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Clinical Trials List

Protocol NumberCC-486-AML-001
NCT Number(ClinicalTrials.gov Identfier)NCT01757535

2016-05-10 - 2022-05-31

Phase III

Terminated5

ICD-10C92.A0

Acute myeloid leukemia with multilineage dysplasia, not having achieved remission

ICD-10C92

Myeloid leukemia

ICD-9205.01

Acute myeloid leukemia, in remission

A phase 3, randomized, double-blind, placebo-controlled study to compare efficacy and safety of oral azacitidine plus best supportive care versus best supportive care as maintenance therapy in subjects with acute myeloid leukemia in complete remission.

  • Trial Applicant

    PPD DEVELOPMENT (HK) LIMITED

  • Sponsor

    Celgene Corporation

  • Trial scale

    Multi-Regional Multi-Center

  • Update

    2025/08/20

Investigators and Locations

Principal Investigator Su-Peng Yeh Division of Hematology & Oncology
China Medical University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Principal Investigator 王銘崇 Division of Hematology & Oncology
Kaoshiung Chang Gung Memorial Hospital of the C.G.M.F.

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Principal Investigator Tsai-Yun Chen Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Audit

None

Principal Investigator Jyh-Pyng Gau Division of Hematology & Oncology
Taipei Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Audit

None

Principal Investigator Su-Peng Yeh 未分科
China Medical University Hospital-Taipei

Co-Principal Investigator

Audit

None

Principal Investigator Wen-Chien Chou Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Audit

None

Condition/Disease

Acute Myeloid Leukemia (AML)

Objectives

Primary Objective The primary objective of the study is to demonstrate if maintenance therapy with oral azacitidine improves overall survival (OS) compared with placebo in subjects with AML, age ≥ 55 years, who have achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) after induction with intensive chemotherapy with or without consolidation chemotherapy. Secondary Objectives The secondary objectives of the study are:  To determine relapse-free survival (RFS);  To determine safety, tolerability; and  To determine the effect of oral azacitidine compared with placebo on health-related quality-of-life (HRQoL) and healthcare resource utilization.

Test Drug

Oral Azacitidine (CC-486)

Active Ingredient

Azacitidine

Dosage Form

oral tablet

Dosage

150 mg 及 200 mg

Endpoints

Primary Outcome Measures :
1. Kaplan-Meier (K-M) Estimate for Overall Survival (OS) [ Time Frame: Day 1 (randomization) up to data cut off date of 15 July 2019; median follow-up for OS estimated by the reverse K-M method was 41.2 months for all participants. ]
Overall survival was defined as time from randomization to death from any cause; participants surviving at the end of the follow-up period, or who withdraw consent, or who were lost to follow up were censored at the date last known alive.


Secondary Outcome Measures :
1. Kaplan-Meier Estimate of Relapse Free Survival (RFS) [ Time Frame: From day 1 (randomization) up to data cut off date of 15 July 2019; approximately 74 months ]
RFS was defined as the time from the date of randomization to the date of documented relapse or death from any cause, whichever occurred first. Participants who were still alive without documented relapse, or who were lost to follow-up or withdrew consent without documented relapse, were censored at the date of their last bone marrow assessment, prior to receiving any other therapy for AML.
Documented relapse was defined as the earliest date of the following:
o ≥ 5% bone marrow blasts (myeloblasts) from Central Pathology report, or
o appearance of > 0% blasts in the peripheral blood with a later bone marrow confirmation (bone marrow blast [myeloblasts] ≥ 5%) within 100 days, or
o at least 2 peripheral blasts ≥ 5% within 30 days.

2. Kaplan-Meier Estimate of Time to Relapse [ Time Frame: Day 1 (randomization) to the date of the data cut off date of 15 July 2019; approximately 74 months ]
Time to relapse was defined as the interval (in months) from the date of randomization to the date of documented relapse. Estimates of relapse rate were based on the cumulative incidence function from a competing risk analysis with death as a competing risk for relapse from complete remission (CR)/ complete remission with incomplete blood count recovery (CRi).
Documented relapse was defined as, the earliest date of the following:
o ≥ 5% bone marrow blasts (myeloblasts) from Central Pathology report, or
o appearance of > 0% blasts in the peripheral blood with a later bone marrow confirmation (bone marrow blast [myeloblasts] ≥ 5%) within 100 days, or
o at least 2 peripheral blasts ≥ 5% within 30 days.

3. Kaplan-Meier Estimates of Time to Discontinuation From Treatment [ Time Frame: From day 1 (randomization) up to data cut off date of 15 July 2019; approximately 74 months ]
Time to discontinuation from treatment was assessed and defined as the interval from the date of randomization to the date of discontinuation from study drug. Participants who were receiving treatment at the time of study closure were censored at the date of last visit. Estimates of relapse rate were based on the cumulative incidence function from a competing risk analysis with death as a competing risk for relapse from CR/ CRi.

4. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Day 1 (randomization) to the data cut off date of 15 July 2019; the median treatment duration was 11.6 months (range: 0.5 to 74.3 months) for the oral aza arm and 5.7 months (range: 0.7 to 68.5 months) for the placebo arm. ]
TEAEs include AEs that started between first dose date and 28 days after the last dose of study drug.
A serious adverse event (SAE) is:
o Death
o Life-threatening event
o Inpatient hospitalization or prolongation of existing hospitalization
o Persistent or significant disability or incapacity
o Congenital anomaly or birth defect
o Other important medical event The severity of AEs were assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0: Grade 1 (Mild): asymptomatic/mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 (Moderate): minimal, local or noninvasive intervention indicated; limiting age-appropriate activities of daily living. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care Grade 4: Life-threatening; urgent intervention indicated. Grade 5: Death due to AE.

5. Mean Change in the Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue Scale V 4.0) Score From Baseline [ Time Frame: Baseline to Cycle 2, Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1C3, C10D1, C11D1, C12D1, C13D1, C14D1, C15D1, C15D1, C16D1, C17D1, C18D1, C19D1, C20D1, C21D1, C22D1, C23D1, C24D1, C25D1 and continued on day 1 at each cycle through C33D1 ]
The functional assessment of chronic illness therapy (FACIT-Fatigue Scale V 4.0) is a subscale of the FACIT-F and has been validated in the oncology setting. The FACIT-Fatigue Scale is a short, 13-item, self-administered tool that measures the level of fatigue in an individual during usually daily activities over the past week. The level of fatigue is measured on a 5-point Likert scale (0 = not at all; 4 = very much. The scores range from 0 to 52, with higher scores indicating less fatigue. If there were missing items, but the participant answered at least 50% of the items, then subscores were prorated.

6. Mean Change in the European Quality of Life-Five Dimensions-Three Levels (EQ-5D-3L) Score From Baseline [ Time Frame: Baseline to Cycle 2, Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1C3, C10D1, C11D1, C12D1, C13D1, C14D1, C15D1, C15D1, C16D1, C17D1, C18D1, C19D1, C20D1, C21D1, C22D1, C23D1, C24D1, C25D1 and continued on day 1 at each cycle through C33D1 ]
The EQ-5D-3L is a self-administered questionnaire consisting of 5 questions, pertaining to specific health dimensions (ie, mobility, self-care, pain, usual activities, and anxiety/depression) and a health status scale. Each question has 3 levels of severity, corresponding to no problems, moderate problems and severe problems. Canadian population sample weights were used to derive health utility scores. A higher utility score represents a better health state. A clinically meaningful improvement or worsening was defined as at least 0.08 points of improvement or 0.10 points of worsening from baseline, respectively, for the EQ-5D-3L Health Utility Index. The instrument is scored using the United Kingdom (UK) index ranges from -0.594 to 1, where 0 equates to death and 1 equates to full health; -0.594 is considered 'worse than death'.

7. Percentage of Participants Experiencing a Clinically Meaningful Change (Improvement, No Change and Deterioration) in the FACIT-Fatigue Scale From Baseline [ Time Frame: Baseline to Cycle 2, Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1C3, C10D1, C11D1, C12D1, C13D1, C14D1, C15D1, C15D1, C16D1, C17D1, C18D1, C19D1, C20D1, C21D1, C22D1, C23D1, C24D1, C25D1 and continued on day 1 at each cycle through C33D1 ]
A clinically meaningful improvement or worsening was defined as at least 3 points of improvement or worsening from baseline, respectively, for FACIT-Fatigue. The functional assessment of chronic illness therapy (FACIT-Fatigue Scale V 4.0) is a subscale of the FACIT-F and has been validated in the oncology setting. The FACIT-Fatigue Scale is a short, 13-item, self-administered tool that measures the level of fatigue in an individual during usually daily activities over the past week. The level of fatigue is measured on a 5-point Likert scale (0 = not at all; 4 = very much. The scores range from 0 to 52, with higher scores indicating less fatigue. If there were missing items, but the participant answered at least 50% of the items, then subscores were prorated.

8. Percentage of Participants Experiencing a Clinically Meaningful Change (Improvement, No Change and Deterioration) in the EQ-5D-3L Scale From Baseline [ Time Frame: Baseline to Cycle 2, Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1C3, C10D1, C11D1, C12D1, C13D1, C14D1, C15D1, C15D1, C16D1, C17D1, C18D1, C19D1, C20D1, C21D1, C22D1, C23D1, C24D1, C25D1 and continued on day 1 at each cycle through C33D1 ]
The EQ-5D-3L is a self-administered questionnaire consisting of 5 questions, pertaining to specific health dimensions (ie, mobility, self-care, pain, usual activities, and anxiety/depression) and a health status scale. Each question has 3 levels of severity, corresponding to no problems, moderate problems and severe problems. Canadian population sample weights were used to derive health utility scores. A higher utility score represents a better health state. A clinically meaningful improvement or worsening was defined as at least 0.08 points of improvement or 0.10 points of worsening from baseline, respectively, for the EQ-5D-3L Health Utility Index. The instrument is scored using the United Kingdom (UK) index ranges from -0.594 to 1, where 0 equates to death and 1 equates to full health; -0.594 is considered 'worse than death'.

9. Time to Definitive Clinically Meaningful Deterioration for ≥ 2 Consecutive Visits as Measured Using the Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue Scale V 4.0) [ Time Frame: From day 1 (randomization) up to data cut off date of 15 July 2019; approximately 74 months ]
Clinically meaningful deterioration was defined as at least 3 points of deterioration from baseline for at least 2 consecutive visits for the FACIT--Fatigue. The FACIT-Fatigue Scale V 4.0) is a subscale of the FACIT-F and has been validated in the oncology setting. The FACIT-Fatigue Scale is a short, 13-item, self-administered tool that measures the level of fatigue in an individual during usually daily activities over the past week. The level of fatigue is measured on a 5-point Likert scale (0 = not at all to 4 = very much. The scores that range from 0 to 52, with higher scores indicating less fatigue. If there were missing items, but the participant answered at least 50% of the items, subscores were prorated.

10. Time to Definitive Clinically Meaningful Deterioration for ≥ 2 Consecutive Visits as Measured Using the EQ-5D HRQoL Scale [ Time Frame: From day 1 (randomization) up to data cut off date of 15 July 2019; approximately 74 months ]
Clinically meaningful deterioration was defined at least 0.10 point of deterioration from baseline for at least 2 consecutive visits for the EQ-5D Health Utility Index. The EQ-5D-3L is a self-administered questionnaire consisting of 5 questions, pertaining to specific health dimensions (ie, mobility, self-care, pain, usual activities, and anxiety/depression) and a health status scale. Each question has 3 levels of severity, corresponding to no problems, moderate problems and severe problems. Canadian population sample weights were used to derive health utility scores. A higher utility score represents a better health state. A clinically meaningful improvement or worsening was defined as at least 0.08 points of improvement or 0.10 points of worsening from baseline, respectively, for the EQ-5D-3L Health Utility Index. The EQ-5D-3L is scored using the UK index ranges from -0.594 to 1, where 0 equates to death and 1 equates to full health; -0.594 is considered 'worse than death'.

11. Healthcare Resource Utilization (HRU): Rate of Hospital Events Per Person Year [ Time Frame: Day 1 (randomization) to the date of the data cut off date of 15 July 2019; approximately 74 months ]
HRU is defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient. HRU is a key component to understand treatment costs and budget impact of new treatments from a provider perspective.

