The Use of Decitabine as Induction Therapy for Acute Myeloid Leukemia With Complex and/or Monosomal Karyotype

Acute myeloid leukemia (AML) is a heterogeneous group of diseases with distinct clinicopathologic features sharing in common an abnormal increase in myeloblasts in blood and bone marrow (BM). In about 5-10% patients, the myeloblasts exhibit chromosomal abnormalities (complex and/or monosomal karyotype, CK/MK*) that are associated with refractoriness to conventional chemotherapy and an extremely bad prognosis.

Standard induction chemotherapy for AML comprises daunorubicin and cytarabine, the "7+3" regimen. However, treatment is largely ineffective for CK/MK AML with a temporary clearance of blasts achieved in only 30-40% cases and the cumulative toxicities resulting from repeated courses of chemotherapy have significantly increased the morbidity and mortality risks in subsequent allogeneic BMT. Therefore, standard treatment is unsatisfactory and there is an unmet clinical need for more effective and less toxic induction regimen.

Both previous and recent studies showed that 10 day course of decitabine (20 mg/m2/day) induced remission in 70-100% patients with CK/MK AML, particularly those with TP53 mutations. In this study, patients with CK/MK AML will be treated with decitabine to induce remission. Bone marrow examination will be performed after each course until complete clearance of blasts or disease progression. Patients achieving CR/CRi (see below) will continue to receive 4 more courses, after which patients eligible for BMT and for whom donors are available will receive curative BMT. We reckon that the time it takes for 4 courses of decitabine will suffice for transplantation workup in HK. . Patients ineligible for BMT will continue to receive decitabine until leukemia progression. The response rate, leukemia free survival (LFS), overall survival (OS) and percentage of patients who can be bridged to BMT will be compared with historical 7+3 regimen control.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia; Complex Karyotype
• Intervention / Treatment: Drug: Decitabine

Detailed Description

This is an open-label interventional study to study the use of decitabine as induction therapy for acute myeloid leukemia with complex and/or monosomal karyotype.

Subjects will receive decitabine for every 28 days, until disease progression or a bone marrow transplantation is carried out, in the schedule as below:

Cycle 1:

Receive decitabine for 10 days

Cycle 2 and Cycle 3:

Based on the result of bone marrow examination, subjects may receive decitabine for 5 days or 10 days

Cycle 4 until disease progression:

Rdecitabine for 5 days. Subjects may also resume a 10 day treatment after cycle 6 if their physician judged as appropriate.

The drug will then be administrated intravenously.

Blood will be drawn every 7 days and bone marrow extraction would be done on Day 28 (+/- 3days) from the day 1 of each cycle of treatment for examination.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Crosby Lu, SC; Phone Number: 852-22554361; Email: khlu@hku.hk

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • The University of Hong Kong
    • Contact: Chunxiao Zhang, SC; Phone Number: 852-22554361; Email: chunxiao@hku.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult patients (age 18-65 years old) with CK/MK AML at diagnosis
2. De novo or secondary AML is allowed
3. ECOG performance ≤ 2
4. Subjects with adequate liver, pancreatic and renal function at screening as demonstrated by :Direct bilirubin < 2 x upper limit of laboratory normal (ULN) Alanine aminotransferase (ALT) < 2.5 x ULN MDRD-eGRF > 30ml/min/1.73m2
5. Negative serum / urine pregnancy test within 7 days before starting study treatment in women with childbearing potential.
6. Subjects with ability to understand the protocol and signed a written informed consent document prior to the participation of the study.

Exclusion Criteria:

1. Patients with CK/MK AML who have received standard induction chemotherapy before
2. Patients with active and uncontrolled infection.
3. Patients with concurrent severe and uncontrolled concomitant medical conditions that could cause unacceptable safety risk or compromise compliance with the protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: decitabine; Decitabine is a white to almost white powder for concentrate for solution for infusion. It is supplied as a lyophilized preparation in a clear colorless 20ml glass vial containing 50 mg decitabine. The concentrate should be aseptically reconstituted with 10 ml of water for injections. After reconstitution, the concentrate must be diluted within 15 minutes using cooled infusion fluids and completely administered to patients within 5 hours. The drug will then be administrated intravenously. Dosage 20 mg/m2 28-day course, for each course, receive decitabine for 10 days

Drug: Decitabine; Decitabine (trade name Dacogen®) is a cytidine deoxynucleoside analogue, which selectively inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation that can result in reactivation of tumor suppressor genes, induction of cellular differentiation or cellular senescence followed by programmed cell death.; Other Names: Dacogen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete remission (CR):	No increase in blasts in BM or PB (<5% of total nucleated cells), with absolute neutrophil count ≥ 1x109/L and platelet count ≥ 100 x109/L.	up to 16 weeks

Collaborators and Investigators

• Sponsor: The University of Hong Kong
• Collaborators: Janssen, LP

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2017
• Primary Completion (Anticipated): September 30, 2021
• Study Completion (Anticipated): December 28, 2021

Study Registration Dates

• First Submitted: February 22, 2017
• First Submitted That Met QC Criteria: March 9, 2017
• First Posted (Actual): March 15, 2017

Study Record Updates

• Last Update Posted (Actual): April 28, 2021
• Last Update Submitted That Met QC Criteria: April 26, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine
• Other Study ID Numbers: AML002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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