Arsenic Trioxide, Ascorbic Acid, Dexamethasone, and Thalidomide in Myelofibrosis/Myeloproliferative Disorder

A Phase II Trial of Combination Therapy With Thalidomide, Arsenic Trioxide, Dexamethasone, and Ascorbic Acid (TADA) in Patients With Chronic Idiopathic Myelofibrosis or Overlap Myelodysplastic/Myeloproliferative Disorders

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. Sometimes when chemotherapy is given, it does not stop the growth of cancer cells. The cancer is said to be resistant to chemotherapy. Giving ascorbic acid may reduce drug resistance and allow the cancer cells to be killed. Thalidomide may stop the growth of cancer cells by blocking blood flow to the cancer. Giving arsenic trioxide together with ascorbic acid, dexamethasone, and thalidomide may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving arsenic trioxide together with ascorbic acid, dexamethasone, and thalidomide works in treating patients with chronic idiopathic myelofibrosis or myelodysplastic or myeloproliferative disorders.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Leukemia; Chronic Myeloproliferative Disorders; Myelodysplastic/Myeloproliferative Diseases
• Intervention / Treatment: Dietary supplement: ascorbic acid; Drug: arsenic trioxide; Drug: dexamethasone; Drug: thalidomide

Detailed Description

OBJECTIVES:

Primary

• Evaluate the efficacy (in terms of response rate) of arsenic trioxide, ascorbic acid, dexamethasone, and thalidomide in patients with chronic idiopathic myelofibrosis or myelodysplastic/myeloproliferative disorders.

Secondary

• Determine the rate of disease progression or progression to acute leukemia in patients treated with this regimen.
• Assess improvement in bone marrow pathology (including degree of fibrosis, percentage of blasts, and resolution of cytogenetic abnormalities) in patients treated with this regimen.
• Determine time to response in patients treated with this regimen.
• Determine the reduction of spleen size in patients treated with this regimen.
• Measure clinical responses and quality of life in subgroups treated with this regimen.
• Determine the safety of this regimen in these patients.

OUTLINE: This is an open-label, multicenter study.

Patients receive arsenic trioxide IV over 1-2 hours for 5 days and oral ascorbic acid once daily for 5 days during week 1. Patients then receive arsenic trioxide and ascorbic acid twice a week in weeks 2-12. Patients also receive oral dexamethasone once daily for 5 days in weeks 1, 5, 9, and 12 and oral thalidomide once or twice daily in weeks 1-12. Courses repeat every 12 weeks in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline and after every course.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center
    • Cleveland, Ohio, United States, 44106-5065
      • Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Chronic idiopathic myelofibrosis or myelodysplastic/myeloproliferative disorders (MDS/MPD), including the following subtypes:

  • Chronic idiopathic myelofibrosis (with extramedullary hematopoiesis)
  • Chronic myelomonocytic leukemia (CMML)
  • Atypical chronic myeloid leukemia

  • MDS/MPD disease, unclassifiable

    • MDS with ≥ 2+ fibrosis present in the bone marrow
    • Patients with MPD must be negative by fluorescent in situ hybridization (FISH) for the BCR/ABL fusion gene

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Life expectancy of at least 3 months
• Platelet count > 10,000/mm³
• Bilirubin ≤ 2.5 times upper limit of normal (ULN)
• SGOT and SGPT ≤ 2.5 times ULN
• Creatinine ≤ 1.5 times ULN
• Potassium ≥ 4.0 mEq/dL (supplemental electrolytes allowed)
• Magnesium > 1.8 mg/dL (supplemental electrolytes allowed)

• Absolute QTc interval < 460 msec

  • Patients who have a QT > 460 after electrolyte repletion and discontinuation of other unessential QT-prolonging drugs will be excluded
• Negative pregnancy test
• Women of childbearing potential must use medically acceptable birth control (two methods of birth control or at least one highly active method and one additional effective method), starting 4 weeks prior to starting thalidomide, all through thalidomide therapy, and for 4 weeks after discontinuing thalidomide
• Male patients with reproductive potential must use a latex condom every time they have sex with a woman from the time that they start taking thalidomide, all through thalidomide therapy, and for 4 weeks after discontinuing thalidomide
• No sperm or blood donation during study treatment
• Must be willing and able to comply with the FDA-mandated System for Thalidomide Educational Prescribing and Safety (S.T.E.P.S™) program
• No other serious medical condition, laboratory abnormality, or psychiatric illness that, in the view of the treating physician, would place the patient at an unacceptable risk if he or she were to participate in the study or would prevent that person from giving informed consent
• No preexisting neurotoxicity/neuropathy ≥ grade 2
• Not pregnant or nursing
• No cardiac conduction defects
• No unstable angina
• No myocardial infarction within the past 6 months
• No congestive heart failure of any cause
• No New York Heart Association class II or greater
• No other significant underlying cardiac dysfunction
• No prior malignancy in the 3 years before treatment in this study (other than curatively treated carcinoma in situ of the cervix or nonmelanoma skin cancer)

• No sulfa allergy that would interfere with administration of trimethoprim sulfamethoxazole prophylaxis

  • Patients with sulfa allergies who could instead receive pentamidine prophylaxis also will be excluded
  • Patients with sulfa allergies who can instead receive atovaquone may be included

PRIOR CONCURRENT THERAPY:

• At least 4 weeks since prior investigational or approved therapy for this disease
• No growth factors within 1 week of study enrollment
• No other concurrent cytotoxic drugs or other investigational agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate at 6 months	Patients with any improvement in disease status (hematologic improvement or partial remission for patients with higher risk disease) may continue on study until a major response or complete remission occurs. Study visits will occur weekly for the first four weeks, then every four weeks, for each cycle. Laboratory monitoring to assess hematological parameters will occur weekly for the first four weeks, then every four weeks, for each cycle.	at 6months of therapy and followed for at least 4 weeks after

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bone marrow response at 6 months	Bone marrow aspirate / biopsy for morphology and blast count, iron stain and cytogenetics.	at 6 months
Spleen size at 12 weeks	Ultrasound of the spleen	at 12 weeks
Quality of life	Patients will complete the FACT-An questionnaire every 12 weeks.	every 12 weeks

Collaborators and Investigators

• Sponsor: Case Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start: October 1, 2005
• Primary Completion (Actual): September 1, 2007
• Study Completion (Actual): October 1, 2007

Study Registration Dates

• First Submitted: January 10, 2006
• First Submitted That Met QC Criteria: January 10, 2006
• First Posted (Estimate): January 11, 2006

Study Record Updates

• Last Update Posted (Actual): July 27, 2020
• Last Update Submitted That Met QC Criteria: July 23, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: chronic myelomonocytic leukemia; de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes; atypical chronic myeloid leukemia; myelodysplastic/myeloproliferative disease, unclassifiable; chronic idiopathic myelofibrosis
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Primary Myelofibrosis; Leukemia; Preleukemia; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protective Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Anti-Bacterial Agents; Leprostatic Agents; Vitamins; Antioxidants; Dexamethasone; Thalidomide; Arsenic Trioxide; Ascorbic Acid
• Other Study ID Numbers: CASE4Y04