2025-521299-76-00
Not yet recruiting
Phase 1/2
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
Overview
- Phase
- Phase 1/2
- Status
- Not yet recruiting
- Sponsor
- AstraZeneca AB
- Enrollment
- 1
- Locations
- 1
- Primary Endpoint
- Module 1 - Incidence of DLT during the DLT evaluation period
Overview
Brief Summary
Module 1: Safety:
- To assess the safety and tolerability of AZD3632 monotherapy in participants with advanced haematologic malignancies
- To identify the optimal biologic dose (OBD) of AZD3632 Module 2: Safety:
- To assess the safety and tolerability of AZD3632 co-administered with posaconazole
Eligibility Criteria
- Ages
- 18 years to 65+ years (18-64 Years, 65+ Years)
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Adequate organ function
- •Module 2 - Advanced haematologic malignancy as specified below: Diagnosis of acute leukaemia according to the WHO 2022 or diagnosis of a myelodysplastic neoplasia (MDS) according to the WHO 2022 and harbouring one of the following genetic alterations (or equivalent gene nomenclature for each) per local testing associated with upregulation of HOX: i. NPM1 mutation ii. KMT2Ar – 11q23 rearrangements iii. KMT2A-PTD with normal karyotype iv. NPM1::MLF1 – t(3;5)(q25;q34) v. NUP98r – 11p15 rearrangements vi. SET::NUP214 – t(9;9)(q34;q34) vii. RUNX1::EVI1 – t(3;21)(q26;q22) viii. MYST3::CREBBP – t(8;16)(p11;p13) ix. CDX2::ETV6 – t(12;13)(p13;q12) x. CALM::AF10 – t(10;11)(p13;q14-21) xi. MN1::ETV6 – t(12;22)(p13;q12) xii. UBTF-TD with Normal karyotype
- •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
- •Contraceptive use by participants or participant partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
- •Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in the Protocol
- •Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics initiative research that supports the Genomic Initiative. Note: inclusion in the Genomics Initiative Research is optional, and participants will not be excluded from the study if they choose not to participate in this optional part of the study and consequently are not required to sign the Optional Genomics Initiative Consent Form.
- •Module 1 - Participants must be at least 18 years of age at the time of signing the informed consent. Note: In the UK, participants must be at least 16 years of age at the time of signing consent
- •Module 1 - Advanced haematologic malignancy as specified below: a) Dose Escalation: Diagnosis of acute leukaemia according to the World Health Organization (WHO) 2022 or diagnosis of a myelodysplastic neoplasia (MDS) according to the WHO 2022 and harbouring one of the following genetic alterations (or equivalent gene nomenclature for each) per local testing associated with upregulation of HOX: i. NPM1 mutation ii. KMT2Ar – 11q23 rearrangements iii. KMT2A-PTD with normal karyotype iv. NPM1::MLF1 – t(3;5)(q25;q34) v. NUP98r – 11p15 rearrangements vi. SET::NUP214 – t(9;9)(q34;q34) vii. RUNX1::EVI1 – t(3;21)(q26;q22) viii. MYST3::CREBBP – t(8;16)(p11;p13) ix. CDX2::ETV6 – t(12;13)(p13;q12) x. CALM::AF10 – t(10;11)(p13;q14-21) xi. MN1::ETV6 – t(12;22)(p13;q12) xii. UBTF-TD with Normal karyotype b) Backfill: Participants must have a diagnosis of AML or ALL/MPAL according to the WHO 2022 harbouring a KMT2Ar or NPM1m per local testing.
- •Module 1 - 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).
