Ofatumumab Plus Bendamustine in Frontline and Relapsed Chronic Lymphocytic Leukaemia (CLL)
Condition: Chronic Lymphocytic Leukemia (CLL); Leukaemia, Lymphocytic, Chronic
MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: Ofatumumab; Bendamustine
Intervention description: Ofatumumab (ARZERRA™) is an immunoglobulin G1κ (IgG1κ) human monoclonal antibody that specifically recognises a distinct epitope encompassing both large and small extracellular loops on the human CD20 molecule expressed on B cells and binds to this site with high affinity with a dissociation half-life of approximately 3 hours. Ofatumumab induces more efficient complement-dependent cytotoxicity (CDC) mediated cell lysis in vitro, compared to rituximab, especially in low CD20 density cells.; Bendamustine is a cytostatic drug which structurally combines a purine-like benzamidazol nucleus and a bifunctional alkylating nitrogen mustard group.
Intervention MeSH terms: Bendamustine Hydrochloride; Ofatumumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 99.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Relapsed or Refractory Chronic Lymphocytic Leukemia; Chronic Lymphocytic Leukemia; CLL; Cancer; Lymphoid leukemia; Lymphoblastic leukemia

Summary:

      This is a Phase II, open label, single arm, multi-centre study investigating the safety and
      efficacy of ofatumumab plus bendamustine in subjects with untreated or relapsed CLL.

      Each subject from the screening phase who is willing to participate in the study and is found
      eligible according to the inclusion and exclusion criteria will enter the treatment phase and
      will receive a maximum of 6 Cycles of study treatment (ofatumumab plus bendamustine). All
      subjects will receive 3 Cycles of study treatment (Cycles 1, 2 and 3). Eligibility to receive
      study treatment for Cycles 4, 5 and 6 will be assessed following the 3rd Cycle. Subjects who
      have achieved at least stable disease with acceptable toxicity following 3 Cycles of
      treatment will be eligible to continue to receive study treatments for a maximum of 3 further
      Cycles. In case of progressive disease, at, or at any time after the start of Cycle 4,
      subjects must discontinue further study treatment and move into the study's follow-up period.

      During the treatment phase, all eligible subjects will be allocated to receive the following
      study treatments:

        1. Subjects with Untreated CLL: Up to 6 monthly intravenous infusions of ofatumumab (Cycle
           1: 300 mg Day 1 and 1000 mg Day 8; subsequent Cycles: 1000 mg at Day 1 every 28 Days) in
           combination with up to 6 Cycles of intravenously infused bendamustine (90 mg/m2, Days 1
           and 2, every 28 Days).

        2. Subjects with Relapsed CLL: Up to 6 monthly intravenous infusions of ofatumumab (Cycle
           1: 300 mg Day 1 and 1000 mg Day 8; subsequent Cycles: 1000 mg at Day 1 every 28 Days) in
           combination with up to 6 Cycles of intravenously infused bendamustine (70 mg/m2, Days 1
           and 2, every 28 Days).

      The studies primary endpoint is overall response rate (ORR) as determined by Investigator
      evaluation. The ORR is the percentage of subjects achieving an objective response (i.e.,
      partial response or better), using the IWCLL updated NCI-WG guidelines. Response assessments
      are planned at the following time-points: After 3 Cycles of ofatumumab plus bendamustine
      treatment, after 6 Cycles of ofatumumab plus bendamustine treatment and after the last dose,
      if not after 6 cycles, of ofatumumab plus bendamustine treatment.

      Follow-up assessments will be performed every 3 months following the last study treatment.
      The follow-up period will last for a maximum of 3 years. Response evaluation assessments to
      determine subject response or progression will be performed during the follow-up period,
      according to the IWCLL updated NCI-WG guidelines. Following progression, only survival status
      and details concerning the subject's next CLL therapy will be recorded.
    

Eligibility criteria:

        Inclusion Criteria:

          -  A diagnosis of CLL defined by a circulating B-lymphocyte count of greater than or
             equal to 5,000/uL at study entry or at any time in the past and flow cytometry
             confirmation of immunophenotype with CD5, CD19, CD20, CD23, CD79b, and surface Ig
             prior to first dose of study treatment.

          -  Active disease and indication for treatment based on the IWCLL updated NCI-WG
             guidelines, defined by presence of at least any one of the following conditions:
             Evidence of progressive marrow failure as manifested by development or worsening of
             anaemia and/or thrombocytopenia; Massive (i.e. at least 6 cm below the left costal
             margin) or progressive or symptomatic splenomegaly; Massive nodes (i.e. at least 10 cm
             in longest diameter) or progressive or symptomatic lymphadenopathy; Progressive
             lymphocytosis with an increase of more than 50% over a two-month period or a
             lymphocyte doubling time of less than 6 months.

