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A Phase I/II Study of Flavopiridol (NSC 649890, IND 46,211) in Timed Sequential Combination With Cytosine Arabinoside (Ara-C) and Mitoxantrone for Adults With Poor-Risk Acute Leukemias

Phase 1/Phase 2
18 Years
Not Enrolling
Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Myeloid Leukemia

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Trial Information

A Phase I/II Study of Flavopiridol (NSC 649890, IND 46,211) in Timed Sequential Combination With Cytosine Arabinoside (Ara-C) and Mitoxantrone for Adults With Poor-Risk Acute Leukemias


I. To determine the toxicities of escalating doses of flavopiridol administered in a timed
sequence with ara-C and mitoxantrone in adults with refractory or relapsed acute leukemias
or high-risk myelodysplasias (MDS).

II. To determine if flavopiridol administered in a timed sequence with ara-C and
Mitoxantrone will induce clinical responses in adults with refractory or relapsed acute
leukemias or MDS.

III. To determine if flavopiridol is directly cytotoxic to leukemic blasts in vivo.

IV. To determine if flavopiridol can recruit and synchronize residual leukemic blasts to
proliferate in vivo.

OUTLINE: This is a dose-escalation study of flavopiridol. (Phase I closed to accrual

Patients receive flavopiridol IV over 1 hour on days 1-3 and cytarabine IV continuously on
days 6-9 followed by mitoxantrone IV over 30-150 minutes on day 9. Patients achieving a
partial or complete response after the first course of therapy may receive an additional
course of therapy beginning 35 ± 7 days after blood count recovery.

Cohorts of 3-6 patients receive escalating doses of flavopiridol until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2
of 3 or 2 of 6 patients experience dose-limiting toxicity. (Phase I closed to accrual
effective 10/24/2003). Once the MTD is reached, additional patients are accrued to receive
flavopiridol at the recommended phase II dose.

Inclusion Criteria:

- Established diagnoses of poor-risk hematologic malignancies will be considered
eligible for this Phase I/II study

- Pathological confirmation of the diagnosis of AML or ALL

- ECOG performance status 0,1,2

- Patients must be able to give informed consent

- Female patients of childbearing age must have negative pregnancy test

- AST and ALT =< 2.5 x normal

- Alkaline phosphatase =< 2.5 x normal

- Bilirubin =< 1.5 x normal

- Serum creatinine =< 2.0 mg/dl

- Left ventricular ejection fraction must >= 45% by MUGA or Echocardiogram

- Acute Myelogenous Leukemia (AML)

- AML arising from MDS

- Secondary AML

- Relapsed or refractory AML, including primary induction failure

- Acute Lymphoblastic Leukemia (ALL)

- Relapsed or refractory ALL, including primary induction failure

- Patients who fail primary induction therapy or who relapse after achieving
complete remission (CR) are eligible if they have undergone no more than 3 prior
courses of induction/reinduction

- There should be an interval of at least 4 weeks from any previous intensive
chemotherapy before beginning flavopiridol, with the exceptions non-aplasia producing
treatments (i.e. hydroxyurea, interferon, imatinib, 6MP, thalidomide); patients
should have recovered completely from any treatment-related toxicities; patients may
have received hematopoietic growth factors previously, but must be off all growth
factors (including EPO, G-CSF, GM-CSF, IL-3, IL-11) for at least 4 days prior to
beginning flavopiridol

- Patients who have undergone stem cell transplantation (SCT), autologous or
allogeneic, are eligible provided that they are >= 4 weeks from stem cell infusion,
have no active GVHD, and meet other eligibility criteria

Exclusion Criteria:

- Hyperleukocytosis with >= 50,000 leukemic blasts/mm^3

- Active, uncontrolled infection

- Disseminated intravascular coagulation

- Active CNS leukemia

- Concomitant chemotherapy, radiation therapy or immunotherapy

- Intrinsic impaired cardiac function (MI within the preceding 3 months or history of
severe coronary artery disease, cardiomyopathy, CHF > Class II)

- History of congestive heart disease, or arrhythmia without regard to time, severity
or resolution

- Women who are pregnant or lactating will not be eligible for this trial, as the
investigational agent may be harmful to the developing fetus or nursing infant

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Dose-limiting toxicity (DLT) as assessed by NCI CTC version 2.0

Outcome Time Frame:

Up to 35 days

Safety Issue:


Principal Investigator

Judith Karp

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University


United States: Food and Drug Administration

Study ID:




Start Date:

February 2001

Completion Date:

Related Keywords:

  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Secondary Acute Myeloid Leukemia
  • Untreated Adult Acute Lymphoblastic Leukemia
  • Untreated Adult Acute Myeloid Leukemia
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid



Johns Hopkins University Baltimore, Maryland  21205