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

Primary Purpose

CLL, Chronic Lymphocytic Leukemia

Status

Completed

Phase

Phase 1

Locations

Austria

Study Type

Interventional

Intervention

Lenalidomide

About this trial

This is an interventional treatment trial for CLL focused on measuring CLL, Lenalidomide, Revlimid, AGMT, T cell

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Universitätsklinik für Innere Medizin Innsbruck, Klinische Abteilung für Hämatologie und Onkologie
Universitätsklinik der PMU Salzburg, Univ-Klinik für Innere Medizin III

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Lenalidomide/Fludarabine/Rituximab

Arm Description

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

Outcomes

Primary Outcome Measures

Tolerability of escalated starting dose

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

Secondary Outcome Measures

Establishment of maximal tolerated dose (MTD) of Lenalidomide in combination with FR

Time to MTD

Safety profile of the FRL combination

Analysis of occuring adverse events during the study treatment according to Common Terminology Criteria for Adverse Events (CTCAE)

Response rates in all phases by 4-colour flow cytometric and ASO-PCR MRD analysis

Risk factor analysis (FISH cytogenetics, CD38/ZAP-70 expression, mutation status)

Longitudinal definition of T cell subsets (including prognostic EM T cells and Treg cells)+/- PD1

Full Information

NCT ID

NCT01703364

First Posted

October 4, 2012

Last Updated

May 25, 2016

Sponsor

Arbeitsgemeinschaft medikamentoese Tumortherapie

Collaborators

Celgene

1. Study Identification

Unique Protocol Identification Number

NCT01703364

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2016

Overall Recruitment Status

Completed

Study Start Date

June 2012 (undefined)

Primary Completion Date

March 2015 (Actual)

Study Completion Date

October 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Arbeitsgemeinschaft medikamentoese Tumortherapie

Collaborators

Celgene

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

CLL, Chronic Lymphocytic Leukemia

Keywords

CLL, Lenalidomide, Revlimid, AGMT, T cell

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

12 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Lenalidomide/Fludarabine/Rituximab

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Lenalidomide

Other Intervention Name(s)

Revlimid

Intervention Description

Primary Outcome Measure Information:

Title

Tolerability of escalated starting dose

Description

Time Frame

12 month, 20 month

Secondary Outcome Measure Information:

Title

Establishment of maximal tolerated dose (MTD) of Lenalidomide in combination with FR

Time Frame

20 month

Title

Time to MTD

Time Frame

20 month

Title

Safety profile of the FRL combination

Description

Analysis of occuring adverse events during the study treatment according to Common Terminology Criteria for Adverse Events (CTCAE)

Time Frame

20 month

Title

Response rates in all phases by 4-colour flow cytometric and ASO-PCR MRD analysis

Time Frame

20 month

Title

Risk factor analysis (FISH cytogenetics, CD38/ZAP-70 expression, mutation status)

Time Frame

20 month

Title

Longitudinal definition of T cell subsets (including prognostic EM T cells and Treg cells)+/- PD1

Time Frame

20 month

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Facility Information:

Facility Name

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

City

Innsbruck

State/Province

Tirol

ZIP/Postal Code

6020

Country

Austria

Facility Name

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

City

Salzburg

ZIP/Postal Code

5020

Country

Austria

12. IPD Sharing Statement

Links:

URL

http://www.agmt.at

Description

AGMT

Learn more about this trial

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

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