Rapid Infusion of Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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This is a Phase II, single-arm study of ofatumumab investigating the safety of an accelerated infusion schedule of ofatumumab in patients who have received at least one prior therapy for CLL. The primary endpoint is to evaluate the number of subjects able to complete infusion number 3 (2000 mg) within 15 minutes of the planned time.

Detailed Description
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The purpose of this study is to develop an accelerated infusion regimen that allows ofatumumab to be delivered in a safe manner while minimizing the time required administering the treatment. We hypothesize there will be fewer infusion-related reactions using the proposed dose-dense approach the first week before accelerating the rate of infusion.

Official Title
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Rapid Infusion of Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia, a Phase II Trial

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Ofatumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CD20+ B-cell chronic lymphocytic leukemia (B-CLL) according to International Workshop on CLL Working Group (IWCLL WG) Diagnostic Criteria. Have received at least one prior therapy for CLL. •If previously treated with ofatumumab must have achieved at least a partial response (PR) and maintained PR for >= 6 months. Requires treatment according to IWCLL-Working Group guidelines. Eastern Cooperative Oncology Group Performance Status (ECOG PS) <=1. Laboratory parameters <=7 days prior to treatment initiation: Creatinine <= 1.5 mg/dL upper limit normal (ULN) Aspartate amino transferase (AST) or alanine amino transferase (ALT) <= 3.0 x ULN Alkaline phosphatase (ALP) <= 3.0 x ULN Total Bilirubin level of < 1.5 mg/dL x the institutional ULN unless secondary to Gilbert's disease (or pattern consistent with Gilbert's) Hepatitis B sAg negative and HepB cAb negative. Note: Patients who are HepB sAg negative but are HepB cAb positive (regardless of HepB sAb status) will NOT be allowed. Women of childbearing potential must have a negative serum pregnancy test performed <=72 hours prior to start of treatment. Women of childbearing potential or men with partners of childbearing potential must use effective birth control measures during treatment. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she must agree to inform her treating physician immediately. Accessible for treatment and follow-up. Able to understand the nature of this study, give written informed consent prior to study entry, and comply with study requirements. No prior antibody therapy for CLL within the previous 3 months. Exclusion Criteria: Previous treatment with ofatumumab that resulted in a Grade 3 or 4 infusion reaction. Treatment for CLL within last 4 weeks. (Patients who have received steroids or IVIG for autoimmune complications of CLL are eligible). Current active hepatic or biliary disease (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease, per assessment by the treating physician). Active bacterial or viral infection or infection requiring intravenous antibiotic treatment at the time of accrual. Central nervous system lymphoma/CLL. Transformation of CLL to aggressive non-Hodgkin lymphoma (NHL) (i.e., Richter's transformation). History of other malignancy <= 2 years of study entry which could affect compliance with the protocol or interpretation of results. History of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix, low grade, early-stage, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ (DCIS) of the breast treated with curative intent, are generally eligible. Active hepatitis B or C or known HIV positive. Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to visit 1, whichever is longer. History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae. Clinically significant cardiac disease including unstable angina, acute myocardial infarction (within 6 months of enrollment), congestive heart failure (NYHA III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient.

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>Rapid Infusion of Ofatumumab | Drug: Ofatumumab<br>* The first dose of ofatumumab administered on Day 1 will be 300 mg to minimize infusion reactions. If the initial 300 mg dose of ofatumumab is well-tolerated, without occurrence of any infusion-associated AEs of >= grade 3, on Day 3 ofatumumab will increase to 1000 mg IV. If the Day 3 dose was well-tolerated (i.e., no infusion-associated AE >= grade 3), on Day 8 the ofatumumab dose will escalate to 2000 mg IV. To achieve the primary endpoint for this study, 20% of the 2000 mg ofatumumab dose only will be administered over the first 30 minutes and if tolerated the remaining 80% of the dose will be infused over the remaining 1.5/hours of each treatment. Ofatumumab doses, weeks 3-8, will remain at 2000 mg IV with no further dose escalations. If the Day 8 (Week 2) dose is tolerated all subsequent doses may be infused in the same manner.<br>* Other names: Arzerra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Patients Who Complete an Accelerated Infusion Regimen Within 15 Minutes of the Planned 2-hour Treatment. | Defined as percent of patients who are able to complete the Day 8 (2000 mg IV Ofatumumab) infusion within 15 minutes of the planned 2-hour treatment goal. | At Week 2, Day 1 of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Time to Complete Individual Infusions of an Accelerated Infusion Schedule of Ofatumumab | Defined as the actual mean infusion times, in minutes, for patients to complete a schedule of 3 infusions with the goal of completing Infusion #3 within 15 minutes of the planned 2-hour treatment time. | Week 1 - Days 1 and 3, and Week 2, Day 1 | 
| Overall Response Rate (ORR) | Defined as the percent of patients having a complete or partial response (CR or PR) assessed by International Workshop on CLL Working Group (IWCLLWG) Diagnostic Criteria (Hallek et al., 2008). CR = (a) Peripheral blood lymphocytes below 4000/µl; (b) Absence of significant lymphadenopathy by physical exam or radiographic scans (c) No hepatomegaly or splenomegaly; (d) Absence of constitutional symptoms; and blood counts above specified values. PR = (a) Decreased blood lymphocytes by 50% or more from the value prior to therapy;(b) No increase in any lymph node, and no new enlarged lymph node. Progressive Disease (PD) = An increase in 50% or more in greatest determined diameter of any previous site. Stable Disease (SD) = No evidence of CR or PR and no evidence of progressive disease. | At weeks 12 and 28 | 
| Progression Free Survival | Defined as the time from first treatment until objective tumor progression or death from any cause. | For 28 weeks during therapy then every 3 months for 2 years and every 6 months thereafter. | 
| Overall Survival | Defined as the time from first treatment until death from any cause. | For 28 weeks during therapy then every 3 months for 2 years and every 6 months thereafter. | 
| Number of Patients With Infusion-related Reactions Assessed According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v. 4.0. | Patients who received at least 1 dose of protocol treatment either Infusion #1 (300 mg), Infusion #2 (1000 mg) or Infusion #3 (2000 mg) are included in the assessment. | up to 28 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Lymphocytic Leukemia, Ofatumumab, Rapid Infusion