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Phase I/II Clinical Study of Idarubicin Dose Intensification for Remission Induction Therapy in Acute Myeloid Leukemia Patients Age of 65 Years or Less


Phase 1/Phase 2
20 Years
65 Years
Open (Enrolling)
Both
Leukemia, Myeloid, Acute

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Trial Information

Phase I/II Clinical Study of Idarubicin Dose Intensification for Remission Induction Therapy in Acute Myeloid Leukemia Patients Age of 65 Years or Less


Up to nowadays, a standard induction therapy for acute myeloid leukemia(AML) has consisted
of cytarabine 100-200 mg per square meter of body surface area(BSA) per day continuous
infusion for 7 days with idarubicin 12 mg per square meter or daunorubicin 45 mg per square
meter of BSA per day for 3 days. This standard therapy induces a complete remission(CR) in
50-75% of young adults and 40-50% of older adults. Recently two cooperative groups
prospectively compared 45 mg per square meter of daunorubicin to 90 mg per square meter of
BSA. They reported high-dose daunorubicin, as compared with a standard dose one, resulted in
a significantly higher CR rate and improved overall survival(OS) up to age 65 without
additional toxic effects.

Daunorubicin has been more commonly used anthracycline; however, idarubicin has a longer
intracellular retention time and has shown more rapid clearance of marrow blasts. In the
early 1990, three prospectively randomized studies showed that a combined regimen of
idarubicin and cytarabine was superior to one of daunorubicin and cytarabine for the
induction therapy of AML in adults. When they compared daunorubicin 45-50 mg per square
meter with idarubicin 12-13 mg per square meter for induction therapy, there were no
significant differences in hematologic and non-hematologic toxicities, including cardiac
toxicity.

Phase I studies of idarubicin in patients with acute leukemia and chronic myelogenous
leukemia in blast crisis reported the dose-limiting toxicities(DLT) were stomatitis and
anorexia at the maximum tolerated dose(MTD) of 15 mg per square meter of BSA per day for 3
days. Based on the results of these studies, the investigators have generally administered
idarubicin 12 mg per square meter per day for 3 days for the remission induction therapy of
AML. Meanwhile Sanz et al. had administered idarubicin 12 mg per square meter per day for 4
days in patients with acute promyelocytic leukemia, and Tedeschi et al. had done a single
high-dose idarubicin 40 mg per square meter combined with high-dose cytarabine 3 g per
square meter per day for 5 days in patients with acute lymphoblastic leukemia, with no
significant increase of severe toxicity. The MTD of idarubicin should be reevaluated in the
treatment of acute leukemia, especially in the era of granulocyte colony-stimulating factor
and better supportive care available.

In this phase I study, idarubicin 12 mg per square meter of BSA per day for 3 days will be
given to three patients at the first stage and then the idarubicin dose will be increased by
3 mg per square meter of BSA each stage. The phase I study consists of 3 stages and the
idarubicin dose will be increased up to 18 mg per square meter of BSA per day for 3 days
unless DLTs do not develop in more than 33% of enrolled patients at each stage. In the
subsequent phase II study, the MTD being determined from the phase I study or 18 mg per
square meter of idarubicin will be given to the enrolled patients. There were three large
studies which enrolled a total of 942 previously untreated adult patients with AML and in
which idarubicin 12-13 mg per square meter of BSA per day for 3 days and cytarabine 100 mg
per square meter daily for 7 days were administered intravenously. Therefore, the
investigators can adopt them as historical control groups in terms of statistical
assessment.

In conclusion, the investigators desire to determine the safety and effectiveness of the
intensified dose of idarubicin in the treatment of acute myeloid leukemia through this phase
I and II study.


Inclusion Criteria:



- Patient has been fully informed, has complete understanding fo this study, and has
given voluntary written informed consent to comply with the protocol requirements.

- previously untreated de novo or secondary acute myeloid leukemia, including
biphenotypic leukemia

- age between 20 and 65 years

- adequate organ functions, unless these abnormalities are attributable to leukemia

- left ventricular ejection fraction > 45%

- serum creatinine < 1.5 x upper limit of normal

- total bilirubin < 1.5 x upper limit of normal

- alanine transferase and aspartate transferase < 2.5 x upper limit of normal if liver
function abnormality is attributable to underlying leukemia, ALT and AST < 5 x upper
limit of normal

- Eastern Cooperative Oncology Group performance status score of 0 to 2

Exclusion Criteria:

- hypersensitivity to the study drug

- any other malignancies within 3 years, except for cured non-melanoma skin cancer and
curatively treated in situ carcinoma of the cervix

- New York Heart Association class III or IV heart failure, severe uncontrolled cardiac
disease or myocardial infarction within the previous 6 months prior to the date of
consent

- incapable of giving voluntary written informed consent to comply with the protocol
requirements, which results from drug or alcohol intoxication, or neurological or
psychiatric disorders

- pregnant or breastfeeding

- recent chemotherapy within 4 weeks prior to this study treatment

- acute promyelocytic leukemia

- current or recent treatment with any other investigational medicinal product within
28 days prior to this study enrollment

- unsuitable for this study, in the investigator's opinion

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Maximum tolerated dose of idarubicin in the phase I study.

Outcome Time Frame:

Within 2 months after induction therapy in the phase I study.

Safety Issue:

Yes

Principal Investigator

Mark H Lee, M.D., Ph.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Konkuk University Medical Center

Authority:

South Korea: Korea Food and Drug Administration (KFDA)

Study ID:

AML-2011-01

NCT ID:

NCT01518556

Start Date:

July 2011

Completion Date:

December 2014

Related Keywords:

  • Leukemia, Myeloid, Acute
  • Idarubicin
  • Remission Induction
  • Maximum Tolerated Dose
  • Survival
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid

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