GIMEMA CLL0809 Study (BendOfa)
Condition: Patients With CLL Relapsing After an Initial Response (CR, PR ≥ 6 Months) Following no More Than Two Prior Treatment Lines; or; Patients With CLL Refractory (SD, PD or CR/PR < 6 Months) Following no More Than Two Prior Treatment Lines
Intervention: Ofatumumab; Bendamustine
Intervention description: Ofatumumab will be administered at the dose of 300 mg IV D1 and 1000 mg IV D8 1st course; 1000 mg IV D1, 2nd -6th courses.; Bendamustine will be infused at the doses of 70 mg/m2 IV on days D1 and D2 of each course.
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: 49.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: CLL; relapsed; refractory; Bendamustine; Ofatumumab

Summary:

      In the last ten years there have been significant developments in CLL treatment. The advent
      of fludarabine, rituximab and the association of chemo-immunotherapy have substantially
      increased overall response rate, CR rate, time to progression and may also have an impact on
      overall survival.

      Even though, CLL remains incurable and all patients eventually relapse and progressively
      become resistant to treatment. The development of an effective therapy that is not
      cross-resistant with the ones currently available as front-line treatment, is one of the
      clinical unmet needs within CLL.

      BendOfa is a non comparative phase II trial designed to determine the therapeutic benefit of
      bendamustine given together to ofatumumab in relapsed or resistant patients with CLL.

      Bendamustine is approved by FDA for CLL treatment, it is an hybrid drug with alkylating
      agents and purine analogue properties that may lack of cross resistance with fludarabine. It
      was utilized in CLL as a single agent and its association with rituximab is currently under
      clinical investigation.

      Ofatumumab is a new fully human anti-CD20 monoclonal antibody with high in vitro efficacy on
      CD20 low-expressing CLL cells. An early report showed that ofatumumab in single therapy is
      effective in highly pre-treated refractory CLL patients.

      Both drugs were generally well tolerated without unexpected untoward toxicity. On the basis
      of these data, bendamustine and ofatumumab could be a new effective and well tolerated
      combination for patients with relapsed and refractory CLL.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients with CLL relapsing after an initial response (CR, PR ≥ 6 months) following no
             more than two prior treatment lines; or

          -  Patients with CLL refractory (SD, PD or CR/PR < 6 months) following no more than two
             prior treatment lines

          -  Patients requiring treatment according to 2008 revised IWCLL guidelines

          -  No more than 2 prior treatment lines

          -  Age older or equal to 18 years

          -  No active malignancies during the previous 5 years, with the exception of currently
             treated basal cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of
             any origin

          -  No prior treatment with conventional chemotherapy within the prior 4 weeks and with
             monoclonal antibodies within the prior 16 weeks

          -  ECOG performance status of ≤2 at study entry

          -  Laboratory test results within these ranges:

        Serum creatinine ≤ 2 x UNL Creatinine clearance ≥ 50 ml/min (Cockcroft and Gault formula)
        Total bilirubin ≤ 2 x UNL (with exception of patients with Gilbert's syndrome) AST (SGOT)
        and ALT (SGPT) ≤ 2 x UNL non attributable to CLL AST (SGOT) and ALT (SGPT) ≤ 10 x UNL
        attributable to CLL

          -  Female subjects of childbearing potential(FCBP) must:

        Understands the potential teratogenic risk to the unborn child and the need for effective
        contraception;

        Be capable of complying with effective contraceptive measures.

        Be informed and understand the potential consequences of pregnancy and the need to notify
        her study doctor immediately if there is a risk of pregnancy.

        Understand the need to commence the study treatment as soon as study drug is dispensed
        following a negative pregnancy test.

        Understand the need and accepts to undergo pregnancy testing based on the frequency
        outlined in this protocol.

        Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two
        reliable forms of contraception simultaneously or to practice complete abstinence from
        heterosexual contact during the following time periods related to this study: 1) before
        starting study drug; 2) while participating in the study; 3) dose interruptions; and 4) for
        at least 28 days after study treatment discontinuation.

        The two methods of reliable contraception must include one highly effective method and one
        additional effective (barrier) method. FCBP must be referred to a qualified provider of
        contraceptive methods if needed. The following are examples of highly effective and
        additional effective methods of contraception:

        Highly effective methods:

          -  Intrauterine device (IUD)

          -  Hormonal (birth control pills, injections, implants)

          -  Tubal ligation

          -  Partner's vasectomy

        Additional effective methods:

          -  Male condom

          -  Diaphragm

          -  Cervical Cap

          -  Implants and levonorgestrel-releasing intrauterine systems are associated with an
             increased risk of infection at the time of insertion and irregular vaginal bleeding.
             Prophylactic antibiotics should be considered particularly in patients with
             neutropenia.

          -  Pregnancy testing.

        FCBP must have two negative pregnancy tests prior to starting study drug.

        FCBP must agree to have a medically supervised pregnancy test every 4 weeks including 4
        weeks after the end of study treatment, except in the case of confirmed tubal
        sterilization. This requirement also applies to women of childbearing potential who
        practice complete and continued abstinence.

        Females must agree to abstain from breastfeeding during study participation and for at
        least 28 days after study drug discontinuation.

        - Male patients must:

        Understand the potential teratogenic risk if engaged in sexual activity with a pregnant
        female or a female of childbearing potential.

        Must practice complete abstinence or agree to use a prophylactic during sexual contact with
        a pregnant female or a female of childbearing potential while participating in the study,
        during dose interruptions and for at least 6 months following study drug discontinuation,
        even if he has undergone a successful vasectomy.

        If pregnancy or a positive pregnancy test does occur in the partner of a male study patient
        during study participation, the investigator must be notified immediately.

        - Female and male patients

        should be instructed never to give this medicinal product to another person and to return
        any unused capsules to the study doctor at the end of treatment.

        Should not donate blood during therapy and for at least 28 days following discontinuation
        of study drug.

        Male patients should not donate semen or sperm while participating in the study, during
        dose interruptions and for at least 6 months following study drug discontinuation

          -  Signed written informed consent according to IGH/EU/GCP and Italian laws.

        Exclusion Criteria:

          -  Concurrent use of other anti-cancer agents

          -  Use of any other experimental drug or therapy within 28 days of baseline

          -  Positive direct antiglobulin test (DAT) with clinical and laboratory signs of
             hemolysis and/or autoimmune thrombocytopenia

          -  Known transformation of CLL

          -  Known CNS involvement of CLL

          -  Known positivity for HIV or active HCV and HBV hepatitis.

          -  Active bacterial, viral or fungal infection requiring systemic anti-viral, antibiotic
             or anti-fungal therapy.

          -  Any serious medical condition, laboratory abnormality, or psychiatric illness that
             would prevent the subject from signing the informed consent form.

          -  Subjects who have current active hepatic or biliary disease (with exception of
             patients with Gilbert's syndrome, asymptomatic gallstones or stable chronic liver
             disease per investigator assessment)

          -  Pregnant or Lactating Females.

          -  Any condition, including the presence of laboratory abnormalities, which places the
             subject at unacceptable risk if he/she was to participate in the study or confounds
             the ability to interpret data from the study