Arsenic Trioxide Plus Vitamin C 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 use different ways to stop cancer cells from dividing so they stop growing or die. Vitamin C may increase the effectiveness of arsenic trioxide by making cancer cells more sensitive to the drug. PURPOSE: Phase I/II trial to determine the effectiveness of arsenic trioxide plus vitamin C in treating patients who have recurrent or refractory multiple myeloma.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose of arsenic trioxide when administered with ascorbic acid in patients with recurrent or refractory multiple myeloma. Determine the therapeutic efficacy of this treatment combination in these patients. Determine the expression of MDR and Bcl-xL genes and the intracellular levels of GSH in these patients before and after this treatment regimen and assess whether these measures have prognostic value. OUTLINE: This is a multicenter, dose-escalation study of arsenic trioxide. Phase I: Patients receive arsenic trioxide IV over 1-4 hours and ascorbic acid IV over 5-10 minutes on days 1-5 weekly for 5 weeks. Treatment continues every 7 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of arsenic trioxide until the maximum tolerated dose (MTD) is reached. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase II: Patients receive the MTD of arsenic trioxide with ascorbic acid as outlined above. Patients are followed monthly for up to 5 years. PROJECTED ACCRUAL: A total of 31-43 patients (6-18 for phase I and 16-25 for phase II) will be accrued for this study within 2.5 years.

Official Title
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Phase I/II Trial of Arsenic Trioxide (As2O3) With Ascorbic Acid in the Treatment of Relapsed/Refractory Multiple Myeloma

Conditions
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Multiple Myeloma and Plasma Cell Neoplasm

Intervention / Treatment
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* Dietary Supplement: ascorbic acid
* Drug: arsenic trioxide


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed multiple myeloma M-protein by serum protein electrophoresis or urine protein electrophoresis Quantitative determination of immunoglobulin Bone marrow biopsy and aspirate with a plasma cell count greater than 10% Refractory or chemoresistant disease defined as failure to respond (less than 50% reduction in M protein level) or progression within 2 months after receiving at least 2 chemotherapy regimens including: Alkylating based regimen (melphalan) in combination with steroids (prednisone) or other chemotherapy regimens (e.g., vincristine, bleomycin, melphalan, cyclophosphamide, and prednisone or vincristine, carmustine, doxorubicin, and prednisone) Vincristine, doxorubicin, and dexamethasone (VAD) regimen Pulse therapy with high dose steroids alone High dose alkylating agent and autologous stem cell transplantation Allogeneic bone marrow transplantation Plateau phase defined as M protein in the serum or urine for more than 6 weeks despite response to prior therapy Must have received at least 2 of the chemotherapy regimens listed above or equivalent regimens Recurrent disease defined as progression more than 2 months after initial therapy and failure to respond (less than 50% reduction or progression in M protein levels) to 1 chemotherapy regimen listed above or other salvage regimens (e.g., high-dose cyclophosphamide or topotecan) Must have received VAD or other equivalent chemotherapy regimen Should be considered for autologous or allogenic transplantation Prior local radiotherapy allowed PATIENT CHARACTERISTICS: Age: Over 18 Performance status: Karnofsky 60-100% Life expectancy: Not specified Hematopoietic: WBC at least 2,000/mm^3* Platelet count at least 50,000/mm^3* NOTE: *Unless attributable to bone marrow infiltration by multiple myeloma Hepatic: Bilirubin less than 3 mg/dL Transaminases less than 2.5 times upper limit of normal (ULN) Renal: Creatinine less than 1.5 times ULN OR Creatinine clearance at least 60 mL/min Cardiovascular: No cardiac arrhythmias including recurrent supraventricular arrhythmia, any type of sustained ventricular arrhythmia, or conduction block (atrioventricular block grade II or III, left bundle branch block) Ejection fraction at least 30% No uncontrolled ischemic heart disease Other: Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception during and for 4 months after study HIV negative No grade 3 or higher neurological disorder, including seizure disorders No underlying medical condition that would preclude study No other active malignancy except adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix PRIOR CONCURRENT THERAPY: Biologic therapy: See Disease Characteristics Chemotherapy: See Disease Characteristics At least 2 weeks since prior chemotherapy Endocrine therapy: See Disease Characteristics Concurrent steroid treatment allowed except for primary treatment of myeloma Radiotherapy: See Disease Characteristics Concurrent local radiotherapy for pain or symptom control allowed provided the pain or symptom is not related to disease progression Surgery: Not specified Other: No other concurrent ascorbic acid supplements No other concurrent investigational drug or therapy Concurrent bisphosphonates allowed

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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

| Intervention/Treatment |
| --- |
|Dietary Supplement: ascorbic acid|nan|
|Drug: arsenic trioxide|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease response as measured by M protein quantitation and the percentage of plasma cell infiltration in bone marrow biopsies after every course |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity as measured by CTCAE criteria |  |  | 

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