death due to any cause, if sooner. For participants who were lost to follow-up, PFS was censored at the date of the last attended visit at which the endpoint was assessed. The Kaplan-Meier method was used to estimate PFS.
Time Frame	From time of randomization to first documented evidence of disease progression or death due to any cause, whichever came first, assessed over 2 years

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	31	30
Median (95% Confidence Interval) [months]	NA	23.5

4. Secondary Outcome

Title	Time to Next Anti-chronic Lymphocytic Leukemia (CLL) Therapy or Death
Description	Time to next anti-CLL (anti-lymphoma) therapy was defined as the time from randomization until the time of first administration of the next anti-lymphoma therapy other than ofatumumab or death. For participants who were lost to follow-up, the time was censored at the date of the last attended visit at which the endpoint was assessed.
Time Frame	From time of randomization to first administration of next anti-CLL therapy other than ofatumumab or death, assessed over 5 years

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	31	30
Median (95% Confidence Interval) [months]	33.4	33.3

5. Secondary Outcome

Title	Median Percent Change in Tumor Size From Baseline (Visit 2, Wk 0) at Visits 9, 21, 25, 29, 33, 34, 35, and 37
Description	Tumor size was measured by physical examination of palpable abnormal lymph nodes. Percent change from Baseline (Visit 2, Week 0) = (value at indicated visits minus value at Visit 2 divided by value at Visit 2) * 100. Visits 33, 34, 35, 36, and 37 are measured in the number of months from the start of the last infusion. The start of the last infusion could have occurred up to Week 20.
Time Frame	Baseline Visit 2 (Week [Wk] 0); Visits 9 (Wk 4), 21 (Wk 12), 25 (Wk 16), 29 (Wk 20), 33 (Month [M] 1 after start of last infusion [LI]), 34 (M 3 after start of LI), 35 (M 6 after start of LI), 36 (M 9 after start of LI), and 37 (M 12 after start of L

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	29	28
Visit 9 (Week 4), n=29, 28	-75.00	-70.90
Visit 21 (Week 12), n=24, 23	-100.00	-100.00
Visit 25 (Week 16), n=23, 20	-100.00	-100.00
Visit 29 (Week 20), n=22, 16	-100.00	-100.00
Visit 33 (Month 1), n=21, 24	-100.00	-100.00
Visit 34 (Month 3), n=22, 23	-100.00	-100.00
Visit 35 (Month 6), n=19, 22	-100.00	-100.00
Visit 36 (Month 9), n=20, 22	-100.00	-100.00
Visit 37 (Month 12), n=20, 18	-100.00	-100.00

6. Secondary Outcome

Title	Median Percent Change in CD5+CD19+ and CD5+CD20+ Cells in Peripheral Blood From Onset of Course 3 Throughout Follow-up (FU) Compared to Screening
Description	Malignant B cells (CD5+CD19+ and CD5+CD20+) were measured in peripheral blood samples by flow cytometry. Percent change from Screening (Visit 1, Week -2) = (value at indicated visits minus value at Visit 1 divided by value at Visit 1) * 100. Visits 33 and 34 are measured in the number of months from the start of the last infusion. The start of the last infusion could have occurred up to Week 20.
Time Frame	Baseline Visit 2 (Week [Wk] 0); Visits 15 (Wk 8), 21 (Wk 12), 25 (Wk 16), 29 (Wk 20), 33 (Month [M] 1 after start of last infusion [LI]), 34 (M 3 after start of LI)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	25	26
CD5+CD19+ cells, Visit 15 (Wk 8), n=25, 26	-100.00	-100.00
CD5+CD19+ cells, Visit 21 (Wk 12), n=24, 24	-100.00	-100.00
CD5+CD19+ cells, Visit 25 (Wk16), n=23, 21	-100.00	-100.00
CD5+CD19+ cells, Visit 29 (Wk 20), n=22, 19	-100.00	-100.00
CD5+CD19+ cells, Visit 33 (Wk 24), n=21, 24	-100.00	-100.00
CD5+CD19+ cells, Visit 34 (Wk 32), n=20, 22	-100.00	-100.00
CD5+CD20+ cells, Visit 15 (Wk 8), n=25, 26	-100.00	-100.00
CD5+CD20+ cells, Visit 21 (Wk 12), n=24, 24	-100.00	-100.00
CD5+CD20+ cells, Visit 25 (Wk16), n=23, 21	-100.00	-100.00
CD5+CD20+ cells, Visit 29 (Wk 20), n=22, 19	-100.00	-100.00
CD5+CD20+ cells, Visit 33 (Wk 24), n=21, 24	-100.00	-100.00
CD5+CD20+ cells, Visit 34 (Wk 32), n=20, 22	-100.00	-100.00

