Fludarabine/Rituximab Combined With Escalating Doses of Lenalidomide in Untreated CLL
Fludarabine/Rituximab Combined With Escalating Doses of Lenalidomide in Untreated Chronic Lymphocytic Leukemia (CLL) - a Dose-finding Study With Escalating Starting Dose of Lenalidomide and Concomitant Evaluation of Safety and Efficacy
This is a trial in patients with previously untreated CLL. Eligible patients will receive Lenalidomide with a backbone of Fludarabine and Rituximab for 6 therapy cycles. Lenalidomide will be increased by dose steps of 5 mg every cycle in the absence of limiting toxicity. If limiting toxicity ensues the patients will be treated with last tolerable dose for the remainder of the 6 treatment cycles.
The first 5 patients will start with dose level 5 mg Lenalidomide and further escalating dose. After the fifth patient is included in the study, enrolment will be interrupted until this patient has finished his first treatment cycle. A safety board will evaluate the toxicities of the first 5 patients. If there are more than 2 patients experiencing a dose limiting toxicity (DLT) in the first treatment cycle, the starting dose will not be escalated and further 5 patients will be enrolled with a starting dose of 5 mg Lenalidomide. If only 2 or less patients experience a DLT in the first treatment cycle, the next 5 patients will start the treatment with 10 mg Lenalidomide.
The rational for the higher starting doses stems from the lack of tumor lysis or tumor flare toxicity in this combination on the one hand and from the observation that the very slow escalation from 2,5 mg on led to a lack of efficacy in monotherapy trials due to early progression in a relevant number of cases. The increase of the Lenalidomide dosage should result in an increased efficacy especially at the beginning and a higher cumulative dose of Lenalidomide.
The identification of patients intolerant to Lenalidomide by immunophenotyping of the T cells for validation is also part of this trial, because intolerance seems to be not dose dependent but may be caused by T cell activation. Therefore, early identification of patients intolerant to this form of modern immunochemotherapy and establishing efficient Lenalidomide based combination therapy is an important part of improvement of current CLL treatment.
Visão geral do estudo
Status
Condições
Intervenção / Tratamento
Tipo de estudo
Inscrição (Real)
Estágio
- Fase 2
- Fase 1
Contactos e Locais
Locais de estudo
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Salzburg, Áustria, 5020
- Universitätsklinik der PMU Salzburg, Univ-Klinik für Innere Medizin III
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Tirol
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Innsbruck, Tirol, Áustria, 6020
- Universitätsklinik für Innere Medizin Innsbruck, Klinische Abteilung für Hämatologie und Onkologie
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Gêneros Elegíveis para o Estudo
Descrição
Inclusion Criteria:
- Signed written informed consent
- Male or female ≥ 18 years of age
- CLL (as determined by CD23+, CD5+, CD19+)
- Treatment indication as defined by the NCI Workshop criteria (see appendix 6 and reference 10)
- ECOG ≤ 2
- No previous treatment of the CLL by chemotherapy, radiotherapy (except localized radiotherapy of 1 lymphatic area) or immunotherapy
- Life expectancy > 6 months (except prognosis due to high risk CLL)
Exclusion Criteria:
- Active bacterial, viral or fungal infection
- Positivity for HIV, Hepatitis B or C
- Patients with known history of thromboembolic events
- Reduced organ functions and bone marrow dysfunction not due to CLL
- Creatinine clearance of below 30 ml/min
- Patients with known history of thromboembolic events
- Patients with a history of other malignancies within 2 years prior to study entry (except for adequately treated carcinoma in situ of the cervix; basal or squamous cell skin cancer; low grade, early stage localized prostate cancer treated surgically with curative intent; good prognosis DCIS of the breast treated with lumpectomy alone with curative intent)
- Patients with medical co-morbid conditions that would require long term use (> 1 month) of systemic corticosteroids during study treatment
- Patients with a history of severe cardiac disease; e.g. NYHA Functional Class III or IV heart failure, myocardial infarction within 6 months, ventricular tachyarrhythmias requiring ongoing treatment, or unstable angina
- Other known co-morbidity with the potential to dominate survival
- Transformation to aggressive B-cell malignancy (e.g., large B-cell lymphoma, Richter's syndrome, or prolymphocytic leukemia (PLL))
- Hypersensitivity with anaphylactic reaction to humanised monoclonal antibodies or any of the applied drugs
- Concurrent chronic systemic immune therapy, chemotherapy, or hormone therapy not indicated in the study protocol
