NCT07155226 - Study of AZD3632 Monotherapy or in Combination With Anticancer Agents in Participants With Advanced Haematologic Malignancies With KMT2Ar, NPM1m, or Other Genotypes Associated With HOX Overexpression | Crick

Eligibility

Sex: ALLMin age: 16 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: Core criteria: * Adequate organ function. * Contraceptive use by participants or participant partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Module 1: * Advanced haematologic malignancy - a) for dose escalation - diagnosis of acute leukemia or myelodysplastic neoplasia (MDS) and harbouring one of the genetic alterations per local testing associated with upregulation of HOX; b) for Backfill - diagnosis of harbouring a KMT2Ar or NPM1m per local testing. * Participants must have measurable disease that is relapsed/refractory to conventional therapies known to be effective for their disease and not have any available approved therapies.: a) Relapsed and primary refractory acute leukaemia after standard of care therapy including but not limited to 2 cycles of intensive chemotherapy, hypomethylating agent (HMA) monotherapy, or HMA combinations such as HMA/venetoclax.; b) Relapsed and primary refractory MDS is defined by ≥ 5% blasts in the bone marrow and/or persistence of peripheral blasts after treatment with at least 2 cycles of HMA. Participants ineligible for the treatment with an HMA and without any other standard of care (SoC) options are allowed to enrol; c) White blood cell count below 25,000/μL. Participants may receive cytoreduction per protocol-specified criteria; d) Performance status: Eastern Cooperative Operative Group (ECOG) ≤ 2; e) Life expectancy: ≥ 8 weeks. Module 2: * Participants must have measurable disease that is relapsed/refractory to conventional therapies known to be effective for their disease and not have any available approved therapies.: a) Relapsed and primary refractory acute leukaemia after standard of care therapy including but not limited to 2 cycles of intensive chemotherapy, HMA monotherapy, or HMA combinations such as HMA/venetoclax.; b) Relapsed and primary refractory MDS is defined by ≥ 5% blasts in the bone marrow and/or persistence of peripheral blasts after treatment with at least 2 cycles of HMA. Participants ineligible for the treatment with an HMA and without any other SoC options are allowed to enrol; c) White blood cell count below 25,000/μL. Participants may receive cytoreduction per protocol-specified criteria; d) Performance status: ECOG ≤ 2; e) Life expectancy: ≥ 8 weeks. Key Exclusion Criteria: Core criteria: * Participants with Burkitt lymphoma/leukaemia or Acute Promyelocytic Leukaemia. * Active testicular or active central nervous system (CNS) (\> CNS1 or radiographic) involvement by leukaemia. * Unresolved treatment-related toxicities Grade ≥ 2 from prior therapy. * Abnormal levels of potassium or magnesium prior to first dose of AZD3632. Module 1: * Receipt of non-CNS radiation therapy within 2 weeks and of CNS radiation within 8 weeks of the first scheduled dose. * Receipt of any investigational or non-investigational anticancer agents, including non-biologic agents, biologic agents and/or prior treatment other menin inhibitors (backfill participants only). * For nested food effect participants - diagnosis of diabetes mellitus (Type I or Type II). Module 2: * Receipt of any non-investigational anticancer agents, including non-biologic agents and/or biologic agents or receipt of non-CNS or CNS radiation therapy. * Participants for whom treatment with posaconazole is contraindicated per the local prescribing information.

Outcomes

Primary Outcomes

Module 1: Number of participants with dose-limiting toxicity (DLT)

Safety and tolerability of AZD3632 monotherapy in participants with advanced haematologic malignancies will be assessed.

Time frame: At the end of Cycle 1 (each cycle is 28 days)

Module 1 and Module 2: Number of participants with dose modification, delay and discontinuations due to adverse events (AEs)

Safety and tolerability of AZD3632 monotherapy in participants with advanced haematologic malignancies will be assessed.

Time frame: Up to 3 years 1 month

Module 1 and Module 2: Number of participants with treatment-emergent adverse events (TEAEs), treatment-related AEs (TRAEs) and serious adverse vents (SAEs)

Safety and tolerability of AZD3632 monotherapy in participants with advanced haematologic malignancies will be assessed. Adverse events will be defined as treatment-emergent if they have an onset or worsen (by investigator report of a change in intensity) during the study treatment or the safety follow-up period but prior to any subsequent cancer therapy.

Time frame: Up to 30 days after last dose (approximately 3 years 1 month)

Secondary Outcomes

Module 1 and Module 2: Maximum concentration (Cmax) of AZD3632

The PK of AZD3632 as monotherapy (module 1) and in combination with posaconazole (module 2) will be assessed.