A trial to learn how safe AZD3632 is, how well it works, and how it moves throughout the body over time in adults with acute leukemia and myelodysplastic syndrome with HOX gene overexpression

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

18 Dec 2025 → ongoing

Decision date (initial)

2025-12-08

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Dose response, Safety, Pharmacodynamic

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

Secondary objectives 5

1. Module 1 – Pharmacokinetics: To characterise the PK of AZD3632 as monotherapy
2. Module 1 – Food effect: To evaluate the preliminary effect of food on plasma PK of AZD3632 (conducted in a nested evaluation during backfills)
3. Module 1 – Efficacy: To evaluate preliminary efficacy of AZD3632 as monotherapy
4. Module 2 – Drug Interaction: To assess the drug-drug interaction potential between AZD3632 and posaconazole
5. Module 2 – Efficacy: To evaluate preliminary efficacy of AZD3632 as monotherapy

Conditions and MedDRA coding

Relapsed or refractory acute leukaemia or Myelodysplastic Syndromes with HOX overexpression genotypes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Adequate organ function
2. Contraceptive use by participants or participant partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
3. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in the Protocol
4. 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.
5. 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
6. 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.
7. 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).
8. 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
9. Module 2 - Participant must be at least 18 years of age at the time of signing the informed consent
10. 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
11. 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

Exclusion criteria 32

1. 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)
2. Isolated extramedullary disease.
3. Active testicular or active CNS (> CNS1 or radiographic) involvement by leukaemia
4. Participants with any of the following are required to have a diagnostic CSF analysis performed during the screening period to ensure CNS1 status: a) Participants with symptoms or signs of CNS involvement. b) Participants with a history of CNS involvement. c) Participants with history of extramedullary disease. d) WBC ≥ 50,000/µL at most recent presentation
5. Acute or active chronic GvHD Grade > 0 within 4 weeks of enrolment except Grade ≤ 2 GvHD of the skin
6. Unresolved treatment-related toxicities Grade ≥ 2 from prior therapy (except alopecia, stable Grade ≤ 2 neuropathy, vitiligo, and endocrine disorders that are controlled with replacement hormone therapy)
7. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antimicrobial or other treatment
8. Clinically significant cardiovascular disorder
9. Abnormal levels of potassium or magnesium prior to first dose of AZD3632 (supplementation is permitted)
10. 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
11. 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
12. 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)
13. Receipt of live attenuated vaccine within 30 days before the first dose of study treatment(s)
14. Major surgery within 28 days of first dose of study treatment
15. 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)
16. 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)
17. Participants with a known hypersensitivity to AZD3632 or any of the excipients of the product
18. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
19. Judgement by the investigator that the participant is unlikely to comply with study procedures, restrictions, and requirements, and should not participate in the study
20. Previous enrolment in the present study
21. For Women of Child-Bearing Potential: Currently pregnant (confirmed by a positive pregnancy test) or breast-feeding, or intending to become pregnant during the study period
22. Module 1 - Prior exposure to other menin inhibitors: a) Participants in dose escalation may be menin-inhibitor naïve or menin-inhibitor exposed. b) Participants in backfill may ONLY be menin-inhibitor naïve (eg, participants with prior menin inhibitor exposure will be excluded from backfill)
23. Module 1 - Prior Donor Lymphocyte Infusion < 4 weeks, cell therapy (eg, CAR-T, NK) or autologous Haematopoietic Stem Cell Transplant (HSCT) < 8 weeks, or prior allogeneic HSCT < 12 weeks of the first scheduled dose. Participants must have completed systemic immunosuppressive therapy for the treatment of acute or active chronic Graft versus Host Disease (GvHD) within 4 weeks prior to AZD3632 treatment. The following are permitted: a) Topical steroids for ≤ Grade 2 GvHD of the skin may continue indefinitely. b) Stable (≤ 10 mg of prednisone or equivalent per day) or tapering systemic steroids for GvHD up to 4 weeks prior to the first dose of study treatment.
24. Module 1 - Receipt of any anticancer agent (non-investigational or investigational): a) For non-biologic agents, therapy within 14 days or 5 half-lives (whichever is shorter) of the first scheduled dose. b) For biologic agents, therapy within 30 days or 5 half-lives (whichever is shorter) of the first scheduled dose. c) Prior treatment with other menin inhibitors (backfill participants ONLY) d) The following are permitted: - Cytoreduction with short-term steroids or hydroxyurea - Intrathecal therapy per institutional guidance. Dose escalation participants may ONLY receive intrathecal therapy after the Dose-limiting Toxicity period
25. Module 1 - Receipt of non-CNS radiation therapy within 2 weeks and of CNS radiation within 8 weeks of the first scheduled dose
26. Module 1 - Any concomitant medications (including St John’s wort) known to be strong or moderate inducers or inhibitors of cytochrome P450 3A4 (CYP3A4) (must be discontinued at least 14 days or 5 half-lives, whichever is longer prior, prior to the first dose of AZD3632)
27. Module 1 - Additional Exclusion Criteria for Nested Food Effect participants: Participants must not participate in the nested food study, if the following exclusion criteria are fulfilled: - Diagnosis of diabetes mellitus (Type I or Type II) - Any other conditions which in the investigator’s judgement increase the risk of incurring AEs or limit compliance with the food effect evaluation
28. Module 2 - Participants may be other menin-inhibitor naïve or menin-inhibitor exposed
29. Module 2 - Prior Donor Lymphocyte Infusion (DLI) < 4 weeks, cell therapy (eg, CAR-T, NK) or autologous Haematopoietic Stem Cell Transplant (HSCT) < 8 weeks, or prior allogeneic HSCT < 12 weeks of the first scheduled dose. Participants must have completed systemic immunosuppressive therapy for the treatment of acute or active chronic Graft versus Host Disease (GvHD) within 4 weeks prior to AZD3632 treatment. The following are permitted: a) Topical steroids for ≤ Grade 2 GvHD of the skin may continue indefinitely. b) Stable (≤ 10 mg of prednisone or equivalent per day) or tapering systemic steroids for GvHD up to 4 weeks prior to the first dose of study treatment
30. Module 2 - Receipt of any non-investigational anticancer agent (non-investigational or investigational): a) For non-biologic agents, therapy within 14 days or 5 half-lives (whichever is shorter) of the first scheduled dose. b) For biologic agents, therapy within 30 days or 5 half-lives (whichever is shorter) of the first scheduled dose. c) The following are permitted - Intrathecal prophylaxis per local standards - Cytoreduction with short-term steroids or hydroxyurea d) Receipt of non-CNS radiation therapy within 2 weeks and of CNS radiation within 4 weeks of the first scheduled dose
31. Module 2 - Any concomitant medications (including St John’s wort) known to be strong or moderate inducers or inhibitors of cytochrome P450 3A4 (CYP3A4) must be discontinued at least 14 days or 5 half-lives, whichever is longer, prior to the first dose of AZD3632. The use of protocol specific CYP3A4 inhibitor(s) is allowed in Module 2. Drugs that are 3A4/5 sensitive substrates and substrates with narrow therapeutic index should be avoided
32. Module 2 - Participants for whom treatment with posaconazole is contraindicated per the local prescribing information

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 7

1. Module 1 - Incidence of DLT during the DLT evaluation period
2. Module 1 - Frequency of dose modifications, delays, and discontinuations due to AEs
3. Module 1 - Incidence TEAEs, TRAEs and SAEs
4. Module 1 - Changes from baseline in laboratory evaluations, 12-lead ECGs, performance status, physical examination, and vital signs
5. Module 2 - Frequency of dose modifications, delays, and discontinuations due to AEs
6. Module 2 - Incidence of TEAEs, TRAEs, and SAEs
7. Module 2 - Changes from baseline in laboratory evaluations, 12-lead ECGs, performance status, physical examination, and vital signs

Secondary endpoints 17

1. 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)
2. Module 1 - Plasma concentrations and PK parameters, including but not limited to Cmax, Cmin, Tmax, AUC0-t, AUCtau under fasted and fed state
3. Module 1 - Ratio of Cmax, AUC0-t and AUCtau between fed and fasted state
4. Module 1 - Acute leukaemia: Complete Response (CR) / Complete Response with partial Haematologic recovery (CRh) rate
5. Module 1 - Acute leukaemia: Time to response (TTR)
6. Module 1 - Acute leukaemia: Duration of response (DoR)
7. Module 1 - Acute leukaemia: Transfusion independence (TI)
8. Module 1 - Acute leukaemia: Event-free survival (EFS)
9. Module 1 - Acute leukaemia: Overall survival (OS)
10. Module 1 - Acute leukaemia: Percentage of participants who receive subsequent allogeneic hematopoietic stem cell transplant (HSCT)
11. Module 1 - Myelodysplastic Syndromes: Overall Response Rate (ORR): CR (or CR equivalent), Partial Response (PR), CRL, CRh, or haematologic improvement (HI)
12. Module 1 - Myelodysplastic Syndromes: TTR, DoR, TI, Time to Progression to AML, EFS, OS, Percentage of participants who receive subsequent HSCT
13. 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
14. Module 2 - Plasma GMR (Cmax and AUC) of AZD3632 evaluated with and without posaconazole
15. Module 2 - Plasma PK of posaconazole
16. Module 2 - Acute leukaemia: CR/CRh, TTR, DoR, TI, EFS, OS, percentage of participants who receive subsequent HSCT
17. Module 2 - Myelodysplastic Syndromes: ORR, TTR, DoR, TI, Time to progression to AML, EFS, OS, percentage of participants who receive subsequent HSCT

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

-

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

Clinical Study Information Center

Third parties 1

Locations

3 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 20 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications