Clinical trial NCT00274820: Arsenic Trioxide, Ascorbic Acid, Dexamethasone, and Thalidomide in Myelofibrosis/Myeloproliferative Disorder
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Myeloproliferative Disorders
Leukemia
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Diseases
Keywords: chronic idiopathic myelofibrosis
chronic myelomonocytic leukemia
atypical chronic myeloid leukemia
myelodysplastic/myeloproliferative disease, unclassifiable
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
Lead sponsor: Case Comprehensive Cancer Center
Sponsor class: OTHER
First posted: 2006-01-11
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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. 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Response rate at 6 months
timeFrame: at 6months of therapy and followed for at least 4 weeks after
Secondary outcomes:
measure: Bone marrow response at 6 months
timeFrame: at 6 months
measure: Spleen size at 12 weeks
timeFrame: at 12 weeks
measure: Quality of life
timeFrame: every 12 weeks
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
state: Ohio
Study officials:
affiliation: The Cleveland Clinic
name: Mikkael A. Sekeres, MD, MS
role: STUDY_CHAIR
References: