Ofatumumab-based Induction Chemoimmunotherapy in Previously Untreated Patients With CLL/SLL

Study Overview
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Brief Summary
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Background: - Ofatumumab was approved by the U.S. Food and Drug Administration to treat patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have not responded to standard chemotherapy. Ofatumumab is a substance that recognizes specific types of white blood cells called B-lymphocytes, which become cancerous in CLL/SLL. Ofatumumab attaches to a molecule called CD20, which is found on the surface of B-cells, and destroys them. Previous studies have shown that ofatumumab can decrease the number of B-cells in patients with CLL/SLL who have been treated with chemotherapy, but more research is needed to determine it if can also be used to treat patients with previously untreated CLL/SLL. Objectives: - To determine a safe and effective dose of ofatumumab, along with chemotherapy, to treat chronic lymphocytic leukemia or small lymphocytic lymphoma. Eligibility: - Individuals at least 18 years of age who have been diagnosed with CLL or SLL that has not been treated with chemotherapy. Design: Eligible participants will be screened with a physical exam, blood samples, lymph node and bone marrow biopsies, and imaging studies. Participants will be separated into 2 groups: all participants will receive ofatumumab and fludarabine, and some participants will be selected to also receive cyclophosphamide (based on results of certain blood tests). Participants will receive the study drugs (ofatumumab and fludarabine, and optional cyclophosphamide) by infusion for a maximum of 6 days, followed by 21 days off drug. Participants will have 6 cycles of treatment according to a schedule set by the study doctors, and may have their dose levels adjusted if side effects develop. Participants who have disease remaining after 6 cycles will receive additional ofatumumab every 2 months, starting 2 months after the end of the 6th cycle and continuing for a total of 4 doses, before entering the follow-up phase of the trial. Participants who do not have residual disease after 6 cycles will not receive additional therapy, and will immediately enter the follow-up phase of the trial. Participants will have a follow-up exam every 2 to 4 months for 2 years after the end of treatment, and then as required by the study doctors for as long as the study remains open. These visits will involve a full medical exam, blood samples, lymph node and bone marrow biopsies, and imaging studies.

Detailed Description
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OUTLINE: Patients with adverse interphase cytogenetics (11q22 or 17p13 deletion) receive FCO induction therapy: Ofatumumab is given IV on day 1 (300 mg) and day 8 (1000 mg) of course 1 and on day 1 (1000 mg) of all subsequent courses. Fludarabine phosphate (25mg/m2/d) and cyclophosphamide (250mg/m2/d) are given IV on days 2 through 4 of course 1 and on days 1 through 3 of all subsequent courses. Patients age 70 or older will be given reduced doses of fludarabine (20mg/m2/d) and cyclophosphamide (150mg/m2/d). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression. Patients without adverse interphase cytogenetics receive FO induction therapy: Ofatumumab is given IV on day 1 (300mg) and day 8 (1000mg) of course 1 and on day 1 (1000mg) of all subsequent courses. Fludarabine phosphate (25mg/m2/d) is given IV on days 2 through 6 of course 1 and on days 1 through 5 of all subsequent courses. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression. All patients are evaluated for minimal residual disease (MRD) by four-color flow cytometric analysis of the peripheral blood after completion of FO or FCO induction therapy, and are subsequently stratified into two groups: Patients who are MRD-positive and without evidence of disease progression proceed to consolidation therapy beginning approximately 5 months after completion of induction therapy, consisting of ofatumumab (1000mg) given IV on day 1 of all courses. Treatment repeats every 2 months for up to 4 courses in the absence of disease progression. Patients are followed clinically 2 and 6 months after the last dose of ofatumumab is given, and then every 6 months thereafter. Patients who are MRD-negative and without evidence of disease progression are followed clinically every 4 months for 1 year and every 6 months thereafter.

Official Title
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A Phase II Study of Ofatumumab-Based Induction Chemoimmunotheraphy Followed by Consolidation Ofatumumab Immunotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Conditions
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Small Lymphocytic Lymphoma, CLL (Chronic Lymphocytic Leukemia)

