Lenalidomide in Combination With Melphalan and Dexamethasone in Newly-diagnosed Light-chain (AL)-Amyloidosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00621400
Recruitment Status : Completed
First Posted : February 22, 2008
Last Update Posted : May 10, 2011
Information provided by:
Nantes University Hospital

Brief Summary:
Amyloidosis results from tissue deposition of amyloid protein, composed mainly by the fragments of monoclonal immunoglobulin heavy chains or light chains. Accumulation of amyloid protein progressively disrupts normal tissue structure and ultimately leads to organ failure, most frequently in the kidneys, heart, liver and peripheral nervous system. A recently completed French prospective randomized trial, in patients presenting with newly AL-amyloidosis, compared two treatment regimens at the time of diagnosis: Melphalan-dexamethasone (conventional oral treatment), versus high dose of Melphalan followed by autologous stem cell transplantation (ASCT) (1). High-dose therapy was not associated with a better outcome. Melphalan-dex given monthly can be considered as the current standard of care, with a median survival of 56 months. The use of a combination of lenalidomide and dexamethasone has already been tested in patients with AL-amyloidosis (2). The initial dose of lenalidomide at 25 mg/day was poorly tolerated. However, a 15 mg/day dose regimen was well tolerated and effective, with an overall hematologic response rate of 67%. Hematologic responses were associated with clinical responses. Dispenzieri et al confirmed that the combination of Lenalidomide + dexamethasone achieved a 75% hematologic response rate, with a 42% organ response, and a median follow-up of 17 months in patients still receiving treatment (2006). These authors also recommended a lower dose of 15mg/day. The rationale for the present investigation is that addition of lenalidomide to the current standard of care (Melphalan-dexamethasone) might improve the hematologic response rate and the organ response rates both associated with a prolonged survival in patients with AL-amyloidosis. As the toxicity of the combination of M-dex + lenalidomide is unknown in patients with AL-amyloidosis, the dose of lenalidomide will start from the lowest one available, i.e., 5 mg/day and increased from 5 to 5 mg up to a maximum dose of 15 mg in combination with M-dex in 3 consecutive cohorts of patients, according to toxicity. When the optimal dose of lenalidomide will be defined, 9 additional patients will be included in the trial at the recommended dose-level to assess the feasibility of the combination M-dex-lenalidomide.

Condition or disease Intervention/treatment Phase
Amyloidosis Drug: Lenalidomide Drug: Melphalan Drug: Dexamethasone Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter Phase I/II Dose Escalation Study of Lenalidomide in Combination With Melphalan and Dexamethasone in Subjects With Newly-diagnosed Light-chain (AL)-Amyloidosis
Study Start Date : January 2008
Actual Primary Completion Date : December 2009
Actual Study Completion Date : December 2009

Intervention Details:
  • Drug: Lenalidomide
    5 mg/day, orally for 21 days with 7 days rest (28 day cycle) for the first cohort; or 10mg/day, orally for 21 days with 7 days rest (28 day cycle) for the second cohort, 15mg/day, orally for 21 days with 7 days rest (28 day cycle) for the third cohort or 20mg/day, orally for 21 days with 7 days rest (28 day cycle) for the last and fourth cohort
    Other Name: Revlimid
  • Drug: Melphalan
    0,18mg/Kg/day from day 1- 4
    Other Name: Alkeran
  • Drug: Dexamethasone
    40mg/day from day 1- 4.

Primary Outcome Measures :
  1. Determination of MTD by evaluation of hematological and non hematological toxicity
    The primary endpoint is to evaluate the incidence of dose limiting toxicities (DLT) during the first cycle of lenalidomide at a given dose level in order to determine the maximal tolerated dose (MTD) in a dose escalating study design.

Secondary Outcome Measures :
  1. Complete (CR) or partial (PR) response, according to criteria defined during the 10th International Symposium on Amyloidosis
    To determine the hematologic response

  2. disease progression from the date of the first dose to the date of the first observation of organ disease progression and observation of response
    To determine the rate of organ response

  3. Value of frequent measurements of free light chain assays
    To determine interest of frequent measurments of free light chain assays for patients

  4. Incidence of Treatment Emergent Adverse Event (TEAE), Serious Adverse Event (SAE) and laboratory abnormalities
    To assess the safety profile of the combination therapy

  5. time between first documentation of hematologic response and disease progression
    To measure hematological duration

  6. disease progression from the date of the first dose to the date of the first observation of hematologic disease progression
    Time to hematologic disease progression

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • De novo systemic biopsy proven AL-amyloidosis.
  • Measurable organ site involvement consistent with the diagnosis.
  • Adequate organ function defined as

    • Absolute neutrophil count > 1.0 x 109/L;
    • platelet count > 100x109/L;
    • AST (SGOT) and ALT (SGPT) < 2 x UNL;
    • Total bilirubin £ 1.5 mg/dL ;
    • creatinin serum level <150µmol/L (1.5mg/dl);
  • Evaluable immunochemical abnormalities, including abnormal serum free light chain assay with an increase of either kappa or lambda light chain level.
  • ECOG performance status of £ 2 at study entry (see Appendix BB).
  • Age between18 and 70 years at the time of signing the informed consent form.
  • Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL at screening visit and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 4 weeks before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree not to father a child and agree to use a condom if his partner is of child bearing potential. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. See Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.
  • Able to understand and voluntarily sign an informed consent form.
  • Able to adhere to the study visit schedule and other protocol requirements.
  • Able to take antithrombotic medicines such as low molecular weight heparin or warfarin (if needed).
  • Disease free of prior malignancies for > 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast.
  • Subjects affiliated with an appropriate social security system.

Exclusion Criteria:

  • Symptomatic multiple myeloma: multiple myeloma with related organ of tissue impairment (ROTI) according to the International Myeloma Working Group (16)
  • Any other uncontrolled medical condition or comorbidity that might interfere with subject's participation.
  • Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide).
  • Use of any other experimental drug or therapy within 28 days of baseline.
  • The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
  • Any prior treatment for amyloidosis.
  • Known positive for HIV or infectious hepatitis, type A, B or C.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00621400

CHRU d'Amiens
Amiens, France, 80054
CHRU de Lille
Lille, France, 59037
CHU de Limoges
Limoges, France, 87042
CHU de Nantes
Nantes, France, 44093
Hôpital Saint-Louis
Paris, France, 75475
Hôpital Pitié Salpetrière
Paris, France, 75651
Hôpital necker
Paris, France, 75743
Hôpitaux Civils de Lyon
Pierre-Bénite, France, 69495
CHU de Poitiers
Poitiers, France, 86021
CHU de Rennes
Rennes, France, 35203
CHU de Toulouse
Toulouse, France, 31059
CHRU deTours
Tours, France, 37044
Sponsors and Collaborators
Nantes University Hospital

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Anne Omnes, Cellule Promotion Recherche Clinique Identifier: NCT00621400     History of Changes
Other Study ID Numbers: BRD 07/7-G
EudraCT 2007-004739-43
First Posted: February 22, 2008    Key Record Dates
Last Update Posted: May 10, 2011
Last Verified: May 2010

Keywords provided by Nantes University Hospital:
newly-diagnosed light-chain (AL)-amyloidosis

Additional relevant MeSH terms:
Proteostasis Deficiencies
Metabolic Diseases
Dexamethasone acetate
BB 1101
Anti-Inflammatory Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Immunosuppressive Agents
Leprostatic Agents