7. Secondary Outcome

Title	Number of Participants Who Experienced Any Adverse Event From First Treatment (Visit 2) to Visit 43 (Month 60)
Description	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 this treatment. A list of AEs experienced in the study at a frequency threshold of 5% can be found in the AE section.
Time Frame	From first treatment (Visit 2) up to Visit 43 (Month 60)

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	31	30
Number [participants]	31 100%	30 100%

8. Secondary Outcome

Title	Number of Participants With Positive Human Anti-human Anti Bodies (HAHA) at Visits 1, 21, 35, and 39
Description	HAHA are indicators of immunogenicity to ofatumumab. Blood samples were drawn from participants at Visits 1, 21, 35, and 39 for analysis of HAHA. Analysis of HAHA was done in batches.
Time Frame	Visits 1 (Screening, Visit -2), 21 (Week 12), 35 (Month 6), and 39 (Month 18)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	31	30
Visit 1 (Week -2), n=31, 30	0 0%	0 0%
Visit 21 (Week 12), n=24, 24	0 0%	0 0%
Visit 35 (Month 6), n=19, 22	0 0%	0 0%
Visit 39 (Month 18), n=14, 13	0 0%	0 0%

9. Secondary Outcome

Title	Number of Participants Who Reported Myelosuppression (Anemia, Leukopenia, Neutropenia, and Thrombocytopenia)
Description	Myelosuppression is one of the expected AEs for FC treatment and is defined as the decrease in the ability of the bone marrow to produce blood cells. The number of participants with myelosuppression was assessed from laboratory measurements with Grades 3(severe)-4 (life-threatening/disabling) (1, mild; 2, moderate; 5, death) according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. The CTCAE is issued by the National Cancer Institute (NCI) and is the standard classification used for the severity grading scale for AEs in cancer therapy clinical studies.
Time Frame	From first treatment (Visit 2) up to Visit 43 (Month 60)

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	31	30
Anemia	6 19.4%	8 26.7%
Leukopenia	23 74.2%	22 73.3%
Neutropenia	29 93.5%	26 86.7%
Thrombocytopenia	4 12.9%	8 26.7%

10. Secondary Outcome

Title	Percent Change From Screening (Visit 1) in Complement (CH50) Levels at Visit 9 (Week 4)
Description	Blood samples were drawn from participants at Visits 1 and 9 for analysis of complement (CH50) levels. Analysis of CH50 was done in batches, and CH50 levels were measured two hours after the end of study medication infusion. Percent change from Screening (Visit 1, Week -2) = (value at Visit 9 minus value at Visit 1 divided by value at Visit 1) * 100.
Time Frame	Visit 1 (Week -2) and Visit 9 (Week 4)

Outcome Measure Data

Analysis Population Description

FAS. Data were provided for the number of participants attending Visit 9. Participants withdrawn during the study were not analyzed.

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	29	26
Median (Full Range) [Percent change in complement levels]	0	0

11. Primary Outcome

Title	Number of Participants (Par.) Who Were Classified as Responders and Non-responders
Description	Par. were evaluated by an IRC in accordance with NCI-WG 1996 guideline. Responders: CR, Nodular Partial Remission (nPR, same as CR, but persistent bone marrow nodules), and Partial Remission (PR, >=50% decrease in lymphocytes from pretreatment baseline (BL) value, >=50% reduction in lymphadenopathy, >=50% reduction of liver/spleen and neutrophils >= 1.5*10^9/L or platelets >100*10^9/L or hemoglobin >11 g/dL (or 50% improvement over BL for neutrophils, platelets, hemoglobin); non-responders: Stable Disease (SD, did not achieve CR/PR, and no PD), Progressive Disease (PD), or Not Evaluable (NE).
Time Frame	From start of treatment (Day 1 of Week 0) until 3 months after start of last infusion (up to Week 32)

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	31	30
All responders	24 77.4%	22 73.3%
Responders, CR	10 32.3%	15 50%
Responders, nPR	1 3.2%	1 3.3%
Responders, PR	13 41.9%	6 20%
All Non-responders	7 22.6%	8 26.7%
Non-responders, SD	3 9.7%	2 6.7%
Non-responders, PD	2 6.5%	5 16.7%
Non-responders, NE	2 6.5%	1 3.3%

12. Secondary Outcome

Title	Number of Participants Classified as Responders Having CR Who Tested Negative for Minimal Residual Disease (MRD)
Description	MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment when the participant has achieved CR. For all participants who achieved CR, the follow-up bone marrow sample was tested for malignant B cells (CD5+CD19+) to determine if there was any MRD.
Time Frame	From start of treatment (Day 1 of Week 0) until 3 months after start of last infusion (up to course 6 or Week 32)

Outcome Measure Data

Analysis Population Description

FAS. Only participants with CR at Visit 34 were analyzed.

