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

Acute Myeloid Leukemia (AML) Clinical Trial

Official title:

A Randomized, Double-Blind, Placebo Controlled Phase 3 Study of Venetoclax Co-Administered With Low Dose Cytarabine Versus Low Dose Cytarabine in Treatment Naïve Patients With Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03069352
• Other study ID #: M16-043
• Secondary ID: 2016-003900-30
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: May 23, 2017
• Est. completion date: July 18, 2024

Study information

• Verified date: June 2023
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 211
• Est. completion date: July 18, 2024
• Est. primary completion date: February 15, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. 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

2. 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

3. Participant must have a projected life expectancy of at least 12 weeks.

4. 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.

5. 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.)

6. 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.

7. 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.

8. 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.

9. 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:

1. 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.

2. 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.

3. Participants that have acute promyelocytic leukemia (APL).

4. Participant has known central nervous system (CNS) involvement with AML.

5. 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.

6. 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.

7. 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).

8. 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.

9. 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.

10. 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.

11. Participant has a malabsorption syndrome or other condition that precludes enteral route of administration.

12. Participant exhibits evidence of other clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial or fungal).

13. 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.

14. Participant has a white blood cell count > 25 × 10^9/L. (Note: hydroxyurea administration or leukapheresis is permitted to meet this criterion).

15. Previous treatment with venetoclax and/or current participation in any other research study with investigational products.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia (AML)
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Placebo
tablet
• Venetoclax
tablet
• Cytarabine
Subcutaneous injection

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
AbbVie

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Brazil,  Canada,  China,  Czechia,  France,  Germany,  Greece,  Hungary,  Ireland,  Japan,  Korea, Republic of,  Mexico,  New Zealand,  Norway,  Puerto Rico,  Russian Federation,  South Africa,  Spain,  Taiwan,  United Kingdom, 

References & Publications (1)

Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi K, Kim I, Stevens DA, Fiedler W, Pagoni M, Samoilova O, Hu Y, Anagnostopoulos A, Bergeron J, Hou JZ, Murthy V, Yamauchi T, McDonald A, Chyla B, Gopalakrishnan S, Jiang Q, Mendes W, Hayslip J, Panayiotidis P. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020 Jun 11;135(24):2137-2145. doi: 10.1182/blood.2020004856. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	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.	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.
Secondary	Percentage of Participants With Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR + CRi)	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.	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.
Secondary	Percentage of Participants With Complete Remission or Complete Remission With Partial Hematologic Recovery (CR + CRh)	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.	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.
Secondary	Percentage of Participants With Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR + CRi) by Initiation of Cycle 2	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.	Cycle 1, 28 days
Secondary	Percentage of Participants With Complete Remission and Complete Remission With Partial Hematologic Recovery (CR + CRh) by Initiation of Cycle 2	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.	Cycle 1, 28 days
Secondary	Percentage of Participants With Complete Remission	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.	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.
Secondary	Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form (SF) 7a	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.	Baseline and Day 1 of Cycles 3, 5, 7, and 9
Secondary	Change From Baseline in Global Health Status / Quality of Life	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.	Baseline and Day 1 of Cycles 3, 5, 7, and 9
Secondary	Event-free Survival (EFS)	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 × 10?/L, and/or platelets to > 50 × 10?/L non-transfused; or; 50% increase in peripheral blasts to > 25 × 10?/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.	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.
Secondary	Percentage of Participants With Post Baseline Red Blood Cell (RBC) Transfusion Independence	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.	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.
Secondary	Percentage of Participants With Post Baseline Platelet Transfusion Independence	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.	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.
Secondary	Percentage of Participants With RBC Transfusion Independence Among Those Who Were Transfusion Dependent at Baseline	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.	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.
Secondary	Percentage of Participants With Platelet Transfusion Independence Among Those Who Were Transfusion Dependent at Baseline	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.	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.
Secondary	Percentage of Participants With Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR + CRi) and Minimal Residual Disease (MRD) Response	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.	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.
Secondary	Percentage of Participants With Complete Remission or Complete Remission With Partial Hematologic Recovery (CR + CRh) and Minimal Residual Disease (MRD) Response	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.	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.
Secondary	Overall Survival (OS) by Mutation Subgroups	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	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.
Secondary	Percentage of Participants With Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR + CRi) by Mutation Subgroup	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	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.
Secondary	Percentage of Participants With Complete Remission or Complete Remission With Partial Hematologic Recovery (CR + CRh) by Mutation Subgroup	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	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.

External Links

•   Related Info