Bortezomib and Dexamethasone Followed by High-Dose Melphalan and Stem Cell Transplantation for Primary (AL) Amyloidosis

Study Overview
=================
Brief Summary
-----------------
The drugs dexamethasone and bortezomib are both FDA-approved for the treatment of multiple myeloma, a disease very similar to amyloidosis. However, they are currently investigational for the treatment of amyloidosis. We want to find out if the addition of dexamethasone and bortezomib to standard high dose chemotherapy and stem cell transplant can help improve response. Standard treatment includes four steps: 1) Stem Cell Mobilization (standard) 2) Stem Cell Collection (standard) 3) Conditioning Regimen (Melphalan chemotherapy). The conditioning regimen helps to kill the abnormal cells in the body and makes room in the bone marrow for new blood stem cells to grow. 4) Stem Cell Infusion Participants in this study will have an additional treatment step called induction therapy, designed as the first step towards reducing the number of abnormal cells in the body. Two cycles of the investigational drugs bortezomib and dexamethasone will be given during induction therapy. In addition, bortezomib will given as part of the conditioning regimen, in addition to the standard melphalan chemotherapy.

Detailed Description
-----------------
The drugs dexamethasone and bortezomib are both FDA-approved drugs for the treatment of multiple myeloma, a disease very similar to amyloidosis. However, they are currently investigational for the treatment of amyloidosis. The investigators want to find out if the addition of dexamethasone and bortezomib to standard treatment of high dose chemotherapy and stem cell transplant can help improve response to treatment.

Official Title
-----------------
Phase II Trial of Induction Therapy With Bortezomib and Dexamethasone Followed by High-Dose Melphalan and Stem Cell Transplantation in Patients With AL Amyloidosis

Conditions
-----------------
Amyloidosis

Intervention / Treatment
-----------------
* Drug: Bortezomib
* Drug: Dexamethasone
* Drug: Melphalan


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histological diagnosis of primary systemic (AL) amyloidosis based on: Deposition of amyloid material by congo red stain showing characteristic green birefringence, and monoclonal light chain protein in the serum or urine or immunohistochemical studies or serum free light chain assay and evidence of tissue involvement other than carpal tunnel syndrome, i.e. positive immunohistochemical staining of bone marrow demonstrating clonal plasma cells; or tissue amyloid deposits with anti-kappa or anti-lambda anti-serum; evidence for a plasma cell dyscrasia (PCD) by serum/urine or bone marrow; or overwhelmingly convincing clinical features e.g. macroglossia, associated with other systemic manifestations. Note: 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. Must be at least 18 years of age. Must have a performance status of 0-2 by Southwest Oncology Group criteria Must have left ventricular ejection fraction (LVEF) at least 45% by echocardiogram within 60 days of enrollment 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 less than 300 mg. Patients should not have received any cytotoxic therapy less than 4 weeks prior to registration and should have fully recovered from the effects of such therapy. Pulmonary Function Tests must show Diffusing capacity of the lungs for carbon monoxide (DLCO) at least 50%. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. Male subject agrees to use an acceptable method for contraception for the duration of the study. Exclusion Criteria: No overt multiple myeloma (over 30% bone marrow plasmacytosis, extensive (great than 2) lytic lesions, 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 3 years. No known to be HIV positive. No platelet count of less than or equal to 70,000 within 14 days before enrollment. No absolute neutrophil count of less than or equal to 1000 within 14 days before enrollment. No greater than or equal to Grade 2 peripheral neuropathy within 14 days before enrollment. No myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant. No hypersensitivity to bortezomib, boron or mannitol. No pregnant or breast-feeding females. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women. Must not have received other investigational drugs with 14 days before enrollment No serious medical or psychiatric illness likely to interfere with participation in this clinical study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm - Investigational<br>Induction: Bortezomib (Velcade) 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Melphalan 70-100 mg/m2/day IV on days -2 and -1 | Drug: Bortezomib<br>* Induction: Velcade 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4<br>* Other names: Velcade;Drug: Dexamethasone<br>* Induction: Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days<br>* Other names: Decadron;Drug: Melphalan<br>* Conditioning: Melphalan 70-100 mg/m2/day IV on days -2 and -1<br>* Other names: Alkeran;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Disease Response | Complete response: Normal serum free light chain ratio and Negative serum and urine immunofixation electrophoresis Very good partial response: Difference in serum free light chains less than 40 mg/L Partial Response: >50% Reduction in the difference in serum free light chains | One year | 
| Number of Participants Surviving at 100 Days Post Transplant |  | 100 days | 
| Number of Participants Proceeding to Transplant Following Induction |  | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Surviving at 5 Years |  | 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Amyloid, Amyloidosis, AL Amyloidosis, Primary Amyloidosis, Stem Cell Transplant