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

Официальное название

A Modular Phase I/II, Open-label, Multi-Centre Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy 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

Обзор

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.

Подробное описание

This is a first in human (FTiH), open-label, multi-centre study of AZD3632 in participants with relapsed or refractory acute leukaemia or myelodysplastic Syndromes (MDS) with HOX overexpression genotypes.

This study includes multiple modules (module 1 and module 2) each investigating AZD3632 in a specific population and/or in combination with other anticancer agents.

Module 1 is a dose escalation of AZD3632 monotherapy. Module 2 will investigate the safety, PK, and tolerability when co-administered with posaconazole.

Вмешательства

• Препарат AZD3632
  AZD3632 will be administered orally.
• Препарат Posaconazole
  Posaconazole will be administered orally.

Первичные конечные точки

• Module 1: Number of participants with dose-limiting toxicity (DLT) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: Up to 30 days after last dose (approximately 3 years 1 month)]

Вторичные конечные точки (12)

• Module 1 and Module 2: Maximum concentration (Cmax) of AZD3632 [Срок оценки: From Day 1 to 3 years 1 month]
• Module 1 and Module 2: Time of maximum concentration (Tmax) of AZD3632 [Срок оценки: From Day 1 to 3 years 1 month]
• Module 1: Trough concentration (Ctrough) of AZD3632 [Срок оценки: From Day 1 to 3 years 1 month]
• Module 1: Area under the plasma concentration-time Curve from Time Zero to Infinity (AUC[inf]) of AZD3632 [Срок оценки: From Day 1 to 3 years 1 month]
• Module 1 and Module 2: Area under the curve from time 0 to the time of last measurable concentration (AUC[0-t]) of AZD3632 [Срок оценки: From Day 1 to 3 years 1 month]
• Module 1: Area under concentration-time curve in the dosing interval (AUCtau) of AZD3632 [Срок оценки: From Day 1 to 3 years 1 month]
• Module 1: Apparent total body clearance (CL/F) of AZD3632 [Срок оценки: From Day 1 to 3 years 1 month]
• Module 1: Apparent volume of distribution based on the terminal phase (VZ/F) of AZD3632 [Срок оценки: From Day 1 to 3 years 1 month]
• Module 1: Half-life (t1/2) of AZD3632 [Срок оценки: From Day 1 to 3 years 1 month]
• Module 1: Maximum concentration (Cmax) of AZD3632 (food effect) [Срок оценки: From Day 1 to 3 years 1 month]
• Module 1: Time of maximum concentration (Tmax) of AZD3632 (food effect) [Срок оценки: From Day 1 to 3 years 1 month]
• Module 1 and Module 2: Area under the curve from time 0 to the time of last measurable concentration (AUC[0-t]) of AZD3632 (food effect) [Срок оценки: From Day 1 to 3 years 1 month]

Критерии участия

Критерии включения

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.

Критерии исключения

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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 6 центров

• Research Site — Decatur
• Research Site — New York
• Research Site — Chapel Hill
• Research Site — Durham
• Research Site — Portland
• Research Site — Houston

Германия · 6 центров

• Research Site — Dresden
• Research Site — Frankfurt A. Main
• Research Site — Halle
• Research Site — Heidelberg
• Research Site — München
• Research Site — Ulm

Великобритания · 5 центров

• Research Site — Edinburgh
• Research Site — London
• Research Site — London
• Research Site — Manchester
• Research Site — Newcastle

Япония · 3 центра

• Research Site — Bunkyō City
• Research Site — Kashiwa
• Research Site — Okayama

South Korea · 3 центра

• Research Site — Seoul
• Research Site — Seoul
• Research Site — Seoul

Австралия · 2 центра

• Research Site — Fitzroy
• Research Site — Perth

Канада · 2 центра

• Research Site — Toronto
• Research Site — Montreal

Италия · 2 центра

• Research Site — Bologna
• Research Site — Ravenna

Дания · 1 центр

• Research Site — Copenhagen

Идентификаторы

NCT: NCT07155226 · D8620C00001 · 2025-521299-76-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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