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
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.
Arms & interventions
- DrugAZD3632
AZD3632 will be administered orally.
- DrugPosaconazole
Posaconazole will be administered orally.
Outcome measures
Primary
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
Module 1 and Module 2: Maximum concentration (Cmax) of AZD3632
Time frame: From Day 1 to 3 years 1 month
Module 1 and Module 2: Time of maximum concentration (Tmax) of AZD3632
Time frame: From Day 1 to 3 years 1 month
Module 1: Trough concentration (Ctrough) of AZD3632
Time frame: 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
Time frame: 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
Time frame: From Day 1 to 3 years 1 month
Module 1: Area under concentration-time curve in the dosing interval (AUCtau) of AZD3632
Time frame: From Day 1 to 3 years 1 month
Module 1: Apparent total body clearance (CL/F) of AZD3632
Time frame: From Day 1 to 3 years 1 month
Module 1: Apparent volume of distribution based on the terminal phase (VZ/F) of AZD3632
Time frame: From Day 1 to 3 years 1 month
Module 1: Half-life (t1/2) of AZD3632
Time frame: From Day 1 to 3 years 1 month
Module 1: Maximum concentration (Cmax) of AZD3632 (food effect)
Time frame: From Day 1 to 3 years 1 month
Module 1: Time of maximum concentration (Tmax) of AZD3632 (food effect)
Time frame: 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)
Time frame: From Day 1 to 3 years 1 month
Module 1: Area under concentration-time curve in the dosing interval (AUCtau) of AZD3632 (food effect)
Time frame: From Day 1 to 3 years 1 month
Module 1: Minimum concentration (Cmin) of AZD3632 (food effect)
Time frame: From Day 1 to 3 years 1 month
Module 1: Ratio of Cmax between fed and fasted state
Time frame: From Day 1 to 3 years 1 month
Module 1: Ratio of AUC(0-t) between fed and fasted state
Time frame: From Day 1 to 3 years 1 month
Module 1: Ratio of AUCtau between fed and fasted state
Time frame: From Day 1 to 3 years 1 month
Module 2: Plasma geometric mean ratio of Cmax
Time frame: From Day 1 to 3 years 1 month
Module 2: Plasma geometric mean ratio of AUC
Time frame: From Day 1 to 3 years 1 month
Module 2: Plasma concentration of posaconazole
Time frame: From Day 1 to 3 years 1 month
Module 1 and Module 2: Complete response rate (CR + CRh)
Time frame: Up to 3 years 1 month
Module 1 and Module 2: Time to response (TTR)
Time frame: Up to 3 years 1 month
Module 1 and Module 2: Duration of response (DoR)
Time frame: Up to 3 years 1 month
Module 1 and Module 2: Transfusion Independence (TI)
Time frame: Up to 3 years 1 month
Module 1 and Module 2: Event-free Survival (EFS)
Time frame: 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)
Time frame: 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)
Time frame: Up to 3 years 1 month
Module 1 and Module 2: Overall Response Rate (ORR)
Time frame: Up to 3 years 1 month
Module 1 and Module 2: Time to Progression to acute myeloid leukaemia (AML)
Time frame: Up to 3 years 1 month
Eligibility criteria
Study locations (6)
Research Site
Decatur, Illinois, 62526
Research Site
New York, New York, 10065
Research Site
Chapel Hill, North Carolina, 27599
Research Site
Durham, North Carolina, 27705
Research Site
Portland, Oregon, 97239
Research Site
Houston, Texas, 77030