A Randomized, Placebo‐Controlled Phase III Study of Induction and Consolidation Chemotherapy With Venetoclax in Adult Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome With Excess Blasts‐2

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Ulm AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

13 Sep 2022 → ongoing

Decision date (initial)

2025-01-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-507518-28-00

EudraCT number

2020-004453-71

ClinicalTrials.gov

NCT04628026

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To assess if treatment with venetoclax, as compared to placebo, in combination with induction and consolidation therapy prolongs event-free survival (EFS) in adult patients with newly diagnosed AML, defining not achieving of CR or CRi as treatment failure.

Secondary objectives 9

1. To assess if treatment with venetoclax, as compared to placebo, in combination with induction and consolidation therapy prolongs overall survival (OS) of adult patients with newly diagnosed AML.
2. To assess the impact of venetoclax on CR/CRi rate by the end of induction chemotherapy in newly diagnosed AML patients.
3. To assess the impact of venetoclax on CR rates by the end of induction chemotherapy in newly diagnosed AML patients.
4. To assess the impact of venetoclax on the rate of CR, CR/CRh and CR/CRi without measurable residual disease (CRMRD-, CR/CRhMRD-, CR/CRiMRD-) by the end of induction chemotherapy in newly diagnosed AML patients.
5. To evaluate the impact of venetoclax on relapse-free survival (RFS) in newly diagnosed AML patients.
6. To evaluate cumulative incidence of relapse (CIR) and death (CID) in newly diagnosed AML patients.
7. To evaluate the impact of venetoclax on quality of life among AML patients as assessed by: EQ-5D-5L visual analogue scale (VAS); EORTC-QLQ-C30 global health status/QoL scale and QLQ-C30 subdomains; PROMIS Cancer Fatigue short form, version 7a
8. To assess if treatment with venetoclax, as compared to placebo, in combination with induction and connewly diagsolidation therapy prolongs event-free survival (EFS) in adult patients with nosed AML, defining not achieving of CR, CRh or CRi as treatment failure.
9. To assess the impact of venetoclax on CR/CRh rate by the end of induction chemotherapy in newly diagnosed AML patients.

Conditions and MedDRA coding

Acute myeloid leukemia

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Patients with newly diagnosed acute myeloid leukemia (AML) according to the International Consensus Classification (ICC)
2. Age ≥ 18 years and ≤ 75 years
3. Patients considered eligible for intensive chemotherapy
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
5. Molecular analysis centrally performed in AMLSG and HOVON laboratories.
6. Adequate renal function as evidenced by serum creatinine ≤ 2.0 × upper limit of normal (ULN) or creatinine clearance >40 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR).
7. Adequate hepatic function as evidenced by: o Serum total bilirubin ≤ 2.5 × ULN unless considered due to Gilbert’s disease, or leukemic involvement following approval by the Principal Investigators or Trial Coordinator of the study o Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following approval by the Principal Investigators or Trial Coordinators of the study
8. No prior chemotherapy for AML except hydroxyurea for up to 14 days during the diagnostic screening phase for the control of peripheral leukemic blasts in patients with leukocytosis (e.g., white blood cell [WBC] counts > 25x109/L); patients may have had previous treatment with erythroid stimulating agents (ESA) or hypomethylating agents (HMAs) for an antecedent phase of MDS; ESA and HMAs have to be stopped at least four weeks before start of study treatment.
9. Patients must not have received a known strong or moderate CYP3A inducer 7 days before start of study treatment. Patients must have no known medical conditions requiring chronic therapy of moderate or strong CYP3A inducers.
10. Female patient must either: o Be of nonchildbearing potential: • Postmenopausal (defined as at least 1 year without any menses) • Documented surgically sterile (e.g. documented hysterectomy, bilateral oophorectomy, bilateral salpingectomy or congenital sterile) or status posthysterectomy (at least 1 month prior to screening) o Or, if of childbearing potential (not surgically sterile and not postmenopausal) • Not planning to become pregnant during the study and for 27 weeks after the final study drug administration • And have a negative urine or serum pregnancy test at screening • And, if heterosexually active, agree to consistently apply one highly effective* method of birth control in combination to a barrier method for the duration of the study and for 27 weeks after the final study drug administration. *Highly effective forms of birth control include  Consistent and correct usage of established hormonal contraceptives that inhibit ovulation, for at least 1 month prior to taking study drug. (Hormonal contraception is only a highly effective method of birth control, if a combined (estrogen and progestogen containing) hormonal contraception or a progestogen-only hormonal contraception – both associated with inhibition of ovulation - is used.)  Established intrauterine device (IUD) or intrauterine system (IUS),  Bilateral tubal occlusion,  Vasectomy - a vasectomy is a highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.  Male is sterile due to a bilateral orchiectomy.  Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. *List is not all inclusive. Prior to enrolment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control in combination with a barrier method according to locally accepted standards during the protocol defined period. • Female patient must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration. • Female patient must not donate ova starting at screening and throughout the study period, and for 27 weeks after the final study drug administration.
11. Men must use a latex condom during any sexual contact with WOCBP, even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 27 weeks after the final study drug administration). In addition, their female partners of childbearing potential have to use a highly effective method of birth control.
12. Male patient must not donate sperm starting at screening and throughout the study period and for 6 months after the final study drug administration.
13. Able to understand and willing to sign an informed consent form (ICF).

