Multicenter phase ii trial of bendamustine in combination with rituximab for patients with relapsed chronic lymphocytic leukemia

FCR versus BR in first line therapy of CLL 1. PROTOCOL SYNOPSIS
CLL10 protocol of the German CLL-Study Group (GCLLSG)
Phase III trial of combined immunochemotherapy with
Fludarabine, Cyclophosphamide and Rituximab (FCR) versus
Bendamustine and Rituximab (BR) alone in patients with
previously untreated chronic lymphocytic leukaemia
Head of German CLL Prof. Dr. Michael Hallek Representative and Coordinating Principal PD Dr. Barbara Eichhorst Although combined chemoimmunotherapy is not a curative treatment for CLL, phase II trials have shown that a high percentage of molecular remissions with very long lasting progression free (PFS) survival can be induced by modern chemoimmunotherapy (FCR) in first line therapy of CLL. The triple combination FCR has been investigated in severalphase II and in one phase III study conducted by the GCLLSG in first line therapy of CLL. These studies show the induction of long lasting remissions and a high number of complete remissions with FCR. However, the FCR regimen causes a relatively high percentage of severe cytopenia during and after therapy. Combination therapies based on Bendamustine plus Rituximab  Mitoxantron (BR or BMR) have shown encouraging activity in patients with relapsed/refractory NHL and in previously treated and untreated CLL. Main side effects of this treatment regimen were cytopenia as well (Table 1). The aim of this phase III trial is to investigate the non-inferiority of the BR combination in comparison to FCR with regard to the efficacy and the incidence of major side effects such as myelosuppression and rate of infections in patients with previously untreated CLL. The recruitment was completed 9 months earlier than calculated, the events needed for the final analysis were already reached in December 2013. With an expected median observation time of 36 months for all patients, data will be sufficient for the analysis of the primary and secondary endpoints. The Registry of the GCLLSG (only active in Germany) has been established to enable the collection of further data (salvage treatments, survival, secondary malignancies) not limited to the duration of an interventional trial. Therefor all German patients will be asked to give consent to the Registry. If in April 2015 at least 80% of the available patients per CLL10 Protokoll Version 5.0 FCR versus BR in first line therapy of CLL site will be enrolled in the Registry, the CLL10 trial will be closed in that site. If less than 80% of available patients per site could be enrolled, the study will be continued until the end of study in 2018 in that site. For exact formula see line "Study Duration". For Austria, the Czech Republic, Denmark and Switzerland the CLL10 trial will continue until January 2018. The hypothesis is that BR has a non-inferior therapeutic efficacy compared with FCR, but a better safety profile causing less myelosuppression, infections and secondary neoplasias. The primary endpoint is the progression free survival (PFS) rate after 24 months. The secondary endpoints of this study are the duration of remission the event free survival (EFS) the overall survival (OS) MRD, complete response rates and partial remission rates response rates and survival times in biological subgroups rates of toxicities Inclusion Criteria 1. 18 years of age or older. 2. Confirmed diagnosis of B-CLL. 3. Stage Binet C or stage Binet B and A requiring treatment. Requiring treatment is defined as: a) Binet stage B or A plus at least one of the following symptoms: - B-Symptoms (night sweats, weight loss  10% within the previous 6 months, fevers > 38°C or 100.4°F for  2 weeks without evidence of infection) or constitutional symptoms (fatigue) - progressive lymphocytosis (lymphocytosis is defined as peripheral lymphocyte count > 5x109/l) (increase > 50% over a 2-month period or doubling of peripheral lymphocyte count < 6 months) - evidence of progressive marrow failure as manifested by the development / worsening of anemia and/or thrombocytopenia - massive, progressive or painful splenomegaly or hypersplenism - massive lymph nodes or lymph node clusters (> 10 cm in longest diameter) or progressive or symptomatic CLL10 Protokoll Version 5.0 FCR versus BR in first line therapy of CLL 4. World Health Organization performance status of 0-2. 5. Life expectancy> 6 months. 6. 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. 7. Willingness of fertile male and female patients to use an highly effective contraceptive method with a Pearl-Index < 1 (such as implants, injectables, oral contraceptives in combination with another contraceptive method, some IUDs, sexual abstinence or vasectomised partner) while on study treatment and for a minimum of six months following study therapy 8. Signed, written informed consent. 