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

Primary Purpose

Amyloidosis

Status
Completed
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
Lenalidomide
Melphalan
Dexamethasone
Sponsored by
Nantes University Hospital
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Amyloidosis focused on measuring newly-diagnosed light-chain (AL)-amyloidosis

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • CHRU d'Amiens
  • CHRU de Lille
  • CHU de Limoges
  • CHU de Nantes
  • Hôpital Saint-Louis
  • Hôpital Pitié Salpetrière
  • Hôpital necker
  • Hôpitaux Civils de Lyon
  • CHU de Poitiers
  • CHU de Rennes
  • CHU de Toulouse
  • CHRU deTours

Outcomes

Primary Outcome Measures

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

Complete (CR) or partial (PR) response, according to criteria defined during the 10th International Symposium on Amyloidosis
To determine the hematologic response
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
Value of frequent measurements of free light chain assays
To determine interest of frequent measurments of free light chain assays for patients
Incidence of Treatment Emergent Adverse Event (TEAE), Serious Adverse Event (SAE) and laboratory abnormalities
To assess the safety profile of the combination therapy
time between first documentation of hematologic response and disease progression
To measure hematological duration
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

Full Information

First Posted
February 12, 2008
Last Updated
May 9, 2011
Sponsor
Nantes University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT00621400
Brief Title
Lenalidomide in Combination With Melphalan and Dexamethasone in Newly-diagnosed Light-chain (AL)-Amyloidosis
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 Type
Interventional

2. Study Status

Record Verification Date
May 2010
Overall Recruitment Status
Completed
Study Start Date
January 2008 (undefined)
Primary Completion Date
December 2009 (Actual)
Study Completion Date
December 2009 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Nantes University Hospital

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amyloidosis
Keywords
newly-diagnosed light-chain (AL)-amyloidosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
27 (Actual)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
Lenalidomide
Other Intervention Name(s)
Revlimid
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Melphalan
Other Intervention Name(s)
Alkeran
Intervention Description
0,18mg/Kg/day from day 1- 4
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Intervention Description
40mg/day from day 1- 4.
Primary Outcome Measure Information:
Title
Determination of MTD by evaluation of hematological and non hematological toxicity
Description
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 Measure Information:
Title
Complete (CR) or partial (PR) response, according to criteria defined during the 10th International Symposium on Amyloidosis
Description
To determine the hematologic response
Title
disease progression from the date of the first dose to the date of the first observation of organ disease progression and observation of response
Description
To determine the rate of organ response
Title
Value of frequent measurements of free light chain assays
Description
To determine interest of frequent measurments of free light chain assays for patients
Title
Incidence of Treatment Emergent Adverse Event (TEAE), Serious Adverse Event (SAE) and laboratory abnormalities
Description
To assess the safety profile of the combination therapy
Title
time between first documentation of hematologic response and disease progression
Description
To measure hematological duration
Title
disease progression from the date of the first dose to the date of the first observation of hematologic disease progression
Description
Time to hematologic disease progression

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Facility Information:
Facility Name
CHRU d'Amiens
City
Amiens
ZIP/Postal Code
80054
Country
France
Facility Name
CHRU de Lille
City
Lille
ZIP/Postal Code
59037
Country
France
Facility Name
CHU de Limoges
City
Limoges
ZIP/Postal Code
87042
Country
France
Facility Name
CHU de Nantes
City
Nantes
ZIP/Postal Code
44093
Country
France
Facility Name
Hôpital Saint-Louis
City
Paris
ZIP/Postal Code
75475
Country
France
Facility Name
Hôpital Pitié Salpetrière
City
Paris
ZIP/Postal Code
75651
Country
France
Facility Name
Hôpital necker
City
Paris
ZIP/Postal Code
75743
Country
France
Facility Name
Hôpitaux Civils de Lyon
City
Pierre-Bénite
ZIP/Postal Code
69495
Country
France
Facility Name
CHU de Poitiers
City
Poitiers
ZIP/Postal Code
86021
Country
France
Facility Name
CHU de Rennes
City
Rennes
ZIP/Postal Code
35203
Country
France
Facility Name
CHU de Toulouse
City
Toulouse
ZIP/Postal Code
31059
Country
France
Facility Name
CHRU deTours
City
Tours
ZIP/Postal Code
37044
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
20724537
Citation
Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. doi: 10.1182/blood-2010-07-294405. Epub 2010 Aug 19.
Results Reference
derived

Learn more about this trial

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

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