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	10	15
Number [participants]	2 6.5%	6 20%

13. Secondary Outcome

Title	Ctrough and Cmax at the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20)
Description	Cmax is defined as the maximum concentration of drug in plasma samples. Ctrough is defined as the trough plasma concentration (measured concentration at the end of a dosing interval [taken directly before next administration]). No drug is present before the first infusion; therefore, there are no Ctrough results for the first infusion.
Time Frame	Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	31	29
First infusion, Cmax, n=31, 29	67.5 (0.47)	57.2 (0.47)
Sixth infusion, Cmax, n=22, 19	201 (0.30)	427 (0.34)
Sixth infusion, Ctrough, n=22, 19	19.9 (12.69)	62.2 (10.36)

14. Secondary Outcome

Title	AUC(0-inf) and AUC(0-672) After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20)
Description	AUC is defined as the area under the ofatumumab concentration-time curve as a measure of drug exposure. AUC(0-672) is AUC from start of infusion to 672 hours after start of infusion; AUC(0-inf) is AUC from start of infusion extrapolated to infinity.
Time Frame	Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	24	26
First infusion, AUC(0-inf), n=24, 26	2453 (1.28)	1915 (0.74)
First infusion, AUC(0-672), n=24, 26	2452 (1.28)	1915 (0.74)
Sixth infusion, AUC(0-inf), n=16, 16	145236 (0.54)	397577 (0.35)
Sixth infusion, AUC(0-672), n=20, 19	74728 (0.39)	149019 (0.75)

15. Secondary Outcome

Title	t1/2 After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20)
Description	t1/2 is defined as terminal half-life and is the time required for the amount of drug in the body to decrease by half.
Time Frame	Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	24	26
First infusion, t1/2, n=24, 26	19.4 (1.13)	18.8 (0.62)
Sixth infusion, t1/2, n=16, 16	551 (0.31)	746 (0.30)

16. Secondary Outcome

Title	CL After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20)
Description	CL is the clearance of drug from plasma, which is defined as the volume of plasma from which the drug is cleared per unit time.
Time Frame	Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	24	26
First infusion, CL, n=24, 26	122 (1.28)	157 (0.74)
Sixth infusion, CL, n=20, 19	6.7 (0.39)	6.7 (0.75)

17. Secondary Outcome

Title	Vss After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20)
Description	Vss is defined as the volume of distribution at steady state of ofatumumab.
Time Frame	Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	24	26
First infusion, Vss, n=24, 26	3.88 (0.37)	4.57 (0.30)
Sixth infusion, Vss, n=16, 16	5.15 (0.27)	5.77 (0.38)

18. Secondary Outcome

Title	Number of Participants With Progression or Death
Description	Disease progression is characterized by at least one of the following, per the Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia: a >=50% increase in the sum of the products of at least two lymph nodes on two consecutive determinations 2 weeks apart (at least one node must be >=2 centimeters); or the appearance of new palpable lymph nodes; or a >=50% increase in liver and/or spleen size (measurement below the costal margin); or the appearance of palpable hepatomegaly or splenomegaly not previously present; or a >=50% increase in the numbers of circulating lymphocytes to at least 5.0 * 10^9/Liter; or transformation to a more aggressive histology (e.g., Richter's syndrome or prolymphocytic leukemia with >55% prolymphocytes). For participants who were lost to follow-up, PFS was censored at the date of the last attended visit at which the endpoint was assessed. The Kaplan-Meier method was used to estimate PFS.
Time Frame	From time of randomization to first documented evidence of disease progression or death due to any cause, whichever came first, assessed over 2 years

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Ofatumumab 500 mg + FC	Ofatumumab 1000 mg + FC
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses
Measure Participants	31	30
Number [Participants]	3 9.7%	7 23.3%

