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Arsenic Trioxide and Ascorbic Acid Combined With Bortezomib, Thalidomide, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma or Plasma Cell Leukemia

Primary Purpose

Multiple Myeloma and Plasma Cell Neoplasm

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
ascorbic acid
arsenic trioxide
bortezomib
dexamethasone
thalidomide
Aspirin
Sponsored by
Barbara Ann Karmanos Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multiple Myeloma and Plasma Cell Neoplasm focused on measuring stage II multiple myeloma, stage III multiple myeloma, refractory multiple myeloma, stage I multiple myeloma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 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 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

Sites / Locations

  • Barbara Ann Karmanos Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Bortezomib, AT, Thalidomide, Dexamethasone, Vit C, ASA

Arm Description

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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

Full Information

First Posted
November 22, 2005
Last Updated
April 25, 2013
Sponsor
Barbara Ann Karmanos Cancer Institute
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00258245
Brief Title
Arsenic Trioxide and Ascorbic Acid Combined With Bortezomib, Thalidomide, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma or Plasma Cell Leukemia
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 Type
Interventional

2. Study Status

Record Verification Date
April 2013
Overall Recruitment Status
Completed
Study Start Date
May 2005 (undefined)
Primary Completion Date
April 2008 (Actual)
Study Completion Date
April 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Barbara Ann Karmanos Cancer Institute
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma and Plasma Cell Neoplasm
Keywords
stage II multiple myeloma, stage III multiple myeloma, refractory multiple myeloma, stage I multiple myeloma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
5 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Bortezomib, AT, Thalidomide, Dexamethasone, Vit C, ASA
Arm Type
Experimental
Arm Description
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
Intervention Type
Dietary Supplement
Intervention Name(s)
ascorbic acid
Other Intervention Name(s)
All Day C CR, Ascot, C Complex, C-500, C-500-Gr, C-Time, Cecon, Cemill 1000, Cemill 500, Centrum Singles-Vitamin C, Cevi-Bid, N Ice with Vitamin C, Special C, Sunkist Vitamin C, Vicks Vitamin C Drops, Vitamin C TR
Intervention Description
Ascorbic Acid (Vit C)- 1000 mg IVPB after Arsenic Trioxide [ATO] days 1, 4, 8, 11
Intervention Type
Drug
Intervention Name(s)
arsenic trioxide
Other Intervention Name(s)
Trisenox®
Intervention Description
Arsenic Trioxide (Trisenox)- 0.10→0.15→0.25 mg/kg/dose IVPB days 1, 4, 8, 11
Intervention Type
Drug
Intervention Name(s)
bortezomib
Other Intervention Name(s)
Velcade®
Intervention Description
Bortezomib (Velcade)- 0.7→1.0 mg/m2 IVP days 1, 4, 8, 11
Intervention Type
Drug
Intervention Name(s)
dexamethasone
Other Intervention Name(s)
Dexasone, Decadron, Diodex, Hexadrol, Maxidex, Dexamethasone Sodium Phosphate, Dexamethasone Acetate
Intervention Description
Dexamethasone (Decadron)- 40 mg/days IVPB or PO d 1, 4, 8, 11
Intervention Type
Drug
Intervention Name(s)
thalidomide
Other Intervention Name(s)
Thalomid
Intervention Description
Thalidomide (Thalomid) - 50 mg/day by mouth (PO)
Intervention Type
Drug
Intervention Name(s)
Aspirin
Other Intervention Name(s)
Acuprin 81, Anacin Aspirin Regimen, Ascriptin, Ascriptin Enteric, Aspergum, Aspidrox, Aspir-Low, Aspir-Mox, Aspir-trin, Aspirtab, Bayer Aspirin, Bufferin, Buffex, Easprin, Ecotrin, Ecpirin, Empirin, Entaprin, Entercote, Fasprin, Genacote, Gennin-FC, Genprin, Halfprin, Magnaprin, Med Aspirin, Migralex, Miniprin, Minitabs, Norwich Aspirin, Ridiprin, Sloprin, St. Joseph Aspirin, Uni-Buff, Uni-Tren, Valomag, Zero-Order Release, Zorprin
Intervention Description
Aspirin - 325 mg by mouth (PO) every day
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
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
Title
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.
Description
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
Time Frame
At baseline and 1 hour after the first dose of Bortezomib in cycles 1, 2, and 3

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeffrey A. Zonder, MD
Organizational Affiliation
Barbara Ann Karmanos Cancer Institute
Official's Role
Study Chair
Facility Information:
Facility Name
Barbara Ann Karmanos Cancer Institute
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201-1379
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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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