Ofatumumab With Fludarabine and Cyclophosphamide in B-CLL Patients

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

Official Title
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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

Conditions
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Leukaemia, Lymphocytic, Chronic

Intervention / Treatment
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* Drug: Ofatumumab 500mg
* Drug: Ofatumumab 1000mg
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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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: Cervical carcinoma Stage 1B or less Non-invasive basal cell and squamous cell skin carcinoma Malignant melanoma with a complete response of a duration of > 10 years 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Comparator 1<br>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<br>* 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.<br>Drug: Fludarabine<br>* 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<br>Drug: Cyclophosphamide<br>* 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.<br>|
| Active Comparator: Active Comparator 2<br>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<br>* 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.<br>Drug: Fludarabine<br>* 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<br>Drug: Cyclophosphamide<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants (Par.) With Complete Remission (CR), Measured From Start of Treatment Until 3 Months After Last Infusion | 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. | Start of treatment (Day 1 of Week 0) until 3 months after start of last infusion (up to Week 32) | 
| Number of Participants (Par.) Who Were Classified as Responders and Non-responders | 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). | From start of treatment (Day 1 of Week 0) until 3 months after start of last infusion (up to Week 32) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | 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. | From time of initial response to disease progression or death, whichever came first, assessed over 2 years | 
| Progression-Free Survival | 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. | From time of randomization to first documented evidence of disease progression or death due to any cause, whichever came first, assessed over 2 years | 
| Time to Next Anti-chronic Lymphocytic Leukemia (CLL) Therapy or Death | 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. | From time of randomization to first administration of next anti-CLL therapy other than ofatumumab or death, assessed over 5 years | 
| Median Percent Change in Tumor Size From Baseline (Visit 2, Wk 0) at Visits 9, 21, 25, 29, 33, 34, 35, and 37 | 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. | 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 | 
| 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 | 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. | 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) | 
| Number of Participants Who Experienced Any Adverse Event From First Treatment (Visit 2) 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. | From first treatment (Visit 2) up to Visit 43 (Month 60) | 
| Number of Participants With Positive Human Anti-human Anti Bodies (HAHA) at Visits 1, 21, 35, and 39 | 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. | Visits 1 (Screening, Visit -2), 21 (Week 12), 35 (Month 6), and 39 (Month 18) | 
| Number of Participants Who Reported Myelosuppression (Anemia, Leukopenia, Neutropenia, and Thrombocytopenia) | 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. | From first treatment (Visit 2) up to Visit 43 (Month 60) | 
| Percent Change From Screening (Visit 1) in Complement (CH50) Levels at 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. | Visit 1 (Week -2) and Visit 9 (Week 4) | 
| Number of Participants Classified as Responders Having CR Who Tested Negative for Minimal Residual Disease (MRD) | 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. | From start of treatment (Day 1 of Week 0) until 3 months after start of last infusion (up to course 6 or Week 32) | 
| Ctrough and Cmax at the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20) | 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. | Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose) | 
| AUC(0-inf) and AUC(0-672) After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20) | 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. | Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose) | 
| t1/2 After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20) | 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. | Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose) | 
| CL After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20) | 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. | Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose) | 
| Vss After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20) | Vss is defined as the volume of distribution at steady state of ofatumumab. | Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose) | 
| Number of Participants With Progression or Death | 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. | From time of randomization to first documented evidence of disease progression or death due to any cause, whichever came first, assessed over 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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B-cell, cyclophosphamide, fludarabine, Chronic Lymphocytic Leukemia, Ofatumumab