Exclusion criteria 18

1. Acute promyelocytic leukemia (APL) with t(15;17)(q24.1;q21.1); PML-RARA; or one of the other pathognomonic variant chromosomal translocations/ fusion genes.
2. AML with t(9;22)(q34.1;q11.2);BCR::ABL1; or myeloid blast crisis of CML.
3. Patients with AML and activating FLT3 mutations who have access (including reimbursement) to treatment with a FLT3 inhibitor approved for first-line therapy of AML.
4. Prior treatment of MDS with intensive chemotherapy or allogeneic hematopoietic cell transplantation (HCT) with a curative intent
5. Significant active cardiac disease within 6 months prior to the start of study treatment, including: o New York Heart Association (NYHA) class III or IV congestive heart failure; o Myocardial infarction; o Unstable angina and/or stroke; o Severe cardiac arrhythmias o Left ventricular ejection fraction (LVEF) <40% by ultrasound obtained within 28 days prior to the start of study treatment.
6. Severe obstructive or restrictive ventilation disorder.
7. Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required, if there is a clinical suspicion of CNS involvement by leukemia during screening.
8. Active infection, including hepatitis B or hepatitis C antibody or Human Immunodeficiency Virus (HIV) infection, that is uncontrolled prior to first dose of study treatment and may interfere with the study objectives or which could expose the patient to undue risk through the participation in the clinical trial; an infection controlled with an approved antibiotic/ antiviral/ antifungal treatment that is not a strong or moderate CYP3A inducer is allowed.
9. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation.
10. Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
11. Patients with a currently active second malignancy. Patients are not considered to have a currently active malignancy, if they have completed therapy and are considered by their physician to be at <30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed: o Basal or squamous cell carcinoma of the skin; o Carcinoma in situ of the cervix; o Carcinoma in situ of the breast; o Incidental histologic finding of prostate cancer.
12. Receipt of live, attenuated vaccine within 30 days prior to the study inclusion (NOTE: patients, if enrolled, should not receive live vaccine during the study and until 6 months after the therapy).
13. Severe neurological or psychiatric disorder interfering with ability to give an informed consent.
14. Known or suspected hypersensitivity to any of the chemotherapeutic agents used.
15. No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician about study participation.
16. No consent for biobanking of patient’s biological specimens.
17. Participation in other prospective studies with anti-leukemic and/or investigational agents.
18. The patient is a pregnant or lactating woman, or plans to become pregnant during the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. EFS in adult patients with newly diagnosed AML, defined as the time from randomization to treatment failure, death from any cause, relapse after achieving CR or CRi, or start of new (non-study) therapy due to confirmed molecular progression or relapse whichever occurs first. Treatment failure is defined as not attaining CR or CRi by induction chemotherapy, and EFS event time for treatment failure is date of randomization.

