NCT01757535 · CITED IN SOURCE DOCUMENTS

Efficacy of Oral Azacitidine Plus Best Supportive Care as Maintenance Therapy in Subjects With Acute Myeloid Leukemia (AML) in Complete Remission

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2025-07-08

This study enrolled 472 participants, aged 55 or older, with a diagnosis of de novo acute myeloid leukemia (AML) or AML secondary to prior myelodysplastic disease or chronic myelomonocytic leukemia (CMML), and who have achieved first complete remission (CR)/ complete remission with incomplete blood count recovery (CRi) following induction with or without consolidation chemotherapy. The study is amended to include an extension phase (EP). The EP allows participants who are currently receiving oral azacitidine and who are demonstrating clinical benefit as assessed by the investigator, to continue receiving oral azacitidine after unblinding by sponsor until the participant meets the criteria for study discontinuation or until oral azacitidine becomes commercially available and reimbursed. In addition, all participants in the placebo arm and participants who had been discontinued from the treatment phase (irrespective of randomization arm) and continuing in the follow-up phase will be followed for survival in the EP.

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Kaplan-Meier (K-M) Estimate for Overall Survival (OS)

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outcome · POSTED

Kaplan-Meier Estimate of Relapse Free Survival (RFS)

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outcome · POSTED

Kaplan-Meier Estimate of Time to Relapse

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outcome · POSTED

Kaplan-Meier Estimates of Time to Discontinuation From Treatment

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outcome · POSTED

Number of Participants With Treatment Emergent Adverse Events (TEAEs)

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outcome · POSTED

Mean Change in the Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue Scale V 4.0) Score From Baseline

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outcome · POSTED

Mean Change in the European Quality of Life-Five Dimensions-Three Levels (EQ-5D-3L) Score From Baseline

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outcome · POSTED

Time to Definitive Clinically Meaningful Deterioration for ≥ 2 Consecutive Visits as Measured Using the EQ-5D HRQoL Scale

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outcome · POSTED

Healthcare Resource Utilization (HRU): Rate of Hospital Events Per Person Year

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outcome · POSTED

Healthcare Resource Utilization (HRU): Number of Days Hospitalized Per Person-Year

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: Key Inclusion Criteria: 1. Male or female participants ≥ 55 years of age 2. Newly diagnosed, histologically confirmed de novo acute myeloid leukemia (AML) or AML secondary to prior myelodysplastic disease or CMML (Chronic myelomonocytic leukemia) 3. First complete remission (CR)/ complete remission with incomplete blood count recovery (CRi) with induction therapy with intensive chemotherapy with or without consolidation therapy within 4 months (+/- 7 days of achieving CR or CRi) 4. Eastern Cooperative Oncology Group (ECOG) performance status - 0, 1, 2, 3 Key Inclusion Criteria in the Extended Phase of the study: At the Investigator's discretion and with approval of the sponsor, participants meeting all of the following eligibility criteria are eligible to enter the extension phase: 1. All participants randomized into the oral azacitidine or placebo arm and are continuing in either the treatment phase or follow-up phase of the CC-486-AML-001 study; * Participants randomized to oral azacitidine treatment arm and continuing in the treatment phase demonstrating clinical benefit as assessed by the investigator are eligible to receive oral azacitidine in the extension phase (EP); * Participants randomized into placebo arm of the study will not receive oral azacitidine in the EP, but will be followed for survival in the EP; * Participants currently in the follow-up phase will continue to be followed for survival in the EP; 2. Participants who have signed the informed consent for the EP of the study; 3. Participants who do not meet any of the criteria for study discontinuation Key Exclusion Criteria: 1. AML with inversion (inv)(16), translocation = t(8;21), t(16;16), t(15;17), or t(9;22) or molecular evidence of such translocations 2. Prior bone marrow or stem cell transplantation 3. Have achieved CR/CRi following therapy with hypomethylating agents 4. Diagnosis of malignant disease within the previous 12 months 5. Proven central nervous system (CNS) leukemia
healthy Volunteers: false
minimum Age: 55 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
300 mg oral azacitidine on days 1 to 14 of each 28-day treatment cycle.
intervention Names
Drug: Oral Azacitidine
label
Oral Azacitidine
type
EXPERIMENTAL
description
Identically matching placebo tablets on days 1 to 14 of each 28-day treatment cycle.
intervention Names
Drug: Placebo
label
Placebo
type
PLACEBO_COMPARATOR

interventions

arm Group Labels
Oral Azacitidine
description
300 mg oral azacitidine on days 1 to 14 of each 28-day treatment cycle.
name
Oral Azacitidine
other Names
CC-486; Onureg®
type
DRUG
arm Group Labels
Placebo
description
Identically matching placebo tablets on days 1 to 14 of each 28-day treatment cycle.
name
Placebo
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: QUADRUPLE
who Masked: PARTICIPANT
CARE_PROVIDER
INVESTIGATOR
OUTCOMES_ASSESSOR

primary Purpose

TREATMENT

Enrollment

count: 472
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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.
measure
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.

secondary Outcomes

description
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: • ≥ 5% bone marrow blasts (myeloblasts) from Central Pathology report, or • appearance of \> 0% blasts in the peripheral blood with a later bone marrow confirmation (bone marrow blast \[myeloblasts\] ≥ 5%) within 100 days, or • at least 2 peripheral blasts ≥ 5% within 30 days.
measure
Kaplan-Meier Estimate of Relapse Free Survival (RFS)
time Frame
From day 1 (randomization) up to data cut off date of 06 August 2024; approximately 135.5 months
description
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: • ≥ 5% bone marrow blasts (myeloblasts) from Central Pathology report, or • appearance of \> 0% blasts in the peripheral blood with a later bone marrow confirmation (bone marrow blast \[myeloblasts\] ≥ 5%) within 100 days, or • at least 2 peripheral blasts ≥ 5% within 30 days.
measure
Kaplan-Meier Estimate of Time to Relapse
time Frame
From day 1 (randomization) up to data cut off date of 06 August 2024; approximately 135.5 months
description
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.
measure
Kaplan-Meier Estimates of Time to Discontinuation From Treatment
time Frame
From day 1 (randomization) up to data cut off date of 06 August 2024; approximately 135.5 months
description
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: • Death • Life-threatening event • Inpatient hospitalization or prolongation of existing hospitalization • Persistent or significant disability or incapacity • Congenital anomaly or birth defect • 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.
measure
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
time Frame
From day 1 (randomization) up to data cut off date of 06 August 2024; approximately 135.5 months
description
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.
measure
Mean Change in the Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue Scale V 4.0) Score From Baseline
time Frame
From day 1 (randomization) up to data cut off date of 06 August 2024; approximately 135.5 months
description
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'.
measure
Mean Change in the European Quality of Life-Five Dimensions-Three Levels (EQ-5D-3L) Score From Baseline
time Frame
From day 1 (randomization) up to data cut off date of 06 August 2024; approximately 135.5 months
description
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'.
measure
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
description
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.
measure
Healthcare Resource Utilization (HRU): Rate of Hospital Events Per Person Year
time Frame
From day 1 (randomization) up to data cut off date of 06 August 2024; approximately 135.5 months
description
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.
measure
Healthcare Resource Utilization (HRU): Number of Days Hospitalized Per Person-Year
time Frame
From day 1 (randomization) up to data cut off date of 06 August 2024; approximately 135.5 months

Full study description

brief Summary: This study enrolled 472 participants, aged 55 or older, with a diagnosis of de novo acute myeloid leukemia (AML) or AML secondary to prior myelodysplastic disease or chronic myelomonocytic leukemia (CMML), and who have achieved first complete remission (CR)/ complete remission with incomplete blood count recovery (CRi) following induction with or without consolidation chemotherapy. The study is amended to include an extension phase (EP). The EP allows participants who are currently receiving oral azacitidine and who are demonstrating clinical benefit as assessed by the investigator, to continue receiving oral azacitidine after unblinding by sponsor until the participant meets the criteria for study discontinuation or until oral azacitidine becomes commercially available and reimbursed. In addition, all participants in the placebo arm and participants who had been discontinued from the treatment phase (irrespective of randomization arm) and continuing in the follow-up phase will be followed for survival in the EP.
detailed Description: This is an international, multicenter, placebo-controlled, Phase 3 study with a double-blind, randomized, parallel-group design in subjects with de novo AML or AML secondary to prior diagnosis of myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) aged ≥ 55 years, who are in first CR/CRi following induction therapy with or without consolidation chemotherapy. The study consists of 3 phases; the pre-randomization phase (screening phase), the treatment phase, and the follow-up phase. The study is amended to include an extension phase (EP). The EP allows participants who are currently receiving oral azacitidine and who are demonstrating clinical benefit as assessed by the Investigator, to continue receiving oral azacitidine after unblinding by sponsor until they meet the criteria for study discontinuation or until oral azacitidine becomes commercially available and reimbursed. In addition, all participants in the placebo arm and participants who had been discontinued from the treatment phase (irrespective of randomization arm) and continuing in the follow-up phase will be followed for survival in the EP.

Source references

references

citation
Roboz GJ, Montesinos P, Selleslag D, Wei A, Jang JH, Falantes J, Voso MT, Sayar H, Porkka K, Marlton P, Almeida A, Mohan S, Ravandi F, Garcia-Manero G, Skikne B, Kantarjian H. Design of the randomized, Phase III, QUAZAR AML Maintenance trial of CC-486 (oral azacitidine) maintenance therapy in acute myeloid leukemia. Future Oncol. 2016 Feb;12(3):293-302. doi: 10.2217/fon.15.326. Epub 2016 Jan 19.
pmid
26785287
type
BACKGROUND
citation
Ravandi F, Dohner H, Wei AH, Montesinos P, Pfeilstocker M, Papayannidis C, Lai Y, Wang K, See WL, de Menezes DL, Petrlik E, Prebet T, Roboz GJ. Survival outcomes in patients with acute myeloid leukaemia who received subsequent therapy for relapse in QUAZAR AML-001. Br J Haematol. 2024 Mar;204(3):877-886. doi: 10.1111/bjh.19202. Epub 2023 Nov 12.
pmid
37952982
type
DERIVED
citation
Wei AH, Roboz GJ, Dombret H, Dohner H, Schuh AC, Montesinos P, Selleslag D, Bondarenko SN, Prebet T, Lai Y, Skikne B, Beach CL, Ravandi F. Survival outcomes with oral azacitidine maintenance in patients with acute myeloid leukemia in remission by receipt of initial chemotherapy: subgroup analyses from the phase III QUAZAR AML-001 trial. Haematologica. 2023 Oct 1;108(10):2820-2825. doi: 10.3324/haematol.2022.282296. No abstract available.
pmid
36951156
type
DERIVED
citation
Dohner H, Wei AH, Roboz GJ, Montesinos P, Thol FR, Ravandi F, Dombret H, Porkka K, Sandhu I, Skikne B, See WL, Ugidos M, Risueno A, Chan ET, Thakurta A, Beach CL, Lopes de Menezes D. Prognostic impact of NPM1 and FLT3 mutations in patients with AML in first remission treated with oral azacitidine. Blood. 2022 Oct 13;140(15):1674-1685. doi: 10.1182/blood.2022016293.
pmid
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type
DERIVED
citation
Zhu J, Wu Q, Wang J, Niu T. Cost-effectiveness analysis of azacitidine maintenance therapy in patients with acute myeloid leukemia. Expert Rev Hematol. 2022 Apr;15(4):375-382. doi: 10.1080/17474086.2022.2061456. Epub 2022 May 11.
pmid
35437111
type
DERIVED
citation
Roboz GJ, Ravandi F, Wei AH, Dombret H, Thol F, Voso MT, Schuh AC, Porkka K, La Torre I, Skikne B, Zhong J, Beach CL, Risueno A, Menezes DL, Ossenkoppele G, Dohner H. Oral azacitidine prolongs survival of patients with AML in remission independently of measurable residual disease status. Blood. 2022 Apr 7;139(14):2145-2155. doi: 10.1182/blood.2021013404.
pmid
34995344
type
DERIVED
citation
Ravandi F, Roboz GJ, Wei AH, Dohner H, Pocock C, Selleslag D, Montesinos P, Sayar H, Musso M, Figuera-Alvarez A, Safah H, Tse W, Sohn SK, Hiwase D, Chevassut T, Pierdomenico F, La Torre I, Skikne B, Bailey R, Zhong J, Beach CL, Dombret H. Management of adverse events in patients with acute myeloid leukemia in remission receiving oral azacitidine: experience from the phase 3 randomized QUAZAR AML-001 trial. J Hematol Oncol. 2021 Aug 28;14(1):133. doi: 10.1186/s13045-021-01142-x.
pmid
34454540
type
DERIVED
citation
Wei AH, Dohner H, Pocock C, Montesinos P, Afanasyev B, Dombret H, Ravandi F, Sayar H, Jang JH, Porkka K, Selleslag D, Sandhu I, Turgut M, Giai V, Ofran Y, Kizil Cakar M, Botelho de Sousa A, Rybka J, Frairia C, Borin L, Beltrami G, Cermak J, Ossenkoppele GJ, La Torre I, Skikne B, Kumar K, Dong Q, Beach CL, Roboz GJ; QUAZAR AML-001 Trial Investigators. Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission. N Engl J Med. 2020 Dec 24;383(26):2526-2537. doi: 10.1056/NEJMoa2004444.
pmid
33369355
type
DERIVED