Efficacy and Safety of Ofatumumab Retreatment and Maintenance Treatment in Patients With B-cell Chronic Lymphocytic Leukemia (CLL)

Study Overview
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Brief Summary
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The purpose of the trial is to investigate the efficacy and safety of ofatumumab retreatment and maintenance in patients with chronic lymphocytic leukemia who have previously responded or had disease stabilization after ofatumumab in an ongoing trial (Hx-CD20-406).

Official Title
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A Single-arm, International, Multi-center Trial Investigating the Efficacy and Safety of Ofatumumab Retreatment and Maintenance in CLL Patients Who Progressed Following Response or Stable Disease After Ofatumumab Treatment in Hx-CD20-406

Conditions
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Leukaemia, Lymphocytic, Chronic

Intervention / Treatment
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* Drug: Ofatumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has responded to ofatumumab treatment (CR, nPR, PR) or has had SD at least up to and including visit number 14 (24 weeks after first infusion) in the Hx-CD20-406 trial. Has disease progression after visit number 14 (24 weeks after first infusion) in the Hx CD20 406 trial. Received at least eight ofatumumab infusions. Has active CLL with an indication for treatment. Has Eastern Cooperative Oncology Group (ECOG) performance status grade 0, 1 or 2. Provides signed informed consent, following receipt of verbal and written information about the trial, before any trial related activity is carried out. If previously treated in GEN416 (this trial), the patient must have achieved CR with subsequent disease progression 24 weeks or later after the first infusion in the GEN416 trial. Exclusion Criteria: The disease has transformed to more aggressive B-cell malignancies (e.g. diffuse large B-cell lymphoma, Richter's syndrome or prolymphocytic leukemia). Has a suspected treatment requiring malignancy other than CLL. Has received treatment other than ofatumumab within two weeks prior to visit 2. Has clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months from visit 1, congestive heart failure (NYHA III IV), and arrhythmia requiring therapy, with the exception of clinically non-significant extra systoles or minor conduction abnormalities. Has significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease. Has a history of significant cerebrovascular disease. Is known HIV positive. Has positive serology for hepatitis B, defined as a positive test for HBsAg and/or positive tests for both anti-HBs and anti-HBc. Has known or suspected hypersensitivity to components of the IMP. Has received treatment with any non-marketed drug substance or experimental therapy other than ofatumumab within four weeks prior to visit 2. Currently participates in any other interventional clinical trial other than Hx-CD20-406. Known or suspected to not being able to comply with a trial protocol (e.g. due to alcoholism, drug dependency or psychiatric disorder). Is breast feeding (women only). Has a positive pregnancy test at screening (women only). Is not willing to use adequate contraception during the trial and one year after last dose of ofatumumab (women only). Adequate contraception is defined as hormonal birth control or intrauterine device. For patients in the US the use of double barrier method is 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ofatumumab<br>Eight once weekly infusions (1 x 300 mg + 7 x 2000 mg), then 2000 mg once monthly for two years | Drug: Ofatumumab<br>* Eight once weekly infusions (1 x 300 mg + 7 x 2000 mg), then 2000 mg once monthly for two years<br>* Other names: HuMax-CD20;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants (Par.) Classified as Responders (Rs) and Non-responders (NRs) for Objective Response in Accordance With the National Cancer Institute Working Group (NCIWG) 1996 Guidelines | Par. with complete remission (CR), nodular partial remission (nPR), and partial remission (PR) on 2 consecutive visits >=56 days apart were classified as Rs; those with stable disease (SD)/progressive disease (PD) were classified as NRs. Per the NCIWG 1996 guidelines: CR; no lymphadenopathy/hepatomegaly/splenomegaly/constitutional symptoms, normal hematology, normocellular bone marrow sample for age, <30% lymphocytes (LC), no lymphoid nodule; PR: >=50% decrease in LC/lymphadenopathy; nPR: persistent bone marrow nodules; PD: new lesion or increase by >=50% from baseline; SD: no CR, PR, or PD. | Start of treatment (Week 0/Visit 2) until Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | Duration of response is defined as the time from the initial response (first visit at which response is observed) to progression or death. If the participant had progression between scheduled visits, no progression at the end of the trial, treatment discontinuation for undocumented progression, treatment discontinuation for toxicity or other reason, new anti-cancer treatment, and experienced death or progression after two or more missed visits in a row the endpoint was censored. | From the time of the initial response until progression or death (average of 14.1 study months) | 
