Leukemia
Conditions
Keywords
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)
Brief summary
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
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.
Interventions
DRUGGemcitabine Hydrochloride
10 mg/m2/ min IV for 12 hours
DRUGMitoxantrone Hydrochloride
12 mg/m2/day IV (administer over 30-60 minutes) on Day 1, 2 and 3
Sponsors
National Cancer Institute (NCI)
Duke University
The Cleveland Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate | 4 Weeks | 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). |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline | 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) |
| 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. | After completion of protocol therapy | Assessing the number of patients who were able to have protocol treatment and have a bone marrow transplant after treatment. |
Countries
United States
Participant flow
Recruitment details
Patients were treated at the Cleveland Clinic or Duke University Medical Center during the years 2005-2008.
Pre-assignment details
If \</= 5 of the initial 18 patients enrolled achieved a CR, the study would be stopped. Accrual was not halted while follow-up of the first 18 evaluable patients was under way. Therefore, 24 patients were enrolled. Only 5 patients (21%) achieved a CR and therefore, the study was terminated.
Participants by arm
| Arm | Count |
|---|---|
| Gemcitabine + Mitoxantrone 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.
Gemcitabine Hydrochloride: 10 mg/m2/ min IV for 12 hours
Mitoxantrone Hydrochloride: 12 mg/m2/day IV (administer over 30-60 minutes) on Day 1, 2 and 3 | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
Baseline characteristics
| Characteristic | Gemcitabine + Mitoxantrone |
|---|---|
| Age, Continuous | 51 years |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 24 |
| serious Total, serious adverse events | 24 / 24 |
Outcome results
Primary
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).
Time frame: 4 Weeks
Population: A total of 5 patients (21%) achieved a complete response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gemcitabine + Mitoxantrone | Complete Response Rate | 5 participants |
Primary
Duration of the First Complete Response
Time frame: 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.
Population: Only 5 patients had a complete response, therefore on 5 patients were analyzed for this measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gemcitabine + Mitoxantrone | Duration of the First Complete Response | 7.3 months |
Secondary
Disease-free and Overall Survival
Time frame: 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.
Population: 1 patient died on day 1 of protocol therapy (secondary to complications from AML).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gemcitabine + Mitoxantrone | Disease-free and Overall Survival | Patient death on Day 1 of Protocol Therapy | 1 participants |
| Gemcitabine + Mitoxantrone | Disease-free and Overall Survival | Patients dead >30 days post-tx, after relapse | 18 participants |
| Gemcitabine + Mitoxantrone | Disease-free and Overall Survival | Patients dead >30 days post-tx, no relapse | 1 participants |
| Gemcitabine + Mitoxantrone | Disease-free and Overall Survival | Patients alive with no evidence of disease relapse | 4 participants |
Secondary
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)
Time frame: Baseline
Population: 23 of 24 patients had available blocks for Immunohistochemical (IHC) analysis; Participants with the SLC29A2 Gene Expression (n=22)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gemcitabine + Mitoxantrone | Laboratory Correlates: Immunohistochemistry | Participants with GSTP1 Gene Expression | 70 percentage of participants |
| Gemcitabine + Mitoxantrone | Laboratory Correlates: Immunohistochemistry | Participants with SLC29A2 Gene Expression | 55 percentage of participants |
| Gemcitabine + Mitoxantrone | Laboratory Correlates: Immunohistochemistry | Participants with MRP1 Gene Expression | 43 percentage of participants |
| Gemcitabine + Mitoxantrone | Laboratory Correlates: Immunohistochemistry | Participants with LRP1 Gene Expression | 35 percentage of participants |
| Gemcitabine + Mitoxantrone | Laboratory Correlates: Immunohistochemistry | Participants with MDR1 Gene Expression | 22 percentage of participants |
Secondary
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.
Time frame: After completion of protocol therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gemcitabine + Mitoxantrone | Percentage of Patients Making it to Bone Marrow Transplant. | 8 percentage of Patients completed a BMT |
Secondary
White Blood Cell Count at Time of Relapse
Time frame: After a CR is achieved, patient will be followed at 3 month intervals for disease progression, typically for up to 5 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gemcitabine + Mitoxantrone | White Blood Cell Count at Time of Relapse | 3450 cells per microliter |