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Efficacy of Oral Azacitidine Plus Best Supportive Care as Maintenance Therapy in Subjects With Acute Myeloid Leukemia (AML) in Complete Remission (QUAZAR AML-001)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01757535
Recruitment Status : Active, not recruiting
First Posted : December 31, 2012
Results First Posted : November 6, 2020
Last Update Posted : May 19, 2021
Sponsor:
Information provided by (Responsible Party):
Celgene

Tracking Information
First Submitted Date  ICMJE November 21, 2012
First Posted Date  ICMJE December 31, 2012
Results First Submitted Date  ICMJE September 29, 2020
Results First Posted Date  ICMJE November 6, 2020
Last Update Posted Date May 19, 2021
Actual Study Start Date  ICMJE April 24, 2013
Actual Primary Completion Date July 15, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 4, 2020)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 21, 2012)
Overall Survival (OS) [ Time Frame: 60 months ]
Number of participants who survive
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 4, 2020)
  • 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:
    • ≥ 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.
  • 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:
    • ≥ 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.
  • 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.
  • 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:
    • 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.
  • 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.
  • 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'.
  • 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.
  • 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'.
  • 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.
  • 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'.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 21, 2012)
  • Relapse free survival (RFS) [ Time Frame: 60 months ]
    Number of participants who survive without relapsing
  • Complete Remission (CR)/Complete Remission with incomplete blood count recovery (CRi) [ Time Frame: 60 months ]
    Time to relapse from Complete Remission (CR)/Complete Remission with incomplete blood count recovery (CRi)
  • Safety and Tolerability [ Time Frame: 60 months ]
    Number of participants with adverse events
  • Healthcare Resource Utilization [ Time Frame: 60 months ]
    Information on each hospitalization will be collected utilizing a specific CRF. Information to be collected may include, the reason for hospitalization (eg, AML relapse, AML-related illness, treatment-related AE), and days of hospitalization by treatment setting (inpatient, special care unit). Other disease- and treatment-related forms of healthcare utilization will be collected through routine study activities. These include diagnostic procedures and treatment interventions not requiring hospitalization such as those required for AML-related illness, or for treatment-related adverse events. Additionally, information on all concomitant medications and resource use associated with treatment for AML will be collected. Healthcare resource utilization information will be collected after a subject signs informed consent through 28 days after the last dose of Investigational Product (IP) or until the date of last study visit, whichever is later
  • Health-related quality-of-life (HRQoL) [ Time Frame: 60 months ]
    FACT-F Functional Assessment of Cancer Therapy-Fatigue, EuroQol-5D (EQ-5D) measure of health outcome and 3 additional exploratory questions
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy of Oral Azacitidine Plus Best Supportive Care as Maintenance Therapy in Subjects With Acute Myeloid Leukemia (AML) in Complete Remission
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Leukemia, Myeloid, Acute
Intervention  ICMJE
  • Drug: Oral Azacitidine
    300 mg oral azacitidine on days 1 to 14 of each 28-day treatment cycle.
    Other Name: CC-486; Onureg®
  • Drug: Placebo
    Identically matching placebo tablets on days 1 to 14 of each 28-day treatment cycle.
Study Arms  ICMJE
  • Experimental: Oral Azacitidine
    300 mg oral azacitidine on days 1 to 14 of each 28-day treatment cycle.
    Intervention: Drug: Oral Azacitidine
  • Placebo Comparator: Placebo
    Identically matching placebo tablets on days 1 to 14 of each 28-day treatment cycle.
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 28, 2018)
472
Original Estimated Enrollment  ICMJE
 (submitted: December 21, 2012)
460
Estimated Study Completion Date  ICMJE December 31, 2021
Actual Primary Completion Date July 15, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 55 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Brazil,   Canada,   Czechia,   Finland,   France,   Germany,   Ireland,   Israel,   Italy,   Korea, Republic of,   Lithuania,   Mexico,   Poland,   Portugal,   Russian Federation,   Spain,   Taiwan,   Turkey,   United Kingdom,   United States
Removed Location Countries Czech Republic,   Denmark
 
Administrative Information
NCT Number  ICMJE NCT01757535
Other Study ID Numbers  ICMJE CC-486-AML-001
2012-003457-28 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Celgene
Study Sponsor  ICMJE Celgene
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Barry Skikne, MD Celgene Corporation
PRS Account Celgene
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP