Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Arsenic Trioxide Plus Vitamin C in Treating Patients With Recurrent or Refractory Multiple Myeloma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Treatment	Completed	Over 18	NCI	SCCC-20010 SCCC-NCI-43, NCI-43, NCT00006021, 43

Objectives

1. Determine the maximum tolerated dose of arsenic trioxide when administered with ascorbic acid in patients with recurrent or refractory multiple myeloma.
2. Determine the therapeutic efficacy of this treatment combination in these patients.
3. 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.

Entry Criteria

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

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

Patient Characteristics:

Age:

• Over 18

Performance status:

• Karnofsky 60-100%

Life expectancy:

• Not specified

Hematopoietic:

• WBC at least 2,000/mm³*
• Platelet count at least 50,000/mm³*

 [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

Expected Enrollment

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.

Outcomes

Disease response as measured by M protein quantitation and the percentage of plasma cell infiltration in bone marrow biopsies after every course

Toxicity as measured by CTCAE criteria

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.

Bahlis NJ, McCafferty-Grad J, Jordan-McMurry I, et al.: Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma. Clin Cancer Res 8 (12): 3658-68, 2002.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

University of Miami Sylvester Comprehensive Cancer Center - Miami

Kelvin Lee, MD, Protocol chair		Ph: 305-243-6636

Registry Information
Official Title		Phase I/II Trial of Arsenic Trioxide (As2O3) with Ascorbic Acid in the Treatment of Relapsed/Refractory Multiple Myeloma
Trial Start Date		2000-06-01
Registered in ClinicalTrials.gov		NCT00006021
Date Submitted to PDQ		2000-05-25
Information Last Verified		2006-04-27

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