Trial of High Dose Melphalan/Stem Cell Transplant With or Without Bortezomib

Study Overview
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Brief Summary
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Standard treatment for AL Amyloidosis is high-dose melphalan and stem cell transplant. This study will compare the safety and effectiveness of standard treatment with high-dose melphalan and stem cell transplant, compared with investigational bortezomib when used in combination with standard treatment with high-dose melphalan and stem cell transplant for AL amyloidosis.

Detailed Description
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This study seeks to enroll patients with AL amyloidosis who have been recommended for standard treatment with high-dose melphalan and stem cell transplant. Standard treatment for this disease is high-dose melphalan and stem cell transplant. The purpose of this study is to compare the safety and effectiveness of standard treatment with high-dose melphalan and stem cell transplant, compared with investigational bortezomib when used in combination with standard treatment with high-dose melphalan and stem cell transplant for AL amyloidosis. Patients enrolled in this study will receive either standard treatment with high-dose melphalan and stem cell transplant, or investigational bortezomib used in combination with standard treatment with high-dose melphalan and stem cell transplant.

Official Title
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Phase III Trial of High-dose Melphalan and Stem Cell Transplantation Versus High-dose Melphalan and Bortezomib and Stem Cell Transplantation in Patients With AL Amyloidosis

Conditions
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AL Amyloidosis

Intervention / Treatment
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* Drug: Bortezomib
* Drug: Melphalan
* Drug: Neupogen
* Procedure: Stem Cell Collection
* Procedure: Stem cell infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological diagnosis of primary systemic (AL) amyloidosis based on: Deposition of amyloid material by Congo red stain showing characteristic apple green birefringence,AND… evidence of a clonal plasma cell dyscrasia with monoclonal protein in the serum or urine by immunofixation electrophoresis studies AND/OR abnormal serum free light chain assay AND/OR clonal plasma cells in the bone marrow exam demonstrated by immunohistochemistry, flow cytometry or in situ hybridization AND… evidence of organ involvement other than carpal tunnel syndrome. Patients with senile, secondary, localized, dialysis-related or familial amyloidosis are not eligible. Confirmation of tissue diagnosis at all sites of organ dysfunction is encouraged, but not required. Patients must be > 18 years of age. Patients must have a performance status of 0-2 by Eastern Cooperative Oncology Group (ECOG) criteria Patients must have left ventricular ejection fraction (LVEF) > 45% by echocardiogram within 60 days of enrollment Pulmonary Function Tests must show diffusing capacity of lung for carbon monoxide (DLCO) > 50%. All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines. Exclusion Criteria: Patients with recent (< 6 months) myocardial infarction, congestive heart failure, New York Heart Association (NYHA) class III/IV or arrhythmia which are refractory to medical therapy are ineligible. Prior chemotherapy with alkylating agent allowed only if no evidence of Myelodysplastic Dysplastic Syndrome (MDS) morphologically or cytogenetically. Total cumulative dose of oral melphalan must be < 300 mg. Patients should not have received any cytotoxic therapy < 4 weeks prior to registration and should have fully recovered from the effects of such therapy. Patients must not have overt multiple myeloma (>30% bone marrow plasmacytosis and, extensive (>2) lytic lesions and hypercalcemia). No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years. Patients must not be HIV positive. Pregnant or nursing women may not participate. Women and men of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: melphalan<br>Neupogen 16mcg/kg x 4 days Stem cell collection Drug: high dose melphalan 140 or 200 mg/m2 stem cell infusion | Drug: Melphalan<br>* Conditioning Regimen: Drug: Melphalan: 70-100 mg/m2/dose D -2, D -1 Stem Cell Transplant: D 0<br>* Other names: Alkeran;Drug: Neupogen<br>* granulocyte colony-stimulating factor (G-CSF) mobilization 16mcg/kg x 4 days<br>* Other names: granulocyte colony-stimulating factor (G-CSF);Procedure: Stem Cell Collection<br>* collect at least 2.5 million cluster of differentiation 34 (CD34)+ stem cells<br>* Other names: apheresis;Procedure: Stem cell infusion<br>* infusion of previously collected autologous stem cells<br>* Other names: infusion;|
| Experimental: melphalan + Bortezomib<br>Neupogen 16mcg/kg x 4 days Stem Cell collection drug: high-dose melphalan 140 or 200 mg/m2 drug: Bortezomib 1.0 mg/m2/dose x 4 doses stem cell infusion | Drug: Bortezomib<br>* Conditioning Regimen: Drug: Bortezomib: 1.0 mg/m2/dose D -6, D -3, D +1, D + 4 Drug: Melphalan: 70-100 mg/m2/dose D -2, D -1<br>* Other names: VELCADE;Drug: Melphalan<br>* Conditioning Regimen: Drug: Melphalan: 70-100 mg/m2/dose D -2, D -1 Stem Cell Transplant: D 0<br>* Other names: Alkeran;Drug: Neupogen<br>* granulocyte colony-stimulating factor (G-CSF) mobilization 16mcg/kg x 4 days<br>* Other names: granulocyte colony-stimulating factor (G-CSF);Procedure: Stem Cell Collection<br>* collect at least 2.5 million cluster of differentiation 34 (CD34)+ stem cells<br>* Other names: apheresis;Procedure: Stem cell infusion<br>* infusion of previously collected autologous stem cells<br>* Other names: infusion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Hematologic Response | Hematologic response defined as: at least 50% improvement in the difference between involved and uninvolved free light chains | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicities | Number of serious adverse events per participant based on Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | 100 days | 
| Overall Survival | duration of overall survival measured in days | 5 years | 
| Number of Participants With Organ Response | analysis of number of patients with organ response, as defined on page 13 of the detailed protocol for kidney, heart and liver. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AL Amyloidosis, Stem Cell Transplantation