Adverse Events

Adverse Event Reporting Description	During the Extended Follow-up Phase, from 2 years to 5 years after first treatment, only serious adverse events (SAEs) were collected; no non-serious AEs were collected during this period.
Arm/Group Title	Ofatumumab 500 mg + Fludarabine and Cyclophosphamide (FC)		Ofatumumab 1000 mg + FC		Ofatumumab 500 mg + FC: Extended Follow-up Phase		Ofatumumab 1000 mg + FC: Extended Follow-up Phase
Arm/Group Description	Ofatumumab intravenous (iv) infusion initiated at 300 milligrams (mg) for course 1, followed by dose of 500 mg for courses 2-6 in combination with fludarabine iv (25 mg/meters squared [m^2] daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses		Ofatumumab iv infusion initiated at 300 mg for course 1, followed by dose of 1000 mg for courses 2-6 in combination with fludarabine iv (25 mg/m^2 daily on Days 1-3) and cyclophosphamide iv (250 mg/m^2 daily on Days 1-3) administered every 4 weeks for a total of 6 courses		Participants were monitored in the Extended Follow-up Phase every 6 months for survival until alternative Chronic Lymphocyte Leukemia (CLL) therapy was initiated, or until Month 60.		Participants were monitored in the Extended Follow-up Phase every 6 months for survival until alternative CLL therapy was initiated, or until Month 60.
All Cause Mortality
	Ofatumumab 500 mg + Fludarabine and Cyclophosphamide (FC)		Ofatumumab 1000 mg + FC		Ofatumumab 500 mg + FC: Extended Follow-up Phase		Ofatumumab 1000 mg + FC: Extended Follow-up Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ofatumumab 500 mg + Fludarabine and Cyclophosphamide (FC)		Ofatumumab 1000 mg + FC		Ofatumumab 500 mg + FC: Extended Follow-up Phase		Ofatumumab 1000 mg + FC: Extended Follow-up Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/31 (54.8%)		23/30 (76.7%)		7/31 (22.6%)		5/30 (16.7%)
Blood and lymphatic system disorders
Neutropenia	10/31 (32.3%)		16/30 (53.3%)		0/31 (0%)		1/30 (3.3%)
Leukopenia	3/31 (9.7%)		7/30 (23.3%)		0/31 (0%)		0/30 (0%)
Febrile neutropenia	4/31 (12.9%)		3/30 (10%)		0/31 (0%)		0/30 (0%)
Thrombocytopenia	2/31 (6.5%)		3/30 (10%)		0/31 (0%)		0/30 (0%)
Lymphopenia	0/31 (0%)		2/30 (6.7%)		0/31 (0%)		0/30 (0%)
Anaemia	1/31 (3.2%)		1/30 (3.3%)		0/31 (0%)		1/30 (3.3%)
Anaemia haemolytic autoimmune	1/31 (3.2%)		0/30 (0%)		1/31 (3.2%)		0/30 (0%)
Cardiac disorders
Myocardial infarction	2/31 (6.5%)		0/30 (0%)		0/31 (0%)		0/30 (0%)
Cardiac failure congestive	1/31 (3.2%)		0/30 (0%)		0/31 (0%)		0/30 (0%)
Gastrointestinal disorders
Nausea	1/31 (3.2%)		0/30 (0%)		0/31 (0%)		0/30 (0%)
Vomiting	1/31 (3.2%)		0/30 (0%)		0/31 (0%)		0/30 (0%)
Aphthous stomatitis	0/31 (0%)		1/30 (3.3%)		0/31 (0%)		0/30 (0%)
Mouth ulceration	0/31 (0%)		1/30 (3.3%)		0/31 (0%)		0/30 (0%)
Subileus	0/31 (0%)		0/30 (0%)		1/31 (3.2%)		0/30 (0%)
