Gemcitabine and Mitoxantrone in Treating Patients With Relapsed Acute Myeloid Leukemia

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as gemcitabine and mitoxantrone, 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 gemcitabine together with mitoxantrone works in treating patients with relapsed acute myeloid leukemia.

Detailed Description
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OBJECTIVES: Primary Determine the complete response (CR) rate (CR and incomplete blood count recovery (CRi)) of patients with acute myeloid leukemia in first relapse treated with gemcitabine hydrochloride and mitoxantrone hydrochloride. Secondary Evaluate disease free and overall survival of patients with acute myeloid leukemia in first relapse treated with this particular chemotherapy regimen. Assess hematologic and non-hematologic toxicity associated with this regimen. Assess laboratory correlates of drug resistance in patients with relapsed acute myeloid leukemia. Assess the percentage of patients receiving subsequent bone marrow transplantation. OUTLINE: This is an open-label, multicenter study. Patients receive gemcitabine hydrochloride IV over 12 hours on day 1 and mitoxantrone hydrochloride IV over 30-60 minutes on days 1, 2, and 3. After completion of a single course of therapy, patients who achieve a complete response may receive 1 additional course of therapy at the discretion of the treating physician. After completion of study treatment, patients are followed periodically for survival. PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

Official Title
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A Phase II Study of Gemcitabine/ Mitoxantrone in Patients With Acute Myeloid Leukemia in First Relapse

Conditions
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Leukemia

Intervention / Treatment
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* Drug: Gemcitabine Hydrochloride
* Drug: Mitoxantrone Hydrochloride


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Bone marrow examination or peripheral blood analysis confirming active acute myeloid leukemia by WHO criteria No M3 acute myeloid leukemia Not a candidate for allogenic bone marrow transplantation Patient must be in first relapse after having received induction chemotherapy Received 1 or 2 courses with remission lasting at least 1 month Patients with chloromas or leukemia cutis are eligible No evidence of leptomeningeal involvement PATIENT CHARACTERISTICS: Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 Liver enzymes (total bilirubin, aspartate aminotransferase (AST) and ALT) ≤ 2.5 times the upper limits of normal Liver enzymes ≥ 2.5 are acceptable if physician documents that it is secondary to the disease Serum creatinine ≤ 3 mg/dL No poorly controlled medical conditions that would seriously complicate compliance with this study No other active primary malignancy other than carcinoma in situ of the cervix or basal cell carcinoma of the skin No New York Heart Association grade III or IV cardiac problems, defined as congestive heart failure or myocardial infarction within 6 months prior to start of study Pregnant or nursing women are ineligible Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after study participation No documented history of human immunodeficiency virus (HIV) infection No history of chronic liver disease Ejection fraction ≥ 45% No significant history of non-compliance to medical regimens or inability to give reliable informed consent PRIOR CONCURRENT THERAPY: Previous treatment related toxicities should be resolved to grade 1 or better No other investigational agents within 14 days prior to the start of study No chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to start of study No major surgery within 2 weeks prior to start of study At least two weeks must have elapsed since the conclusion of radiation therapy and the start of gemcitabine hydrochloride, provided the acute effects of radiation treatment have been resolved

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: Gemcitabine + Mitoxantrone<br>Gemcitabine Hydrochloride as administered as a continuous intravenous infusion (I.V.) at 10mg/m^2/minute for 12 hours, starting on Day 1. Mitoxantrone Hydrochloride was given at a dose of 12mg/m^2/day I.V. on days 1, 2, and 3. | Drug: Gemcitabine Hydrochloride<br>* 10 mg/m2/ min IV for 12 hours<br>* Other names: Gemcitabine;Drug: Mitoxantrone Hydrochloride<br>* 12 mg/m2/day IV (administer over 30-60 minutes) on Day 1, 2 and 3<br>* Other names: Mitoxantrone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate | Assumptions/ hypothesis: A Complete Response (CR) rate of 30% or less is unacceptable, and 50% or more is promising. A two-stage design will be used. Initially, 18 patients will be enrolled. If 5 or fewer achieve CR, the study will be stopped. Otherwise, an additional 22 patients will be accrued. Accrual was not halted while follow-up of the first 18 evaluable patients was under way. Therefore, 24 patients were enrolled. Four weeks is anticipated for observation for response. Only 5 patients (21%) achieved a CR and therefore, the study was terminated. Since response was assessed using the International Working Group criteria, a complete response was determined by Morphologic complete remission: A CR designation requires that the patient achieve the morphologic leukemia-free state and have an absolute neutrophil count of more than 1,000/μL and platelets of ≥ 100,000/μL, a cytogenic CR and a morphologic CR with incomplete blood count recovery (CRi). | 4 Weeks | 
| Duration of the First Complete Response |  | After a CR is achieved, patients are followed at 3 month intervals for disease progression and survival. If a patient has disease progression after achieving a CR, survival will be captured at 6 month intervals, typically for up to 5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free and Overall Survival |  | After a CR is achieved, patients are followed at 3 month intervals for disease progression and survival. If a patient has disease progression after achieving a CR, survival will be captured at 6 month intervals, typically for up to 5 years. | 
| Laboratory Correlates: Immunohistochemistry | Percentage of patients who had a moderate-strong (2-3+) expression of multidrug resistance (MDR) genes by immunohistochemistry. Multidrug resistance gene 1 (MDR1) Equilibrative nucleoside transporter 2(SLC29A2) | Baseline | 
| White Blood Cell Count at Time of Relapse |  | After a CR is achieved, patient will be followed at 3 month intervals for disease progression, typically for up to 5 years. | 
| Percentage of Patients Making it to Bone Marrow Transplant. | Assessing the number of patients who were able to have protocol treatment and have a bone marrow transplant after treatment. | After completion of protocol therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), recurrent adult acute myeloid leukemia, adult acute minimally differentiated myeloid leukemia (M0), adult acute myeloblastic leukemia without maturation (M1), adult acute myeloblastic leukemia with maturation (M2), adult acute myelomonocytic leukemia (M4), adult acute monoblastic leukemia (M5a), adult acute monocytic leukemia (M5b), adult erythroleukemia (M6a), adult pure erythroid leukemia (M6b), adult acute megakaryoblastic leukemia (M7)