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

Phase 1
2 Years
Not Enrolling
Chronic Myeloproliferative Disorders, Leukemia, Myelodysplastic/Myeloproliferative Diseases

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Trial Information

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



- 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.


- 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

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.

Inclusion Criteria


- Histologically confirmed leukemia or myeloproliferative disorders, including 1 of the

- 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


- 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


- 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

Type of Study:


Study Design:

Primary Purpose: Treatment

Principal Investigator

Judith E. Karp, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Sidney Kimmel Comprehensive Cancer Center


United States: Institutional Review Board

Study ID:

J0561 CDR0000456431



Start Date:

November 2005

Completion Date:

Related Keywords:

  • Chronic Myeloproliferative Disorders
  • Leukemia
  • Myelodysplastic/Myeloproliferative Diseases
  • 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)
  • Leukemia
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Myeloproliferative Disorders
  • Myelodysplastic-Myeloproliferative Diseases



Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland  21231-2410