A Clinical Study to Compare the Effectiveness and Safety of Pevonedistat, Venetoclax, and Azacitidine Versus Venetoclax Plus Azacitidine in Adults With Acute Myeloid Leukemia Who Cannot Undergo Intensive Chemotherapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Takeda Development Center Americas Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 Oct 2020 → 7 Oct 2025

Decision date (initial)

2024-10-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Takeda Development Center Americas, Inc.

External identifiers

EU CT number

2024-515424-36-00

EudraCT number

2019-003117-33

WHO UTN

U1111-1239-7581

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Efficacy, Therapy, Pharmacokinetic, Safety, Pharmacogenomic, Pharmacodynamic

To determine whether the combination of pevonedistat + venetoclax + azacitidine improves EFS compared with venetoclax + azacitidine in patients with newly diagnosed AML who are unfit for intensive chemotherapy. EFS is defined as the time from study randomization to the date of failure to achieve CR/CRi (ie, discontinuing treatment without achieving CR/CRi), relapse from CR or CRi, or death from any cause, whichever occurs first.

Secondary objectives 1

1. To determine whether the combination of pevonedistat + venetoclax + azacitidine improves OS when compared with venetoclax + azacitidine in patients with newly diagnosed AML who are unfit for intensive chemotherapy.

Conditions and MedDRA coding

Acute Myeloid Leukemia

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Male or female patients aged ≥18 years with newly diagnosed AML, morphologically confirmed (World Health Organization [WHO] criteria 2008). Patients may have newly diagnosed primary de novo AML or secondary AML (sAML) defined as AML after myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN), or therapy-related AML (t-AML) following cytotoxic therapy, and/or radiotherapy for a malignant or nonmalignant disease.
2. To qualify for this study, a patient must be considered to be unfit for treatment with a standard Ara-C and anthracycline induction regimen due to age or co-morbidities defined by 1 of the following: ≥75 years of age OR ≥18 to <75 years of age with at least one of the following: - ECOG performance status of 2 or 3. - Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina). - Severe pulmonary disorder (eg, carbon monoxide lung diffusion capacity ≤65% or forced expiratory volume in 1 second. - Creatinine clearance <45 mL/min (but ≥30 mL/min as part of general eligibility criteria). - Hepatic disorder with total bilirubin >1.5 times the upper limit of the normal range (ULN)
3. Clinical laboratory values within the following parameters (repeat within 3 days before the first dose of study drug if laboratory values used for randomization were obtained more than 3 days before the first dose of study drug): - Total bilirubin ≤1.5 times the upper limit of the normal range (ULN) except in patients with Gilbert's syndrome. Patients with Gilbert's syndrome may enroll with direct bilirubin ≤3 times the ULN of the direct bilirubin. Elevated indirect bilirubin due to posttransfusion hemolysis is allowed. - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 times the ULN. - Creatinine clearance ≥30 mL/minute (calculated by the Modification of Diet in Renal Disease Study equation). - Albumin >2.7 g/dL.
4. White blood cell count (WBC) <25 × 10^9/L. Patients who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria before starting therapy. (Please refer to protocol for complete list of all inclusion criteria)

Exclusion criteria 14

1. History of myeloproliferative neoplasm with BCR-ABL1 translocation or AML with BCR-ABL1 translocation.
2. Genetic diagnosis of acute promyelocytic leukemia
3. Extramedullary AML without evidence of bone marrow involvement.
4. Prior treatment with hypomethylating agents for AML (treatment with hypomethylating agents for prior myelodysplastic syndromes [MDS] is not exclusionary).
5. Eligible for intensive chemotherapy and/or allogeneic stem cell transplantation.
6. Patients with either clinical evidence of or history of central nervous system involvement by AML.
7. Diagnosed or treated for another malignancy (except for adequately-treated carcinoma in situ of any organ or nonmelanoma skin cancer) within 1 year before randomization or previously diagnosed with another malignancy and have any evidence of residual disease that may compromise the administration of pevonedistat, venetoclax or azacitidine. Prior MDS is also allowed, but the patient cannot have received treatment for MDS within 14 days before first dose of any study drug.
8. Patient has a WBC count >=25 × 10^9/L.
9. Patient with known hypersensitivity to pevonedistat, venetoclax, or azacitidine, and/or their excipients.
10. Uncontrolled HIV infection.
11. Patient is known to be positive for hepatitis B or C infection, with the exception of those with an undetectable viral load within 3 months.
12. Known hepatic cirrhosis.
13. Treatment with strong cytochrome P450 (CYP)3A4 inducers within 14 days before the first dose of the study drug.
14. Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV), and/or ST elevation myocardial infarction within 6 months before first dose, or severe symptomatic pulmonary hypertension requiring pharmacologic therapy, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. • Patient who has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, or cardiovascular disease that, in the medical judgement of the investigator, may compromise the delivery of pevonedistat, venetoclax, and/or azacitidine. • Patients with uncontrolled coagulopathy or bleeding disorder. (Please refer to protocol for complete list of all exclusion criteria)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint of the study is EFS defined as failure to achieve CR/CRi, relapse from CR/CRi, or death.

Secondary endpoints 4

1. The key secondary endpoint is OS (Overall Survival) defined as the time from randomization to death from any cause.
2. 30- and 60-day mortality rates defined as the proportion of patients who survive at most 30/60 days from the first dose of study drug(s).
3. Disease response rates as evaluated by IRC: – CR rate – CCR (CR + CRi) rate – ORR (CR + CRi + PR) rate – CR + CRh rate – Leukemia response rate (CR + CRi + PR + MLFS [marrow CR])
4. Duration of CR and CRi. • Time to first CR, CRi, and PR. • Pevonedistat plasma concentration time.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Takeda Development Center Americas Inc.

Sponsor organisation

Takeda Development Center Americas Inc.

Address

95 Hayden Avenue

City

Lexington

Postcode

02421-7942

Country

United States

Scientific contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Farhad Sedarati

Public contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Takeda

Third parties 4

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications