Study of Lenalidomide in Relapse/Refractory Waldenstrom Macroglobulinemia (RV-WM-0426)

June 6, 2017 updated by: University Hospital, Lille

A Multicenter Phase I/II Dose Escalation Study of Lenalidomide in Relapse/Refractory Waldenstrom Macroglobulinemia

The purpose of this study is to determine the recommended dose of lenalidomide in subjects with relapse and refractory Waldenstrom Macroglobulinemia.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma, WM) is a low-grade lymphoplasmacytic lymphoma characterized by the involvement of the bone marrow with lymphoplasmacytic cells and the production of immunoglobulin M monoclonal protein in the circulation . Waldenstrom Macroglobulinemia is characterized by anemia and cytopenias due in part to the clonal expansion in the bone marrow. In addition, infiltration of the liver, spleen, and lymph nodes may occur in 15-20% of the patients leading to enlargement of these organs. Finally, complications related to elevated serum monoclonal protein such as hyperviscosity may also occur. Waldenstrom macroglobulinemia is an incurable disease with an overall median survival of 5-6 years from the development of symptoms . The median age at diagnosis is 63 years Options of therapy in patients with relapsed/refractory Waldenstrom Macroglobulinemia include rituximab, alkylating agents, nucleoside analogues. Although novel agents, such as bortezomib and thalidomide, are still matter of debate, several phase II studies have demonstrated that novel agents, especially Bortezomib, are active agent in relapsed and refractory Waldenstrom Macroglobulinemia .The overall response rate in single agents bortezomib studies reach 80%, with major responses observed in 30-40% of patients. Therefore, there is a need to identify new therapeutic agents for Waldenstrom Macroglobulinemia patients.

In view of their success in the treatment of patients with Multiple Myeloma, immunomodulatory drugs (IMiDS) were tested in patients with Waldenstrom Macroglobulinemia, although their experience is limited. Thalidomide is nonmyelosuppressive, immunomodulatory, and antiangiogenic and may be a reasonable choice for patients for whom first-line therapies have failed, those who have had disease relapse and are not candidates for alkylating or nucleoside analogue therapy, or patients with pancytopenia . Twenty three Waldenstrom Macroglobulinemia patients were evaluable in a phase II study of thalidomide in combination with rituximab. Although the overall and major response rates were of 78% and 70%, respectively; tolerance was a concern, and dose reduction of thalidomide occurred in all patients and led to discontinuation in 11 patients.

Lenalidomide has been studied in Multiple Myeloma and myelodysplastic syndrome and found to be more potent and also to lack the neurotoxic and prothrombotic adverse effects of thalidomide . Based on the potent activity of lenalidomide in Multiple Myeloma and the lack of neuropathy with this agent, and based on the interesting results reported with thalidomide-rituximab phase II tril in relapse/refractory Waldenstrom Macroglobulinemia, a phase II study of lenalidomide 25mg daily in combination with rituximab was perform in patients with relapsed/refractory Waldenstrom Macroglobulinemia. Lenalidomide was administered for 3 weeks, followed by a one week pause for an intended duration of 48 weeks. Patients received one week of therapy with lenalidomide, after which rituximab (375mg/m2) was administered weekly on weeks 2-5, then 13-16 . Twelve patients were evaluable for an overall and a major response rate of 67% and 33%, and a median time to progression of 15.6 months. Acute decreases in hematocrit were observed during first 2 weeks of lenalidomide therapy in 13/16 (81%) patients with a median hematocrit decrease of 4.4% (1.7-7.2%). Despite reduction of initiation doses to 5mg daily, anemia continued to be problematic without evidence of hemolysis or more general myelosuppression. Therefore, the mechanism for pronounced anemia in Waldenstrom Macroglobulinemia patients receiving lenalidomide remains to be determined and the use of this agent among Waldenstrom Macroglobulinemia patients remains investigational.

Study Type

Interventional

Enrollment (Actual)

17

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

  • France
      • Bayonne, France, 64109
        • Centre Hospitalier de la Cote Basque
      • Clermond Ferrand, France, 63000
        • Ch Clermond Ferrand
      • Lens, France, 62307
        • CH LENS
      • Lille, France, 59037
        • CHRU Lille
      • Nantes, France, 44 093
        • CH Nantes
      • Paris, France, 75651
        • Groupe Hospitalier Pitié Salpétrière
      • Pierre Benite, France, 69495
        • Centre Hospitalier Lyon Sud

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:

The most important criteria for patient eligibility include:

  1. Age >=18 years
  2. Patients must have received prior therapy (any number of therapies) for WM and have relapsed or refractory WM
  3. Eastern Cooperative Oncology Group performance score of 0 - 2
  4. Hemoglobin >= 10g/dL or hematocrit >= 30%
  5. Absolute neutrophil count (ANC) >1000/mm3 and platelet count >75,000/mm3

  6. Adequate organ function defined as

    • serum glutamate pyruvate transaminase and serum glutamate oxaloacetate transaminase < 2 x International Unit/l
    • Total bilirubin >= 1.5 mg/dL
    • Clearance creatinin > 50 ml/mn
  7. Evaluable immunochemical abnormalities including abnormal electrophoresis and serum free light chain assay with an increase of either kappa or lambda light chain lev -

Exclusion Criteria:

Key Exclusion criteria

  1. Any other uncontrolled medical condition or comorbidity that might interfere with subject's participation
  2. Patients treated or requiring corticosteroids >30mg/day
  3. Pregnant or breast feeding females (Lactating females must agree not to breast feed while taking lenalidomide)
  4. Use of any other experimental drug or therapy within 28 days of baseline
  5. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs
  6. Known positive for HIV or infectious hepatitis, type A, B or C -

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
Other: revlimid
a dose-escalation of revlimid
Drug: Revlimid
Three cohorts of subjects will be successively exposed to escalating doses of Lenalidomide (15, 20 and 25mg once daily on days 1-21 of a 28 day cycle).
Other Names:
  • lénalidomide

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants with dose limiting toxicities (DLT) of lenalidomide as a Measure of Safety and Tolerability.
Time Frame: 1 month
To determine the recommended dose of lenalidomide in subjects with relapse and refractory Waldenstrom Macroglobulinemia
1 month

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
number of patients with a response to lenalidomide
Time Frame: 60 months
Response rate will be evaluated following standard criteria for evaluation of response in Waldenstrom Macroglobulinemia recommended by the Second International Waldenstrom Macroglobulinemia Workshop will be used in this study
60 months
Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Time Frame: 60 months
Safety (type, frequency, severity, and relationship of adverse events to study treatment). Incidence of Treatment Emergent Adverse Event (TEAE), Serious Adverse Event (SAE) and laboratory abnormalities
60 months
Measurements of free light chain assays.
Time Frame: Baseline, 2 months, 3 months
To explore the value of frequent measurements of free light chain assays at baseline and after the first 2 cycles, then every 3 cycles and its relationship to response rate.
Baseline, 2 months, 3 months
Response duration.
Time Frame: 60 months
• Response duration (time between first documentation of response and disease progression). Time to disease progression (from the date of the first dose to the date of the first observation of disease progression).
60 months
progression free survival
Time Frame: 60 months
60 months

Collaborators and Investigators

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

Sponsor

University Hospital, Lille

Collaborators

Celgene Corporation

Investigators

  • Principal Investigator: TOURNILLAC Olivier, Dr, Centre Hospitalier CLERMOND FERRAND
  • Principal Investigator: MOREL Pierre, Dr, Centre Hospitalier de LENS
  • Study Director: LELEU Xavier, Dr, CHRU Lille
  • Principal Investigator: LEGOUILL Steven, Dr, Centre Hospitalier de NANTES
  • Principal Investigator: LEBLOND Véronique, Dr, APHP PARIS
  • Principal Investigator: BANOS Anne, Dr, Centre Hospitalier de BAYONNE
  • Principal Investigator: SALLES Gilles, Pr, Centre Hospitalier de LYON

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 (Actual)

March 1, 2009

Primary Completion (Actual)

March 1, 2017

Study Completion (Actual)

April 1, 2017

Study Registration Dates

First Submitted

June 24, 2014

First Submitted That Met QC Criteria

November 24, 2014

First Posted (Estimate)

November 27, 2014

Study Record Updates

Last Update Posted (Actual)

June 7, 2017

Last Update Submitted That Met QC Criteria

June 6, 2017

Last Verified

June 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2008_15/0837
  • 2008-006370-15 (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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