Arsenic Trioxide and Gemtuzumab Ozogamicin in Treating Patients With Advanced Myelodysplastic Syndromes

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as arsenic trioxide and gemtuzumab ozogamicin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving arsenic trioxide together with gemtuzumab ozogamicin works in treating patients with advanced myelodysplastic syndromes.

Detailed Description
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OBJECTIVES: Primary Determine the efficacy of arsenic trioxide and gemtuzumab ozogamicin to achieve complete and partial remissions in patients with advanced myelodysplastic syndromes. Secondary Determine the efficacy of this regimen, in terms of 50% decrease in Red Blood Cell (RBC) transfusion requirements and change in hemoglobin concentration from baseline in patients treated with this regimen. Determine the platelet, neutrophil, bone marrow, and cytogenic response in patients treated with this regimen. Determine the response duration in patients treated with this regimen. Determine the quality of life of patients treated with this regimen. Determine the safety and toxicity of this regimen in these patients. OUTLINE: This is a multicenter, open-label study. Patients receive arsenic trioxide IV over 1 hour once daily on days 1-5 in week 1 and then twice weekly in weeks 2-12. They also receive gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 12 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline, every 12 weeks during study treatment, and then 4 weeks after the completion of study treatment. After completion of study treatment, patients are followed periodically. PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

Official Title
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A Phase II Trial of Combination Therapy With Arsenic Trioxide (Trisenox) and Gemtuzumab Ozogamicin (Mylotarg) for the Treatment of Adult Patients With Advanced Myelodysplastic Syndrome

Conditions
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Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: arsenic trioxide
* Drug: gemtuzumab ozogamicin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of one of the following hematologic malignancies: Myelodysplastic syndromes (MDS) of one of the following French-American-British (FAB) classifications: Refractory anemia with excess blasts (RAEB) (WHO RAEB-1) RAEB in transformation (RAEB-t) (RAEB-2) Chronic myelomonocytic leukemia (CMML) with > 5% myeloblasts (WHO CMML-2) International Prognostic Scoring System (IPSS) score of intermediate-2 or higher in the setting of > 5% myeloblasts Acute myeloid leukemia that has evolved from MDS Must not be a candidate for bone marrow transplantation as first-line therapy or must have declined bone marrow transplantation PATIENT CHARACTERISTICS: Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Life expectancy of at least 4 months Serum potassium ≥ 4.0 milliequivalent (mEq/dL) and serum magnesium ≥ 1.8 mg/dL (supplemental electrolytes allowed) Absolute corrected QT interval (QTc) interval < 460 msec No 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 Not pregnant or nursing Fertile patients must be willing to use adequate contraception (barrier method with spermicidal jelly, intrauterine device (IUD), or oral contraceptives) Negative pregnancy test Creatinine > 2.5 mg/dL serum glutamate oxaloacetate transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) > 1.5 times upper limit of normal Bilirubin > 2.0 mg/dL No history of malignancy within the past 3 years other than MDS except basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast Arsenic trioxide is contraindicated in patients who are hypersensitive to arsenic PRIOR CONCURRENT THERAPY: No prior bone marrow transplantation Must not receive another investigational or approved therapy for MDS within 4 weeks of study enrollment, including growth factors (within 1 week of study enrollment) No prior arsenic trioxide or gemtuzumab ozogamicin No other concurrent cytotoxic drugs or investigational agents

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATO + GO<br>Arsenic Trioxide 0.25 mg/kg D1-5 Week 1/Twice Weekly W2-12 + Gemtuzumab Ozogamicin 3 mg/m^2 D8 for 1 or 2 Cycles of 12 Weeks each | Drug: arsenic trioxide<br>* Arsenic trioxide will be administered at a dose of 0.25 mg/kg/day IV over 1-2 hours for 5 consecutive days during the first week. Subsequently, arsenic trioxide will be given at a dose of 0.25mg/kg/day twice a week for 11 additional weeks (weeks 2-12).<br>* Other names: Trisenox;Drug: gemtuzumab ozogamicin<br>* Gemtuzumab ozogamicin consists of a 2 hr infusion at a dose of 3mg/m2 on day 8 of each 12-week cycle. Gemtuzumab ozogamicin should be administered at a minimum of one hour after the completion of the arsenic trioxide infusion<br>* Other names: Mylotarg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete and Partial Remission Per the International Working Group (IWG) Criteria for Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML) | The null hypothesis to be tested was the percentage who will respond to combination arsenic trioxide (ATO) and gemtuzumab ozogamicin (GO) therapy is <10%. A total of >/= 9 responses observed in 30 evaluable patients was taken as evidence warranting further study of the regimen, provided the toxicity profile also appears favorable. The IWG Criteria standardizes the clinical responses in MDS and AML based upon hematologic improvement, quality of life and cytogenic improvement. These standardizations allow for the responses to be determined as either complete responses or partial responses. | at 12 weeks post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Patient's Overall Survival from date of enrollment to a minimum of three years for survival. | From date of enrollment to a minimum of three years for survival | 
| Tolerability | Tolerability of Therapy was assessed through use of the National Cancer Institute Common Toxicity Criteria (version 3.0). Treatment tolerability was determined based upon whether or not the physician determined therapy was in the patient's best interest, whether the patient wanted to continue therapy or not, whether patients discontinued treatment due to progressive disease, or whether patients discontinued treatment due to toxicity. | 12 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory anemia with excess blasts in transformation, refractory anemia with excess blasts, chronic myelomonocytic leukemia, secondary acute myeloid leukemia, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, de novo myelodysplastic syndromes