- Administration of any investigational agent(s) within 4 weeks prior to entry
- Pregnancy or lactation
- Medical or psychological condition which in the opinion of the Investigator would not permit the patient to complete the study or sign meaningful informed consent
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: N / D
- Modelo Intervencional: Atribuição de grupo único
- Mascaramento: Nenhum (rótulo aberto)
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
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Experimental: Lenalidomide/Fludarabine/Rituximab
Lenalidomide: day 8-21 of cycle 1 and day 1-21 of cycles 2-6; Starting Dose: 5 mg (first 5 patients) and 10 mg (further 5 patients) increase Lenalidomide dose via dose levels (10)/15/20/25 mg/d every 28 days if no limiting toxicity occurs Fludarabine: 25 mg/m2 iv d1-3 or 40 mg/m2 po d1-3; repeat every 28 days Rituximab: 375 mg/m2 iv day 4 on cycle 1 and 500 mg/m2 iv day 1 on cycles 2-6; repeat every 28 days |
Lenalidomide: day 8-21 of cycle 1 and day 1-21 of cycles 2-6; Starting Dose: 5 mg (first 5 patients) and 10 mg (further 5 patients) increase Lenalidomide dose via dose levels (10)/15/20/25 mg/d every 28 days if no limiting toxicity occurs Fludarabine: 25 mg/m2 iv d1-3 or 40 mg/m2 po d1-3; repeat every 28 days Rituximab: 375 mg/m2 iv day 4 on cycle 1 and 500 mg/m2 iv day 1 on cycles 2-6; repeat every 28 days
Outros nomes:
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O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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Tolerability of escalated starting dose
Prazo: 12 month, 20 month
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Interim analysis after completion of cylce 1 of the first 5 patients, final analysis after last pastient last visit Metrics: Number of patients experiencing defined dose limiting toxicities during cycle 1
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12 month, 20 month
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Medidas de resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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Establishment of maximal tolerated dose (MTD) of Lenalidomide in combination with FR
Prazo: 20 month
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20 month
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Time to MTD
Prazo: 20 month
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20 month
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Safety profile of the FRL combination
Prazo: 20 month
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Analysis of occuring adverse events during the study treatment according to Common Terminology Criteria for Adverse Events (CTCAE)
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20 month
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Response rates in all phases by 4-colour flow cytometric and ASO-PCR MRD analysis
Prazo: 20 month
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20 month
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Risk factor analysis (FISH cytogenetics, CD38/ZAP-70 expression, mutation status)
Prazo: 20 month
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20 month
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Longitudinal definition of T cell subsets (including prognostic EM T cells and Treg cells)+/- PD1
Prazo: 20 month
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20 month
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Colaboradores e Investigadores
Patrocinador
Colaboradores
Publicações e links úteis
Links úteis
Datas de registro do estudo
Datas Principais do Estudo
Início do estudo
Conclusão Primária (Real)
Conclusão do estudo (Real)
Datas de inscrição no estudo
Enviado pela primeira vez
Enviado pela primeira vez que atendeu aos critérios de CQ
Primeira postagem (Estimativa)
Atualizações de registro de estudo
Última Atualização Postada (Estimativa)
Última atualização enviada que atendeu aos critérios de controle de qualidade
Última verificação
Mais Informações
Termos relacionados a este estudo
Palavras-chave
Termos MeSH relevantes adicionais
- Doenças do sistema imunológico
- Neoplasias por Tipo Histológico
- Neoplasias
- Distúrbios Linfoproliferativos
- Doenças Linfáticas
- Distúrbios imunoproliferativos
- Leucemia de Células B
- Leucemia
- Leucemia Linfocítica Crônica de Células B
- Leucemia Linfóide
- Efeitos Fisiológicos das Drogas
- Agentes Antineoplásicos
- Fatores imunológicos
- Inibidores de angiogênese
- Agentes Moduladores da Angiogênese
- Substâncias de crescimento
- Inibidores de crescimento
- Lenalidomida
Outros números de identificação do estudo
- AGMT_CLL-9
- 2011-004912-43 (Número EudraCT)
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