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Phase II Study of Arsenic Trioxide in Patients with Multiple Myeloma

   

1.      OBJECTIVES

          a.       Primary Objectives

To determine the rate of response following treatment with Arsenic Trioxide (ATO) in-patients who have relapsed from or are refractory to conventional therapies for multiple myeloma.

b.      Secondary Objectives

To determine the rates of overall and relapse free survival, the pharmacokinetic profile of ATO during cycle 1 (in selected patients), and the safety profile of ATO.

 

  1. BACKGROUND AND RATIONALE

   

    1. Mechanism of action:

  Inorganic arsenic trioxide and the organic arsenical, melarsoprol, were shown to inhibit growth and induce apoptosis in a variety of leukemic cell lines of lymphoid or myeloid origin including acute promyelocytic leukemia (APL) cells; adult T-cell leukemia cells; malignant lymphocytes; megakaryocytic leukemia cell lines; and malignant B cells.Similarly, ATO inhibited the growth and induced apoptosis in a variety of other myeloma cell lines, but not affecting T, myeloid or epithelial lines. ATO also reduced plasma cell differentiation in normal B cells. Melarsoprol caused a dose and time-dependent inhibition of growth and survival in the myeloma cell lines.  ATO and Melarsoprol inhibited viability and growth and induced apoptosis in plasma cell enriched preparations from the bone marrow or blood of patients in either the intramedullary or extramedullary stage of myeloma. Multiple myeloma cells can be refractory to presently available treatments.  The expression of a 170,000P-glycoprotein encoded by a multiple drug resistant (MDR) gene is associated with drug resistance.  Preliminary data showed that arsenic may be active against MDR-expressing cells, as evidenced by increased cell death in doxorubicin-resistant human leukemia and myeloma cells exposed to ATO and melarsoprol.

 

  1. Treatment Plan

   

    1. Trisenoxä (arsenic trioxide) injection (ATO) will be administered intravenously over 1-4 hours. 
    2. The treatment cycle will be every four weeks, with treatments 5 days a week during the first 2 weeks, and no study treatment during the last 2 weeks of each cycle.  Up to 6 cycles of treatment may be administered.

 

4.      Patient selection

  a.       Inclusion Criteria (all responses should be “yes” for numbers (1-11):  

1.        Confirmed diagnosis of multiple myeloma of Durie-Salmon stage II or III (i. e., excluding monoclonal gammopathy, indolent or smoldering myeloma.

2.       Current measurable disease based on serum and urine M protein and/or measurable plasmacytoma.

3.       History of < or equal to 3 prior treatment regimens (excluding focal radiation for symptom control).  These prior regimens must have been completed at least 28 days before entry into this study; and may have included no more than: 

1.       3 cytotoxic regimens

2.       1 high-dose cytotoxic regimen as part of stem cell transplant

4.       Age > 18 years.

5.       Karnofsky performance status of at least 70%.

6.       Serum creatinine of <2.5mg/dL.

7.       Serum bilirubin, SGPT, and SGOT < 2 times the upper limit of normal

8.       Life expectancy > 3 months.

9.       Negative pregnancy test (in women of childbearing potential).

10.   Commitment to use medically acceptable birth control for the duration of the study (both male and female patients with reproductive potential).

11.   Acceptable concurrent therapies include treatment with erythropoeitin if part of prior therapy, bisphosphonates (i.e Aredia), and focal radiation for treatment of disease symptoms.

 

b.      Exclusion Criteria( all responses must be “no” for answers (1-11)

1.       Pregnant or lactating women

2.       Pre-existing neurotoxitity/neuropathy of grade 2 or greater according to the NCI Common Toxicity Criteria Version 2.

3.       Absolute QT interval >460 msec in the presence of serum potassium and magnesium values within normal ranges.

4.       Reduced hematology values that are not secondary to multiple myeloma. 

5.       Concurrent treatment with cytotoxic chemotherapy, high-dose corticosteroids, broad field radiation, or any other investigational agents.

6.       Significant cardiac dysfunction

7.       Prior malignancy in the 5 years before treatment in this study.

8.       Uncontrolled diabetes.

9.       History of seizures (other than infantile febrile seizures)

10.   Active, serious infections not controlled by antibiotics.

11.   Inability or unwillingness to comply with the treatment protocol.

 

5.      Study Measurements

 

1.       Patients will undergo EKG, appropriate serum and urine electrophoresis,  immuno-typing of serum and urine within 48 hours to 5 days prior to the first dose of study drug; as well as during various phases of the treatment cycle.

2.       Bone marrow exam will be done prior to receiving the first dose (within 5 days), and after cycles 2, 4 and 6.

3.        Patients must have a clearly detectable and quantifiable monoclonal M- component in the serum or 24-hour urine collection. Radiologic imaging via MRI or Skeletal survey to document baseline disease will be done within 28 days prior to the first dose of the study drug

4.        Additionally, radiologic imaging, as clinically indicated, will be repeated every 6 cycles to assess the progression of lytic lesions if clinically indicated.

 

 

 
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