Amifostine and Melphalan in Treating Patients With Primary Systemic Amyloidosis Who Are Undergoing Peripheral Stem Cell Transplantation

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of plasma cells, either by killing the cells or by stopping them from dividing. Having a peripheral stem cell transplant to replace the blood-forming cells destroyed by chemotherapy, allows higher dose of chemotherapy to be given so that more plasma cells are killed. Giving a chemoprotective drug such as amifostine may protect kidney cells from the side effects of chemotherapy. PURPOSE: This phase I trial is studying the side effects and best dose of melphalan given together with amifostine in treating patients who are undergoing peripheral stem cell transplant for primary systemic amyloidosis.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose (MTD) of high-dose melphalan administered with amifostine in patients with primary systemic amyloidosis undergoing autologous peripheral blood stem cell transplantation. Determine the toxicity of high-dose melphalan when administered at the MTD in these patients. Determine the response rate in patients treated with this regimen. OUTLINE: This is a nonrandomized, multicenter, dose-escalation study of melphalan. Patients receive filgrastim (G-CSF) subcutaneously once daily until peripheral blood stem cell (PBSC) collection is complete. Apheresis begins on day 5 of G-CSF administration and continues until the target number of PBSCs are collected. Within 6 weeks of PBSC collection, patients receive amifostine IV over 5 minutes on days -2 and -1 and high-dose melphalan IV over 30-60 minutes on day -1. Patients undergo autologous PBSC infusion on day 0. Cohorts of 3-6 patients receive escalating doses of melphalan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, an additional 10 patients are treated at that dose. Patients are followed approximately 3 months following transplantation, then every 6 months for 5 years. PROJECTED ACCRUAL: A total of 3-46 patients will be accrued for this study within 2.3 years.

Official Title
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A Phase I Study of Amifostine Followed by High-Dose Escalation of Melphalan With Stem Cell Reconstitution for Patients With Primary Systemic Amyloidosis

Conditions
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Drug/Agent Toxicity by Tissue/Organ, Multiple Myeloma and Plasma Cell Neoplasm

Intervention / Treatment
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* Biological: filgrastim
* Drug: amifostine trihydrate
* Drug: melphalan
* Procedure: bone marrow ablation with stem cell support
* Procedure: peripheral blood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed amyloidosis No secondary familial or localized amyloidosis Presence of monoclonal protein by immunoelectrophoresis or immunofixation of serum or urine No primary amyloidosis manifested only by carpal tunnel syndrome or purpura Amyloid deposits in a plasmacytoma or in bone marrow vessels in an asymptomatic individual not considered an amyloid syndrome Amyloid syndromes include any of the following: Hepatomegaly Cardiomyopathy Nephrotic range proteinuria Peripheral or autonomic neuropathy No multiple myeloma defined by 1 of the following: Presence of lytic bone disease More than 30% bone marrow plasma cells PATIENT CHARACTERISTICS: Age 18 to 70 Performance status ECOG 0-1 Life expectancy Not specified Hematopoietic Platelet count at least 100,000/mm^3 Hepatic See Disease Characteristics Total or direct bilirubin no greater than 2.0 mg/dL Alkaline phosphatase no greater than 4 times upper limit of normal Renal See Disease Characteristics Creatinine less than 3.0 mg/dL Cardiovascular See Disease Characteristics Ejection fraction at least 45% by echocardiogram No New York Heart Association class III or IV heart disease Systolic blood pressure ≥ 90 mmHg Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No active infection No other malignancy within the past 5 years except surgically treated carcinoma in situ of the cervix, nonmelanoma skin cancer, or indolent prostate cancer PRIOR CONCURRENT THERAPY: Biologic therapy At least 4 weeks since prior interferon Chemotherapy At least 4 weeks since prior melphalan Lifetime total melphalan dose less than 150 mg/m^2 (based on ideal body weight) Endocrine therapy At least 4 weeks since prior dexamethasone Radiotherapy No prior radiotherapy for amyloidosis Surgery Not specified Other No antihypertensive medications for at least 24 hours prior to, during, and for 1 hour after amifostine administration No other prior treatment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Amifostine, Melphalan, and Stem Cell Reconstitution<br>Amifostine, Melphalan, and Stem Cell Reconstitution. Doses of Melphalan tested included 100 mg/m2 and 120 mg/m2 | Biological: filgrastim<br> <br> Drug: amifostine trihydrate<br> <br> Drug: melphalan<br> <br> Procedure: bone marrow ablation with stem cell support<br> <br> Procedure: peripheral blood stem cell transplantation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose | The maximum tolerated dose is the highest dose level at which fewer than 1 of 3 or 2 of 6 patients experience dose-limiting toxicity, defined as any grade 3 or higher toxicity of any of the following: renal failure, alkaline phosphatase elevation, GI bleeding, and cardiac rhythm disturbances, assessed using NCI Common Toxicity Criteria, version 2.0. | Assessed over 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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drug/agent toxicity by tissue/organ, primary systemic amyloidosis