          -  A minimum of any one of the following disease-related symptoms must be present: a.
             Unintentional weight loss greater than or equal to 10% within the previous six months;
             b. Fevers greater than 100.5°F (38.0°C) for greater than or equal to 2 Weeks without
             evidence of infection; Or c. Night sweats for more than 1 month without evidence of
             infection.

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.

          -  Age greater than or equal to 18 years.

          -  Signed written informed consent from either the subject, or their legally acceptable
             representative if the subject is incapable of giving their own consent, prior to
             performing any study-specific tests or procedures.

          -  Subjects enrolled into the previously untreated subject cohort must also meet all of
             the following criteria: No prior treatment for CLL (prior corticosteroid
             immunosuppression treatment for autoimmune hemolytic anaemia and idiopathic
             thrombocytopenic purpura (ITP) is permitted); Be considered inappropriate for
             fludarabine-based therapy for reasons that include, but are not limited to, advanced
             age or presence of co-morbidities.

          -  Subjects enrolled into the relapsed subject cohort must also meet the following
             criteria: Relapsed CLL: defined as a subject who has received at least one prior CLL
             therapy and previously achieved a complete or partial remission/response lasting at
             least 6 months.

        Exclusion Criteria:

          -  Refractory CLL: defined as treatment failure (failure to achieve a CR or PR) or
             disease progression within 6 months of the last anti-CLL therapy.

          -  Previous autologous or allogeneic stem cell transplantation.

          -  Active autoimmune hemolytic anaemia (AIHA) and idiopathic thrombocytopenic purpura
             (ITP) requiring corticosteroid therapy greater than 25 mg prednisone (or equivalent)
             or chemotherapy.

          -  Known transformation of CLL (e.g. Richter's).

          -  Known central nervous system involvement by CLL. Screening laboratory values:
             Platelets less than 100 x 109/L (unless due to CLL involvement of the bone marrow).
             Neutrophils less than 1.5 x 109/L (unless due to CLL involvement of the bone marrow).
             Serum creatinine greater than 1.5 times the upper limit of normal (ULN); subjects with
             a serum creatinine greater than 1.5 x ULN will be eligible if the calculated
             creatinine clearance [Cockcroft, 1976] is greater than or equal to 30 mL/min. Total
             bilirubin greater than 1.5 times ULN (unless due to liver involvement by CLL or
             Gilbert's disease). Transaminases greater than 2.5 times ULN.

          -  Chronic or current active infectious disease requiring systemic antibiotics,
             antifungal, or antiviral treatment such as, but not limited to, chronic renal
             infection, chronic chest infection with bronchiectasis, tuberculosis, active Hepatitis
             C, and known Human Immunodeficiency Virus (HIV) disease. All HIV-positive subjects are
             excluded from this study, regardless of whether they have an Acquired Immunodeficiency
             Syndrome (AIDS) defining disease and/or are on antiviral therapy.

          -  Other past or current malignancy (with the exception of basal cell carcinoma of the
             skin or in situ carcinoma of the cervix or breast) unless the tumour was successfully
             treated with curative intent at least 2 years prior to trial entry.*

          -  Clinically significant cardiac disease including unstable angina, acute myocardial
             infarction within 6 months prior to first study treatment, congestive heart failure,
             and arrhythmia requiring therapy, with the exception of extra systoles or minor
             conduction abnormalities.*

          -  History of significant cerebrovascular disease or event with significant symptoms or
             sequelae.*

          -  Glucocorticoid use, unless given in doses less than or equal to 25mg/Day prednisone
             (or equivalent) for less than 7 Days for exacerbations other than CLL (e.g. asthma).*

          -  Positive serology for Hepatitis B (HB) defined as a positive test for Hepatitis B
             surface antigen (HBsAg). In addition, if negative for HBsAg but Hepatitis B core
             antibody (HBcAb) positive, a Hepatitis B Virus (HBV) DNA test will be performed and if
             positive the subject will be excluded.

          -  Known or suspected hypersensitivity to ofatumumab or bendamustine that in the opinion
             of the investigator is a contraindication to their participation in the present study.

          -  Treatment with any known non-marketed drug substance or experimental therapy within 5
             terminal half lives or 4 Weeks prior to first study treatment dose, whichever is
             longer, or participation in any other interventional clinical study.

          -  Known or suspected inability to comply with the study protocol.

          -  Lactating women, women with a positive pregnancy test at Visit 1 or women (of
             childbearing potential) as well as men with partners of childbearing potential, who
             are not willing to use adequate contraception from study start through one year
             following last ofatumumab dose. Adequate contraception is defined as abstinence, oral
             hormonal birth control, implants of levonorgestrel, estrogenic vaginal ring,
             percutaneous contraceptive patches, intrauterine device, and male partner
             sterilisation if male partner is sole partner for that subject. For females in the
             USA, the use of a double barrier method is also considered adequate (condom or
             occlusive cap plus spermicidal agent).

               -  Subjects can participate in the study if in the opinion of the investigator it is
                  thought not to affect the subject's safety, the conduct of the study or the
                  interpretation of the data.