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Rare Diseases

Leukemia

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

All Drugs and Chemicals

Antineoplastic Agents

Antirheumatic Agents

Antibodies

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Immunoglobulins

Ofatumumab

Antibodies, Monoclonal

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

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

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

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.

Ofatumumab 500mg

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.

Ofatumumab 1000mg

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

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.

GSK Clinical Trials

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

Ofatumumab With Fludarabine and Cyclophosphamide in B-CLL Patients

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

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.

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).

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.

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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

GlaxoSmithKline

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.

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 500 mg + Fludarabine and Cyclophosphamide (FC)

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

Ofatumumab 1000 mg + FC

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 500 mg + FC: Extended Follow-up Phase

Participants were monitored in the Extended Follow-up Phase every 6 months for survival until alternative CLL therapy was initiated, or until Month 60.

Ofatumumab 1000 mg + FC: Extended Follow-up Phase

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 500 mg + FC

Total

Age, Continuous

Sex: Female, Male

White

Black or African American

Race/Ethnicity, Customized

GSK Response Center

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

Number of Participants (Par.) With Complete Remission (CR), Measured From Start of Treatment Until 3 Months After Last Infusion

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

FAS. Only those participants classified as responders were analyzed.

Duration of Response

Progression-Free Survival

Time to Next Anti-chronic Lymphocytic Leukemia (CLL) Therapy or Death

Visit 9 (Week 4), n=29, 28

Visit 21 (Week 12), n=24, 23

Visit 25 (Week 16), n=23, 20

Visit 29 (Week 20), n=22, 16

Visit 33 (Month 1), n=21, 24

Visit 34 (Month 3), n=22, 23

Visit 35 (Month 6), n=19, 22

Visit 36 (Month 9), n=20, 22

Visit 37 (Month 12), n=20, 18

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

Median Percent Change in Tumor Size From Baseline (Visit 2, Wk 0) at Visits 9, 21, 25, 29, 33, 34, 35, and 37

CD5+CD19+ cells, Visit 15 (Wk 8), n=25, 26

CD5+CD19+ cells, Visit 21 (Wk 12), n=24, 24

CD5+CD19+ cells, Visit 25 (Wk16), n=23, 21

CD5+CD19+ cells, Visit 29 (Wk 20), n=22, 19

CD5+CD19+ cells, Visit 33 (Wk 24), n=21, 24

CD5+CD19+ cells, Visit 34 (Wk 32), n=20, 22

CD5+CD20+ cells, Visit 15 (Wk 8), n=25, 26

CD5+CD20+ cells, Visit 21 (Wk 12), n=24, 24

CD5+CD20+ cells, Visit 25 (Wk16), n=23, 21

CD5+CD20+ cells, Visit 29 (Wk 20), n=22, 19

CD5+CD20+ cells, Visit 33 (Wk 24), n=21, 24

CD5+CD20+ cells, Visit 34 (Wk 32), n=20, 22

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

Number of Participants Who Experienced Any Adverse Event From First Treatment (Visit 2) to Visit 43 (Month 60)

Visit 1 (Week -2), n=31, 30

Visit 21 (Week 12), n=24, 24

Visit 39 (Month 18), n=14, 13

Number of Participants With Positive Human Anti-human Anti Bodies (HAHA) at Visits 1, 21, 35, and 39

Anemia

Leukopenia

Neutropenia

Thrombocytopenia

Number of Participants Who Reported Myelosuppression (Anemia, Leukopenia, Neutropenia, and Thrombocytopenia)

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

Percent Change From Screening (Visit 1) in Complement (CH50) Levels at Visit 9 (Week 4)

All responders

Responders, CR

Responders, nPR

Responders, PR

All Non-responders

Non-responders, SD

Non-responders, PD

Non-responders, NE

Number of Participants (Par.) Who Were Classified as Responders and Non-responders

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

Number of Participants Classified as Responders Having CR Who Tested Negative for Minimal Residual Disease (MRD)

First infusion, Cmax, n=31, 29

Sixth infusion, Cmax, n=22, 19

Sixth infusion, Ctrough, n=22, 19

Ctrough and Cmax at the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20)

First infusion, AUC(0-inf), n=24, 26

First infusion, AUC(0-672), n=24, 26

Sixth infusion, AUC(0-inf), n=16, 16

Sixth infusion, AUC(0-672), n=20, 19

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.

AUC(0-inf) and AUC(0-672) After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20)

First infusion, t1/2, n=24, 26

Sixth infusion, t1/2, n=16, 16

t1/2 After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20)

First infusion, CL, n=24, 26

Sixth infusion, CL, n=20, 19

CL After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20)

First infusion, Vss, n=24, 26

Sixth infusion, Vss, n=16, 16

Vss After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20)

Number of Participants With Progression or Death

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.

Spots Global Cancer Trial Database for Ofatumumab With Fludarabine and Cyclophosphamide in B-CLL Patients

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