The purpose of this study is to understand the safety, tolerability, efficacy, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy of orally administered AZD3632 in participants with advanced haematologic malignancies with KMT2Ar, NPM1m, or other genotypes associated with homeobox (HOX) overexpression.
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.
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.
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.
Sequential
AZD3632
DrugAZD3632 will be administered orally.
Posaconazole
DrugPosaconazole will be administered orally.
7
Treatment groupsSee each treatment group below.
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.
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.
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.
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.
Module 1 and Module 2: Time of maximum concentration (Tmax) of AZD3632
The PK of AZD3632 as monotherapy (module 1) and in combination with posaconazole (module 2) will be assessed.
Module 1: Trough concentration (Ctrough) of AZD3632
The PK of AZD3632 as monotherapy will be assessed.
Module 1: Area under the plasma concentration-time Curve from Time Zero to Infinity (AUC[inf]) of AZD3632
The PK of AZD3632 as monotherapy will be assessed.
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