Study of Lenalidomide in Relapse/Refractory Waldenstrom Macroglobulinemia

Brief Title

Study of Lenalidomide in Relapse/Refractory Waldenstrom Macroglobulinemia

Official Title

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

Brief Summary

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

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 Phase

Phase 1/Phase 2

Study Type

Interventional

Primary Outcome

Number of Participants with dose limiting toxicities (DLT) of lenalidomide as a Measure of Safety and Tolerability.

Secondary Outcome

 number of patients with a response to lenalidomide

Condition

Waldenstrom Macroglobulinemia

Intervention

Revlimid

Study Arms / Comparison Groups

 revlimid

Description:  a dose-escalation of revlimid

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Status

Drug

Estimated Enrollment

17

Start Date

March 2009

Completion Date

April 2017

Primary Completion Date

March 2017

Eligibility Criteria

        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 -
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

TOURNILLAC Olivier, Dr, , 

Location Countries

France

Location Countries

France

NCT ID

NCT02302469

Organization ID

2008_15/0837

Secondary IDs

2008-006370-15

Responsible Party

Sponsor

Study Sponsor

University Hospital, Lille

Collaborators

 Celgene Corporation

Study Sponsor

TOURNILLAC Olivier, Dr, Principal Investigator, Centre Hospitalier CLERMOND FERRAND

Verification Date

June 2017