Cyclophosphamide, Lenalidomide and Dexamethasone (CLD) for Previously Treated Patients With AL Amyloidosis

Amyloidosis Clinical Trial

Official title:

An Open-label, Phase II Study of Cyclophosphamide, Lenalidomide and Dexamethasone (CLD) for Previously Treated Patients With AL Amyloidosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00607581
• Other study ID #: AC-003-IT
• Secondary ID: RV-AMYL-PI-303
• Status: Completed
• Phase: Phase 2
• First received: January 22, 2008
• Last updated: February 9, 2012
• Start date: February 2008
• Est. completion date: January 2012

Study information

• Verified date: February 2012
• Source: IRCCS Policlinico S. Matteo
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

The treatment of light-chain (AL) amyloidosis is directed against the plasma cells that produce the light-chain forming the amyloid deposits. The plasma cells can be killed and their growth can be stopped by drugs used in chemotherapy, such as cyclophosphamide, steroids, such as dexamethasone, and drugs that stimulate the immune system, such as lenalidomide.

The present trial studies the efficacy and safety of the combination of cyclophosphamide, lenalidomide and dexamethasone in patients with AL amyloidosis who were previously treated and need further therapy.

Description:

This study will include previously treated patients with AL amyloidosis.

Primary objectives to determine the hematologic and organ response rate to the association of cyclophosphamide, lenalidomide and dexamethasone (CLD).

Secondary objectives

• to determine the safety of CLD,

• to determine time to response to CLD,

• to determine the duration of response to CLD,

• to assess survival of AL amyloidosis patients treated with CLD.

Patients receive 28-day cycles cyclophosphamide on days 1, 8 and 15, oral lenalidomide on days 1-21 and oral dexamethasone on days 1, 8, 15, and 22.

Up to 9 courses can be performed until one of the following endpoints is met:

• completion of cycle 9,

• complete hematologic remission observed after cycle 3 or 6,

• partial hematologic response associated with organ response after cycle 6.

• no response at cycle 3 or 6. After completion of study treatment, patients are followed every 3 months for up to 3 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: January 2012
• Est. primary completion date: December 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

• Diagnosis of AL amyloidosis.

• Evidence of a monoclonal light chain at serum and/or urine immunofixation electrophoresis.

• Elevated circulating free light chain (of the type identified by immunofixation) above the upper limit of the normal range and abnormal kappa/lambda ratio.

• Previously treated and requiring further treatment.

• Symptomatic organ involvement.

• Bone marrow plasma cell <30%.

• Echocardiographic ejection fraction >40%.

• Troponin I <0.1 ng/mL.

• Hemoglobin >10 g/dL.

• Absolute neutrophil count >1500/uL.

• Platelet count >140000/uL.

• Total bilirubin <2.5 mg/dL.

• Alkaline phosphatase <4 x upper reference limit (u.r.l.).

• ALT <3 x u.r.l..

• Glomerular filtration rate >30 mL/min.

• Performance status ECOG 1-3.

• Female subjects of childbearing potential must have two negative pregnancy tests prior to starting study drug.

Exclusion Criteria:

• Prior treatment with the association of cyclophosphamide, lenalidomide and dexamethasone or with lenalidomide.

• Requirement for other concomitant chemotherapy, immunotherapy or radiotherapy, or any investigational ancillary therapy.

• Presence of other active malignancies, with the exception of nonmelanoma skin cancer, cervical cancer, treated early-stage prostate cancer provided that prostate specific antigen is within normal limits.

• Clinically overt multiple myeloma.

• Uncontrolled infection.

• New York Heart Association (NYHA) class 4 heart failure.

• Enzyme documented myocardial infarction within 6 months before enrollment.

• Grade 2 or 3 atrioventricular block (Mobitz type I is permitted).

• Repetitive ventricular arrhythmias at 24 h Holter electrocardiogram in spite of treatment with amiodarone.

• Supine systolic blood pressure <90 mmHg, or symptomatic orthostatic hypotension, or a decrease in systolic blood pressure on standing of >20 mmHg in spite of being treated for orthostatic hypotension.

• Prior history of thrombosis or venous thromboembolism or pulmonary embolism. Prior diagnosis of antiphospholipid antibodies or lupus anticoagulant, factor V Leiden mutation, prothrombin G21210A mutation, antithrombin, protein C or S deficiency.

• Indication to receive clopidogrel, ticlopidine or warfarin.

• Factor X level <20%.

• Poorly controlled diabetes mellitus (if receiving antidiabetic agents, subjects must be on a stable dose for at least 3 months).

• Previous or ongoing psychiatric illness (with the exclusion of reactive depression).

• Pregnant or nursing women.

Study Design

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

Related Conditions & MeSH terms

• Amyloidosis

Intervention

Drug:
• cyclophosphamide
cyclophosphamide: 500 mg orally on days 1, 8, 15
• lenalidomide
lenalidomide: 15 mg orally on days 1-21
• dexamethasone
dexamethasone: 40 mg orally on days on days 1, 8, 15, 22

Locations

Country	Name	City	State
Italy	Amyloidosis Research and Treatment Center - Fondazione IRCCS Policlinico San Matteo	Pavia

Sponsors (2)

Lead Sponsor	Collaborator
IRCCS Policlinico S. Matteo	Celgene Corporation

Country where clinical trial is conducted

Italy, 

References & Publications (5)

Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. — View Citation

Merlini G, Stone MJ. Dangerous small B-cell clones. Blood. 2006 Oct 15;108(8):2520-30. Epub 2006 Jun 22. Review. — View Citation

Palladini G, Perfetti V, Perlini S, Obici L, Lavatelli F, Caccialanza R, Invernizzi R, Comotti B, Merlini G. The combination of thalidomide and intermediate-dose dexamethasone is an effective but toxic treatment for patients with primary amyloidosis (AL). Blood. 2005 Apr 1;105(7):2949-51. Epub 2004 Nov 30. — View Citation

Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. — View Citation

Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	hematologic response rate		at 3 months	No
Secondary	organ response rate		at 3 months	No
Secondary	time to response		every 28 days	No
Secondary	time to progression		every 3 months for 3 years	No
Secondary	survival		up to 3 years after treatment discontinuation	No
Secondary	toxicity		continuous during treatment	Yes