Ofatumumab-based Induction Chemoimmunotherapy in Previously Untreated Patients With CLL/SLL
Ofatumumab-based Induction Chemoimmunotherapy in Previously Untreated Patients With CLL/SLL
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.
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 <TAB>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 <TAB>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.
-  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.