A Safety and Efficacy Trial of a Combination of Bendamustine, Rituximab and Lenalidomid in Patients With Chronic Lymphocytic Leukemia (CLL2P)

This study has been terminated.
(delayed recruitment)
Sponsor:
Collaborators:
Mundipharma Research GmbH & Co KG
Roche Pharma AG
Celgene Corporation
Information provided by (Responsible Party):
German CLL Study Group
ClinicalTrials.gov Identifier:
NCT01558167
First received: May 19, 2011
Last updated: April 17, 2014
Last verified: April 2014
  Purpose

This is a prospective, multicenter, open label, non-randomized, phase I/II-study to define saftey and efficacy of BRL combination in relapsed/refractory patients and to recommend a safe and efficacious dose for future phase II/III study.

Hypothesis: The simultaneous administration of BRL in relapsed CLL is feasible, safe and efficient.


Condition Intervention Phase
Chronic Lymphatic Leukemia
Drug: Bendamustine, Rituximab, Lenalidomide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A phaseI/II Safety and Efficacy Trial of a Combination of Bendamustine, Rituximab and Lenalidomid (BRL) in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

Resource links provided by NLM:


Further study details as provided by German CLL Study Group:

Primary Outcome Measures:
  • dose limiting toxicity [ Time Frame: After 28 days of dosing at the respective target dose level of lenalidomide ] [ Designated as safety issue: Yes ]

    DLT defined as

    • absolute neutrophil count < 500/µl for 7 consecutive days or more
    • febrile neutropenia
    • platelet count < 20.000/µl
    • grade 4 tumour flare
    • grade 4 non-hematologic toxicity


Secondary Outcome Measures:
  • Response rate [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]
    response will be evaluated according to criteria of the CLL-Guidelines on CLL of the IWCLL-working Group.

  • progression free survival [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]

    Progression-free survival based on investigator's assessment:

    PFS is defined as the time from registration to the first occurrence of progression, relapse or death from any cause. Disease progression will be assessed by the investigators using the IWCLL criteria.


  • Overall Survival [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]
    Overall survival is defined as the time from registration to death.


Enrollment: 22
Study Start Date: February 2011
Estimated Study Completion Date: June 2015
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Bendamustine, Rituximab,Lenalidomid
Dose modification treatment plan of lenalidomide
Drug: Bendamustine, Rituximab, Lenalidomide

Bendamustine: 50 mg/m2, i.v., day 1+2 Rituximab: Cycle 1: 375 mg/m2, i.v. day 0; Cycle 2-6: 500mg/m2, i.v., day 1

Lenalidomide:

  • Doselevel 1: Cycle 1-6: 2,5mg p.o., d1-28
  • Doselevel 2: Cycle 1: 2,5mg p.o., d1-28; Cycle 2-6: 5mg p.o., d1-28
  • Doselevel 3: Cycle 1: 2,5mg p.o., d1-28; Cycle 2:5mg p.o., d1-28; Cycle 3-6: 10 mg p.o., d1-28
  • Doselevel 4: Cycle 1: 2,5mg p.o., d1-28; Cycle 2:5mg p.o., d1-28; Cycle 3: 10 mg p.o.,d1-28, Cycle 4-6: 15 mg p.o.,d1-28
  • Doselevel 5: maximal tolerated dose
Other Names:
  • Ribomustine
  • MabThera
  • Revlimid

Detailed Description:

