Safety Study of Oral Azacitidine (CC-486) as Maintenance Therapy After Allogeneic Hematopoietic Stem Cell Transplantation in Subjects With Acute Myeloid Leukemia or Myelodysplastic Syndromes

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
Celgene ( Celgene Corporation ) Identifier:
First received: April 17, 2013
Last updated: January 21, 2016
Last verified: January 2016
The purpose of the study is to determine the maximal tolerated dose and schedule of CC-486 (also known as oral Azacitidine) in patients with AML or MDS after allogeneic HSCT. Allogeneic hematopoietic stem cell transplantation (HSCT) is more frequently used in Acute Myloid leukemia (AML) or Myelodysplastic Syndromes (MDS) as a potential curative therapy. However, disease recurrence/relapse and graft-versus-host disease (GVHD) remain the principal causes of fatal complications after transplantation. Azacitidine has significant activity in MDS and AML. Azacitidine has also demonstrated immunomodulatory activity in AML patients after allogeneic HSCT. An oral formulation of Azacitidine provides a convenient route of administration and an opportunity to deliver the drug over a prolonged schedule.

Condition Intervention Phase
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Drug: Oral Azacitidine
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1/2 Dose and Schedule Finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Oral Azacitidine (CC-486) in Subjects With Acute Myelogenous Leukemia and Myelodysplastic Syndromes After Allogeneic Hematopoietic Stem Cell Transplantation

Resource links provided by NLM:

Further study details as provided by Celgene:

Primary Outcome Measures:
  • Maximum tolerated dose [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]
    To determine the maximal tolerated dose of oral Azacitidine in participants with AML or MDS after allogeneic HSCT

Secondary Outcome Measures:
  • Adverse Events [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]
    Safety and tolerability of oral Azacitidine in this patient population

  • Acute and Chronic GVHD [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]
    Incidence of acute and chronic GVHD

  • Time to discontinuation from treatment [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]
    Duration of treatment until the occurrence of any of the events for treatment discontinuation

  • Pharmacokinetics - Cmax [ Time Frame: Day 1 of cycles 1 and 2 ] [ Designated as safety issue: No ]
    Maximum observed concentration in plasma

  • Pharmacokinetics - Tmax [ Time Frame: Day 1 of cycles 1 and 2 ] [ Designated as safety issue: No ]
    Time to first maximum concentration in plasma

  • Pharmacokinetics - AUC (0-t) [ Time Frame: Day 1 of cycles 1 and 2 ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve from time zero to the last quantifiable time point

  • Pharmacokinetics - AUC (0-∞) [ Time Frame: Day 1 of cycles 1 and 2 ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve from time zero to infinity

  • Pharmacokinetics - λz [ Time Frame: Day 1 of cycles 1 and 2 ] [ Designated as safety issue: No ]
    Terminal phase rate constant

  • Pharmacokinetics - t ½ [ Time Frame: Day 1 of cycles 1 and 2 ] [ Designated as safety issue: No ]
    Terminal half-life (t ½ )

  • Pharmacokinetics - CL/F [ Time Frame: Day 1 of cycles 1 and 2 ] [ Designated as safety issue: No ]
    Apparent total body clearance

  • Pharmacokinetics - Vd/F [ Time Frame: Day 1 of cycles 1 and 2 ] [ Designated as safety issue: No ]
    Apparent volume of distribution

  • Relapse Rate [ Time Frame: 30 months ] [ Designated as safety issue: No ]
    # of participants who relapse

  • Relapse Time [ Time Frame: 30 months ] [ Designated as safety issue: No ]
    Time to relapse

  • Overall survival at one year [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    # of participants who survive

  • Relapse-free survival (RFS) at one year [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    # of participants who survive without relapse

Enrollment: 30
Study Start Date: July 2013
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Oral Azacitidine
Dose of 150mg, 200mg, or 300mg once daily (QD) for the first 7, 10, or 14 days of each 28-day cycle, starting 42-84 days after transplantation.
Drug: Oral Azacitidine
Cohorts of 3 to 6 subjects will be treated at escalating or de-escalating sequential dose levels until a preliminary MTD is identified.

Detailed Description:
This is an open-label, multicenter study of oral Azacitidine in MDS or AML patients who have undergone allogeneic HSCT. The study consists of three phases: Screening, Treatment and Follow-up. During the Screening phase, which will take place within 4 weeks before starting oral Azacitidine, the study doctor will do tests to see if the patient is suitable for this study. The patient meeting protocol-specified entry criteria will enter the Treatment phase and be assigned to receive oral Azacitidine at 200 or 300 mg once daily (QD) for the first 7 or 14 days of each 28-day cycle. The dosing group of 200 mg QD on Days 1 to 7 will be evaluated first (ie, Cohort 1). In the event that unacceptable toxicity occurs in Cohort 1, then oral Azacitidine may be evaluated at lower dose levels (eg, 150 mg). If the dosing regimen is confirmed to be safe in Cohort 1, other cohorts will be evaluated sequentially. During the treatment phase, subjects will be monitored closely for safety and tolerability. Dosing interruption or delay, dose or schedule reduction, intra-subject dose/schedule escalation or re-escalation may occur on the basis of protocol-specified dosing adjustment guidelines. Safety will be monitored throughout the study at predetermined intervals and as clinically indicated by vital signs, physical examination, performance status, laboratory tests and evaluation of adverse events. The patient can continue to receive the study treatment for up to 12 months provided that they benefit from the study treatment and all protocol-specified criteria are met. However, the patient may receive the study treatment for less than 12 months due to adverse event, disease recurrence or progression. When the study treatment is discontinued, all patients who have received at least one dose of oral Azacitidine will be asked to see the study doctor for the Treatment Discontinuation visit. Thereafter, all patients discontinued from the study treatment will enter the Follow-up phase for safety and survival follow up.

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically confirmed (Myelodysplastic Syndromes) MDS or Acute Myeloid Leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (HSCT) with either peripheral blood or bone marrow as the source of hematopoietic stem cells

At the time of allogeneic HSCT:

  • No prior allogeneic HSCT; and
  • No more than 1 antigen mismatch at Human Leukocyte Antigen (HLA)-A, -B, -C, -DRB1 or -DQB1 locus for either related or unrelated donor; and
  • Bone marrow blast < 20% if MDS or ≤ 10% if AML; and
  • Peripheral blood blast ≤ 5%

Be able to start study therapy between 42 to 84 days following allogeneic HSCT

Post transplant bone marrow blast count ≤ 5% confirmed within 21 days prior to starting study therapy

Adequate engraftment within 14 days prior to starting study therapy:

  • Absolute Neutrophil count (ANC) ≥ 1.0 x 109/L without daily use of myeloid growth factor; and
  • Platelet count 75 x 109/L without platelet transfusion within one week.

Adequate organ function:

  • Serum aspartate transaminase (AST) and alanine transaminase (ALT) < 3 x upper limit of normal (ULN)
  • Serum bilirubin < 2 x ULN
  • Serum creatinine < 2 x ULN

Adequate coagulation (Prothrombin time [PT] ≤ 15 seconds, Partial thromboplastin time (PTT) ≤ 40 seconds, and/or International normalized ratio [INR] ≤ 1.5)

Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL at screening).

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

Must agree to follow protocol-specified pregnancy precautions

Exclusion Criteria:

  • Use of any of the following after transplantation and prior to starting oral Azacitidine:

    • Chemotherapeutic agents for chemotherapy
    • Investigational agents/therapies
    • Azacitidine, decitabine or other demethylating agents
    • Lenalidomide, thalidomide and pomalidomide

Active Graft-versus-host disease (GVHD) grade II or higher

Any evidence of gastrointestinal (GI) GVHD

Concurrent use of corticosteroids equivalent of prednisone at a dose > 0.5 mg/kg

Known active viral infection with Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV)

Active uncontrolled systemic fungal, bacterial or viral infection

Presence of malignancies, other than MDS or AML, within the previous 12 months

Significant active cardiac disease within the previous 6 months

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01835587

United States, New York
Memorial Sloan-Kettering Cancer Center.
New York, New York, United States, 10065
United States, Ohio
Case Western Reserve University Hospitals of Cleveland
Cleveland, Ohio, United States, 44106
United States, Texas
MD Anderson Cancer Center The University of Texas
Houston, Texas, United States, 77030
United States, Washington
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States, 98109-4417
United Kingdom
Queen Elizabeth Hospital UHB NHS Foundation Trust
Birmingham, United Kingdom, B15 2TH
Sponsors and Collaborators
Celgene Corporation
Study Director: Barry Skikne, M.D., FACP; FCP (SA) Celgene Corporation
  More Information

Responsible Party: Celgene ( Celgene Corporation ) Identifier: NCT01835587     History of Changes
Other Study ID Numbers: CC-486-AML-002 
Study First Received: April 17, 2013
Last Updated: January 21, 2016
Health Authority: United States: Food and Drug Administration
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Celgene:
Acute myeloid leukemia,
myelodysplastic syndromes,
CC-486, oral Azacitidine,

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Bone Marrow Diseases
Hematologic Diseases
Neoplasms by Histologic Type
Pathologic Processes
Precancerous Conditions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action processed this record on May 23, 2016