9. Patient is a) male b) female and  2 years after the onset of menopause c) female and < 2 years after the onset of menopause and has a negative serum pregnancy test one week prior treatment. 10. Negative serological Hepatitis B test, negative testing of Hepatitis C RNA, negative HIV test within 6 weeks prior to Exclusion Criteria 1. CIRS-Score > 6 or a single score of 4 for one organ category. 2. Patients with a 17p deletion detected by FISH (these patients will be treated within the CLL2O or CLL2L protocol of the GCLLSG) 3. Creatinine clearance <70ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured after 24h-urine collection. Creatinine Clearance is to be calculated only in patients with serum creatinine ≥ 1.1 mg/dl 4. Any prior CLL-specific chemotherapy and/or radiotherapy and/or immunotherapy, except for prednisolone treatment administered due to very high lymphocyte counts immediately before first FCR or BR treatment. 5. Patients who have progressed with more aggressive B-cell cancers such as Richter's syndrome. 6. Active secondary malignancy requiring treatment (except basal cell carcinoma or malignant tumour curatively treated by surgery or successfully treated secondary malignancies in complete remission more than 5 years before enrollment ). 7. History of anaphylaxis following exposure to monoclonal CLL10 Protokoll Version 5.0 FCR versus BR in first line therapy of CLL antibodies or any of the study drugs. 8. Active bacterial, viral or fungal infection. corticosteroids (> 1 month). 10. Cerebral dysfunction, legal incapacity. 11. Pregnant or nursing women, fertile men or women of childbearing potential not using adequate contraception. 12. Any circumstance at the time of study entry that would preclude completion of the study or the required follow-up. 13. Participation in any other clinical trial This is a prospective, international, multicentre, open label, 2-arm randomized (1:1) phase III study that compares the efficacy and tolerability of the chemotherapy FC (fludarabine and cyclophosphamide) with a possibly better tolerable chemotherapy B (Bendamustine) on the backbone of the future standard in CLL treatment 6x Rituximab 500mg/m2. Significance level: α = 0.05 (one sided, with one interim analysis and one final analysis using the method of O'Brien and Fleming). Power: 80%. Calculated drop out: 7.5%. Statistical assumptions for sample size calculation: Expected PFS 2 years after FCR therapy = 75%. Test of non-inferiority with less than 7.5% difference in PFS after BR therapy. Start of recruitment: 10/2008 End of recruitment: 04/2012 End of study for Austria, Czech Republic, Denmark and Switzerland: 01/2018 End of study for Germany is either 04/2015 or 01/2018 depending on the percentage of patients of one site who will enter the Registry. End of study per site will be calculated as following: (Total number of patients which have entered the Registry + Number of Patients which are not available) / Total Number of Patients per site >= 80%. Furthermore, all CLL10-sites which have completed their documentation will be closed. 550 patients (275 in each arm) will be enrolled in the study. Participating Countries Austria, Czech Republic, Germany, Switzerland, Denmark Prednisolone 100mg p.o./day for a maximum of 10 days in case of an initial leukocyte count above 100 x 109/l may be administered before the first course. Any other prephase is not allowed. CLL10 Protokoll Version 5.0 FCR versus BR in first line therapy of CLL Total of 6 cycles, each with a duration of 28 days: Fludarabine 25 mg/m² i.v., days 1-3 Cyclophosphamide 250 mg/m², days 1-3, Rituximab: 375 mg/ m2 i.v. on day 0, cycle 1 Rituximab: 500 mg/m² i.v. on day 1, cycle 2-6 BR-arm: Bendamustine 90mg/m² day 1-2 Rituximab 375 mg/m² day 0, cycle 1 Rituximab 500 mg/m² day 1, cycle 2-6 Concomitant therapy Premedication: antihistamines, paracetamol/acetaminophen, prednisolon (allopurinol if clinically indicated) prior to first administration of rituximab and thereafter when indicated. Efficacy Parameters The primary efficacy endpoint is time from randomization to progression/death. The secondary efficacy parameters overall survival and event-free survival will be measured from randomization to death and from randomization to progressive disease, death or new treatment, respectively. Duration of remission is defined as time from date of first documentation of response to date of the initial documentation of progressive disease or death. Overall response rate includes the number of patients with CRs, incomplete CR or PRs as well as MRD-negative patients. Safety Assessments Safety assessments will include safety profile, clinical laboratory tests, and toxicities by using appropriate techniques. CLL10 Protokoll Version 5.0

Source: http://www.dcllsg.de/studie/cll10/CLL10_Synopsis_Amd4_v5.0_150528.pdf