GIMEMA CLL0809 Study (BendOfa)

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