Official Title: “Risk-Adapted Intravenous Melphalan With Stem Cell Transplant and Adjuvant Bortezomib and Dexamethasone for Recently Diagnosed Untreated Patients With Systemic Light-Chain (AL) Amyloidosis”

RATIONALE: Giving chemotherapy, such as melphalan, before a peripheral stem cell transplant stops the growth of plasma cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as G-CSF, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Bortezomib may stop the growth of plasma cells by blocking some of the enzymes needed for cell growth. Giving bortezomib and dexamethasone after transplant may kill any plasma cells that remain after transplant.

PURPOSE: This phase II trial is studying how well giving melphalan together with an autologous stem cell transplant followed by bortezomib and dexamethasone works in treating patients with previously untreated systemic amyloidosis.

Study Type: Interventional

Study Design: Treatment, Open Label

Study Primary Completion Date: February 2010

OBJECTIVES:

Primary - Determine the response rate in patients with systemic light chain amyloidosis treated with melphalan and autologous stem cell transplantation followed by adjuvant bortezomib and dexamethasone.

Secondary - Determine the toxicity of this regimen in these patients. - Assess amyloid disease response to this regimen. - Determine the progression-free survival of patients treated with this regimen. - Determine the overall survival of patients treated with this regimen.

OUTLINE: - Stem cell mobilization and collection: Patients undergo peripheral blood stem cell (PBSC) mobilization comprising filgrastim (G-CSF) subcutaneously (SC) for 4-6 days. PBSC collection continues for 2-3 days until the target number of stem cells is reached. - Conditioning regimen: One week after PBSC collection, patients receive melphalan IV on days -3 and -2 and autologous PBSC infusion on day 0. Patients receive G-CSF SC beginning on day 1 and continuing until blood counts recover. - Adjuvant therapy: Between 2-3 months after PBSC transplantation, patients are assigned to 1 of 2 groups. - Group 1 (patients with plasma cell disease): Patients receive bortezomib IV on days 1, 4, 8, and 11 and oral dexamethasone once daily on days 1, 2, 4, 5, 8, 9, 11, and 12. Treatment repeats every 3 weeks for 2 courses. Patients then receive bortezomib on days 1, 8, 15, and 22 and dexamethasone on days 1, 2, 8, 9, 15, 16, 22, and 23.

Treatment repeats every 5 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Patients who achieve complete response (CR) receive bortezomib and dexamethasone for 2 additional courses after CR. - Group 2 (patients with plasma cell disease and peripheral neuropathy): Patients receive oral dexamethasone once daily on days 1-4, 9-12, and 17-20. Treatment repeats every 30 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve CR receive dexamethasone for 2 additional courses after CR. Patients undergo blood and bone marrow collection and tissue biopsies at baseline and periodically after completion of study treatment for biomarker correlative studies.

After completion of study treatment, patients are followed every 2 months for 1 year and then annually thereafter.

PROJECTED ACCRUAL: A total of 45 patients will be accrued for this study.

Intervention(s) in this Clinical Trial

• Drug: bortezomib
  • Given IV
• Drug: dexamethasone
  • Given orally

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Group 1
  • Patients receive bortezomib IV on days 1, 4, 8, and 11 and oral dexamethasone once daily on days 1, 2, 4, 5, 8, 9, 11, and 12. Treatment repeats every 3 weeks for 2 courses. Patients then receive bortezomib on days 1, 8, 15, and 22 and dexamethasone on days 1, 2, 8, 9, 15, 16, 22, and 23. Treatment repeats every 5 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response (CR) receive bortezomib and dexamethasone for 2 additional courses after CR.
• Experimental: Group 2
  • Patients receive oral dexamethasone once daily on days 1-4, 9-12, and 17-20. Treatment repeats every 30 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve CR receive dexamethasone for 2 additional courses after CR.

Primary Measures

• Response rate at 12 months
  • Safety Issue?: No

Secondary Measures

• Toxicity
  • Safety Issue?: Yes
• Amyloid disease response at 12 and 24 months
  • Safety Issue?: No
• Progression-free survival at 12 and 24 months
  • Safety Issue?: No
• Overall survival at 12 and 24 months
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Histologically confirmed amyloidosis
• Diagnosed within the past 12 months
• Clonal plasma cell disorder, as demonstrated by any of the following:
• Presence of M-protein in serum and/or urine by immunofixation and/or serum free light chain assay
• Clonal population of plasma cells in the bone marrow based on kappa/lambda staining of a marrow biopsy
• Negative genetic testing for hereditary forms of amyloidosis
• No amyloid-specific syndrome (e.g., carpal tunnel syndrome or skin purpura) as the only evidence of disease
• Vascular amyloidosis only in a bone marrow biopsy specimen or in plasmacytoma is not indicative of systemic amyloidosis
• No advanced cardiac amyloidosis
• Must have symptomatic involvement of no more than 2 of the following visceral organ systems:
• Kidneys
• Liver/gastrointestinal
• Peripheral/autonomic nervous system
• Heart
• No persistent pleural effusions
• No clinically overt multiple myeloma with > 30% plasma cells in the bone marrow or lytic bone lesions
• Able to undergo autologous stem cell transplantation

PATIENT CHARACTERISTICS:

• SWOG performance status 0-3
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Bilirubin < 2.0 mg/dL
• Creatinine clearance < 51 mL/min allowed
• LVEF > 45% by echocardiogram
• No New York Heart Association class III-IV congestive heart failure
• No history of cardiac syncope
• No recurrent symptomatic arrhythmias
• No oxygen-dependent restrictive cardiomyopathy
• No myocardial infarction within the past 6 months
• Pulmonary diffusion capacity > 50% predicted by pulmonary function testing
• No uncontrolled infection
• No other active malignancy, except for any of the following:
• Adequately treated basal cell or squamous cell skin cancer
• In situ cervical cancer
• Adequately treated stage I cancer from which the patient is currently in complete remission
• Any other cancer from which the patient has been disease-free for 5 years
• No hypersensitivity to bortezomib, boron, or mannitol
• No HIV positivity
• No serious medical or psychiatric illness that would preclude study compliance

PRIOR CONCURRENT THERAPY:

• At least 14 days since prior investigational drugs
• No prior therapy for monoclonal plasma disease

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 70 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Memorial Sloan-Kettering Cancer Center

Overall Clinical Trial Officials and Contacts

Raymond L. Comenzo, MD Principal Investigator Memorial Sloan-Kettering Cancer Center  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00458822

Study ID Number: CDR0000537913

ClinicalTrials.gov Identifier: NCT00458822

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database