FCR or BR in Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia

• ClinicalTrials.gov Identifier: NCT00769522
• Recruitment Status: Completed
• First Posted: October 9, 2008
• Last Update Posted: August 6, 2019
• Sponsor: German CLL Study Group
• Collaborators: Roche Pharma AG; Mundipharma Pte Ltd.
• Information provided by (Responsible Party): German CLL Study Group

Tracking Information

• First Submitted Date: October 8, 2008
• First Posted Date: October 9, 2008
• Last Update Posted Date: August 6, 2019
• Actual Study Start Date: October 2, 2008
• Actual Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 14, 2012)

Progression-free survival rate after 24 months [ Time Frame: 2008-2015 ]

estimated time point when 198 needed events for the final analysis(PD or deaths) have occured.

• Original Primary Outcome Measures (submitted: October 8, 2008): Progression-free survival rate after 24 months

Current Secondary Outcome Measures (submitted: March 14, 2012)

• Minimal residual disease, complete response rates, and partial response rates [ Time Frame: 2008-2015 ]
  done within the final analysis
• Duration of remission [ Time Frame: 2008-2015 ]
  done within the final analysis
• Event-free survival [ Time Frame: 2008-2015 ]
  done within the final analysis
• Overall survival [ Time Frame: 2008-2015 ]
  done within the final analysis
• Overall response rate [ Time Frame: 2008-2015 ]
  done within the final analysis
• Response rates in and survival times in biological subgroups [ Time Frame: 2008-2015 ]
  done within the final analysis
• Toxicity rates [ Time Frame: 2008-2015 ]
  done within the final analysis
• Quality of life [ Time Frame: 2008-2015 ]
  done within the final analysis
• Standard safety analysis [ Time Frame: 2008-2015 ]
  done within the final analysis

Original Secondary Outcome Measures (submitted: October 8, 2008)

• Duration of remission
• Event-free survival
• Overall survival
• Minimal residual disease, complete response rates, and partial response rates
• Response rates and survival times in biological subgroups
• Toxicity rates
• Quality of life

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: FCR or BR in Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia
• Official Title: Phase III Trial of Combined Immunochemotherapy With Fludarabine, Cyclophosphamide and Rituximab (FCR) Versus Bendamustine and Rituximab (BR) in Patients With Previously Untreated Chronic Lymphocytic Leukaemia

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as fludarabine, cyclophosphamide, and bendamustine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. It is not yet known whether giving fludarabine and cyclophosphamide together with rituximab is more effective than giving bendamustine together with rituximab in treating chronic lymphocytic leukemia.

PURPOSE: This randomized phase III trial is studying fludarabine, cyclophosphamide, and rituximab to see how well they work compared with bendamustine and rituximab in treating patients with previously untreated B-cell chronic lymphocytic leukemia.

Detailed Description

OBJECTIVES:

• To compare the therapeutic efficacy of fludarabine phosphate, cyclophosphamide, and rituximab vs bendamustine hydrochloride and rituximab in patients with previously untreated B-cell chronic lymphocytic leukemia.
• To compare the incidence of major side effects (e.g., myelosuppression) associated with these regimens in these patients.
• To compare the rate of infections and secondary neoplasias in patients treated with these regimens.

OUTLINE: This is a multicenter study. Patients are stratified according to country and disease stage. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive fludarabine phosphate IV and cyclophosphamide IV on days 1-3. Patients also receive rituximab IV on day 0 of course 1 and on day 1 of courses 2-6. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive bendamustine hydrochloride IV on days 1 and 2. Patients also receive rituximab as in arm I. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Patients complete quality of life questionnaires (EORTC-C30 and EURO-QOL) at baseline and then at 12, 24, 36, 48, and 60 months.

After completion of study therapy, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then once a year thereafter.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Chronic Lymphocytic Leukemia

Intervention

• Biological: Rituximab

  cycle 1: 375 mg/m² i.v., day 0, q28d

  cycle 2-6: 500 mg/m² i.v., day 1, q28d

  Other Names:

  • Mabthera
  • Rituxan
• Drug: Bendamustine
  cycle 1-6: 90mg/m² i.v., day 1-2, q28d
  Other Names:

  • Levact
  • Ribomustin
  • Treanda
• Drug: Cyclophosphamide
  cycle 1-6: 250 mg/m² i.v., days 1-3, q28d
  Other Name: Endoxan
• Drug: Fludarabine
  cycle 1-6: 25 mg/m² i.v., days 1-3, q28d
  Other Name: Fludura

Study Arms

• Experimental: FCR
  Interventions:

  • Biological: Rituximab
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
• Experimental: BR
  Interventions:

