Homoharringtonine Plus Low-Dose Cytarabine in Treating Patients With Newly Diagnosed Chronic Myelogenous Leukemia in Chronic Phase

Study Overview
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Brief Summary
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Phase II trial to study the effectiveness of homoharringtonine plus low-dose cytarabine in treating patients who have newly diagnosed chronic phase chronic myelogenous leukemia. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the hematologic and cytogenetic response rate of newly diagnosed patients with BCR/ABL (+) chronic myelogenous leukemia (CML) treated with combined homoharringtonine (omacetaxine mepesuccinate) and low dose cytarabine. II. To estimate the toxicity of these two drugs given in combination in a cooperative group setting. SECONDARY OBJECTIVES: I. To assess duration of hematological response and incidence of hematological progression for all patients. II. To assess duration of cytogenetic response in patients continuing protocol therapy beyond the initial nine months. III. To use quantitative Southern blot monitoring of blood samples to monitor molecular response rates in patients entered onto CALGB treatment studies for CML. IV. To compare quantitative Southern blot results of blood samples with marrow cytogenetics at the time of complete molecular response. V. To use RT-PCR to monitor the frequency of residual disease in patients who have achieved a complete blood Southern blot and marrow cytogenetic response (elimination of BCR/ABL positivity by Southern blot and absence of the Philadelphia chromosome by cytogenetics). OUTLINE: Patients receive cytarabine and homoharringtonine concurrently by continuous intravenous infusion for 7 days. Courses repeat every 28 days. Patients receive a minimum of 9 courses of therapy in the absence of disease progression and unacceptable toxicity. Patients who are major cytogenetic responders at 9 months may continue therapy or switch to interferon. Minor cytogenetic responders are switched to interferon, and nonresponders are removed from therapy and given the option to switch to interferon. Patients are followed every 6 months for 10 years.

Official Title
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A Phase II Study of Newly Diagnosed Patients With BCR/ABL (+) Chronic Myelogenous Leukemia Treated With Combined Homoharringtonine (NSC #141633) and Low-Dose Cytarabine

Conditions
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Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Chronic Phase Chronic Myelogenous Leukemia

Intervention / Treatment
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* Drug: omacetaxine mepesuccinate
* Drug: cytarabine
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic diagnosis of chronic myelogenous leukemia (CML) in chronic phase; patients in either accelerated or blastic phases are not eligible; clonal cytogenetic evolution alone does not exclude patients Patients must meet one or more of the following criteria: Cytogenetically determined Philadelphia chromosome (Ph+) BCR/ABL protein detectable by immunoblotting Polymerase chain reaction (PCR) positive fusion transcripts for BCR/ABL BCR/ABL translocation present by fluorescence in situ hybridization (FISH) Registration within eight weeks of the diagnosis and confirmation of Ph+ or BCR/ABL+ CML No more than eight weeks of prior hydroxyurea therapy No previous therapy with homoharringtonine (HHT) No prior treatment for CML with agents other than hydroxyurea; thus, prior treatment for CML with agents such as interferon, busulfan or cytarabine will render patients ineligible Must not be a candidate for an early allogeneic bone marrow transplant; potential transplant candidates must be counseled about alternative donor transplants and must decline that treatment option ECOG performance status 0-2 Non-pregnant and non-nursing; treatment under this protocol would expose an unborn child to significant risks; women and men of reproductive potential should agree to use an effective means of birth control Bilirubin =< x upper limit of normal Creatinine =< 1.5 mg/dl

Ages Eligible for Study
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Minimum Age: 16 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: Treatment (omacetaxine mepesuccinate, cytarabine)<br>Patients receive cytarabine and homoharringtonine concurrently by continuous intravenous infusion for 7 days. Courses repeat every 28 days. Patients receive a minimum of 9 courses of therapy in the absence of disease progression and unacceptable toxicity. Patients who are major cytogenetic responders at 9 months may continue therapy or switch to interferon. Minor cytogenetic responders are switched to interferon, and nonresponders are removed from therapy and given the option to switch to interferon. | Drug: omacetaxine mepesuccinate<br>* Given IV<br>* Other names: homoharringtonine;Drug: cytarabine<br>* Given IV<br>* Other names: cytosine arabinoside;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete cytogenetic, major cytogenetic, and hematologic response rate | Two separate single-stage Fleming designs will be used to test hypotheses regarding the major cytogenetic response rate and the complete cytogenetic response rate. Calculated and presented with their 95% confidence intervals. | Up to 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity rates as assessed by Common Terminology Criterial version 2.0 |  | Up to 9 months | 
| Duration of hematological response | Described with Kaplan-Meier curves. | Up to 10 years | 
| Time to hematological progression | Described with Kaplan-Meier curves. | Up to 10 years |