A Study to Assess How Well the Study Medicine IPN60340 Works in Combination With Azacitidine and Venetoclax, Compared to Placebo in Combination With Azacitidine and Venetoclax, in Participants With Newly Diagnosed Acute Myeloid Leukemia Who Cannot Receive Intensive Chemotherapy

Phase 3Not Yet RecruitingNCT07623187

Ipsen540 enrolled

Overview

The purpose of this study is to find out how well the study drug IPN60340 works to treat participants with acute myeloid leukemia. Acute myeloid leukemia is a rare blood cancer that grows quickly. This study's main aim is to compare the percentage of participants who reach complete remission within the first 6 months of treatment between the 2 study arms (study drug and standard medicines compared to placebo and standard medicines). In this study all participants will receive azacitidine and venetoclax plus either the study drug IPN60340 or placebo. Venetoclax will be given as a tablet by mouth once each day in 28-day cycles. Azacitidine will be given by injection under the skin (subcutaneously) or through the veins (intravenously) daily for the first 7 days of each 28-day cycle. IPN60340 or placebo (depending on which arm of the study the participant is assigned to) will be given through the veins (intravenously) on day 1 of each 28-day cycle. There will be 4 periods in this study: * A screening period (up to 28 days) to assess whether the participant can take part requiring at least 1 visit to the study center. * A treatment period where all eligible participants will receive azacitidine and venetoclax plus either the study drug IPN60340 or placebo. The study requires 8 visits for the first month followed by 1 visit every month until unacceptable toxicity, disease progression, the start of new cancer treatment, or study closure, whichever is first. * A safety follow-up period (at 28 days (±3 days) after the last dose of study medicine) to assess safety after participants have finished treatment. * A long-term follow-up period where participants' health will be monitored using a telephone call or clinic visit every 12 weeks until the end of study. Participants will undergo blood sampling, urine collections, physical examinations, clinical evaluations, electrocardiograms (ECG: recording of the electrical activity of heart), bone marrow aspirates (sampling of the liquid part of the bone marrow). Some participants will also undergo pregnancy testing. Participants in the Phase 3 portion of the study will also be asked to fill in questionnaires. The time each participant will be in this study will vary based on how well the medicine works to treat the participant's AML. Azacitidine and venetoclax plus either IPN60340 or placebo will be provided to participants who tolerate it for as long as their disease does not progress. Participants may withdraw consent to participate at any time.

Study Type

INTERVENTIONAL

Allocation

Interventions

IPN60340 + azacitidine + venetoclaxBIOLOGICAL

: IPN60340 + azacitidine + venetoclax Participants will receive: * IPN60340 per protocol by intravenous (IV) infusion in each 28-day treatment cycle * azacitidine by subcutaneous (SC) or IV daily for the first week in each 28-day treatment cycle * venetoclax orally daily every day of each 28-day treatment cycle

Placebo + azacitidine + venetoclaxDRUG

Participants will receive: * Placebo per protocol by intravenous (IV) infusion in each 28-day treatment cycle * azacitidine by subcutaneous (SC) or IV daily for the first week in each 28-day treatment cycle * venetoclax orally daily every day of each 28-day treatment cycle

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Participant must be 18 years of age or older, at the time of signing the informed consent. 2. Have newly diagnosed AML, as per WHO 2022 criteria. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 1 to 2 for participants ≥75 years of age, or 1 to 3 for participants \<75 years of age 4. Participants must be considered ineligible for intensive chemotherapy, due to age or comorbidities, 5. Adequate organ function as indicated in the protocol 6. Contraceptive use by participant or participant partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical trials. 7. Signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: 1. Current diagnosis of: I. Acute promyelocytic leukemia (APL) II. Active or uncontrolled central nervous system (CNS) leukemia III. Any γ9δ2TC neoplasm 2. History of myeloproliferative neoplasms (MPN) including primary myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia, or MDS/MPN as per WHO 2022 or treatment-related AML 3. History of other malignancy within the last 2 years. 4. Rapidly progressing disease in the opinion of the clinical investigator which may preclude treatment in this study. 5. History of clinically significant or uncontrolled cardiac disorders, within 6 months prior to Cycle 1 Day 1 (C1D1) 6. White blood cell (WBC) count \>25 × 10\^9/L . Cytoreduction can be used before C1D1 and beyond as needed to keep WBC \< 25 × 10\^9. 7. Participants with severe hepatic impairment, e.g., Child-Pugh C, are excluded. 8. Major surgery within 4 weeks prior to C1D1 or planned during the foreseeable duration of the study. 9. Any gastrointestinal disorder or malabsorption syndrome that may impair absorption of venetoclax 10. Uncontrolled or severe bacterial, fungal, viral, and/or parasitic infections treated with therapeutic oral or intravenous anti-infective agents. Prophylactic antimicrobials are allowed. 11. Uncontrolled human immunodeficiency virus (HIV) disease will be excluded. Participants on anti-retroviral therapy should be included as long as their disease is under control, taking precautions to modify their highly active antiretroviral therapy (HAART) regimen to minimize drug interactions. 12. Presence of hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (HBcAb) at screening or within 3 months prior to randomization. NOTE: Participants with known positive HBsAb may be randomized provided they are hepatitis B-vaccinated and have negative HBsAg and HBcAb. 13. Positive hepatitis C antibody test result at screening or within 3 months of randomization unless HCV-RNA negative test is documented. NOTE: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled if a confirmatory negative hepatitis C ribonucleic acid (RNA) test is obtained. 14. Participant has received strong and/or moderate cytochrome P450 (CYP)3A inducers within 7 days prior to the initiation of study treatment. 15. Participant is unable to swallow capsules or tablets 16. Prior treatment with hypomethylating agents, chemotherapy, B-cell lymphoma protein (BCL) 2 inhibitors, clinical trial therapy, cellular therapy or allogenic hematopoietic cell transplantation (HCT) for MDS. 17. Treatment with systemic corticosteroids of \>10 mg/day prednisone (or equivalent) or other systemic immunosuppressive medications within 5 half-lives prior to C1D1, or anticipated requirement for systemic immunosuppressive medications during the study. 18. Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator \[or medical monitor\], contraindicates participation in the study.

