A Modular Phase I/IIa, Open-label, Multi-centre Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of Ascending Doses of AZD9574 as Monotherapy and in Combination with Anti-cancer Agents in Patients with Advanced Solid Malignancies

BRCA2, BRCA2m, breast, breast cancer (without BM), endometrial, HER2 activating mutation, IDH-mutant recurrent glioma, Module 1: advanced/relapsed ovarian, Module 2: IDH-mutant glioma, Module 3: advanced/relapsed HER2-negative breast, Module 4: advanced, Module 5: advanced, or pancreatic cancer and expressing BRCA1m, or RAD51D, ovarian, ovarian and prostate cancer, PALB2, PALB2m, pancreatic or prostate cancer where patients loss of function or predicted loss of function mutation in BRCA1, prostate, RAD51C, RAD51Cm or RAD51Dm, unresectable and HER2+ metastatic solid tumours; NSCLC, unresectable or metastatic solid tumours in breast

Incidence of AEs/SAEs; DLTs; MTD; Changes from baseline in laboratory findings, ECOG PS, ECGs and vital signs.

Plasma concentrations of AZD9574 and plasma PK parameters including but not limited to • Area under the curve after a single dose and after multiple doses • Maximum plasma concentration after a single dose and after multiple doses • Time to reach maximum plasma concentration • Minimum plasma concentration at steady state • Half-life • Accumulation ratio • Dose proportionality, Module 1: Assessment of pH2AX PD biomarker modulations at baseline and during treatment or pre-treatment in PD biomarkers, Module 1: Radiological response evaluated according to response evaluation criteria in solid tumours (RECIST v1.1) − Percentage change in target lesion size − ORR, DoR, TTR, PFS/rPFS. For ovarian cancer participants: CA125 response evaluated according to the GCIG criteria., Module 1: For prostate cancer participants: • Proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later (PSA50 response) • Radiological response evaluated according to RECIST v1.1 + PCWG3 response evaluation criteria, Module 1: PK parameters, including but not limited to AUC and/or AUC(0-t), Cmax, Tmax, AUC(0-t) and Cmax ratio, with and without a high fat meal., Module 1: PK parameters, including but not limited to AUC and/or AUC(0-t), Cmax, Tmax, AUC(0-t) and Cmax ratio, with and without famotidine., Module 2: Radiological response evaluated according to RANO-HGG or RANO-LGG • Percentage change in target lesions size • ORR, DoR, TTR, PFS, Module 3: Plasma concentrations of AZD9574 and plasma PK parameters including but not limited to • Area under the curve (AUC) after a single dose and after multiple doses • Maximum plasma concentration (Cmax) after a single dose and after multiple doses • Time to reach maximum plasma concentration (tmax) • Minimum plasma concentration at steady state (Cmin,ss) • Half-life (t1/2) • Accumulation ratio, Module 3: Difference in radioligand binding to PARP1 from baseline to study intervention administration (occupancy [%]), Module 3: Radiological response evaluated according to RECIST v1.1 − Percentage change in target lesion size − ORR, DoR, TTR, PFS/rPFS • For ovarian cancer participants: CA125 response evaluated according to the GCIG criteria, Module 3: For prostate cancer participants: − Participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later (PSA50 response) − Radiological response evaluated according to RECIST v1.1 (soft tissue) + PCWG3 (bone) response evaluation criteria, Module 3: Radiological response evaluated according to RANO-HGG or RANO-LGG • Percentage change in target lesions size • ORR, DoR, TTR, PFS, Module 4: Measurement of plasma concentrations AZD9574 and serum concentrations of T-DXd after administration of a single dose and multiple doses; and derivation of the following PK parameters including, but not limited to (as data allow): • AUC • Cmax • Tmax, Module 4: Assessment of modulation from baseline (Visit 1) or pre-treatment in PD biomarkers from (optional) tumour samples; including, but not limited to assessment of pH2AX (Ser139), Module 4: Presence of ADAs for T-DXd, Module 4: Incidence of: • ILD/pneumonitis • LVEF • ≥ Grade 3 Neutropenia (Part B only), Module 4: Radiological response evaluated according to response evaluation criteria in solid tumours (RECIST v1.1) percentage change in target lesion size • ORR, DoR, PFS, TTR • Where appropriate, tumour marker response data will be summarized depending on the cancer type, eg, CA125 for ovarian cancer • PFS6 (Part B only), Module 5: Measurement of plasma concentrations of AZD9574 and Dato-DXd after a single dose and multiple doses; and derivation of the following PK parameters, including, but not limited to (as data allow): − AUC − Cmax − Tmax, Module 5: Assessment of modulation from baseline (Visit 1) or pre-treatment in PD biomarkers from (optional) tumour samples; includes, but is not limited to assessment of pH2AX (Ser139), Module 5: Presence of ADAs for Dato-DXd, Module 5: Radiological response evaluated according to response evaluation criteria in solid tumours (RECIST v1.1) − percentage change in target lesion size − ORR, DoR, PFS, TTR • Where appropriate, tumour marker response data will be summarized depending on the cancer type, eg, CA125 for ovarian cancer., Module 5 : • For participants with prostate cancer: − ORR and rPFS according to RECIST v1.1 (soft tissue) + PCWG3 (bone) response evaluation criteria − Proportion of patients achieving a ≥ 50% decrease in PSA from baseline to the post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later (PSA50 response), Module 5: Incidence of: • Interstitial Lung Disease/Pneumonitis • Infusion-related Reactions • Oral Mucositis/Stomatitis • Mucosal Inflammation Other than Oral Mucositis/Stomatitis • Ocular Surface Events

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