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

May 9, 2018 updated by: German CLL Study Group

A phaseI/II Safety and Efficacy Trial of a Combination of Bendamustine, Rituximab and Lenalidomide (BRL) in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

This is a prospective, multicenter, open label, non-randomized, phase I/II-study to define safety 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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

22

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
      • Cologne, Germany, 50924
        • University Hospital of Cologne

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Bendamustine, Rituximab,Lenalidomide
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:

  • Dose level 1: Cycle 1-6: 2,5mg p.o., d1-28
  • Dose level 2: Cycle 1: 2,5mg p.o., d1-28; Cycle 2-6: 5mg p.o., d1-28
  • Dose level 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
  • Dose level 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
  • Dose level 5: maximal tolerated dose
Other Names:
  • Revlimid
  • MabThera
  • Ribomustine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
dose limiting toxicity
Time Frame: After 28 days of dosing at the respective target dose level of lenalidomide

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
After 28 days of dosing at the respective target dose level of lenalidomide

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Response rate
Time Frame: up to 4 years
response will be evaluated according to criteria of the CLL-Guidelines on CLL of the IWCLL-working Group.
up to 4 years
progression free survival
Time Frame: up to 4 years

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.
up to 4 years
Overall Survival
Time Frame: up to 4 years
Overall survival is defined as the time from registration to death.
up to 4 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

German CLL Study Group

Collaborators

Roche Pharma AG
Celgene
Mundipharma Research GmbH & Co KG

Investigators

  • Study Chair: Michael Hallek, Prof.Dr., German CLL Study Group
  • Study Director: Clemens Wendtner, Prof.Dr., German CLL Study Group

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2011

Primary Completion (Actual)

October 1, 2013

Study Completion (Actual)

June 1, 2015

Study Registration Dates

First Submitted

May 19, 2011

First Submitted That Met QC Criteria

March 16, 2012

First Posted (Estimate)

March 20, 2012

Study Record Updates

Last Update Posted (Actual)

May 15, 2018

Last Update Submitted That Met QC Criteria

May 9, 2018

Last Verified

May 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CLL2P
  • 2009-012957-39 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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