AZD3632 for Acute myeloid leukaemia | Acute lymphoblastic leukaemia | Myelodysplastic syndromes

Inclusion criteria

• {"criterion_text":"- Adequate organ function\n- 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\n- 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\n- Contraceptive use by participants or participant partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies\n- Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in the Protocol\n- 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.\n- 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\n- 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.\n- 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).\n- 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\n- Module 2 - Participant must be at least 18 years of age at the time of signing the informed consent"}

Exclusion criteria

• {"criterion_text":"- 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)\n- 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\n- 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\n- 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)\n- Receipt of live attenuated vaccine within 30 days before the first dose of study treatment(s)\n- Major surgery within 28 days of first dose of study treatment\n- 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)\n- 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)\n- Participants with a known hypersensitivity to AZD3632 or any of the excipients of the product\n- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)\n- Judgement by the investigator that the participant is unlikely to comply with study procedures, restrictions, and requirements, and should not participate in the study\n- Isolated extramedullary disease.\n- Previous enrolment in the present study\n- 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\n- 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)\n- 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.\n- 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\n- Module 1 - Receipt of non-CNS radiation therapy within 2 weeks and of CNS radiation within 8 weeks of the first scheduled dose\n- 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)\n- 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\n- Module 2 - Participants may be other menin-inhibitor naïve or menin-inhibitor exposed\n- 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\n- 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\n- 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\n- Module 2 - Participants for whom treatment with posaconazole is contraindicated per the local prescribing information\n- Active testicular or active CNS (> CNS1 or radiographic) involvement by leukaemia\n- 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\n- Acute or active chronic GvHD Grade > 0 within 4 weeks of enrolment except Grade ≤ 2 GvHD of the skin\n- 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)\n- 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\n- Clinically significant cardiovascular disorder\n- Abnormal levels of potassium or magnesium prior to first dose of AZD3632 (supplementation is permitted)"}

Primary endpoints

• {"endpoint_text":"- Module 1 - Incidence of DLT during the DLT evaluation period","definition_or_measurement_approach":"Incidence of dose-limiting toxicities observed during the protocol-defined DLT evaluation period (safety assessments to identify DLTs)."}
• {"endpoint_text":"- Module 1 - Frequency of dose modifications, delays, and discontinuations due to AEs","definition_or_measurement_approach":"Counting and reporting frequency of dose modifications, treatment delays, and discontinuations that occur as a result of adverse events."}
• {"endpoint_text":"- Module 1 - Incidence TEAEs, TRAEs and SAEs","definition_or_measurement_approach":"Incidence rates of treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), and serious adverse events (SAEs) as captured per safety reporting procedures."}
• {"endpoint_text":"- Module 1 - Changes from baseline in laboratory evaluations, 12-lead ECGs, performance status, physical examination, and vital signs","definition_or_measurement_approach":"Assessment of changes from baseline in laboratory test results, 12-lead ECG parameters, performance status scores, physical exam findings, and vital sign measurements."}
• {"endpoint_text":"- Module 2 -\tFrequency of dose modifications, delays, and discontinuations due to AEs","definition_or_measurement_approach":"As Module 1: frequency of dose modifications, delays, and discontinuations attributable to adverse events while AZD3632 is co-administered with posaconazole."}
• {"endpoint_text":"- Module 2 - Incidence of TEAEs, TRAEs, and SAEs","definition_or_measurement_approach":"Incidence rates of TEAEs, TRAEs and SAEs during combination administration with posaconazole."}
• {"endpoint_text":"- Module 2 - Changes from baseline in laboratory evaluations, 12-lead ECGs, performance status, physical examination, and vital signs","definition_or_measurement_approach":"Assessment of changes from baseline in labs, ECGs, performance status, physical examination and vital signs during Module 2 treatment."}

