Clinical trial NCT01835587: 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).
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Keywords: Acute myeloid leukemia,
myelodysplastic syndromes,
CC-486, oral Azacitidine,
transplantation,
allogeneic,
HSCT.
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2013-04-19
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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, the study doctor will do tests to see if the patient is suitable for this study. The patients meeting protocol-specified entry criteria will enter the treatment phase and be assigned to receive one of the oral azacitidine cohorts. 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, patients 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.

Eligibility criteria: Inclusion Criteria:

* 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

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

Primary outcomes:
measure: The Number of Participants With Dose Limiting Toxicities (DLT)
timeFrame: 2 months (Cycles 1 and 2)
measure: Number of Participants With Treatment Emergent Adverse Events (TEAE)
timeFrame: 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:
measure: Percentage of Participants With Graft Versus Host Disease During the Entire Course of the Study
timeFrame: 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
measure: Kaplan Meier Estimate of Time to Discontinuation From Treatment
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration Of CC-486 (AUC-t)
timeFrame: 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.
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to Extrapolated to Infinity (AUC-inf; AUC0-∞) Of CC-486
timeFrame: 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.
measure: Maximum Observed Concentration (Cmax) Of CC-486
timeFrame: 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.
measure: Time to Reach Maximum Concentration (Tmax) of CC-486
timeFrame: 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.
measure: Terminal Half-Life (T1/2) of CC-486
timeFrame: 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.
measure: Apparent Total Clearance (CL/F) of CC-486
timeFrame: 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.
measure: Apparent Volume of Distribution (Vz/F) of CC-486
timeFrame: 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.
measure: Percentage of Participants With Disease Relapse or Progression
timeFrame: Date of first dose of IP to disease relapse or progression; up to data cut-off date of 14 July 2017; median number of days assessed was 963.0 days for Cohort 1, 743.5 days for Cohort 2, 675.5 days for Cohort 3A and 559.0 days for Cohort 3.
measure: Time to Disease Recurrence/Progression
timeFrame: Date of allogenic HSCT to disease progression or relaopse; up to data cut-off date of 14 July 2017; median number of days assessed was 963.0 days for Cohort 1, 743.5 days for Cohort 2, 675.5 days for Cohort 3A and 559.0 days for Cohort 3.
measure: Overall Survival
timeFrame: Date of the allogeneic HSCT to death from any cause. Median number of days participants were assessed from first dose to last contact was 963.0 days for Cohort 1, 743.5 days for Cohort 2, 675.5 days for Cohort 3A and 559.0 days for Cohort 3.
measure: Kaplan Meier Estimate of Relapse-Free Survival (RFS)
timeFrame: Date of allogenic HSCT to date of progression or death from any cause; Median number of days participants were assessed from first dose to last contact was 963 days for Cohort 1, 674.8 days for Cohort 2, 577.5 days for Cohort 3A and 553 days for Cohort 3
Other outcomes:
Locations:
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center.
state: New York
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Houston
country: United States
facility: MD Anderson Cancer Center The University of Texas
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital UHB NHS Foundation Trust
Study officials:
affiliation: Celgene Corporation
name: Barry Skikne, M.D., FACP; FCP (SA)
role: STUDY_DIRECTOR
References:
citation: 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.