| Progression-Free Survival (PFS) | PFS is defined as the time from randomization until progression (prog.)/death. Prog. events are defined by well-documented and verifiable data; other data are censored. If the par. had prog. between scheduled visits, died before the first assessment, or died between adequate visits, the endpoint was considered progressed. If there was no prog. at the end of the trial, treatment discontinuation for undocumented prog./toxicity/other reason, new anti-cancer treatment, and death/prog. after >=2 missed visits in a row, the endpoint was censored. Clinical prog. is not considered as a prog. endpoint. | Start of treatment (Week 0 of Visit 2) until progression or death (average of 14.1 study months) | 
| Time to Next Chronic Lymphocytic Leukemia (CLL) Treatment | Time to next chronic lymphocytic leukemia (CLL) treatment is defined as the time from treatment allocation/randomization (Visit 2) until the time of the first administration of the next CLL treatment other than ofatumumab (or HuMaxCD20, a fully human monoclonal antibody to CD20 that is expressed on the surface of B-cells). | Time from start of study treatment (Week 0 of Visit 2) until the time of first administration of a CLL treatment other than ofatumumab (average of 14.8 study months) | 
| Overall Survival (OS) | OS is defined as the time from allocation to death. | Time from start of study treatment (Week 0 of Visit 2) until date of death or time that participant was no longer followed (median of 18.0 months) | 
| Median Percent Change of Tumor Size (Sum of Products Dimensions [SPD]) From Baseline (Visit 2) at Month 4 | Reduction in tumor size was measured as the percent change in the sum of the products of the diameters of the largest abnormal lymph nodes from Baseline to Week 24. Percent change was calculated as (Week 24 SPD minus Baseline SPD)/Baseline SPD * 100. | Baseline (Visit 2) and Month 4 | 
| Median Percent Change of Tumor Size (Sum of Products Dimensions [SPD]) From Baseline (Visit 2) at Month 12 | Reduction in tumor size was measured by the percentage change in the sum of products of the diameters of the largest abnormal lymph nodes from Baseline to Month 12. Percent change was calculated as (Month 12 SPD minus Baseline SPD)/Baseline SPD * 100. | Baseline (Visit 2) and Month 12 | 
| Median Percent Change of Tumor Size (Sum of Products Dimensions [SPD]) From Baseline (Visit 2) at Month 24 | Reduction in tumor size was measured by the percentage change in the sum of products of the diameters of the largest abnormal lymph nodes from Baseline to Month 24. Percent change was calculated as (Month 24 SPD minus Baseline SPD)/Baseline SPD * 100. | Baseline (Visit 2) and Month 24 | 
| Number of Participants With Negative and Positive Human Anti-human Antibody (HAHA) Results at the Time of Screening and Post Ofatumumab | HAHAs are indicators of immunogenicity to ofatumumab. HAHA levels were assessed for each participant at the end of participation in the study (at their last visit). A positive HAHA status indicates a positive enzyme-linked immunosorbent assay (ELISA) result, an inconclusive status indicates a negative ELISA result at ofatumumab concentration above the threshold at which ofatumumab may interfere with the assay, and a negative status indicates a negative ELISA result at ofatumumab concentration below the threshold. | Screening and post ofatumumab (up to Study Month 32) | 
| Number of Participants Who Experienced Any Adverse Event | An adverse event (AE) is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with the treatment. A list of AEs experienced in the study with a frequency threshold of 5% can be found in the AE section of this results record. | From the first infusion (Visit 2/Week 0) until the last visit of the Extended Follow-up Phase (up to Study Month 26 [visit 34]) | 
| Number of Participants With the Indicated Major Infections | The data collected for this analysis are reported in the overall Serious Adverse Events (SAEs) of infections rather than reported separately for this specific analysis. This is a conservative approach for reporting all infectious SAEs in order to ensure that all of the infectious SAEs are represented. | From the first infusion (Visit 2/Week 0) until the last visit of the Extended Follow-up Phase (up to Study Month 26 [visit 34]) | 
| Number of Participants With Infections Requiring Hospitalization or Intravenous Antibiotics | The data collected for this analysis are reported in the overall SAEs of infections rather than reported separately for this specific analysis. This is a conservative approach for reporting all infectious SAEs in order to ensure that all of the infectious SAEs are represented. | From the first infusion (Visit 2/Week 0) until the last visit of the Extended Follow-up Phase (up to Study Month 26 [visit 34]) | 
| Cmax and Ctrough at Visit 2 (Week 0) and at Visit 14 (Month 4) | Cmax is defined as the maximum concentration of drug in plasma samples (collected at the end of the infusion). Ctrough is defined as the concentration of drug in plasma samples at the end of a dosing interval (collected directly before next administration). Ctrough before the first infusion represents residual ofatumumab from participation in Study Hx-CD20-406. | Visit 2 (Week 0) and Visit 14 (Month 4) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Maintenance, Retreatment, Chronic lymphocytic leukemia, B-Cell Chronic Lymphocytic Leukemia, Ofatumumab