Fludarabine/Rituximab Combined With Escalating Doses of Lenalidomide in Untreated CLL

NCT ID: NCT01703364

Last Updated: 2016-05-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-06-30
• Study Completion Date: 2015-10-31

Brief Summary

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.

Conditions

CLL; Chronic Lymphocytic Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Lenalidomide

Intervention Type: DRUG

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

Interventions

Lenalidomide

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

Intervention Type: DRUG

Other Intervention Names

Revlimid

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Celgene

INDUSTRY

Sponsor Role: collaborator

Arbeitsgemeinschaft medikamentoese Tumortherapie

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Universitätsklinik der PMU Salzburg, Univ-Klinik für Innere Medizin III

Salzburg, Salzburg, Austria

Universitätsklinik für Innere Medizin Innsbruck, Klinische Abteilung für Hämatologie und Onkologie

Innsbruck, Tyrol, Austria

Countries

Austria

Related Links

http://www.agmt.at

AGMT

Other Identifiers

2011-004912-43

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

AGMT_CLL-9

Identifier Type: -

Identifier Source: org_study_id