Doxorubicin Hydrochloride Liposome, Melphalan, and Bortezomib in Treating Patients With Relapsed or Refractory Stage I, Stage II, or Stage III Multiple Myeloma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as doxorubicin hydrochloride liposome and melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving doxorubicin hydrochloride liposome and melphalan together with bortezomib may kill more cancer cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of doxorubicin hydrochloride liposome , melphalan, and bortezomib and to see how well they work in treating patients with relapsed or refractory stage I, stage II, or stage III multiple myeloma.

Detailed Description
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OBJECTIVES: Primary Determine the safety and tolerability of doxorubicin HCl liposome, melphalan, and bortezomib in patients with relapsed or refractory stage I-III multiple myeloma. Determine the maximum tolerated dose (MTD) of this regimen in these patients. Secondary Determine the overall response rate, including complete, near-complete, partial, and minimal response rate, in patients treated with this regimen. Determine the time to response, progression-free survival, and overall survival of patients treated with this regimen. Determine the toxic effects of this regimen at the MTD in these patients. OUTLINE: This is a multicenter, phase I, dose-escalation study followed by a phase II study. Phase I: Patients receive doxorubicin HCl liposome IV over 30-60 minutes and melphalan IV over 30 minutes on day 1 and bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of doxorubicin HCl liposome, melphalan, and bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 4 of 6 patients experience dose-limiting toxicity after 2 courses of therapy. Phase II: Patients receive doxorubicin HCl liposome, melphalan, and bortezomib at the MTD as in phase I. After completion of study treatment, patients are followed every 3 months. PROJECTED ACCRUAL: Approximately 32 patients will be accrued for this study.

Official Title
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Phase I/II Study of Liposomal Doxorubicin (Doxil®)/ Melphalan/Bortezomib (Velcade®) in Relapsed/Refractory Multiple Myeloma

Conditions
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Multiple Myeloma and Plasma Cell Neoplasm

Intervention / Treatment
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* Drug: bortezomib
* Drug: melphalan
* Drug: pegylated liposomal doxorubicin hydrochloride


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of multiple myeloma Stage I, II, or III disease according to Durie-Salmon staging criteria Progressive disease, defined as one of the following: For secretory disease: A 25% increase in serum M-protein or Bence Jones protein (an absolute increase of 0.5 g/dL serum M-protein or ≥ 200 mg/24 hours of urine light chain excretion) For nonsecretory disease: Bone marrow biopsy with > 25% increase in plasma cells or an absolute increase of ≥ 10% over prior known level Development of new or worsening existing lytic bone lesions or soft tissue plasmacytomas Hypercalcemia (i.e., calcium > 11.5 mg/dL) Relapsed after complete response Must have received ≥ 2 of the following therapeutic regimens for multiple myeloma: Nonmyeloablative transplantation No significant graft-versus-host disease At least 30 days since prior immunosuppressive therapy (concurrent prednisone allowed provided dose is ≤ 10 mg daily) Mobilization with chemotherapy followed by either single or tandem autologous stem cell transplantation (considered 1 prior regimen) Mobilization with chemotherapy followed by autologous and subsequent nonmyeloablative allogeneic stem cell transplantation (considered 1 prior regimen) Any combination of drugs given concurrently (considered 1 prior regimen) PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy ≥ 3 months Absolute neutrophil count > 1,000/mm^3 (no colony-stimulating factors) Platelet count > 50,000/mm^3 (no transfusion support) Bilirubin ≤ 2.0 mg/dL AST ≤ 4 times upper limit of normal Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 4 weeks after completion of study treatment No history of allergic reaction to compounds containing boron or mannitol No active uncontrolled viral (including HIV), bacterial, or fungal infection No motor or sensory neuropathy ≥ grade 2 No myocardial infarction within the past 6 months No New York Heart Association class III or IV heart failure No uncontrolled angina No severe uncontrolled arrhythmia No acute ischemia by EKG LVEF ≥ 35% by MUGA (MUGA required in patients whose lifetime cumulative doxorubicin hydrochloride dose > 400 mg/m^2) PRIOR CONCURRENT THERAPY: See Disease Characteristics No grade III or IV toxicity due to previous antineoplastic therapy (except alopecia) At least 3 weeks since prior chemotherapy No prior doxorubicin HCl liposome, melphalan, and bortezomib as combination therapy (single or two-drug combinations of these are allowed) No concurrent corticosteroids (≤ 10 mg prednisone/day or equivalent allowed) No other concurrent chemotherapy No concurrent thalidomide No other concurrent investigational therapy No other concurrent antineoplastic treatment for multiple myeloma, including clarithromycin No concurrent radiation therapy No concurrent nonsteroidal anti-inflammatory agents

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


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: bortezomib|nan|
|Drug: melphalan|nan|
|Drug: pegylated liposomal doxorubicin hydrochloride|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients experiencing treatment-related ≥ grade 3 hematologic or nonhematologic toxicity or treatment-related death (phase I) |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to response (phase II) |  |  | 
| Progression-free survival (phase II) |  |  | 
| Overall survival (phase II) |  |  | 
| Toxicities by NCI criteria (phase II) |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory multiple myeloma, stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma