Arsenic Trioxide and Ascorbic Acid Combined With Bortezomib, Thalidomide, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma or Plasma Cell Leukemia
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ClinicalTrials.gov Identifier: NCT00258245 |
Recruitment Status
:
Completed
First Posted
: November 24, 2005
Last Update Posted
: April 29, 2013
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RATIONALE: Drugs used in chemotherapy, such as arsenic trioxide and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Ascorbic acid may help arsenic trioxide work better by making cancer cells more sensitive to the drug. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Thalidomide may stop the growth of cancer cells by stopping blood flow to the cancer. Giving arsenic trioxide and ascorbic acid together with bortezomib, thalidomide, and dexamethasone may stop the growth of and kill more cancer cells.
PURPOSE: This phase I trial is studying the side effects and best dose of arsenic trioxide when given together with ascorbic acid, bortezomib, thalidomide, and dexamethasone in treating patients with relapsed or refractory multiple myeloma or plasma cell leukemia.
Condition or disease | Intervention/treatment | Phase |
---|---|---|
Multiple Myeloma and Plasma Cell Neoplasm | Dietary Supplement: ascorbic acid Drug: arsenic trioxide Drug: bortezomib Drug: dexamethasone Drug: thalidomide Drug: Aspirin | Phase 1 |
OBJECTIVES:
Primary
- Determine the dose-limiting toxicity of arsenic trioxide when given in combination with ascorbic acid, bortezomib, thalidomide, and dexamethasone, particularly in terms of sensory neuropathy, in patients with relapsed or refractory multiple myeloma or plasma cell leukemia.
Secondary
- Determine the overall response rate, complete response rate, and response duration in patients treated with the maximum tolerated dose of this regimen.
- Determine whether the addition of arsenic trioxide and ascorbic acid to the treatment regimen (beginning in course 2) increases NFKB inhibition in these patients during courses 2 and 3 compared to course 1.
OUTLINE: This is a multicenter, dose-escalation study of arsenic trioxide.
- Induction therapy: Patients receive bortezomib IV over 3-5 seconds and dexamethasone IV or orally on days 1, 4, 8, and 11 and oral thalidomide once daily on days 1-21 (course 1). For course 2 and all subsequent courses, patients receive arsenic trioxide IV over 1-2 hours, ascorbic acid IV over 15 minutes, bortezomib IV over 3-5 seconds, and dexamethasone IV or orally on days 1, 4, 8, and 11 and thalidomide once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who achieve a plateau in response proceed to maintenance therapy.
- Maintenance therapy: Patients receive oral dexamethasone every other day and oral thalidomide once daily 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 determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
PROJECTED ACCRUAL: A total of 24 patients will be accrued for this study.
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 5 participants |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | A Phase I Study of Arsenic Trioxide and Ascorbic Acid (ATO/AA) in Combination With Low Dose Velcade-Thalidomide-Dexamethasone (VTD) in Relapsed/Refractory Multiple Myeloma (MM) |
Study Start Date : | May 2005 |
Actual Primary Completion Date : | April 2008 |
Actual Study Completion Date : | April 2008 |

Arm | Intervention/treatment |
---|---|
Experimental: Bortezomib, AT, Thalidomide, Dexamethasone, Vit C, ASA
Bortezomib (Velcade)- 0.7→1.0 mg/m2 IVP d 1, 4, 8, 11; Arsenic Trioxide [AT] (Trisenox)- 0.10→0.15→0.25 mg/kg/dose IVPB days 1, 4, 8, 11; Thalidomide (Thalomid)- 50 mg/day by mouth (PO); Dexamethasone (Decadron)- 40 mg/d IVPB or by mouth (PO) d 1, 4, 8, 11; Ascorbic Acid (Vit C)- 1000 mg IVPB p Arsenic Trioxide (ATO) days 1, 4, 8, 11; Aspirin (ASA)- 325 mg by mouth (PO) every day
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Dietary Supplement: ascorbic acid
Ascorbic Acid (Vit C)- 1000 mg IVPB after Arsenic Trioxide [ATO] days 1, 4, 8, 11
Other Names:
Drug: arsenic trioxide
Arsenic Trioxide (Trisenox)- 0.10→0.15→0.25 mg/kg/dose IVPB days 1, 4, 8, 11
Other Name: Trisenox®
Drug: bortezomib
Bortezomib (Velcade)- 0.7→1.0 mg/m2 IVP days 1, 4, 8, 11
Other Name: Velcade®
Drug: dexamethasone
Dexamethasone (Decadron)- 40 mg/days IVPB or PO d 1, 4, 8, 11
Other Names:
Drug: thalidomide
Thalidomide (Thalomid) - 50 mg/day by mouth (PO)
Other Name: Thalomid
Drug: Aspirin
Aspirin - 325 mg by mouth (PO) every day
Other Names:
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- To determine if arsenic trioxide and ascorbic acid at doses up to 0.25 mg/mg/dose can be given in combination with reduced-dose dexamethasone, bortezomib and thalidomide without dose limiting toxicity, especially sensory neuropathies. [ Time Frame: Days 1, 4, 8 & 11 of each 21 day cycle ]
- Estimate the Overall Response Rate (ORR), Complete Response Rate (CRR), and Response Duration (RD) in patients treated with the Maximally Tolerated Dose (MTD) of this regimen. [ Time Frame: at cycle 2 and 6 weeks after ]
- Determine if addition of Arsenic Trioxide[AT]/Ascorbic Acid (Vit C)[AA] starting in cycle 2 of treatment increases NF-kappa-B [NFKB] inhibition in cycles 2 and 3 compared to cycle 1. [ Time Frame: At baseline and 1 hour after the first dose of Bortezomib in cycles 1, 2, and 3 ]Peripheral blood samples are to be obtained at baseline, and 1 hour after the first dose of Bortezomib in cycles 1, 2, and 3 for Pharmacodynamic studies

