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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02993523




Registration number
NCT02993523
Ethics application status
Date submitted
13/12/2016
Date registered
15/12/2016
Date last updated
27/06/2024

Titles & IDs
Public title
A Study of Venetoclax in Combination With Azacitidine Versus Azacitidine in Treatment Naïve Participants With Acute Myeloid Leukemia Who Are Ineligible for Standard Induction Therapy
Scientific title
A Randomized, Double-Blind, Placebo Controlled Phase 3 Study of Venetoclax in Combination With Azacitidine Versus Azacitidine in Treatment Naïve Subjects With Acute Myeloid Leukemia Who Are Ineligible for Standard Induction Therapy
Secondary ID [1] 0 0
2016-001466-28
Secondary ID [2] 0 0
M15-656
Universal Trial Number (UTN)
Trial acronym
Viale-a
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukemia (AML) 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional(has expanded access)
Description of intervention(s) / exposure
Treatment: Drugs - Azacitidine
Treatment: Drugs - Venetoclax
Treatment: Drugs - Placebo

Placebo comparator: Group 1 and Group 2: Placebo + Azacitidine 75 mg/m^2 - Participants enrolled under original protocol and enrolled during or after protocol amendment 1 received venetoclax-matching placebo, orally, every day (QD), from Day 1 to Day 28 of each 28 day cycle along with azacitidine 75 mg/m\^2, subcutaneously (SC) or intravenously (IV), QD for 7 days from Day 1 of each 28-day cycle until documented disease progression, unacceptable toxicity, withdrawal of consent, or other protocol criteria for discontinuation (whichever occurred first).

Active comparator: Group 1 and Group 2: Venetoclax 100 mg/200 mg/400 mg + Azacitidine 75 mg/m^2 - Participants enrolled under original protocol and enrolled during or after protocol amendment 1 received venetoclax 100 mg, once orally, on Day 1 of Cycle 1 followed by venetoclax 200 mg, once orally, on Day 2 of Cycle 1 and venetoclax 400 mg, orally, QD, on Day 3 to Day 28 of each 28 day cycle along with azacitidine 75 mg/m\^2, SC or IV, QD for 7 days from Day 1 of each 28-day cycle until documented disease progression, unacceptable toxicity, withdrawal of consent, or other protocol criteria for discontinuation (whichever occurred first).

Active comparator: Open Label China Cohort: Venetoclax 400 mg + Azacitidine 75 mg/m^2 - Participants received venetoclax 400 mg, orally, QD, from Day 1 to Day 28 of each 28 day cycle along with azacitidine 75 mg/m\^2, SC, QD for 7 days from Day 1 of each 28-day cycle until documented disease progression, unacceptable toxicity, withdrawal of consent, or other protocol criteria for discontinuation (whichever occurred first).


Treatment: Drugs: Azacitidine
Solution for subcutaneous or intravenous administration.

Treatment: Drugs: Venetoclax
Tablet

Treatment: Drugs: Placebo
Matching placebo tablet
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Overall Survival (OS)
Timepoint [1] 0 0
From the study start up to death or alive or lost to follow-up (up to approximately 4.8 years; data cut off date: 1 December 2021)
Primary outcome [2] 0 0
Percentage of Participants With Complete Remission (CR) and Complete Remission With Incomplete Marrow Recovery (CRi)
Timepoint [2] 0 0
From the study start up to death (up to approximately 4.8 years; data cut-off date: 1 December 2021)
Secondary outcome [1] 0 0
Event-free Survival (EFS)
Timepoint [1] 0 0
Measured up to 2 years after the last participant is randomized
Secondary outcome [2] 0 0
Global Health Status/Quality of Life (GHS/QoL)
Timepoint [2] 0 0
Measured at participant's Day 1 of Cycle 1 (each cycle is 28 days) and at Day 1 of every Cycle thereafter for up to 2 years following the last subject last visit
Secondary outcome [3] 0 0
Percentage of Participants Achieving Composite Complete Remission (CR or CRi)
Timepoint [3] 0 0
Up to 6 months after the first 225 participants are randomized
Secondary outcome [4] 0 0
Complete Remission or Complete Remission With Partial Hematologic Recovery Rate (CR+CRh)
Timepoint [4] 0 0
Measured up to 2 years after the last participant is randomized
Secondary outcome [5] 0 0
Post Baseline Transfusion Independence Rate
Timepoint [5] 0 0
Measured up to 2 years after the last participant is randomized
Secondary outcome [6] 0 0
Complete Remission (CR) Rate
Timepoint [6] 0 0
Measured up to 2 years after the last participant is randomized
Secondary outcome [7] 0 0
Fatigue/Quality of Life (QoL)
Timepoint [7] 0 0
Measured at participant's Day 1 of Cycle 1 (each cycle is 28 days) and at Day 1 of every Cycle thereafter for up to 2 years following the last participant last visit

