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

Amyloidosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00621400
• Other study ID #: BRD 07/7-G
• Secondary ID: EudraCT 2007-004
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: February 12, 2008
• Last updated: May 9, 2011
• Start date: January 2008
• Est. completion date: December 2009

Study information

• Verified date: May 2010
• Source: Nantes University Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 27
• Est. completion date: December 2009
• Est. primary completion date: December 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Amyloidosis

Intervention

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
• Melphalan
0,18mg/Kg/day from day 1- 4
• Dexamethasone
40mg/day from day 1- 4.

Locations

Country	Name	City	State
France	CHRU d'Amiens	Amiens
France	CHRU de Lille	Lille
France	CHU de Limoges	Limoges
France	CHU de Nantes	Nantes
France	Hôpital necker	Paris
France	Hôpital Pitié Salpetrière	Paris
France	Hôpital Saint-Louis	Paris
France	Hôpitaux Civils de Lyon	Pierre-Bénite
France	CHU de Poitiers	Poitiers
France	CHU de Rennes	Rennes
France	CHU de Toulouse	Toulouse
France	CHRU deTours	Tours

Sponsors (1)

Lead Sponsor	Collaborator
Nantes University Hospital

Country where clinical trial is conducted

France, 

Outcome

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