A Study of Venetoclax in Combination With Low Dose Cytarabine Versus Low Dose Cytarabine Alone in Treatment Naive Patients With Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy

Phase 3

Active, not recruiting

Conditions: Acute Myeloid Leukemia (AML)

Interventions: Drug: Placebo
Drug: Venetoclax
Drug: Cytarabine

Registration Number: NCT03069352

Lead Sponsor: AbbVie

Brief Summary: The primary objective of this study is to evaluate if venetoclax when co administered with low-dose cytarabine (LDAC) improves overall survival (OS) versus LDAC and placebo, in treatment-naïve patients with acute myeloid leukemia (AML).

Detailed Description: Acute myeloid leukemia (AML) is an aggressive and rare cancer of myeloid cells (a white blood cell responsible for fighting infections). Successful treatment of AML is dependent on what subtype of AML the patient has, and the age of the patient when diagnosed.

Venetoclax is an experimental drug that kills cancer cells by blocking a protein (part of a cell) that allows cancer cells to stay alive. This study is designed to see if adding venetoclax to cytarabine works better than cytarabine on its own.

This is a Phase 3, randomized, double-blind (treatment unknown to patients and doctors), placebo-controlled, multicenter study in patients with AML who are 18 or more years old and have not been treated before. Patients who take part in this study should not be suitable for intensive induction chemotherapy (usual starting treatment). Abbvie is funding this study which will take place at approximately 125 hospitals globally. In this study, 2/3 of patients will receive venetoclax every day with cytarabine and the remaining 1/3 will receive placebo (dummy) tablets with cytarabine.

Participants will continue to have study visits and receive treatment for as long as they are having a clinical benefit. The effect of the treatment on AML will be checked by taking blood, bone marrow, scans, measuring side effects and by completing health questionnaires. Blood and bone marrow tests will be completed to see why some people respond better than others.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 211

Inclusion Criteria

Participant must have histological confirmation of acute myeloid leukemia (AML) by World Health Organization criteria, be ineligible for intensive induction chemotherapy and either be:
- ≥ 75 years of age OR
- ≥ 18 to 74 years of age and fulfill at least one criteria associated with lack of fitness for intensive induction chemotherapy:
  - Eastern Cooperative Oncology Group (ECOG) performance status of 2 - 3
  - Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction ≤ 50% or chronic stable angina
  - Diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 65% or forced expiratory volume in 1 second (FEV1) ≤ 65%
  - Creatinine clearance ≥ 30 mL/min to < 45 ml/min
  - Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 × upper limit of normal (ULN)
  - Other comorbidity that the physician judges to be incompatible with conventional intensive chemotherapy which must be reviewed and approved by the study medical monitor before study enrollment
Participant must have an ECOG performance status:
- of 0 to 2 for subjects ≥ 75 years of age OR
- of 0 to 3 for subjects between 18 to 74 years of age
Participant must have a projected life expectancy of at least 12 weeks.
Participant must have adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24-hour urine collection.
Participant must have adequate liver function as demonstrated by:
- aspartate aminotransferase (AST) ≤ 3.0 × ULN*
- alanine aminotransferase (ALT) ≤ 3.0 × ULN*
- bilirubin ≤ 1.5 × ULN*
  - Subjects who are < 75 years of age may have bilirubin of ≤ 3.0 × ULN
(*Unless considered to be due to leukemic organ involvement.)
Female participants must be either postmenopausal defined as:
- Age > 55 years with no menses for 12 or more months without an alternative medical cause.
- Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause AND a follicle-stimulating hormone (FSH) level > 40 IU/L.
OR
- Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
OR
- A woman of childbearing potential (WOCBP) practicing at least one protocol specified method of birth control starting at Study Day 1 through at least 180 days after the last dose of study drug.
Male participants who are sexually active, must agree, from Study Day 1 through at least 180 days after the last dose of study drug, to practice protocol specified methods of contraception. Male subjects must agree to refrain from sperm donation from initial study drug administration through at least 180 days after the last dose of study drug.
Females of childbearing potential must have negative results for pregnancy test performed:
- At Screening with a serum sample obtained within 14 days prior to the first study drug administration, and
- Prior to dosing with urine sample obtained on Cycle 1 Day 1, if it has been > 7 days since obtaining the serum pregnancy test results.
- Subjects with borderline pregnancy tests at Screening must have a serum pregnancy test ≥ 3 days later to document continued lack of a positive result.
Participant must voluntarily sign and date an informed consent form, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.

Exclusion Criteria

Participant has received any prior treatment for AML with the exception of hydroxyurea, allowed through the first cycle of study treatment. Note: Prior treatment for myelodysplastic syndrome is allowed except for use of cytarabine.
Participant had an antecedent myeloproliferative neoplasm (MPN) including myelofibrosis, essential thrombocytosis, polycythemia vera, or chronic myelogenous leukemia (CML) with or without BCR-ABL 1 translocation and AML with BCR-ABL 1 translocation.
Participants that have acute promyelocytic leukemia (APL).
Participant has known central nervous system (CNS) involvement with AML.
Participant has known human immunodeficiency virus (HIV) infection (due to potential drug-drug interactions between antiretroviral medications and venetoclax). HIV testing will be performed at Screening, if required per local guidelines or institutional standards.
Participant is known to be positive for hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Inactive hepatitis carrier status or low viral hepatitis titer on antivirals (non-exclusionary medications) are not excluded.
Participant has received strong or moderate cytochrome P450 3A4 (CYP3A) inducers 7 days prior to the initiation of study treatment.
- Chinese subjects are excluded from receiving strong and/or moderate CYP3A inhibitors 7 days prior to the initiation of study treatment through the end of intensive pharmacokinetic (PK) collection (24 hours post dose on Cycle 1 Day 10).
Participant has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit within 3 days prior to the initiation of study treatment.
Participant has cardiovascular disability status of New York Heart Association Class > 2. Class 2 is defined as cardiac disease which subjects are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or angina pain. Class 3 is defined as cardiac disease which subjects are comfortable at rest but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class 4 is defined as cardiac disease which subjects have an inability to carry on any physical activity without discomfort, symptoms of heart failure at rest, and if any physical activity is undertaken then discomfort increases.
Participant has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition or known hypersensitivity to any of the study medications including excipients of LDAC that in the opinion of the investigator would adversely affect his/her participating in this study.
Participant has a malabsorption syndrome or other condition that precludes enteral route of administration.
Participant exhibits evidence of other clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial or fungal).
Participant has a history of other malignancies prior to study entry, with the exception of:
- Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;
- Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
- Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
Participant has a white blood cell count > 25 × 10^9/L. (Note: hydroxyurea administration or leukapheresis is permitted to meet this criterion).
Previous treatment with venetoclax and/or current participation in any other research study with investigational products.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo + LDAC	Placebo	Matching placebo to venetoclax orally QD plus LDAC 20 mg/m² subcutaneously on Days 1 to 10 of each 28-day cycle.
Venetoclax + Low Dose Cytarabine (LDAC)	Venetoclax	Venetoclax 600 mg orally every day (QD) plus LDAC 20 mg/m² subcutaneously on Days 1 to 10 of each 28-day cycle.
Venetoclax + Low Dose Cytarabine (LDAC)	Cytarabine	Venetoclax 600 mg orally every day (QD) plus LDAC 20 mg/m² subcutaneously on Days 1 to 10 of each 28-day cycle.
Placebo + LDAC	Cytarabine	Matching placebo to venetoclax orally QD plus LDAC 20 mg/m² subcutaneously on Days 1 to 10 of each 28-day cycle.

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS)	From randomization until the primary analysis cut-off date of February 15 2019; the median follow-up time was 12.0 months (range: 0.2-17.0) in the placebo arm and 12.0 months (range: 0.1-17.6) in the venetoclax arm.	Overall survival is defined as the time from the date of randomization to the date of death. Participants who had not died were censored at the date they were last known to be alive on or before the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR + CRi) by Initiation of Cycle 2	Cycle 1, 28 days	The composite complete remission rate is defined as the percentage of participants with complete remission (CR) or complete remission with incomplete blood count recovery (CRi) before initiation of Cycle 2, assessed by the investigator. Response was based on physical examination, bone marrow results and hematology values according to the revised guidelines by the IWG for AML: CR: No morphologic evidence of AML and absolute neutrophil count ≥ 10³/μL, platelets ≥ 10⁵/μL, red cell transfusion independence, and bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRi: All criteria as CR except for residual neutropenia \< 10³/μL or thrombocytopenia \< 10⁵/μL. If all criteria for CR are met except for RBC transfusion independence, CRi criteria are met. Participants who had no IWG disease assessments were considered to be non-responders.
Percentage of Participants With Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR + CRi)	Response was assessed at the end of Cycle 1 and every 3 cycles thereafter to the end of treatment. Median treatment duration at the 15 February 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively.	The composite complete remission rate is defined as the percentage of participants with complete remission (CR) or complete remission with incomplete blood count recovery (CRi) at any time during the study as assessed by the investigator. Response was based on physical examination, bone marrow results and hematology values according to the revised guidelines by the International Working Group (IWG) for AML: CR: No morphologic evidence of AML and absolute neutrophil count (ANC) ≥ 10³/μL (1,000/μL), platelets ≥ 10⁵/μL (100,000/μL), red blood cell (RBC) transfusion independence, and bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRi: All criteria as CR except for residual neutropenia \< 10³/μL or thrombocytopenia \< 10⁵/μL. If all criteria for CR are met except RBC transfusion independence, the CRi criteria are met. Participants who had no IWG disease assessments were considered to be non-responders.
Percentage of Participants With Complete Remission or Complete Remission With Partial Hematologic Recovery (CR + CRh)	Response was assessed at the end of Cycle 1 and every 3 cycles thereafter to the end of treatment. Median treatment duration at the 15 February 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively.	The percentage of participants who achieved a complete remission (CR) or complete remission with partial hematologic recovery (CRh) at any time point during the study assessed by the investigator. CR is defined according to the revised guidelines by the IWG for AML as no morphologic evidence of AML, ANC count ≥ 10³/μL, platelets ≥ 10⁵/μL, RBC transfusion independence, and bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRh is a derived response based on bone marrow blast and hematology lab values, achieved when the following criteria are met: * Bone marrow with \< 5% blasts and * Peripheral blood neutrophil count of \> 0.5 × 10³/μL and * Peripheral blood platelet count of \> 0.5 × 10⁵/μL and * A 1 week platelet transfusion-free period prior to the hematology lab collection. Participants with no disease assessments were considered to be non-responders.
Event-free Survival (EFS)	From randomization until the primary analysis cut-off date of February 15, 2019; the median follow-up time was 12.0 months (range: 0.2-17.0) in the placebo arm and 12.0 months (range: 0.1-17.6) in the venetoclax arm.	Event-free survival is defined as the time from randomization to the date of progressive disease (PD), confirmed morphologic relapse from CR or CRi, treatment failure (failure to achieve CR, CRi or morphologic leukemia free state (MLFS) after at least 6 cycles of study treatment), or death from any cause, assessed by the investigator according to the modified IWG criteria. PD: * \> 50% increase in marrow blasts (minimum 15% increase required if blasts \< 30% at baseline); or persistent marrow blast \> 70% for ≥ 3 months; without at least a 100% improvement in ANC to an absolute level \> 0.5 × 10⁹/L, and/or platelets to \> 50 × 10⁹/L non-transfused; or * 50% increase in peripheral blasts to \> 25 × 10⁹/L; or * New extramedullary disease Participants with no events prior to the cut-off date were censored at their last assessment date; participants with no events prior to post-treatment therapy initiated before the cut-off date were censored on the start date of post-treatment therapy.
Percentage of Participants With Complete Remission	Response was assessed at the end of Cycle 1 and every 3 cycles thereafter to the end of treatment. Median treatment duration at the 15 February 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively.	The complete remission rate is defined as the percentage of participants with complete remission (CR) at any time during the study as assessed by the investigator. Response was based on physical examination, bone marrow results and hematology values according to the revised guidelines by the International Working Group (IWG) for AML. CR is defined as no morphologic evidence of AML and absolute neutrophil count ≥ 10³/μL, platelets ≥ 10⁵/μL, red blood cell transfusion independence, and bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. Participants who had no IWG disease assessments were considered to be non-responders.
Change From Baseline in Global Health Status / Quality of Life	Baseline and Day 1 of Cycles 3, 5, 7, and 9	The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30) consists of a Global Health Status/Quality of Life (GHS/QoL) scale, a Financial Difficulties scale, 5 functional scales (Cognitive, Social, Physical, Emotional, and Role Functioning), and 8 symptom scales/items (Fatigue, Insomnia, Appetite Loss, Pain, Constipation, Diarrhea, Dyspnea, and Nausea and Vomiting). The GHS/QoL scale includes 2 questions in which participants were asked to rate their overall health and overall quality of life during the past week on a scale from 1 (very poor) to 7 (excellent). The 2 scores were averaged and transformed to a scale from 0 to 100, where a high score represents a high QoL. A positive change from baseline indicates better quality of life.
Overall Survival (OS) by Mutation Subgroups	From randomization until the primary analysis cut-off date of February 15, 2019; the median follow-up time was 12.0 months (range: 0.2-17.0) in the placebo arm and 12.0 months (range: 0.1-17.6) in the venetoclax arm.	Overall survival is defined as the time from the date of randomization to the date of death. Participants who had not died were censored at the date they were last known to be alive on or before the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology. Overall survival was analyzed in participants with the following molecular markers: * Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutation * FMS (Feline McDonough Sarcoma)-like tyrosine kinase 3 (FLT3) mutation
Percentage of Participants With Post Baseline Red Blood Cell (RBC) Transfusion Independence	From first dose of study drug until 30 days after last dose up to the data cut-off date of 15 February 2019; Median time on treatment was 1.7 months (range: 0.1-14.2) in the placebo arm and 3.9 months (range: 0.0-17.1) in the venetoclax arm.	The post baseline red blood cell (RBC) transfusion independence rate was calculated as the percentage of participants who achieved RBC transfusion independence post baseline. RBC transfusion independence is defined as a period of at least 56 consecutive days with no RBC transfusion after the first dose of study drug and on or before the last dose of study drug plus 30 days, or disease progression, or confirmed morphological relapse, or death, or the data cut-off date, whichever occurred earlier.
Percentage of Participants With RBC Transfusion Independence Among Those Who Were Transfusion Dependent at Baseline	From first dose of study drug until 30 days after last dose up to the data cut-off date of 15 February 2019; Median time on treatment was 1.7 months (range: 0.1-14.2) in the placebo arm and 3.9 months (range: 0.0-17.1) in the venetoclax arm.	The rate of conversion was calculated as the percentage of participants who were post-baseline RBC transfusion independent among participants who had an RBC transfusion within 8 weeks prior to the first dose of study drug (i.e. were transfusion dependent at Baseline). RBC transfusion independence is defined as a period of at least 56 days with no RBC transfusion after the first dose of study drug and on or before the last dose of study drug plus 30 days, or disease progression, or confirmed morphological relapse, or death, or the data cut-off date, whichever occurred earlier.
Percentage of Participants With Complete Remission and Complete Remission With Partial Hematologic Recovery (CR + CRh) by Initiation of Cycle 2	Cycle 1, 28 days	The percentage of participants who achieved a complete remission (CR) or complete remission with partial hematologic recovery (CRh) before initiation of Cycle 2 assessed by the investigator. CR is defined according to the revised guidelines by the IWG for AML as no morphologic evidence of AML, ANC count ≥ 10³/μL, platelets ≥ 10⁵/μL, RBC transfusion independence, and bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRh is a derived response based on bone marrow blast and hematology lab values, achieved when when the following criteria are met: * Bone marrow with \< 5% blasts and * Peripheral blood neutrophil count of \> 0.5 × 10³/μL and * Peripheral blood platelet count of \> 0.5 × 10⁵/μL and * A 1-week platelet transfusion-free period prior to the hematology lab collection. Participants with no disease assessments were considered to be non-responders.
Percentage of Participants With Platelet Transfusion Independence Among Those Who Were Transfusion Dependent at Baseline	From first dose of study drug until 30 days after last dose up to the data cut-off date of 15 February 2019; Median time on treatment was 1.7 months (range: 0.1-14.2) in the placebo arm and 3.9 months (range: 0.0-17.1) in the venetoclax arm.	The rate of conversion was calculated as the percentage of participants who were post-baseline platelet transfusion independent among participants who had a platelet transfusion within 8 weeks prior to the first dose of study drug (i.e. were transfusion dependent at Baseline). Platelet transfusion independence is defined as a period of at least 56 days with no platelet transfusion after the first dose of study drug and on or before the last dose of study drug plus 30 days, or disease progression, or confirmed morphological relapse, or death, or the data cut-off date, whichever occurred earlier.
Percentage of Participants With Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR + CRi) by Mutation Subgroup	Response was assessed at the end of Cycle 1 and every 3 cycles thereafter to the end of treatment. Median treatment duration at the 15 February 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively.	Response was based on physical examination, bone marrow results and hematology values according to the revised guidelines by the IWG for AML: CR: No morphologic evidence of AML and ANC ≥ 10³/μL, platelets ≥ 10⁵/μL, RBC transfusion independence, and bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRi: All criteria as CR except for residual neutropenia \< 10³/μL or thrombocytopenia \< 10⁵/μL. If all criteria for CR are met except RBC transfusion independence, CRi criteria is met. Participants who had no IWG disease assessments were considered to be non-responders. Response was analyzed in participants with the following mutations: * Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutation * FMS-like tyrosine kinase 3 (FLT3) mutation
Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form (SF) 7a	Baseline and Day 1 of Cycles 3, 5, 7, and 9	PROMIS Fatigue SF 7a is a seven-item questionnaire that assesses the impact and experience of fatigue over the past 7 days. All questions employ the following five response options: 1 = Never, 2 = Rarely, 3 = Sometimes, 4 = Often, and 5 = Always. The PROMIS Fatigue 7a score is calculated as a T-score, which is a standardized score with a mean of 50 (based on the average for the United States general population) and a standard deviation (SD) of 10. Higher scores indicate higher levels of fatigue. A decrease in score (negative change from Baseline) indicates improvement in fatigue; the minimum important difference used in this study was 3 points.
Percentage of Participants With Post Baseline Platelet Transfusion Independence	From first dose of study drug until 30 days after last dose up to the data cut-off date of 15 February 2019; Median time on treatment was 1.7 months (range: 0.1-14.2) in the placebo arm and 3.9 months (range: 0.0-17.1) in the venetoclax arm.	The post baseline platelet transfusion independence rate was calculated as the percentage of participants who achieved platelet transfusion independence post Baseline. Platelet transfusion independence is defined as a period of at least 56 consecutive days with no platelet transfusion after the first dose of study drug and on or before the last dose of study drug plus 30 days, or disease progression, or confirmed morphological relapse, or death, or the data cut--off date, whichever occurred earlier.
Percentage of Participants With Complete Remission or Complete Remission With Partial Hematologic Recovery (CR + CRh) and Minimal Residual Disease (MRD) Response	Response was assessed at the end of Cycle 1 and every 3 cycles thereafter to the end of treatment. Median treatment duration at the 15 February 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively.	The percentage of participants with complete remission or complete remission with partial hematologic recovery (CRh) AND MRD response as assessed by the investigator. CR is defined according to the modified IWG response criteria for AML as no morphologic evidence of AML, ANC ≥ 10³/μL, platelets ≥ 10⁵/μL, RBC transfusion independence, and bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRh is achieved when the following criteria are met: * Bone marrow with \< 5% blasts and * Peripheral blood neutrophil count of \> 0.5 × 10³/μL and * Peripheral blood platelet count of \> 0.5 × 10⁵/μL and * A 1 week platelet transfusion-free period prior to the hematology lab collection. MRD response (at lowest-point MRD value) was defined as less than 10-³ residual blasts per leukocyte measured in the bone marrow, per ELN recommendations. Participants who had no disease or MRD assessments were considered to be non-responders.
Percentage of Participants With Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR + CRi) and Minimal Residual Disease (MRD) Response	Response was assessed at the end of Cycle 1 and every 3 cycles thereafter to the end of treatment. Median treatment duration at the 15 February 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively.	The percentage of participants with complete remission or complete remission with incomplete blood count recovery AND minimal residual disease (MRD) as assessed by the investigator. Response was based on the modified IWG response criteria for AML: CR: No morphologic evidence of AML and ANC ≥ 10³/μL, platelets ≥ 10⁵/μL, red blood cell (RBC) transfusion independence, and bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRi: All criteria as CR except for residual neutropenia \< 10³/μL or thrombocytopenia \< 10⁵/μL. If all criteria for CR are met except RBC transfusion independence, CRi criteria are met. MRD response (at lowest-point MRD value) was defined as having less than 10-³ residual blasts per leukocyte measured in the bone marrow, per European LeukemiaNet (ELN) recommendations. Participants who had no disease or MRD assessments were considered to be non-responders.
Percentage of Participants With Complete Remission or Complete Remission With Partial Hematologic Recovery (CR + CRh) by Mutation Subgroup	Response was assessed at the end of Cycle 1 and every 3 cycles thereafter to the end of treatment. Median treatment duration at the 15 February 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively.	The percentage of participants who achieved a complete remission or complete remission with partial hematologic recovery assessed by the investigator for participants with the following mutations: * Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutation * FMS-like tyrosine kinase 3 (FLT3) mutation CR is defined according to the modified IWG criteria for AML as no morphologic evidence of AML, ANC ≥ 10³/μL, platelets ≥ 10⁵/μL, RBC transfusion independence, bone marrow with \< 5% blasts, absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRh is achieved when the following criteria are met: * Bone marrow with \< 5% blasts and * Peripheral blood neutrophil count \> 0.5 × 10³/μL and * Peripheral blood platelet count \> 0.5 × 10⁵/μL and * A 1 week platelet transfusion-free period prior to hematology lab collection. Participants with no disease assessments were considered non-responders

Trial Locations

Locations (109): H. Lee Moffit Cancer Center /ID# 164273
🇺🇸
Tampa, Florida, United States
Norton Cancer Institute /ID# 158998
🇺🇸
Louisville, Kentucky, United States
Cemic /Id# 159676
🇦🇷
Buenos Aires, Argentina
Sanatorio Allende /ID# 159675
🇦🇷
Cordoba, Argentina
Westmead Hospital /ID# 160121
🇦🇺
Westmead, New South Wales, Australia
Box Hill Hospital /ID# 162920
🇦🇺
Melbourne, Victoria, Australia
Cliniques Universitaires Saint Luc /ID# 159567
🇧🇪
Woluwe-Saint-Lambert, Bruxelles-Capitale, Belgium
Hospital de Cancer de Barretos /ID# 163568
🇧🇷
Barretos, Sao Paulo, Brazil
Hospital do Cancer Mae de Deus /ID# 163416
🇧🇷
Porto Alegre, Brazil
Casa de Saúde Santa Marcelina /ID# 163413
🇧🇷
Sao Paulo, Brazil
CISSS de la Monteregie /ID# 159782
🇨🇦
Greenfield Park, Quebec, Canada
Hopital Sacre Coeur Montreal /ID# 160982
🇨🇦
Montreal, Quebec, Canada
Osaka City University Hospital /ID# 159722
🇯🇵
Osaka-shi, Osaka, Japan
Pusan National University Hosp /ID# 158725
🇰🇷
Busan, Busan Gwang Yeogsi, Korea, Republic of
University Hospital of Wales /ID# 162726
🇬🇧
Cardiff, United Kingdom
Univ of Pittsburgh Med Ctr /ID# 158997
🇺🇸
Pittsburgh, Pennsylvania, United States
Univ TX, MD Anderson /ID# 159678
🇺🇸
Houston, Texas, United States
Swedish Medical Center /ID# 161280
🇺🇸
Seattle, Washington, United States
Fujian Medical Univ Union Hosp /ID# 167321
🇨🇳
Fuzhou, Fujian, China
Nanfang Hospital of Southern Medical University /ID# 170147
🇨🇳
Guangzhou, Guangdong, China
St. James's Hospital /ID# 162730
🇮🇪
Dublin 8, Dublin, Ireland
Hospital Maisonneuve-Rosemont /ID# 159780
🇨🇦
Montreal, Quebec, Canada
University Hospital Galway /ID# 162734
🇮🇪
Galway, Ireland
Gen Univ Hosp Alexandroupolis /ID# 157868
🇬🇷
Alexandroupolis, Greece
Alfred Hospital /ID# 160125
🇦🇺
Melbourne, Victoria, Australia
Universitair Ziekenhuis Antwerpen /ID# 159566
🇧🇪
Edegem, Antwerpen, Belgium
Centro de Pesquisas Oncologicas /ID# 163567
🇧🇷
Florianopolis, Santa Catarina, Brazil
Petz Aladar Megyei Oktato Korh /ID# 161739
🇭🇺
Gyor, Hungary
Kaposi Mor Oktato Korhaz /ID# 158175
🇭🇺
Kaposvar, Hungary
Tokyo Metropolitan Komagome Hospital /ID# 160759
🇯🇵
Bunkyo-ku, Tokyo, Japan
VA Caribbean Healthcare System /ID# 158999
🇵🇷
San Juan, Puerto Rico
City Clinical Hospital Botkina /ID# 164086
🇷🇺
Moscow, Russian Federation
Kyushu University Hospital /ID# 159688
🇯🇵
Fukuoka-shi, Fukuoka, Japan
Gunmaken Saiseikai Maebashi Hospital /ID# 160597
🇯🇵
Maebashi-shi, Gunma, Japan
Yamagata University Hospital /ID# 161223
🇯🇵
Yamagata-shi, Yamagata, Japan
Juntendo University Hospital /ID# 159781
🇯🇵
Tokyo, Japan
Kemerovo Regional Clinical Hospital n.a. S.V. Belyaev /ID# 162991
🇷🇺
Kemerovo, Kemerovskaya Oblast, Russian Federation
Gundersen Health System /ID# 164272
🇺🇸
La Crosse, Wisconsin, United States
University of Alberta Hospital /ID# 159646
🇨🇦
Edmonton, Alberta, Canada
Centre Hospitalier Le Mans /ID# 159702
🇫🇷
Le Mans CEDEX 9, Sarthe, France
General Hospital of Athens Evaggelismos and Ophthalmiatrio of Athens Polyclinic /ID# 157869
🇬🇷
Athens, Greece
University of Fukui Hospital /ID# 159770
🇯🇵
Yoshida-gun, Fukui, Japan
Centro de Invest Clin Chapulte /ID# 162625
🇲🇽
Morelia, Michoacan, Mexico
Kyoto Prefect Univ Med /ID# 160101
🇯🇵
Kyoto-shi, Kyoto, Japan
Sykehuset Ostfold Kalnes /ID# 165632
🇳🇴
Gralum, Norway
Kaohsiung Medical University /ID# 161693
🇨🇳
Kaohsiung, Taiwan
Instituto Nacional de Cancerol /ID# 159269
🇲🇽
Ciudad de México, Ciudad De Mexico, Mexico
Haukeland University Hospital /ID# 165630
🇳🇴
Bergen, Hordaland, Norway
saratov state medical /ID# 163130
🇷🇺
Saratov, Russian Federation
Hosp. Univ. Dr. Jose E. Gonz /ID# 159268
🇲🇽
Monterrey, Nuevo Leon, Mexico
State Institution of Health of the Ryazan Regional Clinical Hospital /ID# 163126
🇷🇺
Ryazan, Ryazanskaya Oblast, Russian Federation
Samara State Medical Universit /ID# 164173
🇷🇺
Samara, Russian Federation
Nizhniy Novgorod regional clinical hospital named N. A. Semashko /ID# 163186
🇷🇺
Nizhnij Novgorod, Nizhegorodskaya Oblast, Russian Federation
Almazov North-West Federal Med /ID# 162170
🇷🇺
Sankt-peterburg, Russian Federation
Ruijin Hospital, Shanghai Jiaotong /ID# 167325
🇨🇳
Shanghai, Shanghai, China
Blood disease hosp of Chinese Academy of Med Sciences(Institute of Hematology) /ID# 167509
🇨🇳
Tianjin, Tianjin, China
The First Hosp of Jilin Univ /ID# 167512
🇨🇳
Changchun, Jilin, China
West China Hospital /ID# 167514
🇨🇳
Chengdu, Sichuan, China
Jiangsu Province People's Hospital /ID# 167511
🇨🇳
Nanjing, Jiangsu, China
Qilu Hospital of Shandong Univ /ID# 167507
🇨🇳
Jinan, China
The First Affiliated Hospital,College of Medicine, Zhejiang University /ID# 167324
🇨🇳
Hangzhou, Zhejiang, China
Union Hospital Tongji Medical College Huazhong University of Science and Technol /ID# 167515
🇨🇳
Wuhan, China
Henan Cancer Hospital /ID# 167327
🇨🇳
Zhengzhou, Henan, China
Fakultni Nemocnice Brno /ID# 159247
🇨🇿
Brno, Czechia
Univ Hosp Ostrava-Poruba /ID# 159246
🇨🇿
Ostrava, Czechia
Centre Hospitalier Lyon Sud /ID# 159705
🇫🇷
Pierre Benite CEDEX, Rhone, France
Fakult Nem Kralovske Vinohrady /ID# 159248
🇨🇿
Prague, Czechia
Centre Hospitalier de la Cote /ID# 159697
🇫🇷
Bayonne, France
CHU Bordeaux /ID# 159704
🇫🇷
Pessac, France
CHU De Nancy /ID# 159700
🇫🇷
Vandoeuvre Les Nancy Cedex, France
Schwarzwald-Baar-Klinikum /ID# 159571
🇩🇪
Villingen-Schwenningen, Baden-Wuerttemberg, Germany
Vivantes Klinikum Am Urban /ID# 159569
🇩🇪
Berlin, Germany
University Gen Hosp of Patra /ID# 157871
🇬🇷
Patras, Greece
Universitaetsklinikum Hamburg /ID# 161760
🇩🇪
Hamburg, Germany
General Hospital of Athens Laiko /ID# 157870
🇬🇷
Athens, Attiki, Greece
General Hospital of Thessaloniki George Papanikolaou /ID# 157867
🇬🇷
Thessaloniki, Greece
Semmelweis Egyetem I. Belklini /ID# 158180
🇭🇺
Budapest, Hungary
Pecsi Tudomanyegyetem /ID# 163161
🇭🇺
Pécs, Pecs, Hungary
Debreceni Egyetem Klinikai Koz /ID# 158178
🇭🇺
Debrecen, Hungary
Dél-pesti Centrumkórház- Országos Hematológiai és Infektológiai Intézet /ID# 159127
🇭🇺
Budapest IX, Budapest, Hungary
Bacs-Kiskun Megyei Korhaz /ID# 160973
🇭🇺
Kecskemét, Hungary
Beaumont Hospital /ID# 162733
🇮🇪
Dublin, Ireland
University Hospital Limerick /ID# 162735
🇮🇪
Limerick, Ireland
Tohoku University Hospital /ID# 161151
🇯🇵
Sendai-shi, Miyagi, Japan
Nagasaki University Hospital /ID# 160233
🇯🇵
Nagasaki-shi, Nagasaki, Japan
National Hospital Organization Mito Medical Center /ID# 162988
🇯🇵
Higashi Ibaraki-gun, Ibaraki, Japan
Kinki University -Osakasayama Campus /ID# 160777
🇯🇵
Osakasayama-shi, Osaka, Japan
Tokyo Jikei Daisan Hospital /ID# 159769
🇯🇵
Komae-shi, Tokyo, Japan
Akita University Hospital /ID# 160602
🇯🇵
Akita, Japan
Saitama Med Univ Int Med Ctr /ID# 161308
🇯🇵
Hidaka, Japan
NHO Nagoya Medical Center /ID# 159768
🇯🇵
Nagoya, Japan
Dokkyo Medical University Hosp /ID# 159650
🇯🇵
Shimotsuga, Japan
Seoul National University Hospital /ID# 162253
🇰🇷
Seoul, Korea, Republic of
Cath Univ Seoul St Mary's Hosp /ID# 158724
🇰🇷
Seoul, Seoul Teugbyeolsi, Korea, Republic of
Chungnam National University Hospital /ID# 158726
🇰🇷
Jung-gu, Daejeon Gwang Yeogsi, Korea, Republic of
North Shore Hospital /ID# 160132
🇳🇿
Auckland, New Zealand
Middlemore Clinical Trials /ID# 160131
🇳🇿
Auckland, New Zealand
Yaroslavl Regional Clinic Hosp /ID# 162172
🇷🇺
Yaroslavl, Russian Federation
Saint Petersburg State Institu /ID# 162171
🇷🇺
St. Petersburg, Russian Federation
Netcare Pretoria East Hospital /ID# 157373
🇿🇦
Pretoria, Gauteng, South Africa
Hospital Universitario y Politecnico La Fe /ID# 161181
🇪🇸
Valencia, Valenciana, Spain
National Taiwan Univ Hosp /ID# 162781
🇨🇳
Taipei City, Taipei, Taiwan
Hospital Infanta Leonor /ID# 161180
🇪🇸
Madrid, Spain
Tshwane District Hospital /ID# 157361
🇿🇦
Pretoria, Gauteng, South Africa
Tri-Service General Hospital /ID# 161683
🇨🇳
Taipei City, Taipei, Taiwan
Heartlands Hospital /ID# 163534
🇬🇧
Birmingham, United Kingdom
Northwick Park Hospital /ID# 162727
🇬🇧
Harrow, United Kingdom
NTT Medical Center Tokyo /ID# 160678
🇯🇵
Shinagawa-ku, Tokyo, Japan
Calvary Mater Newcastle /ID# 160123
🇦🇺
Waratah, New South Wales, Australia