- •Module 1 - Additional Inclusion Criteria for Nested Food Effect participants: To participate in the nested food effect study, participants must: - Be at least 18 years of age. - For the fed assessment portion, be willing to fast overnight (for at least 10 hours) prior to consuming a high-fat meal
Exclusion Criteria
- •Participants with Burkitt lymphoma/leukaemia based on WHO 2022 (Alaggio et al, 2022) or Acute Promyelocytic Leukaemia based on WHO 2022 criteria (Khoury et al, 2022)
- •History of a prior non-haematological malignancy, except for adequately treated basal cell or squamous cell skin, carcinoma in situ, or other cancer from which the participant has been disease free with no evidence of recurrence for ≥ 2 years
- •Any severe and uncontrolled medical condition requiring treatment including but not limited to bleeding disorders, unstable respiratory, uncontrolled psychiatric illness, substance abuse, or social situations which in the investigator’s judgement substantially increase risk of incurring AEs or limit compliance with study requirements
- •Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal diseases, previous significant bowel resection, or other condition or procedure (eg, gastric bypass, gastroparesis) that would preclude adequate absorption of AZD3632 or inability to swallow the formulated product (tablets or capsules)
- •Receipt of live attenuated vaccine within 30 days before the first dose of study treatment(s)
- •Major surgery within 28 days of first dose of study treatment
- •Any concomitant medications known to be associated with Torsades de Pointes or QT/QTcF prolongation (must be discontinued at least 5 half-lives prior to the first dose of AZD3632). Note: Drugs with low risk of QT/QTc prolongation used as standard supportive therapies are permitted with caution (eg, diphenhydramine, famotidine, ondansetron, Bactrim)
- •Participation in another clinical study with a study intervention administered in the last 14 days or 5 half-lives whichever is shorter (for investigational biologic or cell therapies, refer to individual module exclusion criteria)
- •Participants with a known hypersensitivity to AZD3632 or any of the excipients of the product
- •Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
Outcomes
Primary Outcomes
Module 1 - Incidence of DLT during the DLT evaluation period
Module 1 - Incidence of DLT during the DLT evaluation period
Module 1 - Frequency of dose modifications, delays, and discontinuations due to AEs
Module 1 - Frequency of dose modifications, delays, and discontinuations due to AEs
Module 1 - Incidence TEAEs, TRAEs and SAEs
Module 1 - Incidence TEAEs, TRAEs and SAEs
Module 1 - Changes from baseline in laboratory evaluations, 12-lead ECGs, performance status, physical examination, and vital signs
Module 1 - Changes from baseline in laboratory evaluations, 12-lead ECGs, performance status, physical examination, and vital signs
Module 2 - Frequency of dose modifications, delays, and discontinuations due to AEs
Module 2 - Frequency of dose modifications, delays, and discontinuations due to AEs
Module 2 - Incidence of TEAEs, TRAEs, and SAEs
Module 2 - Incidence of TEAEs, TRAEs, and SAEs
Module 2 - Changes from baseline in laboratory evaluations, 12-lead ECGs, performance status, physical examination, and vital signs
Module 2 - Changes from baseline in laboratory evaluations, 12-lead ECGs, performance status, physical examination, and vital signs
Secondary Outcomes
- Module 1 - Plasma concentrations and PK parameters, including but not limited to Cmax, Tmax, Ctrough, AUCinf, AUC0-t, AUCtau, CL/F, Vz/F, and t1/2 of AZD3632 as permitted by the data (additional PK parameters may be determined where appropriate)
- Module 1 - Plasma concentrations and PK parameters, including but not limited to Cmax, Cmin, Tmax, AUC0-t, AUCtau under fasted and fed state
- Module 1 - Ratio of Cmax, AUC0-t and AUCtau between fed and fasted state
- Module 1 - Acute leukaemia: Complete Response (CR) / Complete Response with partial Haematologic recovery (CRh) rate
- Module 1 - Acute leukaemia: Time to response (TTR)
- Module 1 - Acute leukaemia: Duration of response (DoR)
- Module 1 - Acute leukaemia: Transfusion independence (TI)
- Module 1 - Acute leukaemia: Event-free survival (EFS)
- Module 1 - Acute leukaemia: Overall survival (OS)
- Module 1 - Acute leukaemia: Percentage of participants who receive subsequent allogeneic hematopoietic stem cell transplant (HSCT)
- Module 1 - Myelodysplastic Syndromes: Overall Response Rate (ORR): CR (or CR equivalent), Partial Response (PR), CRL, CRh, or haematologic improvement (HI)
- Module 1 - Myelodysplastic Syndromes: TTR, DoR, TI, Time to Progression to AML, EFS, OS, Percentage of participants who receive subsequent HSCT
- Module 2 - Plasma PK parameters including but not limited to (AUC0-t, Cmax, and Tmax) of AZD3632 after administration of AZD3632 alone and in combination with posaconazole
- Module 2 - Plasma GMR (Cmax and AUC) of AZD3632 evaluated with and without posaconazole
- Module 2 - Plasma PK of posaconazole
- Module 2 - Acute leukaemia: CR/CRh, TTR, DoR, TI, EFS, OS, percentage of participants who receive subsequent HSCT
- Module 2 - Myelodysplastic Syndromes: ORR, TTR, DoR, TI, Time to progression to AML, EFS, OS, percentage of participants who receive subsequent HSCT
Investigators
Clinical Study Information Center
Scientific
AstraZeneca AB
Study Sites (1)
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