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).

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Leukemia, Myeloid, Acute, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: CC-486


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CC-486<br>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<br>* 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.<br>* Other names: Oral Azacitdine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Graft Versus Host Disease During the Entire Course of the Study | Acute graft versus host disease generally occurs after allogeneic hematopoietic stem cell transplantation. It is a reaction of donor immune cells against host tissues. The 3 main tissues that acute GVHD affects are the skin, liver, and gastrointestinal tract. Chronic GVHD is scored per the National Institute of Health consensus conference grading system. Clinical manifestations of chronic GVHD include skin involvement resembling lichen planus or the cutaneous manifestations of scleroderma; dry oral mucosa with ulcerations and sclerosis of the gastrointestinal tract; and a rising serum bilirubin concentration. | 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 | The time to discontinuation from treatment was assessed as an estimate of treatment tolerability and was defined as the interval from the date of the first IP dose to the date of discontinuation from IP as indicated on the discontinuation from treatment Case Report Form page. Time to discontinuation from study treatment was analyzed using the Kaplan-Meier method where participants who did not discontinue were censored at the date of last visit. | 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) | Area under the plasma concentration-time curve from Time 0 to the time of the last quantifiable concentration, calculated by linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing. | 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 | Area under the plasma concentration-time curve from time 0 extrapolated to infinity, calculated as [AUCt + Ct/ λz]. Ct is the last quantifiable concentration. No AUC extrapolation was performed with unreliable λz. If AUC %Extrap was ≥25%, AUC inf was not reported. | 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 | Maximum observed plasma concentration, obtained directly from the observed concentration versus time data. | 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. | 
| Time to Reach Maximum Concentration (Tmax) of CC-486 | Time to Cmax, obtained directly from the observed concentration versus time data. | 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. | 
| Terminal Half-Life (T1/2) of CC-486 | Terminal phase half-life in plasma, calculated as [(ln 2)/λz]. t1/2 will only be calculated when a reliable estimate for λz can be obtained. | 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. | 
| Apparent Total Clearance (CL/F) of CC-486 | Apparent total clearance, calculated as [Dose/AUCinf]. | 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. | 
| Apparent Volume of Distribution (Vz/F) of CC-486 | Apparent volume of distribution, calculated as [(CL/F)/λz].Apparent volume of distribution, calculated as [(CL/F)/λz]. | 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. | 
| Percentage of Participants With Disease Relapse or Progression | Disease relapse was defined as the reappearance of > 5% blasts in the bone marrow that persists for at least 4 weeks. Disease progression was defined as the reappearance of > 10% of blasts in the bone marrow that persisted for at least 4 weeks. | 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. | 
| Time to Disease Recurrence/Progression | Time to disease relapse/progression was defined as the interval from the date of allogeneic HSCT to the date of treatment discontinuation or study discontinuation where reason for discontinuation is disease relapse or disease progression, or the date of disease progression recorded on the survival electronic Case Report Form page, whichever occurred first. Time to disease relapse/progression was analyzed using competing risk methods where death without documented relapse/progression was treated as a competing risk for relapse/progression. relapse/progression. | 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. | 
| Overall Survival | Overall Survival was defined as the time from the date of allogeneic hematopoietic stem cell transplantation to death from any cause. | 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. | 
| Kaplan Meier Estimate of Relapse-Free Survival (RFS) | Relapse-free survival was defined as the interval from the date of allogeneic HSCT to the date of first documented > 5% blasts in the bone marrow or death from any cause, whichever occurs first. Participants who were still alive and continued to have less than or equal to 5% blasts in the bone marrow or who were lost to follow-up were censored at the date of their last response assessment. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute myeloid leukemia,, myelodysplastic syndromes,, CC-486, oral Azacitidine,, transplantation,, allogeneic,, HSCT.