As too its mechanism of action lenalidomide seems to work rather by immunomodulation than by a direct anti-proliferative activity against CLL cells. Lenalidomide stimulates T- and NK-cells, modulates the tumour microenvironment in CLL and inhibits bone marrow angiogenesis. There is a rationale to combine lenalidomide with the alpha-CD20 mAb rituximab because lenalidomide enhances NK cell mediated antibody dependent cytotoxicity of rituximab treated NHL cells. On the other hand, there is increasing evidence that the combination of chemotherapy (FC) and rituximab results in highest response rates and longest progression-free survival in treatment naive and relapsed CLL. Besides FCR the combination of bendamustine, a hybrid alkylating agent with properties of a purine-analogue, with rituximab (BR) seems to be very active in relapsed and treatment-naive CLL based on results of a phase II trial of the GCLLSG. Preliminary results with lenalidomide showed a promising response rate of 32% including high risk patients. Thus, the combination of BRL could improve the therapeutic activity in high risk CLL by combining two immunomodulatory with a classic cytotoxic principle.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed written informed consent.
  2. 18 years of age or older.
  3. Medically fit patients without relevant comorbidity, defined as total CIRS score ≤ 6.
  4. WHO performance status of 0-2.
  5. Confirmed diagnosis of CLL in need of treatment (Binet C or A/B with active disease) according to the updated IWCLL guidelines (Hallek et al. 2008).
  6. Life expectancy > 12 weeks.
  7. Relapsed or refractory disease after at least one, but no more than 3 prior regimens. Patients who previously received bendamustine (with or without rituximab) must have had at least a partial response with duration of response of at least six months.
  8. CLL therapy, major surgery, or irradiation for CLL was completed > 4 weeks before registration in this study. Patients must have recovered from the acute side effects incurred as a result of previous therapy.
  9. Patient is able and willing to receive adequate anticoagulation as specified in this protocol.
  10. 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.
  11. Creatinine clearance >60ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured after 24h-urine collection.
  12. ANC > 1500/µl and platelet count > 75.000/μl, unless decrease is due to bone marrow involvement of CLL
  13. Negative serological hepatitis B test, negative testing of hepatitis C RNA, negative HIV test within 6 weeks prior to registration.
  14. Females of childbearing potential (FOCP) must understand that the study medication has a teratogenic risk and must agree to use, and be able to comply with effective contraception without interruption, 4 weeks before starting study drug, throughout study drug therapy (including dose interruptions) and for 6 months after the end of study drug therapy, even if she has amenorrhea. This applies unless the subject commits to absolute and continued abstinence confirmed on a monthly basis.

Exclusion Criteria:

  1. Previously treated with > 3 prior regimens for CLL.
  2. Known central nervous system (CNS) involvement of CLL.
  3. Patients who have progressed with more aggressive B-cell cancers such as Richter's syndrome or are diagnosed with B-PLL.
  4. History of anaphylaxis following exposure to any of the used study-drugs and/or thalidomide.
  5. Evidence of TLS per the Cairo-Bishop definition of laboratory TLS (subjects may be enrolled upon correction of electrolyte abnormalities).
  6. Participation in another clinical trial and/or use of investigational agents or concurrent anti cancer treatment within the last 4 weeks of registration.
  7. 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 (COPD with hypoxemia), or major organ malfunction that could interfere with the patient's ability to participate in the study.
  8. Pregnant or lactating women.
  9. Any circumstance at the time of study entry that would preclude completion of the study or the required follow-up.
  10. Active secondary malignancy requiring treatment (except basal cell carcinoma or malignant tumor curatively treated by surgery) within the last 5 years before registration.
  11. Active bacterial, viral or fungal infection.
  12. Medical condition requiring prolonged use of oral corticosteroids (> 1 month).
  13. Cerebral dysfunction, legal incapacity.
  14. Patients with contraindications according to Summary of Product Characteristics or Investigator's Brochure.
  15. Patients who are employees of the Sponsor (University of Cologne) or the study sites.
  16. Persons placed in an institution by legal or official order.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01558167

Locations
Germany
University Hospital of Cologne
Cologne, Germany, 50924
Sponsors and Collaborators
German CLL Study Group
Mundipharma Research GmbH & Co KG
Roche Pharma AG
Celgene Corporation
Investigators
Study Chair: Michael Hallek, Prof.Dr. German CLL Study Group
Study Director: Clemens Wendtner, Prof.Dr. German CLL Study Group
  More Information

No publications provided

Responsible Party: German CLL Study Group
ClinicalTrials.gov Identifier: NCT01558167     History of Changes
Other Study ID Numbers: CLL2P, 2009-012957-39
Study First Received: May 19, 2011
Last Updated: April 17, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by German CLL Study Group:
Dose limiting toxicity of Lenalidomide
Chronic lymphocytic leukemia

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Bendamustine
Rituximab
Lenalidomide
Nitrogen Mustard Compounds
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents

ClinicalTrials.gov processed this record on July 29, 2014