12. Healthcare Resource Utilization (HRU): Number of Days Hospitalized Per Person-Year [ Time Frame: Day 1 (randomization) to the date of the data cut off date of 15 July 2019; approximately 74 months ]
HRU is defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient. HRU is a key component to understand treatment costs and budget impact of new treatments from a provider perspective.

Inclution Criteria

Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Male or female subjects ≥55 years of age at the time of signing the ICD;
2. Newly diagnosed, histologically confirmed de novo AML or AML secondary to prior
myelodysplastic disease;
3. Should have undergone induction therapy with intensive chemotherapy with or without
consolidation therapy;
4. Should have achieved first CR/CRi status within 3 months prior to randomization, as
evidenced by the following;
5. ECOG performance status of 0, 1, 2 or 3 (Appendix B);
6. Adequate bone marrow function based on ANCs ≥ 0.5 x 109
/L and platelet counts
≥ 20,000 x 109
/L
7. Adequate organ function, defined as:
 Serum bilirubin ≤1.5 times the upper limit of normal (ULN);
 Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5
times the ULN;
 Serum creatinine ≤ 2.5 times the ULN;
8. FCBP* may participate, providing they meet the following conditions:
 Agree to practice abstinence; or
 Agree to use at least two effective contraceptive methods (oral, injectable, or
implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier
contraceptive with spermicide; or vasectomized partner) throughout the study, and for
3 months following the last dose of oral azacitidine; and
 Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at
screening; and
 Have a negative serum or urine pregnancy test (Investigator’s discretion) within 72
hours prior to starting study therapy in the double-blind treatment phase (note that the
screening serum pregnancy test can be used as the test prior to starting study therapy
in the double-blind treatment phase if it is performed within the 72-hour timeframe).
9. Male subjects with a female partner of childbearing potential must agree to practice
abstinence or to the use of a physician-approved contraceptive method throughout the
course of the study and avoid fathering a child during the course of the study and for 3
months following the last dose of azacitidine;
10. Understand and voluntarily sign an ICD prior to any study related
assessments/procedures are conducted;
11. Able to adhere to the study visit schedule and other protocol requirements;
12. Ability to swallow study medication.

Exclusion Criteria

Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Suspected or proven acute promyelocytic leukemia (FAB M3) based on morphology,
immunophenotype, molecular assay, or karyotype; or AML with previous hematologic
disorder such as chronic myeloid leukemia or myeloproliferative neoplasms, excluding
MDS;
2. AML associated with inv(16), t(8;21), t(16;16), t(15;17), or t(9;22) karyotypes or
molecular evidence of such translocations;
3. Prior bone marrow or stem cell transplantation;
4. Have achieved CR/CRi following therapy with hypomethylating agents;
5. Received therapy with hypomethylating agents for MDS and went on to develop AML
within four months of discontinuing the therapy with hypomethylating agents;
6. Proven central nervous system leukemia;
7. Candidate for allogeneic bone marrow or stem cell transplant at screening;
8. Diagnosis of malignant disease within the previous 12 months (excluding basal cell
carcinoma of the skin without complications, “in-situ” carcinoma of the cervix or breast,
or other local malignancy excised or irradiated with a high probability of cure);
9. Unstable angina, significant cardiac arrhythmia, or New York Heart Association (NYHA)
class 3 or 4 congestive heart failure (Appendix D);
10. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing
signs/symptoms related to the infection without improvement despite appropriate
antibiotics or other treatment);
11. Known active viral infection with known human immunodeficiency virus (HIV) or viral
hepatitis type B (HBV) or C (HCV);
12. Known or suspected hypersensitivity to azacitidine or mannitol;
13. Use of any other experimental drug or therapy within 28 days prior to Day 1 of Cycle 1;
14. Unwilling or unable to complete patient reported outcome assessments without assistance
or with minimal assistance from trained site personnel and/or caregiver;
15. Any condition, including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study;
16. Any significant medical condition, laboratory abnormality, or psychiatric illness that
would interfere or prevent the subject from participating in the study;
17. Any condition that confounds the ability to interpret data from the study;
18. Any condition causing an inability to swallow tablets;
19. Any condition that would impair absorption of the study medication (i.e. short gut,
malabso12rption syndrome)

The Estimated Number of Participants

  • Taiwan

    20 participants

  • Global

    460 participants

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