Brostallicin in Treating Patients With Recurrent or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy such as brostallicin use different ways to stop cancer cells from dividing so they stop growing or die. PURPOSE: Phase I/II trial to study the effectiveness of brostallicin in treating patients who have recurrent or refractory multiple myeloma.

Detailed Description
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OBJECTIVES: Determine the objective tumor response rate (confirmed complete response and confirmed partial response) of brostallicin in patients with recurrent or refractory multiple myeloma. Determine the maximum tolerated dose of this drug in these patients. Determine the time to and duration of response, time to treatment failure, time to tumor progression, and survival in patients treated with this drug. Determine the safety and tolerability of this drug in these patients. Determine the pharmacokinetics of this drug in these patients. Correlate baseline whole blood levels and activity of glutathione with clinical outcome in patients treated with this drug. OUTLINE: This is an open-label, multicenter, dose-escalation study. Phase I: Patients receive brostallicin IV over 10-30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of brostallicin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity. Phase II: Additional patients are accrued and treated at the MTD of brostallicin as in phase I. Patients are followed every 2 months. PROJECTED ACCRUAL: A total of 23-52 patients will be accrued for this study.

Official Title
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A Phase I/II Study of the Safety and Efficacy of Brostallicin (PNU-166196A) in Adult Patients With Multiple Myeloma That Has Progressed on Prior Chemotherapy

Conditions
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Multiple Myeloma and Plasma Cell Neoplasm

Intervention / Treatment
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* Drug: brostallicin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Confirmed diagnosis of multiple myeloma based on prior or current demonstration of the following criteria*: Major criteria: Plasmacytoma on tissue biopsy Bone marrow plasmacytosis with at least 30% plasma cells Monoclonal globulin spike on serum electrophoresis exceeding 3.5 g/dL for IgG peaks or 2.0 g/dL for IgA peaks; greater than 1,000 mg/24hr of kappa or gamma light chain excretion on urine electrophoresis in the absence of amyloidosis Minor criteria: Bone marrow plasmacytosis with 10% to 30% plasma cells Monoclonal globulin spike present but less than levels in major criterion III above Lytic bone lesions Residual normal immunoglobulin M (IgM) no greater than 0.5 g/dL, IgA no greater than 0.1 g/dL, or IgG no greater than 0.6 g/dL NOTE: *Diagnosis of multiple myeloma requires a minimum of 1 major and 1 minor criterion (I and a together is not sufficient; must be I and b, I and c, I and d; II and b, II and c, II and d; III and a, III and c, III and d) or 3 minor criteria that must include a and b (a, b, and c; a, b, and d) Measurable disease defined by 1 of the following values: Serum myeloma (M) protein (IgG or IgA) level greater than 1.0 g/dL Urine M protein (light chain disease) at least 300 mg/24hr Soft tissue plasmacytoma with bidimensional measurement at least 20 x 20 mm (10 x 10 mm if spiral CT scan is used) Must have progressed during or within 12 months of discontinuing prior myelosuppressive chemotherapy (e.g., vincristine, doxorubicin, and dexamethasone (VAD) or melphalan) OR not responded after 2 courses of prior myelosuppressive chemotherapy No indolent or smoldering myeloma or localized plasmacytoma No known brain or leptomeningeal disease unless such lesions were previously irradiated, are currently not being treated with corticosteroids, and are associated with no clinical symptoms PATIENT CHARACTERISTICS: Age 18 and over Performance status Eastern Cooperative Oncology Group (ECOG) 0-2 Life expectancy At least 12 weeks Hematopoietic Absolute neutrophil count at least 1,500/mm^3 (at least 1,000/mm^3 if neutropenia due to replacement of the normal bone marrow cells by myeloma cells) Platelet count at least 100,000/mm^3 (at least 50,000/mm^3 if thrombocytopenia due to replacement of the normal bone marrow cells by myeloma cells) Hemoglobin at least 8.0 g/dL (no transfusion allowed) No hyperviscosity syndrome Hepatic Bilirubin no greater than 1.5 times upper limit of normal (ULN) Serum glutamate oxaloacetate transaminase (SGOT) no greater than 2.5 times ULN Alkaline phosphatase no greater than 2.5 times ULN Renal Creatinine no greater than 3.0 times ULN Calcium no greater than 12 mg/dL Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and sampling for study analysis HIV negative No other malignancy within the past 5 years except adequately treated nonmelanoma skin cancer or carcinoma in situ of the cervix No AIDS-related illness No active infectious process or other severe concurrent disease that would make the patient inappropriate for study entry No mental incapacity or psychiatric illness that would preclude giving informed consent or completing follow-up PRIOR CONCURRENT THERAPY: Biologic therapy See Chemotherapy No concurrent anticancer biological response modifiers No concurrent immunotherapy No concurrent sargramostim (GM-CSF) Chemotherapy See Disease Characteristics More than 2 years since prior high-dose chemotherapy with autologous bone marrow transplantation or stem cell support More than 4 weeks since prior myelosuppressive chemotherapy No other concurrent anticancer chemotherapy Endocrine therapy See Disease Characteristics No concurrent anticancer hormonal therapy No concurrent chronic steroids Acute pulse dosing required for treatment of a concurrent medical condition is allowed, provided treatment duration is no greater than 2 weeks No concurrent corticosteroids (e.g., dexamethasone) Radiotherapy More than 14 days since prior radiotherapy No prior radiotherapy to more than 25% of bone marrow No plans for radiotherapy within the next 6 months Concurrent palliative radiotherapy for skeletal pain allowed Surgery More than 14 days since prior surgery No plans for surgery within the next 6 months Other Acute toxic effects of prior therapy (except for alopecia and neurotoxicity) must have resolved to grade 0, 1, or the patient's baseline Treatment-related neurotoxicity must have resolved to the patient's baseline, not to exceed grade 2 Chronic bisphosphonates for bone pain allowed only for maintenance doses More than 2 weeks since prior nonmyelosuppressive antimyeloma therapy More than 2 weeks since prior macrolide antibiotics No other concurrent investigational agents No concurrent macrolide antibiotics No concurrent participation in another treatment clinical study

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brostallicin<br> | Drug: brostallicin<br>* Patients receive brostallicin IV over 10-30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of brostallicin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Tumor Response Rate | • Determine the objective tumor response rate (confirmed complete response and confirmed partial response) of brostallicin in patients with recurrent or refractory multiple myeloma | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of brostallicin |  | 1 year | 
| Time to response |  | 1 year | 
| Duration of Response |  | 1 year | 
| Time to treatment failure |  | 1 year | 
| Time to tumor progression |  | 1 year | 
| Overall Survival |  | 1 year | 

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