Eligibility
Key inclusion criteria
* Participant must have confirmation of Acute Myeloid Leukemia (AML) by World Health Organization (WHO) criteria, previously untreated and be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due age or comorbidities.
* Participant must be >= 18 years of age.
* Participant must have a projected life expectancy of at least 12 weeks.
* Participant must be considered ineligible for induction therapy defined by the following:

a. >= 75 years of age; or b. >= 18 to 74 years of age with at least one of the following comorbidities: i. Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or 3; ii. Cardiac history of Congestive Heart Failure (CHF) requiring treatment or Ejection Fraction <= 50% or chronic stable angina; iii. Diffusing capacity of the Lung for Carbon Monoxide (DLCO) <= 65% or Forced Expiratory Volume in 1 second (FEV1) <= 65%; iv. Creatinine clearance >= 30 mL/min to < 45 ml/min; v. Moderate hepatic impairment with total bilirubin > 1.5 to <= 3.0 × Upper Limit of Normal (ULN); vi. Any other comorbidity that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the AbbVie Therapeutic Medical Director during screening and before study enrollment.
* Participant must have an ECOG Performance status:

1. 0 to 2 for Participants >= 75 years of age or
2. 0 to 3 for Participants >= 18 to 74 years of age.
* Participant must have adequate renal function as demonstrated by a creatinine >= 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection.
* Participant must have adequate liver function as demonstrated by:

1. aspartate aminotransferase (AST) <= 3.0 x ULN*
2. alanine aminotransferase (ALT) <= 3.0 x ULN*
3. bilirubin <= 1.5 x ULN* * Unless considered to be due to leukemic organ involvement

i. Participants who are < 75 years of age may have a bilirubin of <= 3.0 x ULN
* Female participants must be either postmenopausal defined as:

1. Age > 55 years with no menses for 12 or more months without an alternative medical cause.
2. Age = 55 years with no menses for 12 or more months without an alternative medical cause AND an follicle stimulating hormone (FSH) level >40 international units per liter (IU/L); or
3. Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy); or
4. Women of Childbearing Potential (WOCBP) practicing at least one protocol specified method of birth control, starting at Study Day 1 through at least 90 days after the last dose of study drug.
* Male participants who are sexually active, must agree, from Study Day 1 through at least 90 days after the last dose of study drug, to practice the protocol specified contraception. Male subjects must agree to refrain from sperm donation from initial study drug administration through at least 90 days after the last dose of study drug.
* Female participants of childbearing potential must have negative results for pregnancy test performed:

1. At Screening with a serum sample obtained within 14 days prior to the first study drug administration, and
2. 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.
* Participant must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Participant has received treatment with the following:

1. A hypomethylating agent, venetoclax and/or chemo therapeutic agent for Myelodysplastic syndrome (MDS).
2. Chimeric Antigen Receptor (CAR)-T cell therapy.
3. Experimental therapies for MDS or Acute Myeloid Leukemia (AML).
4. Current participation in another research or observational study.
* Participant has history of myeloproliferative neoplasm (MPN) including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia (CML) with or without BCR-ABL1 translocation and AML with BCR-ABL1 translocation.
* Participant has the following:

a. Favorable risk cytogenetics such as t(8;21), inv(16) or t(16;16) or t(15;17) as per the National Comprehensive Cancer Network (NCCN) Guidelines Version 2, 2016 for Acute Myeloid Leukemia.
* Participant has acute promyelocytic leukemia
* Participant has known active 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, only if required per local guidelines or institutional standards.
* Participant is known to be positive for hepatitis B or C infection [HCV Ab indicative of a previous or current infection; and/or positive HBs Ag or detected sensitivity on hepatitis B virus (HBV) deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) test for HBc Ab and/or HBs Ab positivity] with the exception of those with an undetectable viral load within 3 months screening. Hepatitis B or C testing is not required.
* Participant has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment; additional details as described in the protocol.
* Participant has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment.
* Participant has a cardiovascular disability status of New York Heart Association Class > 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.
* 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 azacitidine 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 within 2 years prior to study entry, with the exception of:

1. Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;
2. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
3. Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent; requires discussion with TA MD.
* Participant has a white blood cell count > 25 × 10^9/L. (Hydroxyurea or leukapheresis are permitted to meet this criterion.)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
2/02/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
23/01/2026
Actual
Sample size
Target
Accrual to date
Final
443
Recruitment in Australia
Recruitment state(s)
QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
Princess Alexandra Hospital /ID# 154272 - Woolloongabba
Recruitment hospital [2] 0 0
Royal Adelaide Hospital /ID# 154271 - Adelaide
Recruitment hospital [3] 0 0
Alfred Health /ID# 154275 - Melbourne
Recruitment hospital [4] 0 0
St Vincent's Hospital Melbourne /ID# 155094 - Melbourne
Recruitment hospital [5] 0 0
The Royal Melbourne Hospital /ID# 155095 - Parkville
Recruitment hospital [6] 0 0
Sir Charles Gairdner Hospital /ID# 163924 - Nedlands
Recruitment hospital [7] 0 0
Royal Perth Hospital /ID# 154274 - Perth
Recruitment postcode(s) [1] 0 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 0 0
5000 - Adelaide
Recruitment postcode(s) [3] 0 0
3004 - Melbourne
Recruitment postcode(s) [4] 0 0
3065 - Melbourne
Recruitment postcode(s) [5] 0 0
3050 - Parkville
Recruitment postcode(s) [6] 0 0
6009 - Nedlands
Recruitment postcode(s) [7] 0 0
6000 - Perth
Recruitment outside Australia
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Moscow
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Madrid
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Malaga
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Valencia
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Sweden
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Uppsala Lan
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Lund
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Stockholm
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Taiwan
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Changhua County
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Kaohsiung
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Taichung City
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Taipei City
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Turkey
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Ankara
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Samsun
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Ukraine
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Vinnytska Oblast
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Ukraine
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Dnipro
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Ukraine
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Kyiv
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Ukraine
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Poltava