Outcomes

Primary Outcomes

(Phase 2b and Phase 3) Percentage of participants with Complete Remission (CR)

Complete remission (CR) as defined according to ELN 2022 criteria

Time frame: From randomization to end of Cycle 6 (approximately 6 months)

Secondary Outcomes

(Phase 2b) Overall Survival (OS)

Defined as time from randomization to the date of death from any cause

Time frame: From randomization until end of study (up to approximately 6 years)

(Phase 2b) Duration of Complete Remission (DoCR)

Defined as time from achievement of CR to hematological relapse or death from any cause, whichever occurs first

Time frame: From first documented CR until end of study (up to approximately 6 years)

(Phase 2b) Event-Free Survival (EFS)

Defined as time from randomization to the date of induction treatment failure (ITF), relapse from complete remission (CR), or death from any cause, whichever occurs first.

Time frame: From randomization to end of study (up to 6 years)

(Phase 2b) Composite Complete Remission Rate (CRc)

Composite complete remission (CRc), defined as the composite of complete remission (CR), complete remission with partial hematologic recovery (CRh), and complete remission with incomplete hematologic recovery (CRi), according to ELN 2022 criteria

Time frame: From randomization to end of Cycle 6 (approximately 6 months)

(Phase 2b) Complete Remission with Minimal Residual Disease Negative (CR MRD-negative)

Complete remission with minimal residual disease negativity (CR MRD-negative) according to ELN criteria

Time frame: From randomization to end of cycle 6 (6 months)

(Phase 2b) Composite Complete Remission with MRD Negative (CRc MRD-negative)

Composite complete remission (CRc), defined as CR, CRh, and CRi, with minimal residual disease (MRD) negativity according to ELN 2022 criteria

Time frame: From randomization to end of Cycle 6 (approximately 6 months)

(Phase 2b) Transfusion Independence (TI) Conversion Rate

Transfusion independence (TI) conversion rate, defined as a ≥56-day period without red blood cell (RBC) or platelet transfusion after start of treatment in participants requiring transfusion within 28 days prior to the first dose of study treatment.

Time frame: From randomization until end of study (up to approximately 6 years)

(Phase 2b) Percentage of participants with Treatment-Related Adverse Events (TEAEs)

TEAEs with severity grading according to the NCI CTCAE version 6.0, except the severity of CRS and ICANS which will be graded according to the ASTCT Consensus Grading Criteria, from the first administration of study drug up to 28 days after the last dose.

Time frame: From first administration of study drug up to 28 days after last dose

(Phase 3) Overall Survival (OS)

Overall survival (OS), defined as the time from randomization to death from any cause

Time frame: From randomization until end of study (up to approximately 6 years)

(Phase 3) Duration of Complete Remission (DoCR)

Duration of complete remission (DoCR), defined as the time from achievement of CR to hematological relapse or death from any cause, whichever occurs first

Time frame: From first documented CR until end of study (up to approximately 6 years)

(Phase 3) Event-Free Survival (EFS)

Event-free survival (EFS), defined as the time from randomization to induction treatment failure (ITF), relapse from CR, or death from any cause, whichever occurs first

Time frame: From randomization until end of study (up to approximately 6 years)

(Phase 3) Composite Complete Remission (CRc)

Composite complete remission (CRc), defined as CR, CRh, and CRi according to ELN 2022 criteria

Time frame: From randomization to end of Cycle 6 (approximately 6 months)

(Phase 3) Complete Remission with Minimal Residual Disease Negative (CR MRD-negative)

Complete remission with minimal residual disease negativity (CR MRD-negative) according to ELN criteria

Time frame: From randomization to end of Cycle 6 (approximately 6 months)

(Phase 3) Composite Complete Remission with MRD Negative (CRc MRD-negative)

Composite complete remission (CRc), defined as CR, CRh, and CRi, with MRD negativity

Time frame: From randomization to end of Cycle 6 (approximately 6 months)

(Phase 3) Transfusion Independence (TI) Conversion Rate

Time frame: From randomization until end of study (up to approximately 6 years)

(Phase 3) Change from baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) global health status, fatigue, and physical functioning subscales

Change from baseline in global health status, fatigue, and physical functioning subscales

Time frame: From baseline until end of study (up to approximately 6 years)

(Phase 3) Percentage of Participants Undergoing Hematopoietic Stem Cell Transplantation (HSCT)

Percentage of participants undergoing HSCT in remission following study treatment

Time frame: From baseline until end of study (up to approximately 6 years)

A Study to Assess How Well the Study Medicine IPN60340 Works in Combination With Azacitidine and Venetoclax, Compared to Placebo in Combination With Azacitidine and Venetoclax, in Participants With Newly Diagnosed Acute Myeloid Leukemia Who Cannot Receive Intensive Chemotherapy

Overview

Conditions

Interventions

Eligibility

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts