Ofatumumab and High-dose Methylprednisolone in Patients With Chronic Lymphocytic Leukemia (CLL)

Study Overview
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Brief Summary
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Patients who have relapsed/refractory CLL and require therapy as per iwCLL guidelines will be eligible. Subjects will receive a treatment with ofatumumab and HDMP for three consecutive 4 week cycles. The primary endpoint is to determine the complete response (CR) to therapy and the secondary endpoints will assess the safety and tolerability of the regimen, the impact of the treatment on progression free, treatment free, overall survival, and pharmacokinetics of ofatumumab. Patients will receive allopurinol for tumor-lysis prophylaxis and antimicrobial prophylaxis.

Detailed Description
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Patients who have relapsed/refractory CLL and require therapy as per iwCLL guidelines will be eligible. Subjects will receive a treatment with ofatumumab and HDMP for three consecutive 4 week cycles. The primary endpoint is to determine the complete response (CR) to therapy and the secondary endpoints will assess the safety and tolerability of the regimen, the impact of the treatment on progression free, treatment free, overall survival, and pharmacokinetics of ofatumumab. Cycles 1-3 will be administered without scheduled interruption every 28 days for a total of 12 weeks of therapy. Patients will receive allopurinol for tumor-lysis prophylaxis and antimicrobial prophylaxis. Blood glucose levels will be monitored immediately after HDMP infusion by finger stick glucometry. Two months following completion of treatment a response assessment will occur per iwCLL guidelines. The treatment will be administered as outpatient, and each cycle will be four weeks in duration.

Official Title
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A Phase II Study of Ofatumumab in Combination With High-dose Methylprednisolone in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Conditions
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CLL

Intervention / Treatment
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* Drug: Ofatumumab/HDMP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously treated patients with a diagnosis of CLL Previous treatment with any monoclonal antibody or chemotherapy regardless of response as defined by the iwCLL Working Group Guidelines as evidenced by: progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia massive (i.e. at least 6cm below the left costal margin) or progressive or symptomatic splenomegaly massive nodes (i.e. at least 10cm in longest diameter) or progressive or symptomatic lymphadenopathy. progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months. autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy (See Section 10.2) Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs: unintentional weight loss of 10% or more within the previous 6 months significant fatigue (i.e. ECOG PS 2 or worse, inability to work or perform usual activities), fevers higher than 100.5ºF or 38.0ºC for 2 or more weeks without other evidence of infection, night sweats for more than 1 month without evidence of infection Subjects must be 18 years of age or older, male or female. ECOG performance status of 0-2. Subjects must be able to give informed consent. Females of child bearing potential(FCBP)† must have a negative serum or urine pregnancy test within 10 - 14 days prior to and again within 24 hours of starting treatment and agree to use a medically accepted contraceptive method for the duration of this study. Exclusion Criteria: Hepatitis BsAg positive, Hepatitis BcAb positive, and Hepatitis C positive patients. Known HIV positive patients. Diabetics. Patients with uncontrolled Autoimmune Hemolytic Anemia (AIHA) or autoimmune thrombocytopenia (ITP). Screening laboratory values within these ranges: platelets <50 x 109/L, neutrophils <1.0 x 109/L, creatinine >2.0 times upper normal limit,total bilirubin >1.5 times upper normal limit (unless a known history of Gilbert's disease), ALT >2.5 times upper normal limit (unless due to disease involvement of liver), alkaline phosphatase >2.5 times upper normal limit (unless due to disease involvement of the liver or bone marrow) Inability to provide informed consent. Concurrent malignancy (excluding basal and squamous cell skin cancers). Active fungal, bacterial, and/or viral infection. History of peptic ulcer disease resulting in GI bleeding within the last 6 months. Untreated metabolic disorders such as hypothyroidism and Cushing's disease. History of steroid-induced psychosis. Estimated life expectancy of less than 3 months by the investigator's best clinical judgment. Serious medical condition that would render the subject medically unstable. Women who are pregnant or breast-feeding. History of Pancreatitis. History of Diverticulitis. Patients with known hypersensitivity to ofatumumab or known history of anaphylaxis to Rituximab or alemtuzumab. Concurrent use of other anti-cancer agents or treatments. Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).

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/HDMP<br>High dose methylprednisolone sodium succinate (HDMP) at 1gm/m2 daily as infusion for 3 consecutive days every cycle. Ofatumumab 300mg administered Day1 of cycle 1 followed by 12 doses of 1000mg administered. Each patient may receive 3 cycles of treatment in the absence of progressive disease or significant toxicity. | Drug: Ofatumumab/HDMP<br>* High dose methylprednisolone sodium succinate (HDMP) at 1gm/m2 daily as infusion for 3 consecutive days every cycle. Ofatumumab 300mg administered Day1 of cycle 1 followed by 12 doses of 1000mg administered based on specific schedule. Each patient will receive a maximum of 3 cycles (one cycle is 28 days)<br>* Other names: HuMax-CD20;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IwCLL-WG Defined Complete Response (CR) | Responses were assessed two months after completion of therapy. Criteria for complete remission is assessed with: a bone marrow biopsy and repeat CT scan (abdominal, chest and pelvis if initial was abnormal) to confirm iwCLL-WG defined CR. iwCLL-WG Complete Response is defined as: Peripheral blood lymphocytes (evaluated by blood and differential count) below 4 x 109/L (4000/L). Absence of lymphadenopathy (>1.5 cm)of physical exam; AND No hepatomegaly and splenomegaly on physical exam; AND Absence of constitutional symptoms; AND Normal complete blood count as exhibited by neutrophils ≥ 1,500/μl, platelets > 100,000/μl, hemoglobin > 11.0g/dL (non-transfused), and lymphocyte count < 5,000/μl; AND Bone marrow aspirate and biopsy must be normocellular for age with <30% of nucleated cells being lymphocytes. Lymphoid nodules must be absent | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IwCLL-WG Defined Overall Response Rate (ORR) | Responses were assessed two months after completion of therapy. Overall Response Rate (ORR) = CR + PR | 2 months | 
| IwCLL-WG Defined Nodular Partial Response (PR) | Responses were assessed two months after completion of therapy. Partial Response is defined as: Greater than or equal to 50% decrease in blood absolute lymphocyte count from pre-treatment value; AND Greater than or equal to 50% reduction in lymphadenopathy from pre-treatment value; AND Greater than or equal to 50% reduction in splenomegaly/hepatomegaly from pre-treatment value. In addition, patients need to have at least ONE of the following: Neutrophils ≥ 1,500/μl or ≥ 50% improvement from pre-treatment value; AND / OR Platelets > 100,000/μl or 50% improvement from pre-treatment value; AND / OR Hemoglobin > 11.0 gm/dl (non-transfused) or 50% improvement from pre-treatment value. | 2 months | 
| IwCLL-WG Defined Partial Response (PR) | Responses were assessed two months after completion of therapy | 2 months | 
| IwCLL-WG Defined Stable Disease (SD) | Responses were assessed two months after completion of therapy. Subjects who do not fulfill the criteria for complete or partial response as defined above but do not exhibit progressive disease will be considered as having stable disease. | 2 months | 
| IwCLL-WG Defined Progressive Disease (PD) | Responses were assessed two months after completion of therapy Progressive Disease is defined as: Greater than or equal to 50% increase in the products of at least two lymph nodes on two consecutive determinations two weeks apart (at least one lymph node must be ≥ 2 cm; or the appearance of a new palpable lymph node; OR Greater than or equal to 50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margins; or appearance of palpable hepatomegaly or splenomegaly, which was not previously present; OR Greater than or equal to 50% increase in the absolute number of circulating lymphocytes to at least 5,000μl; OR Transformation to a more aggressive histology (i.e., Richter's syndrome or prolymphocytic leukemia with ≥ 56% prolymphocytes); | 2 months | 
| Progression-free Survival (PFS) |  | 2 years | 
| Treatment-Free Survival |  | 2 years | 
| Safety and Tolerability Measured Via Adverse Events | Please see Adverse Event module for additional details. | 2 years | 
| Detectable Minimal Residual Disease (MRD) | The patient who achieved a CR did not have detectable MRD in the bone marrow by four-color flow cytometry (<0.1% of cells). | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Chronic leukemia, Chronic Lymphocytic Leukemia, Relapsed, Refractory