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Ages Eligible for Study: | 18 Years and older (Adult, Senior) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
DISEASE CHARACTERISTICS:
-
Histologically confirmed multiple myeloma (MM) or plasma cell leukemia meeting 1 of the following criteria:
- Relapsed or refractory disease after treatment with prior effective therapy
- Exhibited < a partial response to the last therapy
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Measurable disease, defined by 1 of the following:
- Serum M protein ≥ 1.0 g/dL
- Urine M-protein ≥ 500 mg/24 hours
- Plasmacytoma with bidimensional measurements on CT scan or MRI (each axis ≥ 1 cm)
- Previously treated with ≥ 1 induction chemotherapy regimen for MM
- No known CNS involvement by multiple myeloma
PATIENT CHARACTERISTICS:
Age
- 18 and over
Performance status
- Zubrod or SWOG 0-2 OR
- Karnofsky 60-100%
Life expectancy
- More than 12 weeks
Hematopoietic
- WBC ≥ 1,500/mm^3
- Absolute neutrophil count ≥ 1,000/mm^3
- Platelet count ≥ 80,000/mm^3
- Hemoglobin ≥ 8.5 g/dL
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No history of heparin-induced thrombocytopenia
- Low blood counts allowed if marrow is heavily infiltrated by multiple myeloma
Hepatic
- Bilirubin ≤ 1.5 times upper limit normal (ULN)
- AST and ALT ≤ 2.5 times ULN
Renal
- Creatinine ≤ 2.5 mg/dL
Cardiovascular
- QTc < 480 msec on EKG in the presence of serum potassium ≥ 4.0 mEq/dL and serum magnesium ≥ 1.8 mg/dL
- LVEF ≥ 55% by ECHO or MUGA
- No prior deep vein thrombosis, unless on concurrent anticoagulation
- No symptomatic congestive heart failure
- No unstable angina pectoris
- No history of ventricular arrhythmia
Other
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for 6 months after completion of study treatment
- No history of allergic reactions or severe adverse reactions attributed to compounds of similar chemical or biological composition to study drugs
- No other malignancy in the past 2 years except adequately treated nonmelanoma skin cancer or carcinoma in situ of the cervix
- No peripheral neuropathy ≥ grade 2
- No ongoing or active infection requiring IV antibiotics
- No psychiatric illness or social situation that would preclude study compliance
- No other uncontrolled illness
- Controlled HIV disease allowed as long as there are no associated comorbid complications
- No active peptic ulcer disease
- No other condition that would confer a high risk of bleeding complications
PRIOR CONCURRENT THERAPY:
Biologic therapy
- More than 4 weeks since prior thalidomide or lenalidomide for MM
- Prior autologous or allogeneic stem cell transplant for MM allowed
- Concurrent hematopoietic growth factors (e.g., epoetin alfa, filgrastim [G-CSF]) for MM allowed
Chemotherapy
- See Disease Characteristics
- More than 4 weeks since prior arsenic trioxide for MM
Endocrine therapy
- More than 4 weeks since prior corticosteroids for MM
Radiotherapy
-
More than 4 weeks since prior therapeutic radiotherapy (e.g., to plasmacytomas)
- Palliative radiotherapy for painful symptomatic lytic skeletal lesions allowed within the past 4 weeks
Surgery
- Not specified
Other
- More than 4 weeks since prior cytotoxic agents or other therapy (e.g., bortezomib) for MM
- More than 30 days (or 5 half-lives) since prior investigational agents
- Concurrent bisphosphonates for MM allowed
- No other concurrent anticancer therapy
- No other concurrent investigational agents

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00258245
United States, Michigan | |
Barbara Ann Karmanos Cancer Institute | |
Detroit, Michigan, United States, 48201-1379 |
Study Chair: | Jeffrey A. Zonder, MD | Barbara Ann Karmanos Cancer Institute |
Responsible Party: | Barbara Ann Karmanos Cancer Institute |
ClinicalTrials.gov Identifier: | NCT00258245 History of Changes |
Other Study ID Numbers: |
CDR0000445464 P30CA022453 ( U.S. NIH Grant/Contract ) WSU-D-2869 WSU-HIC-01705M1F |
First Posted: | November 24, 2005 Key Record Dates |
Last Update Posted: | April 29, 2013 |
Last Verified: | April 2013 |
Keywords provided by Barbara Ann Karmanos Cancer Institute:
stage II multiple myeloma stage III multiple myeloma refractory multiple myeloma stage I multiple myeloma |
Additional relevant MeSH terms:
Multiple Myeloma Neoplasms, Plasma Cell Plasmacytoma Neoplasms by Histologic Type Neoplasms Hemostatic Disorders Vascular Diseases Cardiovascular Diseases Paraproteinemias Blood Protein Disorders Hematologic Diseases Hemorrhagic Disorders Lymphoproliferative Disorders Immunoproliferative Disorders Immune System Diseases |
Vitamins Ascorbic Acid Dexamethasone acetate Aspirin, aluminum hydroxide, magnesium hydroxide drug combination Dexamethasone Aspirin Dexamethasone 21-phosphate Arsenic trioxide Bortezomib Thalidomide BB 1101 Micronutrients Growth Substances Physiological Effects of Drugs Anti-Inflammatory Agents |