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
Overview
- Phase
- Phase 1
- Intervention
- Bendamustine, Rituximab, Lenalidomide
- Conditions
- Chronic Lymphocytic Leukemia
- Sponsor
- German CLL Study Group
- Enrollment
- 22
- Locations
- 1
- Primary Endpoint
- dose limiting toxicity
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
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.
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Signed written informed consent.
- •18 years of age or older.
- •Medically fit patients without relevant comorbidity, defined as total CIRS score ≤
- •WHO performance status of 0-
- •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).
- •Life expectancy \> 12 weeks.
- •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.
- •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.
- •Patient is able and willing to receive adequate anticoagulation as specified in this protocol.
- •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.
Exclusion Criteria
- •Previously treated with \> 3 prior regimens for CLL.
- •Known central nervous system (CNS) involvement of CLL.
- •Patients who have progressed with more aggressive B-cell cancers such as Richter's syndrome or are diagnosed with B-PLL.
- •History of anaphylaxis following exposure to any of the used study-drugs and/or thalidomide.
- •Evidence of TLS per the Cairo-Bishop definition of laboratory TLS (subjects may be enrolled upon correction of electrolyte abnormalities).
- •Participation in another clinical trial and/or use of investigational agents or concurrent anti cancer treatment within the last 4 weeks of registration.
- •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.
- •Pregnant or lactating women.
- •Any circumstance at the time of study entry that would preclude completion of the study or the required follow-up.
- •Active secondary malignancy requiring treatment (except basal cell carcinoma or malignant tumor curatively treated by surgery) within the last 5 years before registration.
Arms & Interventions
Bendamustine, Rituximab,Lenalidomide
Dose modification treatment plan of lenalidomide
Intervention: Bendamustine, Rituximab, Lenalidomide
Outcomes
Primary Outcomes
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
Secondary Outcomes
- Response rate(up to 4 years)
- progression free survival(up to 4 years)
- Overall Survival(up to 4 years)