BR for previously untreated or relapsed CLL

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1 1 Protocol synopsis Title Rationale Study Objectives Multicentre phase II trial of bendamustine in combination with rituximab for patients with previously untreated or relapsed chronic lymphocytic leukemia CLL2M protocol of the German CLL-Study Group (GCLLSG) Conventional chemotherapy and also high dose chemotherapy with autologous stem cell transplantation are not curative treatment options in B-CLL; nearly all patients will eventually relapse. Also monoclonal antibodies are not curative for B-CLL patients in monotherapy, their impact on survival in combination with conventional chemotherapy is currently validated. In addition, there is no standard combination therapy for patients with relapsed CLL. Therefore there is an urgent medical need to identify new strategies. Bendamustine is an alkylating agent with properties of a purine analog and is a promising agent in the treatment of CLL. Bendamustine can be used with a wide range of anticancer drugs and one promising treatment option might be the combination of Bendamustine with monoclonal antibodies, particularly with rituximab. Rituximab is a chimeric monoclonal antibody and binds with high affinity to cells expressing the CD20 antigen, which is found on the surface of malignant and normal B lymphocytes. Rituximab is a novel agent for the treatment of hematologic malignancies and has been shown to have synergistic actions with other chemotherapeutic agents. The combination of rituximab and bendamustine has shown encouraging activity in patients with relapsed/refractory NHL or mantle cell lymphoma. In vitro studies have been used to investigate the effects of bendamustine and rituximab on apoptosis and have shown synergistic effects of both drugs. The mechanisms of action of these two active drugs may provide a treatment with good therapeutic potential in CLL. However, though bendamustine has been used for over 30 years there is still a need to define a standard regimen for the use of bendamustine in combination with monoclonal antibodies (mab) especially in the treatment of CLL. The goal of this phase II trial is to investigate the possible therapeutic benefits of using bendamustine in combination with rituximab for the treatment of patients with previously untreated or relapsed CLL. The primary objective of this study is to assess the overall response rate The secondary objectives of this study are to assess the overall response rate in biological defined CLL2M Final Version 2.0 including Amendment

2 risk groups assess the duration of response assess the event-free survival assess the MRD response rate assess the complete response rate assess the toxicity assess treatment administration Inclusion Criteria years of age or older 2. Diagnosis of B-CLL in need of treatment Previously untreated Binet stage C or Binet B with need of treatment according to NCI-criteria Relapsed or refractory disease after at least one but not more than 3 prior regimens. Patients who previously received bendamustine must have had at least a partial response with duration of response of at least six months. 3. World Health Organization performance status of Life expectancy >12 weeks 5. Anti-cancer therapy, major surgery, or irradiation was completed >3 weeks before registration in this study. Patient must have recovered from the acute side effects incurred as a result of previous therapy. 6. Serum creatinine 1.5 the institutional upper limit of normal (ULN) or Creatinine clearance >30 ml/min/1.73 m² 7. Adequate liver function as indicated by a total bilirubin, AST, and ALT 2 the institutional ULN value, unless directly attributable to the patient s tumor. 8. Female patients with childbearing potential must have a negative serum pregnancy test within two weeks of first dose of study drug(s). Male and female patients must agree to use an effective contraceptive method while on study treatment and for a minimum of six months following study therapy. 9. Signed, written informed consent. Exclusion Criteria 1. Previously treated with >3 prior regimens for B-CLL. 2. Known central nervous system (CNS) involvement with B-CLL. 3. Patients who have progressed with more aggressive B-cell cancers positive. CLL2M Final Version 2.0 including Amendment

3 such as Richter s syndrome. 4. History of anaphylaxis following exposure to monoclonal antibodies. 5. Known to be human immunodeficiency virus (HIV), hepatitis B, or C 6. Active infection or history of severe infection (grade 4) within 3 months prior to study registration. 7. Medical condition requiring prolonged use of oral corticosteroids.. (> 1 month). 8. Use of investigational agents within 30 days prior to study randomization. 9. Active secondary malignancy. 10. ANC <1.5x10 9 /L or platelet count <75x10 9 /L, unless due to bone marrow involvement of CLL. 11. Other severe, concurrent diseases, including tuberculosis, mental disorders, serious cardiac functional capacity (Class III or IV as defined by the New York Heart Association Classification), severe diabetes, severe hypertension, pulmonary disease (chronic obstructive pulmonary disease [COPD] with hypoxemia), or major organ malfunction (liver, kidney) that could interfere with the patient s ability to participate in the study. 12. Pregnant or nursing women. 13. Any circumstance at the time of study entry that would preclude completion of the study or the required follow-up. 14. Participation in another clinical trial Study Design This is a prospective, multicentre, open label, non-randomized, phase II study. The Simon optimal two stage design will be used. Fist-line therapy 37 consecutive evaluable patients will be entered into the first stage of the trial. If there are only 30 or fewer responses observed during that first stage, the study will be terminated. If 31 or more responses are observed, 58 additional patients will be recruited. If, by the end of the second stage, 81 or more responses are observed in the 95 patients, then the relevant activity level hypothesis (>90% overall response rate) will be confirmed. In this case a description of efficacy in biological defined risk groups could eventually be performed. 2 nd to 4 th -line therapy 24 consecutive evaluable patients will be entered into the first stage of CLL2M Final Version 2.0 including Amendment

4 the trial. If there are only 13 or fewer responses observed during that first stage, the study will be terminated. If 14 or more responses are observed, 37 additional patients will be recruited. If, by the end of the second stage, 37 or more responses are observed in the 61 patients, then the relevant activity level hypothesis (70% overall response rate) will be confirmed. In this case a description of efficacy in biological defined risk groups could eventually be performed. No. of Patients Study Drug Administration First-line therapy: 37 to 95 fully evaluable patients will be enrolled in the study 2 nd to 4 th -line therapy 24 to 61 fully evaluable patients will be enrolled in the study First-Line Therapy Bendamustine 90 mg/m² day 1-2 q4wks, cycle 1 to 6 Rituximab 375 mg/m² day 0, cycle 1 Rituximab 500 mg/m² day 1 q4wks, cycle nd to 4 th -Line Thepary Bendamustine 70 mg/m² day 1-2 q4wks, cycle 1 to 6 Rituximab 375 mg/m² day 0, cycle 1 Rituximab 500 mg/m² day 1 q4wks, cycle 2-6 Concomitant therapy Premedication: Prophylaxis: antihistamines, paracetamol/acetaminophen, prednisolon (allopurinol if clinically indicated) antimycotic and antibiotic prophylaxis if clinically indicated Evaluation Criteria Efficacy Parameters Overall response rate Complete response rate MRD response rate Response rates in biological defined risk groups Duration of response Safety parameters Absolute dose intensity The antitumor activity will be assessed after three cycles and after six cycles. The primary efficacy endpoint is objective overall response rate. Patients will be treated for 3-6 cycles. Patients will be withdrawn for disease progression, withdrawal of consent, or unacceptable toxicity. Response will be assessed using clinical examination, hematology, bone marrow examination, plain radiograph of the chest (chest X-ray), ultrasound or CT of the abdomen, and MRD testing (for the molecular response rate only). CLL2M Final Version 2.0 including Amendment

5 All patients will be followed until disease progression or for a maximum of three years after end of therapy if no progression occurs. Safety Assessments Safety assessments will include safety profile, clinical laboratory tests, and toxicities by using appropriate techniques. CLL2M Final Version 2.0 including Amendment

6 CLL2M Final Version 2.0 including Amendment