Secondary endpoints

• {"endpoint_text":"- Module 1 -\tPlasma 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)","definition_or_measurement_approach":"Measurement of plasma AZD3632 concentrations and calculation of PK parameters (Cmax, Tmax, Ctrough, AUCinf, AUC0-t, AUCtau, CL/F, Vz/F, t1/2) from blood samples."}
• {"endpoint_text":"- Module 1 - Plasma concentrations and PK parameters, including but not limited to Cmax, Cmin, Tmax, AUC0-t, AUCtau under fasted and fed state","definition_or_measurement_approach":"PK profiling under fasted and fed conditions comparing parameters such as Cmax, Cmin, Tmax, AUC0-t, AUCtau."}
• {"endpoint_text":"- Module 1 - Ratio of Cmax, AUC0-t and AUCtau between fed and fasted state","definition_or_measurement_approach":"Calculation of fed/fasted geometric mean ratios for Cmax, AUC0-t and AUCtau."}
• {"endpoint_text":"- Module 1 - Acute leukaemia: Complete Response (CR) / Complete Response with partial Haematologic recovery (CRh) rate","definition_or_measurement_approach":"Efficacy assessment of CR and CRh rates per disease-specific response criteria for acute leukaemia."}
• {"endpoint_text":"- Module 1 - Acute leukaemia: Time to response (TTR)","definition_or_measurement_approach":"Time from first dose to documented response as defined by trial response criteria."}
• {"endpoint_text":"- Module 1 - Acute leukaemia: Duration of response (DoR)","definition_or_measurement_approach":"Time from first documented response to relapse or death per protocol-defined response criteria."}
• {"endpoint_text":"- Module 1 - Acute leukaemia: Transfusion independence (TI)","definition_or_measurement_approach":"Assessment of transfusion independence according to protocol-specified definitions (e.g., time period without transfusions)."}
• {"endpoint_text":"- Module 1 - Acute leukaemia: Event-free survival (EFS)","definition_or_measurement_approach":"Time to event (progression, relapse, or death) as defined by protocol EFS criteria."}
• {"endpoint_text":"- Module 1 - Acute leukaemia: Overall survival (OS)","definition_or_measurement_approach":"Time from first dose to death from any cause."}
• {"endpoint_text":"- Module 1 - Acute leukaemia: Percentage of participants who receive subsequent allogeneic hematopoietic stem cell transplant (HSCT)","definition_or_measurement_approach":"Proportion of participants undergoing subsequent allogeneic HSCT during follow-up."}
• {"endpoint_text":"- Module 1 - Myelodysplastic Syndromes: Overall Response Rate (ORR): CR (or CR equivalent), Partial Response (PR), CRL, CRh, or haematologic improvement (HI)","definition_or_measurement_approach":"Assessment of ORR including CR/CR equivalent, PR, CRL, CRh, or HI per MDS response criteria."}
• {"endpoint_text":"- Module 1 - Myelodysplastic Syndromes: TTR, DoR, TI, Time to Progression to AML, EFS, OS, Percentage of participants who receive subsequent HSCT","definition_or_measurement_approach":"Time-to-event and response duration measures for MDS, including progression to AML and subsequent HSCT rates."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"PK comparisons of AZD3632 when administered alone versus with posaconazole (AUC0-t, Cmax, Tmax)."}
• {"endpoint_text":"- Module 2 - Plasma GMR (Cmax and AUC) of AZD3632 evaluated with and without posaconazole","definition_or_measurement_approach":"Geometric mean ratio analyses for Cmax and AUC of AZD3632 ± posaconazole."}
• {"endpoint_text":"- Module 2 - Plasma PK of posaconazole","definition_or_measurement_approach":"Measurement of plasma posaconazole concentrations and PK parameters per protocol."}
• {"endpoint_text":"- Module 2 - Acute leukaemia: CR/CRh, TTR, DoR, TI, EFS, OS, percentage of participants who receive subsequent HSCT","definition_or_measurement_approach":"Efficacy and time-to-event measures for acute leukaemia in Module 2, using standard response and survival metrics."}
• {"endpoint_text":"- Module 2 - Myelodysplastic Syndromes: ORR, TTR, DoR, TI, Time to progression to AML, EFS, OS, percentage of participants who receive subsequent HSCT","definition_or_measurement_approach":"Efficacy and time-to-event measures for MDS in Module 2, including progression to AML and HSCT rates."}

Denmark

Earliest CTIS Part Ii Submission Date

01-12-2025

Latest Decision Or Authorization Date

08-12-2025

Processing Time Days

7

Number Of Sites

1

Number Of Participants

1

Germany

Earliest CTIS Part Ii Submission Date

28-11-2025

Latest Decision Or Authorization Date

09-12-2025

Processing Time Days

11

Number Of Sites

6

Number Of Participants

11

Italy

Earliest CTIS Part Ii Submission Date

27-11-2025

Latest Decision Or Authorization Date

10-12-2025

Processing Time Days

13

Number Of Sites

2

Number Of Participants

5

Primary sponsor

Full Name

AstraZeneca AB

Organisation Type

Pharmaceutical company

Country Of Registered Address

Sweden

Contract research organisations

Name

Parexel International (IRL) Limited

Responsibilities

Sponsor duties codes: 1,10,11,12,13,2,5,6,8; contact Clinicaltrial.Enquiries@parexel.com

Third parties

• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"1,10,11,12,13,2,5,6,8","organisation_type":"Pharmaceutical company"}