Ofatumumab With Fludarabine and Cyclophosphamide in B-CLL Patients

Phase 2

Completed

Conditions: Leukaemia, Lymphocytic, Chronic

Interventions: Drug: Ofatumumab 500mg
Drug: Ofatumumab 1000mg
Drug: Fludarabine
Drug: Cyclophosphamide

Registration Number: NCT00410163

Lead Sponsor: GlaxoSmithKline

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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 61

Inclusion Criteria

Patients with active B-CLL and with an indication for treatment
Age ≥ 18 years
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

Any previous treatment for B-CLL or any other treatments that can be considered active against B-CLL
Glucocorticoid unless given in doses ≤ 10 mg /day for other indications than B-CLL (e.g. asthma)
Known transformation of B-CLL
Known CNS involvement of B-CLL
Past or current malignancy, except for:
1. Cervical carcinoma Stage 1B or less
2. Non-invasive basal cell and squamous cell skin carcinoma
3. Malignant melanoma with a complete response of a duration of > 10 years
4. Other cancer diagnoses with a complete response of a duration of > 5 years
Chronic or current infectious disease requiring systemic treatment
Clinically significant cardiac disease
Significant concurrent, uncontrolled medical condition
History of significant cerebrovascular disease
Known HIV positive
Positive serology for hepatitis B, unless due to vaccination
Leukapheresis, except as a safety measure before chemotherapy
ECOG Performance Status of 3 or 4
Patients who at the time of inclusion are not expected to be able to complete the ofatumumab-FC regimen
Patients who have received treatment with any non-marketed drug substance or experimental therapy within 4 weeks prior to Visit 1
Current participation in any other interventional clinical study
Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder)
Breast feeding women or women with a positive pregnancy test at Visit 1
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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Active Comparator 1	Ofatumumab 500mg	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
Active Comparator 2	Ofatumumab 1000mg	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
Active Comparator 1	Fludarabine	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
Active Comparator 1	Cyclophosphamide	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
Active Comparator 2	Fludarabine	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
Active Comparator 2	Cyclophosphamide	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

Primary Outcome Measures

Name	Time	Method
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.
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

Name	Time	Method
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.