Intervention / Treatment
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* Drug: Fludarabine Phosphate
* Biological: Ofatumumab
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Histologically confirmed CLL or SLL as defined by the following: B-lymphocytosis greater than 5000 cells/micro L (may be less than 5000 cells/micro L if lymphadenopathy is present with histologic confirmation of lymph node involvement by SLL). Immunophenotypic profile consistent with CLL as demonstrated by flow cytometry Appropriate immunophonotype (CD5/19/23+) Clonality of lymphocytosis confirmed by flow cytometry large lymphocytes less than 55 % of blood lymphocytes Active disease as defined by at least one of the following: Weight loss greater than or equal to10 percent within the previous 6 months Extreme fatigue Fevers of greater than 100.5 degree F for greater than or equal to 2 weeks without evidence of infection Night sweats for more than one month without evidence of infection Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia Massive or progressive splenomegaly Massive nodes or clusters or progressive lymphadenopathy Progressive lymphocytosis with an increase of greater than 50% over a 2 month period, or an anticipated doubling time of less than 6 months 0 Measurable disease (defined as two dimensional disease on imaging or quantifiable leukemic disease). Ages 18 and over. EXCLUSION CRITERIA: Prior monoclonal antibody therapy with agents having anti-CLL activity Prior cytotoxic chemotherapy with agents having anti-CLL activity (Fludarabine, Cyclophosphamide, Bendamustine, Chlorambucil) Transformed CLL Active autoimmune hemolytic anemia or thrombocytopenia Any medical condition that requires the chronic use of corticosteroids Active or latent Hepatitis B infection HIV infection Severe chronic obstructive pulmonary disease, severe cardiac disease, or other uncontrolled medical condition that would, in the opinion of the principal investigator, place the subject at an unreasonable risk of life-threatening adverse events due to chemoimmunotherapy ECOG performance status 3 or worse Creatinine greater than or equal to 2 mg/dL or creatinine clearance less than or equal to 30 mL/min Bilirubin greater than or equal to 2 mg/dL or active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment) Female patients: Current pregnancy or unwilling to take oral contraceptives or refrain from pregnancy if of childbearing potential or currently breastfeeding. Male patients who are unwilling to follow the contraception requirements described in this protocol. Psychiatric illness/social situations that would limit the patient s ability to tolerate and/or comply with study requirements. Unable to understand the investigational nature of the study or give informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FO Arm (fludarabine and ofatumumab)<br>For patients with non-high risk FISH changes | Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: Fludara;Biological: Ofatumumab<br>* Given IV<br>* Other names: Arzerra;|
| Experimental: FCO Arm (fludarabine, cyclophosphamide, and ofatumumab)<br>For patients with high risk FISH changes | Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: Fludara;Biological: Ofatumumab<br>* Given IV<br>* Other names: Arzerra;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: Neosar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival Rate 2 Years After Initiation of Induction Therapy | Death or disease progression defined by the 2008 IWCLL guideline as follows; Greater than or equal to 50% increase in the SPD of at least 2 lymph nodes (at least one node must be greater than or equal to 2 cm); appearance of any new lymph nodes on physical examination or imaging Greater than or equal to 50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin or CT scan or appearance of palpable hepatomegaly or splenomegaly, which was not previously present Greater than or equal to 50% increase in the absolute number of circulating lymphocytes to at least 5000/ul Transformation to a more aggressive histology Occurrence of any cytopenia attributable to CLL. After treatment: the progression of any cytopenia (unrelated to autoimmune cytopenia), as documented by a decrease of Hb levels by more than 20 g/L (2 g/dL) or to less than 100 g/L (10 g/dL), or by a decrease of platelet counts by more than 50% or to les | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Grade 3 and 4 Treatment Related Adverse Events | Number of Grade 3 and 4 treatment related adverse events as defined by CTCAE version 3.0 criteria. CTCAE (Common Terminology Criteria for Adverse Events) provides a list of adverse event (AE) terms commonly reported. Each AE term is defined and accompanied by a grading scale that indicates the severity of the AE. The CTCAE v3.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 is a Mild AE; Grade 2 is a Moderate AE; Grade 3 is a Severe AE; Grade 4 is a Life-threatening or disabling AE; and Grade 5 is a Death related to AE | 2 years | 
| Participants With Minimal Residual Disease (MRD) Negativity | Participants with minimal residual disease (MRD) negativity following the completion of induction chemoimmunotherapy. | 2 years | 
| Participants With MRD Negativity at the Completion of Consolidation Immunotherapy Who Failed to Achieve MRD Negativity | Participants with MRD negativity at the completion of consolidation immunotherapy who failed to achieve MRD negativity following completion of induction chemoimmunotherapy | 2 years | 
| Participants With Complete Response Rates Following Induction Chemoimmunotherapy. | Participants with complete response rates to induction chemoimmunotherapy. Criteria for complete response (CR): CR requires all of the following: Peripheral blood lymphocytes < 4000/uL Absence of significant lymphadenopathy by physical examination and appropriate radiographic techniques (CT or MRI). All lymph nodes must have regressed to <=1.5cm in greatest diameter Absence of hepatomegaly or splenomegaly by physical examination, or appropriate radiographic techniques. Spleen, if enlarged before therapy must have regressed in size and must not be palpable by physical exam. Absence of constitutional symptoms Normal CBC, defined as: - Polymorphonuclear cells ≥ 1,500/uL - Platelets > 100,000/uL (untransfused) - Hemoglobin > 11 g/dL (untransfused) Bone marrow biopsy demonstrates normal cellularity for age, with less than 30% of nucleated cells being lymphocytes. Lymphoid nodules should be absent | 2 years | 
| Participants Overall Response Rates Following Induction Chemoimmunotherapy. | Participants with complete response rates to induction chemoimmunotherapy. Criteria for complete response (CR) requires all of the following: Peripheral blood lymphocytes < 4000/uL. No significant lymphadenopathy. Lymph nodes regressed to <=1.5cm. No hepatomegaly or splenomegaly. Spleen, if enlarged before therapy must have regressed in size and not be palpable. Absence of constitutional symptoms. Bone marrow biopsy demonstrates normal cellularity for age, with less than 30% of nucleated cells being lymphocytes. No lymphoid nodules. Criteria for partial response (PR) requires at least one element of an abnormal CBC and at least one of the following: ≥ 50% decrease in peripheral blood lymphocyte count; ≥ 50% reduction in the sum of the products of lymph nodes up to 6 nodes or nodal masses. No new sites or increase in size of nodes; ≥ 50% reduction in pathologic enlargement of the liver and/or spleen by 50%. | 2 years | 
| Participants Overall Survival Rate After Initiation of Induction Chemoimmunotherapy | Participants overall survival rate 2 years after initiation of induction chemoimmunotherapy | Up to 2 years | 
| Median Relationship of CD20 Expression With MRD Negativity Rate | Median relationship of biomarker, CD20 expression with MRD negativity clinical response rate. Flow cytometry was use to quantified surface CD20 on peripheral blood. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arzerra, Chemoimmunotherapy, SLL, Monoclonal Antibody Therapy, CLL, Ofatumumab