A Prospective Randomized Comparison of HDAC vs AD in the Induction Chemothrapy for AML.

A Prospective Randomized Comparison of High-dose Cytarabine an High-dose Daunorubicin in the Induction Chemothrapy for Acute Myeloid Leukemia

This trial is a single-center, non-blind, two-arm randomized prospective controlled trial to compare the effectiveness of two induction chemotherapy regimens (high-dose cytarabine plus daunorubicin [HDAC] vs. cytarabine plus high-dose daunorubicin [AD]) in acute myeloid leukemia (AML). The primary hypothesis of the study is that AD is superior to HDAC in terms of event-free survival (EFS, time from registration to induction failure, relapse, or death).

Study Overview

• Status: Unknown
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: High dose Cytarabine; Drug: Cytarabine; Drug: Hign dose Daunorubicin

Detailed Description

• Induction chemotherapy

  • Arm I [HDAC]: cytarabine 3.0 g/m2 q12hr 3-hour iv infusion on days 1, 3, 5 plus daunorubicin 45 mg/m2/day continuous iv infusion for 3 days (D1-3).
  • Arm II [AD]: cytarabine 200 mg/m2/day continuous iv infusion for 7 days (D1-7) plus daunorubicin 90 mg/m2/day continuous iv infusion for 3 days (D1-3).
• Interim bone marrow examination Interim bone marrow aspiration and biopsy will be done between 14 and 21 days after start of induction chemotherapy. If bone marrow has blasts < 10%, no additional chemotherapy will be given until the recovery of blood counts (absolute neutrophil counts rise over 1,000/μL and platelet counts over 100,000/μL) or post-induction day 35, when bone marrow examination will be repeated to evaluate CR. After the marrow examination, re-induction course will be given. If interim bone marrow examination shows persistent leukemia (blasts ≥ 10%), re-induction course could be given. Patients who did not attain CR after the re-induction chemotherapy will be eliminated from the study.

• Re-induction chemotherapy

  • Cytarabine 200 mg/m2/day iv infusion for 5 days (D1-5) plus daunorubicin 45 mg/m2/day iv infusion for 2 days (D1-2) Post-remission consolidation chemotherapy
  • Adverse risk group: up to 3 courses of intermediate-dose cytarabine (1.0 g/m2/day iv for 5 days [D1-5]) plus etoposide (150 mg/m2/day iv for 3 days [D1-3])
  • Favorable/intermediate risk group: up to 3 courses of high-dose cytarabine (3.0 g/m2/day q12 hr iv for 3 days [D1, 3, 5])
  • Autologous or allogeneic hematopoietic cell transplantation (HCT) can be performed based on the risk of relapse.
  • The bone marrow examination will be done after the completion of consolidation chemotherapy or before HCT.

• Study Type: Interventional
• Enrollment (Actual): 380
• Phase: Phase 3

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center, University of Ulsan College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years to 58 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Previously-untreated AML (≥ 20% blasts in bone marrow and/or peripheral blood)
• Age of 15 years or older, 60 years or younger
• Adequate performance status (Karnofsky score of 50 or more)
• Adequate hepatic and renal function (AST, ALT, and bilirubin < 2.5 x upper normal limit and creatinine < 2.0 mg/dL & creatinine clearance ≥ 50 mL/min). Elevation of AST or ALT due to hepatic infiltration of leukemic cells will be permitted.
• Adequate cardiac function (left ventricular ejection fraction ≥45% on heart scan or echocardiogram)
• Signed informed consent

Exclusion Criteria:

• Patients with history of chemotherapy for leukemia or cytarabine and anthracycline treatment for any malignancy. Hydroxyurea for reduction of leukemic cell burden before induction chemotherapy will be permitted.
• Patients with acute promyelocytic leukemia
• Patients with blast crisis of chronic myeloid leukemia
• Patients with central nervous system (CNS) leukemia or granulocytic sarcoma without bone marrow involvement
• Presence of uncontrolled and/or severe medical condition (infection, bleeding, cardiovascular disease including myocardial infarction within previous 6 months.)
• Nursing women, pregnant women, women of childbearing potential who do not want adequate contraception
• Patients with a diagnosis of prior malignancy unless disease-free for at least 5 years following therapy with curative intent (except curatively treated nonmelanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High-dose cytarabine; High-dose cytarabine 3.0 g/m2 q12hr 3-hour iv infusion on days 1, 3, 5 plus daunorubicin 45 mg/m2/day continuous iv infusion for 3 days (D1-3).	Drug: High dose Cytarabine; High dose Cytarabine 3.0 g/m2 q12hr 3-hour iv infusion on days 1, 3, 5 plus daunorubicin 45 mg/m2/day continuous iv infusion for 3 days (D1-3).; Other Names: HDAC
Experimental: high-dose daunorubicin; cytarabine 200 mg/m2/day continuous iv infusion for 7 days (D1-7) plus high-dose daunorubicin 90 mg/m2/day continuous iv infusion for 3 days (D1-3).	Drug: Cytarabine; cytarabine 200 mg/m2/day continuous iv infusion for 7 days (D1-7); Other Names: AD; Drug: Hign dose Daunorubicin; Hign dose Daunorubicin 90 mg/m2/day continuous iv infusion for 3 days (D1-3).; Other Names: AD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of relapse	defined for all patients achieving CR; measured from the date of CR achievement until the date of relapse; patients not known to have relapsed are censored on the date they were last examined; patients who died without relapse are counted as a competing cause of failure	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival	Defined for all patients; measured from the starting date of registration to the date of induction treatment failure, or relapse from CR, or death from any cause; patients not known to have any of these events are censored on the date they were examined	3years
Overall survival	Defined for all patients; measured from the starting date of registration to the date of death from any cause-patients not known to have died at last follow-up are censored on the date they were last known to be alive	3years

Collaborators and Investigators

• Sponsor: Asan Medical Center
• Investigators: Principal Investigator: Je-Hwan Lee, MD, Asan Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2018
• Primary Completion (Anticipated): December 31, 2020
• Study Completion (Anticipated): December 31, 2020

Study Registration Dates

• First Submitted: April 4, 2018
• First Submitted That Met QC Criteria: April 16, 2018
• First Posted (Actual): April 25, 2018

Study Record Updates

• Last Update Posted (Actual): January 13, 2020
• Last Update Submitted That Met QC Criteria: January 8, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cytarabine; Daunorubicin
• Other Study ID Numbers: AMC_HDAC vs AD in AML

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No