Secondary endpoints 10

1. Overall survival (OS) in newly diagnosed AML patients, defined as the time from randomization to death due to any cause. Patients still alive or lost to follow up will be censored at the time they were last known to be alive.
2. Rate of complete remission (CR) or CR with incomplete blood count recovery (CRi) rate in newly diagnosed AML patients defined as the proportion of AML patients with CR/CRi by the end of induction chemotherapy.
3. Complete remission (CR) rates in newly diagnosed AML patients defined as the proportion of AML patients with CR by the end of induction chemotherapy.
4. Rates of CR CR/CRh, and CR/CRi without measurable residual disease (CRMRD-, CR/CRhMRD-, CR/CRiMRD-) by the end of induction therapy, defined as the proportion of AML patients achieving CR, CR/CRh and CR/CRi with negativity for a genetic marker by RT-qPCR, and/or with negativity by multi-parameter flow cytometry, if studied pre-treatment.
5. Relapse-free survival (RFS) in newly diagnosed AML patients, defined as the time from achievement of a remission (CR/CRh/CRi) following induction therapy, to morphologic relapse, start of new (non-study) therapy due to confirmed molecular progression or relapse or death from any cause. Patients who are not known to have relapsed, died or started new therapy due to confirmed molecular progression or relapse will be censored at the date of last clinical response assessment.
6. Cumulative incidence of relapse (CIR) in newly diagnosed AML patients, measured from the date of achievement of a remission (CR/CRh/CRi) to date of relapse, or date of start of new (non-study) therapy due to confirmed molecular progression or relapse. Death in remission will be considered as a competing event. Patients who are not known to have relapsed, died or started new therapy due to molecular progression or relapse will be censored at the date of last clinical response assessment.
7. Cumulative incidence of death (CID) in newly diagnosed AML patients, measured from the date of achievement of a remission (CR/CRh/CRi) to death without prior relapse (may it be morphologic relapse or confirmed molecular progression or relapse with subsequent start of new non-study therapy). Relapse after achieving CR/CRh/CRi or start of new therapy due to confirmed molecular progression or relapse will be considered as a competing event.
8. Quality of life among AML patients as assessed by o EQ-5D-5L visual analogue scale (VAS) among AML patients o EORTC-QLQ-C30 global health status/QoL scale and QLQ-C30 subdomains and o PROMIS Cancer Fatigue short form, version 7a.
9. Event-free survival in newly diagnosed AML patients, defined as the time from randomization to treatment failure, death from any cause, relapse after achieving CR, CRh or CRi, or start of new (non-study) therapy due to confirmed molecular progression or relapse whichever occurs first. Treatment failure is defined as not attaining CR, CRh or CRi by induction chemotherapy, i.e. if a patient’s best response during or at completion of the induction treatment is less than CR/CRh/CRi.
10. Rate of complete remission (CR) or CR with partial hematologic recovery (CRh) in newly diagnosed AML patients defined as the proportion of AML patients with CR/CRh by the end of induction chemotherapy.

Investigational products

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

Test 3

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Ulm AöR

Sponsor organisation

Universitaetsklinikum Ulm AöR

Address

Albert-Einstein-Allee 29, Eselsberg Eselsberg

City

Ulm

Postcode

89081

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Ulm AöR

Contact name

Hartmut Doehner

Public contact point

Organisation

Universitaetsklinikum Ulm AöR

Contact name

Hartmut Doehner

Third parties 12

Locations

8 EU/EEA countries · 90 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 43 files

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

Application history

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