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

NCT01835587 | Completed Phase 1 Results

• 1 other identifier: CC-486-AML-002
• Study Type: interventional
• Target: 31
• Locations: 2 countries
• Sites: 5

Brief Summary

The purpose of the study is to determine the maximal tolerated dose and schedule of CC-486, known as oral azacitidine, in patients with AML or MDS after allogeneic hematopoetic stem cell transplant (HSCT). HSCT is more frequently used in AML or 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. Oral azacitidine has significant activity in MDS and AML. Oral azacitidine has also demonstrated immunomodulatory activity in AML patients after allogeneic HSCT. An oral formulation of oral azacitidine provides a convenient route of administration and an opportunity to deliver the drug over a prolonged schedule.

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Keywords

Acute myeloid leukemia,; myelodysplastic syndromes,; CC-486, oral Azacitidine,; transplantation,; allogeneic,; HSCT.

Outcome Measures

Primary Outcomes (2)

• The Number of Participants With Dose Limiting Toxicities (DLT)

  A DLT included events that started within 28 days of the first dose of CC-486 in a 28-day cycle, constituted a change from baseline irrespective of outcome, as decided by the investigator to be related to CC-486 including: * ≥ Grade (GR) 3 nausea, diarrhea, or vomiting despite the use of medical support * Other significant nonhematologic toxicity of ≥ GR 3 considered not related to the disease or intercurrent illness • Absolute neutrophil count (ANC) \< 0.5 x 10\^9/L for \> 1 week despite growth factor support * Platelets \< 25 x 10\^9/L for \> 1 week despite transfusion support * Failure of recovery to an ANC ≥ 1.0 x 10\^9/L and/or platelets ≥ 50 x 10\^9/L with a hypocellular marrow by 56 days after the start of a cycle of CC-486 not due to relapse or progressive disease. The maximum tolerated dose is defined as the cohort delivering the highest dose in which no more than 33% of the evaluable subjects had a DLT The safety population included subjects who received ≥ 1 dose of CC-486

  2 months (Cycles 1 and 2)

• Number of Participants With Treatment Emergent Adverse Events (TEAE)

  A TEAE was defined as any AE with an onset date on or after the first dose of IP or any event already present that worsened in severity or increased in frequency after exposure to IP up to 28 days after the last dose. In addition, an AE that occurred beyond the timeframe and was assessed by the doctor as possibly related to IP was considered to be treatment-emergent. Severity was assessed using National Cancer Institute Common Toxicity Terminology Criteria for AEs (NCI CTCAE) version 4.0, where 1= Mild; 2= Moderate; 3= Severe; 4= Life-threatening; 5= Death related to AE. Serious AEs resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in a medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes above.

  From the first dose of investigational product (IP) up to 28 days after the last dose of IP. The median duration of exposure was 252.5 days overall; up to the final data cut off date of 14 July 2017

Secondary Outcomes (13)

• Percentage of Participants With Graft Versus Host Disease During the Entire Course of the Study

  From the first dose of CC-486 up to study discontinuation or death. Up to final data cut off date of 14 July 2017; up to 186 weeks and 4 days

• Kaplan Meier Estimate of Time to Discontinuation From Treatment

  From the first dose of IP dose to the date of discontinuation from IP; the overall median time to discontinuation of IP was 283.5 days

• Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration Of CC-486 (AUC-t)

  On Day 1, pharmacokinetic (PK) samples were collected at predose and over a 6-hour period following drug administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose; Cycle 1 or 2 until 6 hours after CC-486 administration.

• Area Under the Plasma Concentration-Time Curve From Time 0 to Extrapolated to Infinity (AUC-inf; AUC0-∞) Of CC-486

  On Day 1, PK samples were collected at predose and over the 6-hour period following CC-486 administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose at Cycle 1 or 2 until 6 hours after CC-486 administration.

• Maximum Observed Concentration (Cmax) Of CC-486

  On Day 1, PK samples were collected at predose and over the 6-hour period following CC-486 administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose at Cycle 1 or 2 until 6 hours after CC-486 administration.

Study Arms (1)

CC-486

EXPERIMENTAL

Dose of 150 mg, 200 mg, or 300 mg once daily (QD) for the first 7, 10, or 14 days of each 28-day cycle, starting 42-84 days after transplantation.

Drug: CC-486

Interventions

CC-486 DRUG

Cohorts of 3 to 6 subjects will be treated at escalating or de-escalating sequential dose levels until a preliminary Maximum Tolerated Dose (MTD) is identified.

Also known as: Oral Azacitdine

CC-486

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed Myelodysplastic Syndromes or Acute Myeloid Leukemia undergoing allogeneic hematopoietic stem cell transplantation 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 drug 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 10\^9/L without daily use of myeloid growth factor; and
• Platelet count 75 x 10\^9/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

You may not qualify if:

• 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

Sponsors & Collaborators

• Celgene: lead

Study Sites (5)

Memorial Sloan-Kettering Cancer Center.

New York, New York, 10065, United States

Location

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44106, United States

Location

MD Anderson Cancer Center The University of Texas

Houston, Texas, 77030, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109-4417, United States

Location

Queen Elizabeth Hospital UHB NHS Foundation Trust

Birmingham, B15 2TH, United Kingdom

Location

Related Publications (1)

• de Lima M, Oran B, Champlin RE, Papadopoulos EB, Giralt SA, Scott BL, William BM, Hetzer J, Laille E, Hubbell B, Skikne BS, Craddock C. CC-486 Maintenance after Stem Cell Transplantation in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes. Biol Blood Marrow Transplant. 2018 Oct;24(10):2017-2024. doi: 10.1016/j.bbmt.2018.06.016. Epub 2018 Jun 20.

  PMID: 29933073 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

cc-486

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Results Point of Contact

• Title: Anne McClain, Senior Manager
• Organization: Celgene Corporation

ClinicalTrialDisclosure@Celgene.com

888-260-1599

Study Officials

• Barry Skikne, M.D., FACP; FCP (SA)

  Celgene Corporation

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 17, 2013
• First Posted: April 19, 2013
• Study Start: October 25, 2013
• Primary Completion: November 13, 2016
• Study Completion: May 26, 2017
• Last Updated: November 20, 2018
• Results First Posted: November 20, 2018

Record last verified: 2018-10

Locations

GB (1); US (4)