General disorders
Pyrexia	3/31 (9.7%)		0/30 (0%)		0/31 (0%)		0/30 (0%)
Disease progression	0/31 (0%)		1/30 (3.3%)		0/31 (0%)		0/30 (0%)
Oedema peripheral	1/31 (3.2%)		0/30 (0%)		0/31 (0%)		0/30 (0%)
Infections and infestations
Sepsis	0/31 (0%)		2/30 (6.7%)		0/31 (0%)		0/30 (0%)
Herpes virus infection	0/31 (0%)		1/30 (3.3%)		0/31 (0%)		0/30 (0%)
Infection	0/31 (0%)		1/30 (3.3%)		0/31 (0%)		0/30 (0%)
Bronchitis acute	0/31 (0%)		1/30 (3.3%)		0/31 (0%)		0/30 (0%)
Pneumonia	2/31 (6.5%)		2/30 (6.7%)		0/31 (0%)		1/30 (3.3%)
Pneumonia fungal	0/31 (0%)		1/30 (3.3%)		0/31 (0%)		0/30 (0%)
Respiratory tract infection	0/31 (0%)		1/30 (3.3%)		0/31 (0%)		0/30 (0%)
Acarodermatitis	1/31 (3.2%)		0/30 (0%)		0/31 (0%)		0/30 (0%)
Eczema infected	1/31 (3.2%)		0/30 (0%)		0/31 (0%)		0/30 (0%)
Gastroenteritis rotavirus	1/31 (3.2%)		0/30 (0%)		0/31 (0%)		0/30 (0%)
Urinary tract infection	1/31 (3.2%)		0/30 (0%)		0/31 (0%)		0/30 (0%)
Laryngitis	0/31 (0%)		0/30 (0%)		1/31 (3.2%)		0/30 (0%)
Progressive multifocal leukoencephalopathy	0/31 (0%)		0/30 (0%)		0/31 (0%)		1/30 (3.3%)
Investigations
Neutrophil count decreased	1/31 (3.2%)		1/30 (3.3%)		0/31 (0%)		0/30 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	1/31 (3.2%)		0/30 (0%)		0/31 (0%)		0/30 (0%)
Musculoskeletal and connective tissue disorders
Arthritis reactive	0/31 (0%)		1/30 (3.3%)		0/31 (0%)		0/30 (0%)
Rhabdomyolysis	0/31 (0%)		1/30 (3.3%)		0/31 (0%)		0/30 (0%)
Back pain	1/31 (3.2%)		0/30 (0%)		0/31 (0%)		0/30 (0%)
Exostosis	0/31 (0%)		0/30 (0%)		1/31 (3.2%)		0/30 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma	0/31 (0%)		1/30 (3.3%)		0/31 (0%)		0/30 (0%)
Renal cell carcinoma stage unspecified	0/31 (0%)		1/30 (3.3%)		0/31 (0%)		0/30 (0%)
Acute myeloid leukemia	0/31 (0%)		0/30 (0%)		1/31 (3.2%)		0/30 (0%)
Adenocarcinoma of colon	0/31 (0%)		0/30 (0%)		1/31 (3.2%)		0/30 (0%)
Myelodysplastic syndrome	0/31 (0%)		0/30 (0%)		1/31 (3.2%)		0/30 (0%)
Prostate cancer	0/31 (0%)		0/30 (0%)		0/31 (0%)		1/30 (3.3%)
Small cell lung cancer	0/31 (0%)		0/30 (0%)		1/31 (3.2%)		0/30 (0%)
Nervous system disorders
Cerebrovascular accident	1/31 (3.2%)		0/30 (0%)		0/31 (0%)		0/30 (0%)
Psychiatric disorders
Alcohol abuse	0/31 (0%)		1/30 (3.3%)		0/31 (0%)		0/30 (0%)
Depression	0/31 (0%)		0/30 (0%)		1/31 (3.2%)		0/30 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/31 (3.2%)		1/30 (3.3%)		0/31 (0%)		0/30 (0%)
Bronchitis chronic	0/31 (0%)		0/30 (0%)		1/31 (3.2%)		0/30 (0%)
Vascular disorders
Subclavian vein thrombosis	1/31 (3.2%)		0/30 (0%)		0/31 (0%)		0/30 (0%)
Other (Not Including Serious) Adverse Events
	Ofatumumab 500 mg + Fludarabine and Cyclophosphamide (FC)		Ofatumumab 1000 mg + FC		Ofatumumab 500 mg + FC: Extended Follow-up Phase		Ofatumumab 1000 mg + FC: Extended Follow-up Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/31 (100%)		30/30 (100%)		0/0 (NaN)		0/0 (NaN)
