Clofarabine and Cyclophosphamide in Treating Patients With Relapsed or Refractory Acute Leukemia, Chronic Myelogenous Leukemia, or Myeloproliferative Disorders

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as clofarabine and cyclophosphamide, 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 I trial is studying the side effects and best dose of clofarabine and cyclophosphamide in treating patients with relapsed or refractory acute leukemia, chronic myelogenous leukemia, or myeloproliferative disorders.

Detailed Description
-----------------
OBJECTIVES: Primary Determine the feasibility and tolerability of administering clofarabine and fractionated cyclophosphamide in patients with relapsed or refractory acute leukemia, chronic myelogenous leukemia, or high-risk myeloproliferative disorders Determine the maximum tolerated dose of clofarabine and fractionated cyclophosphamide in these patients. Determine the toxic effects of these drugs in these patients. Secondary Obtain preliminary data of biologic and pharmacodynamic effects of this regimen on marrow and circulating leukemic blasts in these patients. OUTLINE: This is a dose-escalation study. Patients are stratified according to age (adult vs child). Patients receive cyclophosphamide IV over 2 hours on day 0. Patients then receive clofarabine IV over 2 hours and cyclophosphamide IV over 2 hours on days 1-3 and 8-10. Treatment with clofarabine and cyclophosphamide repeats every 28 days for at least 2 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of clofarabine and cyclophosphamide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 10 patients are treated at the MTD. After completion of study treatment, patients are followed periodically for 1 year. PROJECTED ACCRUAL: A total of 70 patients will be accrued for this study.

Official Title
-----------------
Phase I Dose-Escalation Trial of Clofarabine Followed by Escalating Doses of Fractionated Cyclophosphamide in Adults and Children With Relapsed or Refractory Acute Leukemias

Conditions
-----------------
Chronic Myeloproliferative Disorders, Leukemia, Myelodysplastic/Myeloproliferative Diseases

Intervention / Treatment
-----------------
* Drug: clofarabine
* Drug: cyclophosphamide


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed leukemia or myeloproliferative disorders, including 1 of the following: Acute myeloid leukemia (AML) of any subtype Treatment-related AML OR AML evolving from myeloproliferative disorders (MPD) or transformed from myelodysplastic syndrome Acute lymphocytic leukemia Acute progranulocytic leukemia Must not be eligible for arsenic or retinoic acid therapy Chronic myelogenous leukemia in accelerated phase or blast crisis High-risk MPD, including any of the following: Myelofibrosis Chronic myelomonocytic leukemia with 5%-19% blasts Relapsed or refractory juvenile myelomonocytic leukemia Relapsed and/or refractory disease with progressive disease since last therapy No more than 3 prior induction regimens with cytotoxic agents for adults Must be in second relapse for patients < 21 years of age PATIENT CHARACTERISTICS: ECOG performance status 0-2 (for adults) OR Lansky 50-100% (for pediatric patients) Bilirubin ≤ 1.5 mg/dL (may be elevated due to hemolysis in adult patients) AST and ALT ≤ 5 times upper limit of normal Creatinine ≤ 2.0 mg/dL (for adults) Normal renal function (for pediatric patients) Cardiac function normal as measured by MUGA scan or echocardiogram Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception during and for at least 6 months after completion of study treatment HIV negative No active graft-versus-host disease ≥ grade 2 No active, uncontrolled infection No fever No unstable CT scans of the lungs, sinuses, or abdomen within the past 4 weeks No arrhythmias (other than atrial flutter or fibrillation) requiring medication No dyspnea at rest or with minimal exertion No uncontrolled congestive heart failure No myocardial infarction within the past 3 months No history of severe coronary artery disease No other significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance or interfere with consent, study participation, follow up, or interpretation of study results PRIOR CONCURRENT THERAPY: Must have recovered from all acute toxic effects from prior treatment More than 30 days since prior investigational cytotoxic agents At least 3 days since prior azacitidine, thalidomide, hydroxyurea, imatinib mesylate, or interferon At least 1 week since prior growth factors except epoetin alfa More than 3 weeks since any other prior anticancer therapy No concurrent chemotherapy, radiotherapy, or immunotherapy No other concurrent anticancer investigational or commercial agents No routine prophylactic use of a colony-stimulating factor (filgrastim [G-CSF] or sargramostim [GM-CSF]) Therapeutic use of colony-stimulating factors may be considered at the discretion of the investigator No prolonged use of corticosteroids to prevent or treat emesis or as a chemotherapeutic agent

Ages Eligible for Study
-----------------
Minimum Age: 2 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: clofarabine|nan|
|Drug: cyclophosphamide|nan|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), 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, recurrent childhood acute myeloid leukemia, secondary acute myeloid leukemia, myelodysplastic/myeloproliferative disease, unclassifiable, accelerated phase chronic myelogenous leukemia, chronic idiopathic myelofibrosis, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, recurrent adult acute lymphoblastic leukemia, recurrent childhood acute lymphoblastic leukemia, acute undifferentiated leukemia, blastic phase chronic myelogenous leukemia, childhood chronic myelogenous leukemia, adult acute basophilic leukemia, adult acute eosinophilic leukemia, adult acute megakaryoblastic leukemia (M7), adult acute minimally differentiated myeloid leukemia (M0), adult acute monoblastic leukemia (M5a), adult acute monocytic leukemia (M5b), adult acute myeloblastic leukemia with maturation (M2), adult acute myeloblastic leukemia without maturation (M1), adult acute myelomonocytic leukemia (M4), adult acute promyelocytic leukemia (M3), adult erythroleukemia (M6a), adult pure erythroid leukemia (M6b), childhood acute basophilic leukemia, childhood acute monocytic leukemia (M5b), childhood acute eosinophilic leukemia, childhood acute erythroleukemia (M6), childhood acute megakaryocytic leukemia (M7), childhood acute minimally differentiated myeloid leukemia (M0), childhood acute myeloblastic leukemia with maturation (M2), childhood acute myeloblastic leukemia without maturation (M1), childhood acute myelomonocytic leukemia (M4), childhood acute monoblastic leukemia (M5a), childhood acute promyelocytic leukemia (M3)