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
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- AstraZeneca
- Enrollment
- 84
- Locations
- 30
- Primary Endpoint
- Module 1: Number of participants with dose-limiting toxicity (DLT)
Study Overview
Brief Summary
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.
Detailed Description
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 16 Years to — (Child, Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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.
- •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 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.
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 AZD
- •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).
- •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.
Arms & Interventions
Module 1: AZD3632 dose 6
Participants will receive AZD3632 (dose 6) through the treatment period.
Intervention: AZD3632 (Drug)
Module 2: AZD3632 + posaconazole
Participants will receive AZD3632 alone, then will receive AZD3632 in combination with posaconazole through treatment period.
Intervention: AZD3632 (Drug)
Module 1: AZD3632 dose 2
Participants will receive AZD3632 (dose 2) through the treatment period.
Intervention: AZD3632 (Drug)
Module 1: AZD3632 dose 3
Participants will receive AZD3632 (dose 3) through the treatment period.
Intervention: AZD3632 (Drug)
Module 1: AZD3632 dose 1
Participants will receive AZD3632 (dose 1) through the treatment period.
Intervention: AZD3632 (Drug)
Module 2: AZD3632 + posaconazole
Participants will receive AZD3632 alone, then will receive AZD3632 in combination with posaconazole through treatment period.
Intervention: Posaconazole (Drug)
Module 1: AZD3632 dose 5
Participants will receive AZD3632 (dose 5) through the treatment period.
Intervention: AZD3632 (Drug)
Module 1: AZD3632 dose 4
Participants will receive AZD3632 (dose 4) through the treatment period.
Intervention: AZD3632 (Drug)
Outcomes
Primary Outcomes
Module 1: Number of participants with dose-limiting toxicity (DLT)
Time Frame: At the end of Cycle 1 (each cycle is 28 days)
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)
Time Frame: Up to 3 years 1 month
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)
Time Frame: Up to 30 days after last dose (approximately 3 years 1 month)
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: Number of participants with dose-limiting toxicity (DLT)
Time Frame: At the end of Cycle 1 (each cycle is 28 days)
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)
Time Frame: Up to 3 years 1 month
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)
Time Frame: Up to 30 days after last dose (approximately 3 years 1 month)
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.
Secondary Outcomes
- Module 1 and Module 2: Complete response rate (CR + CRh)(Up to 3 years 1 month)
- Module 1 and Module 2: Maximum concentration (Cmax) of AZD3632(From Day 1 to 3 years 1 month)
- Module 1 and Module 2: Time of maximum concentration (Tmax) of AZD3632(From Day 1 to 3 years 1 month)
- Module 1: Trough concentration (Ctrough) of AZD3632(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(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(From Day 1 to 3 years 1 month)
- Module 1: Ratio of Cmax between fed and fasted state(From Day 1 to 3 years 1 month)
- Module 1: Ratio of AUC(0-t) between fed and fasted state(From Day 1 to 3 years 1 month)
- Module 1: Ratio of AUCtau between fed and fasted state(From Day 1 to 3 years 1 month)
- Module 2: Plasma geometric mean ratio of Cmax(From Day 1 to 3 years 1 month)
- Module 2: Plasma geometric mean ratio of AUC(From Day 1 to 3 years 1 month)
- Module 2: Plasma concentration of posaconazole(From Day 1 to 3 years 1 month)
- Module 1 and Module 2: Time to response (TTR)(Up to 3 years 1 month)
- Module 1 and Module 2: Duration of response (DoR)(Up to 3 years 1 month)
- Module 1 and Module 2: Transfusion Independence (TI)(Up to 3 years 1 month)
- Module 1 and Module 2: Event-free Survival (EFS)(From Cycle 2 Day 1 (each cycle is 28 days) up to disease follow-up (approximately 3 years 1 month))
- Module 1 and Module 2: Overall Survival (OS)(From Cycle 2 Day 1 (each cycle is 28 days) up to disease follow-up (approximately 3 years 1 month))
- Module 1 and Module 2: Percentage of participants who receive subsequent allogeneic hematopoietic stem cell transplant (HSCT)(Up to 3 years 1 month)
- Module 1 and Module 2: Overall Response Rate (ORR)(Up to 3 years 1 month)
- Module 1 and Module 2: Time to Progression to acute myeloid leukaemia (AML)(Up to 3 years 1 month)
- Module 1: Minimum concentration (Cmin) of AZD3632 (food effect)(From Day 1 to 3 years 1 month)
- Module 1: Ratio of Cmax between fed and fasted state(From Day 1 to 3 years 1 month)
- Module 1: Ratio of AUC(0-t) between fed and fasted state(From Day 1 to 3 years 1 month)
- Module 1 and Module 2: Overall Survival (OS)(From Cycle 2 Day 1 (each cycle is 28 days) up to disease follow-up (approximately 3 years 1 month))
- Module 1 and Module 2: Percentage of participants who receive subsequent allogeneic hematopoietic stem cell transplant (HSCT)(Up to 3 years 1 month)
- Module 1: Ratio of AUCtau between fed and fasted state(From Day 1 to 3 years 1 month)
- Module 2: Plasma geometric mean ratio of Cmax(From Day 1 to 3 years 1 month)
- Module 2: Plasma geometric mean ratio of AUC(From Day 1 to 3 years 1 month)
- Module 2: Plasma concentration of posaconazole(From Day 1 to 3 years 1 month)
- Module 1 and Module 2: Complete response rate (CR + CRh)(Up to 3 years 1 month)
- Module 1 and Module 2: Overall Response Rate (ORR)(Up to 3 years 1 month)
- Module 1 and Module 2: Maximum concentration (Cmax) of AZD3632(From Day 1 to 3 years 1 month)
- Module 1 and Module 2: Time of maximum concentration (Tmax) of AZD3632(From Day 1 to 3 years 1 month)
- Module 1: Trough concentration (Ctrough) of AZD3632(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(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(From Day 1 to 3 years 1 month)
- Module 1: Area under concentration-time curve in the dosing interval (AUCtau) of AZD3632(From Day 1 to 3 years 1 month)
- Module 1: Apparent total body clearance (CL/F) of AZD3632(From Day 1 to 3 years 1 month)
- Module 1: Apparent volume of distribution based on the terminal phase (VZ/F) of AZD3632(From Day 1 to 3 years 1 month)
- Module 1: Half-life (t1/2) of AZD3632(From Day 1 to 3 years 1 month)
- Module 1: Maximum concentration (Cmax) of AZD3632 (food effect)(From Day 1 to 3 years 1 month)
- Module 1: Time of maximum concentration (Tmax) of AZD3632 (food effect)(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)(From Day 1 to 3 years 1 month)
- Module 1: Area under concentration-time curve in the dosing interval (AUCtau) of AZD3632 (food effect)(From Day 1 to 3 years 1 month)
- Module 1 and Module 2: Time to response (TTR)(Up to 3 years 1 month)
- Module 1 and Module 2: Duration of response (DoR)(Up to 3 years 1 month)
- Module 1 and Module 2: Transfusion Independence (TI)(Up to 3 years 1 month)
- Module 1 and Module 2: Event-free Survival (EFS)(From Cycle 2 Day 1 (each cycle is 28 days) up to disease follow-up (approximately 3 years 1 month))
- Module 1 and Module 2: Time to Progression to acute myeloid leukaemia (AML)(Up to 3 years 1 month)