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
AbbVie
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Genentech, Inc.
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Acute Myeloid Leukaemia (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 participant has, and the age of the participant 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 azacitidine works better than azacitidine on its own.

This is a Phase 3, randomized, double-blind (treatment is unknown to participants and doctors), placebo controlled study in patients with AML who are \>= 18 or more years old and have not been treated before. Participants who take part in this study should not be suitable for standard induction therapy (usual starting treatment). AbbVie is funding this study which will take place at approximately 180 hospitals globally and enroll approximately 400 participants.

In this study, 2/3 of participants will receive venetoclax every day with azacitidine and the remaining 1/3 will receive placebo (dummy) tablets with azacitidine.

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. Additional blood tests will be completed for genetic factors and to see how long the drug remains in the body.
Trial website
https://clinicaltrials.gov/study/NCT02993523
Trial related presentations / publications
Badawi M, Chen X, Marroum P, Suleiman AA, Mensing S, Koenigsdorfer A, Schiele JT, Palenski T, Samineni D, Hoffman D, Menon R, Salem AH. Bioavailability Evaluation of Venetoclax Lower-Strength Tablets and Oral Powder Formulations to Establish Interchangeability with the 100 mg Tablet. Clin Drug Investig. 2022 Aug;42(8):657-668. doi: 10.1007/s40261-022-01172-4. Epub 2022 Jul 13.
Pratz KW, Chai X, Xie J, Yin L, Nie X, Montez M, Iantuono E, Downs L, Ma E. Cost-Effectiveness Analysis of Venetoclax in Combination with Azacitidine Versus Azacitidine Monotherapy in Patients with Acute Myeloid Leukemia Who are Ineligible for Intensive Chemotherapy: From a US Third Party Payer Perspective. Pharmacoeconomics. 2022 Aug;40(8):777-790. doi: 10.1007/s40273-022-01145-7. Epub 2022 Jun 13.
Konopleva M, Thirman MJ, Pratz KW, Garcia JS, Recher C, Pullarkat V, Kantarjian HM, DiNardo CD, Dail M, Duan Y, Chyla B, Potluri J, Miller CL, Wei AH. Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naive Acute Myeloid Leukemia. Clin Cancer Res. 2022 Jul 1;28(13):2744-2752. doi: 10.1158/1078-0432.CCR-21-3405.
Pollyea DA, DiNardo CD, Arellano ML, Pigneux A, Fiedler W, Konopleva M, Rizzieri DA, Smith BD, Shinagawa A, Lemoli RM, Dail M, Duan Y, Chyla B, Potluri J, Miller CL, Kantarjian HM. Impact of Venetoclax and Azacitidine in Treatment-Naive Patients with Acute Myeloid Leukemia and IDH1/2 Mutations. Clin Cancer Res. 2022 Jul 1;28(13):2753-2761. doi: 10.1158/1078-0432.CCR-21-3467.
Pratz KW, Jonas BA, Pullarkat V, Recher C, Schuh AC, Thirman MJ, Garcia JS, DiNardo CD, Vorobyev V, Fracchiolla NS, Yeh SP, Jang JH, Ozcan M, Yamamoto K, Illes A, Zhou Y, Dail M, Chyla B, Potluri J, Dohner H. Measurable Residual Disease Response and Prognosis in Treatment-Naive Acute Myeloid Leukemia With Venetoclax and Azacitidine. J Clin Oncol. 2022 Mar 10;40(8):855-865. doi: 10.1200/JCO.21.01546. Epub 2021 Dec 15.
DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, Konopleva M, Dohner H, Letai A, Fenaux P, Koller E, Havelange V, Leber B, Esteve J, Wang J, Pejsa V, Hajek R, Porkka K, Illes A, Lavie D, Lemoli RM, Yamamoto K, Yoon SS, Jang JH, Yeh SP, Turgut M, Hong WJ, Zhou Y, Potluri J, Pratz KW. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020 Aug 13;383(7):617-629. doi: 10.1056/NEJMoa2012971.
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ABBVIE INC.
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AbbVie
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Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT02993523