Blood and lymphatic system disorders
Neutropenia	14/31 (45.2%)		23/30 (76.7%)		0/0 (NaN)		0/0 (NaN)
Leukopenia	8/31 (25.8%)		16/30 (53.3%)		0/0 (NaN)		0/0 (NaN)
Thrombocytopenia	7/31 (22.6%)		12/30 (40%)		0/0 (NaN)		0/0 (NaN)
Febrile neutropenia	5/31 (16.1%)		5/30 (16.7%)		0/0 (NaN)		0/0 (NaN)
Lymphopenia	5/31 (16.1%)		5/30 (16.7%)		0/0 (NaN)		0/0 (NaN)
Anaemia	4/31 (12.9%)		5/30 (16.7%)		0/0 (NaN)		0/0 (NaN)
Ear and labyrinth disorders
Vertigo	3/31 (9.7%)		1/30 (3.3%)		0/0 (NaN)		0/0 (NaN)
Gastrointestinal disorders
Nausea	14/31 (45.2%)		13/30 (43.3%)		0/0 (NaN)		0/0 (NaN)
Vomiting	9/31 (29%)		6/30 (20%)		0/0 (NaN)		0/0 (NaN)
Constipation	5/31 (16.1%)		5/30 (16.7%)		0/0 (NaN)		0/0 (NaN)
Diarrhoea	5/31 (16.1%)		4/30 (13.3%)		0/0 (NaN)		0/0 (NaN)
Dispepsia	4/31 (12.9%)		0/30 (0%)		0/0 (NaN)		0/0 (NaN)
Abdominal pain	1/31 (3.2%)		2/30 (6.7%)		0/0 (NaN)		0/0 (NaN)
General disorders
Pyrexia	9/31 (29%)		7/30 (23.3%)		0/0 (NaN)		0/0 (NaN)
Fatigue	8/31 (25.8%)		6/30 (20%)		0/0 (NaN)		0/0 (NaN)
Chills	4/31 (12.9%)		5/30 (16.7%)		0/0 (NaN)		0/0 (NaN)
Oedema	3/31 (9.7%)		2/30 (6.7%)		0/0 (NaN)		0/0 (NaN)
Oedema peripheral	4/31 (12.9%)		1/30 (3.3%)		0/0 (NaN)		0/0 (NaN)
Infections and infestations
Nasopharyngitis	5/31 (16.1%)		4/30 (13.3%)		0/0 (NaN)		0/0 (NaN)
Bronchitis	4/31 (12.9%)		2/30 (6.7%)		0/0 (NaN)		0/0 (NaN)
Sinusitis	4/31 (12.9%)		2/30 (6.7%)		0/0 (NaN)		0/0 (NaN)
Upper respiratory tract infections	4/31 (12.9%)		2/30 (6.7%)		0/0 (NaN)		0/0 (NaN)
Herpes zoster	4/31 (12.9%)		1/30 (3.3%)		0/0 (NaN)		0/0 (NaN)
Rhinitis	3/31 (9.7%)		2/30 (6.7%)		0/0 (NaN)		0/0 (NaN)
Pneumonia	2/31 (6.5%)		2/30 (6.7%)		0/0 (NaN)		0/0 (NaN)
Investigations
Blood creatinine increased	1/31 (3.2%)		4/30 (13.3%)		0/0 (NaN)		0/0 (NaN)
Metabolism and nutrition disorders
Hyperkalaemia	2/31 (6.5%)		2/30 (6.7%)		0/0 (NaN)		0/0 (NaN)
Musculoskeletal and connective tissue disorders
Arthralgia	5/31 (16.1%)		5/30 (16.7%)		0/0 (NaN)		0/0 (NaN)
Back pain	4/31 (12.9%)		1/30 (3.3%)		0/0 (NaN)		0/0 (NaN)
Joint swelling	3/31 (9.7%)		1/30 (3.3%)		0/0 (NaN)		0/0 (NaN)
Nervous system disorders
Headache	7/31 (22.6%)		5/30 (16.7%)		0/0 (NaN)		0/0 (NaN)
Psychiatric disorders
Insomnia	2/31 (6.5%)		4/30 (13.3%)		0/0 (NaN)		0/0 (NaN)
Respiratory, thoracic and mediastinal disorders
Cough	4/31 (12.9%)		7/30 (23.3%)		0/0 (NaN)		0/0 (NaN)
Dyspnoea	4/31 (12.9%)		4/30 (13.3%)		0/0 (NaN)		0/0 (NaN)
Pharyngolaryngeal pain	2/31 (6.5%)		2/30 (6.7%)		0/0 (NaN)		0/0 (NaN)
Skin and subcutaneous tissue disorders
Rash	10/31 (32.3%)		8/30 (26.7%)		0/0 (NaN)		0/0 (NaN)
Urticaria	6/31 (19.4%)		3/30 (10%)		0/0 (NaN)		0/0 (NaN)
Pruritus	3/31 (9.7%)		3/30 (10%)		0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.