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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)


Phase 1
18 Years
N/A
Not Enrolling
Both
Multiple Myeloma and Plasma Cell Neoplasm

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Trial Information

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)


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.

Inclusion 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

Type of Study:

Interventional

Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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.

Outcome Time Frame:

Days 1, 4, 8 & 11 of each 21 day cycle

Safety Issue:

Yes

Principal Investigator

Jeffrey A. Zonder, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Barbara Ann Karmanos Cancer Institute

Authority:

United States: Federal Government

Study ID:

CDR0000445464

NCT ID:

NCT00258245

Start Date:

May 2005

Completion Date:

April 2008

Related Keywords:

  • Multiple Myeloma and Plasma Cell Neoplasm
  • stage II multiple myeloma
  • stage III multiple myeloma
  • refractory multiple myeloma
  • stage I multiple myeloma
  • Neoplasms
  • Leukemia, Plasma Cell
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Plasmacytoma

Name

Location

Barbara Ann Karmanos Cancer InstituteDetroit, Michigan  48201