  • Biological: Rituximab
  • Drug: Bendamustine

Publications *

• Kovacs G, Robrecht S, Fink AM, Bahlo J, Cramer P, von Tresckow J, Maurer C, Langerbeins P, Fingerle-Rowson G, Ritgen M, Kneba M, Dohner H, Stilgenbauer S, Klapper W, Wendtner CM, Fischer K, Hallek M, Eichhorst B, Bottcher S. Minimal Residual Disease Assessment Improves Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia (CLL) Who Achieve Partial Response: Comprehensive Analysis of Two Phase III Studies of the German CLL Study Group. J Clin Oncol. 2016 Nov 1;34(31):3758-3765. doi: 10.1200/JCO.2016.67.1305.
• Al-Sawaf O, Robrecht S, Bahlo J, Fink AM, Cramer P, von Tresckow J, Maurer C, Bergmann M, Seiler T, Lange E, Kneba M, Stilgenbauer S, Dohner H, Kiehl MG, Jager U, Wendtner CM, Fischer K, Goede V, Hallek M, Eichhorst B, Hopfinger G. Impact of gender on outcome after chemoimmunotherapy in patients with chronic lymphocytic leukemia: a meta-analysis by the German CLL study group. Leukemia. 2017 Oct;31(10):2251-2253. doi: 10.1038/leu.2017.221. Epub 2017 Jul 12. No abstract available.
• Dimier N, Delmar P, Ward C, Morariu-Zamfir R, Fingerle-Rowson G, Bahlo J, Fischer K, Eichhorst B, Goede V, van Dongen JJM, Ritgen M, Bottcher S, Langerak AW, Kneba M, Hallek M. A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL. Blood. 2018 Mar 1;131(9):955-962. doi: 10.1182/blood-2017-06-792333. Epub 2017 Dec 18.
• Kurtz DM, Esfahani MS, Scherer F, Soo J, Jin MC, Liu CL, Newman AM, Duhrsen U, Huttmann A, Casasnovas O, Westin JR, Ritgen M, Bottcher S, Langerak AW, Roschewski M, Wilson WH, Gaidano G, Rossi D, Bahlo J, Hallek M, Tibshirani R, Diehn M, Alizadeh AA. Dynamic Risk Profiling Using Serial Tumor Biomarkers for Personalized Outcome Prediction. Cell. 2019 Jul 25;178(3):699-713.e19. doi: 10.1016/j.cell.2019.06.011. Epub 2019 Jul 4.
• Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, Lange E, Koppler H, Kiehl M, Sokler M, Schlag R, Vehling-Kaiser U, Kochling G, Ploger C, Gregor M, Plesner T, Trneny M, Fischer K, Dohner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Stilgenbauer S, Bottcher S, Hallek M; international group of investigators; German CLL Study Group (GCLLSG). First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016 Jul;17(7):928-942. doi: 10.1016/S1470-2045(16)30051-1. Epub 2016 May 20.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 14, 2012): 564
• Original Estimated Enrollment (submitted: October 8, 2008): 550
• Actual Study Completion Date: January 2018
• Actual Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Confirmed diagnosis of B-cell chronic lymphocytic leukemia (CLL) meeting 1 of the following criteria:
• Binet stage C disease or stage B or A disease requiring treatment
• Binet stage B or A disease meeting ≥ 1 of the following:

• B-symptoms (e.g., night sweats, weight loss ≥ 10% within the past 6 months, fevers > 38°C or 100.4°F for ≥ 2 weeks without evidence of infection) or constitutional symptoms (e.g., fatigue)

  • Progressive lymphocytosis, defined as peripheral lymphocyte count > 5 x 10^9/L (i.e., > 50% increase over a 2-month period or doubling of peripheral blood 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 lymphadenopathy

    • No 17p deletion by FISH
    • No aggressive B-cell cancer, such as Richter syndrome

PATIENT CHARACTERISTICS:

• WHO performance status 0-2
• Life expectancy ≥ 6 months
• Total bilirubin ≤ 2 times upper limit of normal (ULN) (unless directly attributable to CLL)
• AST and ALT ≤ 2 times ULN (unless directly attributable to CLL)
• Creatinine clearance ≥ 70 mL/min (creatinine clearance is to be calculated only in patients with serum creatinine ≥ 1.1 mg/dL)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 6 months after completion of study therapy
• Hepatitis B and C negative
• HIV negative
• CIRS score > 6 or a single score of 4 for one organ category
• No active secondary malignancy requiring treatment, except basal cell carcinoma or malignant tumor curatively treated by surgery, or successfully treated secondary malignancies in complete remission > 5 years prior to enrollment
• No history of anaphylaxis following exposure to monoclonal antibodies
• No active bacterial, viral, or fungal infection
• No medical condition requiring prolonged use of oral corticosteroids (i.e., > 1 month)
• No cerebral dysfunction or legal incapacity
• No circumstance that would preclude completion of the study or the required follow-up

PRIOR CONCURRENT THERAPY:

• No prior CLL specific-chemotherapy, radiotherapy, and/or immunotherapy

  • Prednisolone administered immediately prior to initiation of study therapy allowed for very high lymphocyte counts
• No concurrent participation in another clinical trial

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT00769522
• Other Study ID Numbers: CLL10; CDR0000616169 ( Other Identifier: Clinical Data Repository ); 2007-007587-21 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: German CLL Study Group
• Original Responsible Party: Not Provided
• Current Study Sponsor: German CLL Study Group
• Original Study Sponsor: Same as current

Collaborators

• Roche Pharma AG
• Mundipharma Pte Ltd.

Investigators

• Principal Investigator: Barbara Eichhorst, MD; Medizinische Universitaetsklinik I at the University of Cologne

• PRS Account: German CLL Study Group
• Verification Date: August 2019