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 (CERTIS1)

Inclusion Criteria: * Eastern Cooperative Oncology Group performance status (ECOG PS) with no deterioration over the previous 2 weeks. * Progressive cancer at the time of enrollment. * Adequate organ and marrow function. Module 1: Part A: \- Participants must have one of the following: (i) Histologically or cytologically confirmed relapsed advanced ovarian, fallopian tube or primary peritoneal cancer and evidence of a predicted loss of function germline or tumour mutation in one of the following homologous recombination repair genes: BRCA1, BRCA2, PALB2, RAD51C or RAD51D (ii) Histologically or cytologically confirmed HER2-negative carcinoma of the breast with recurrent locally advanced or metastatic disease and evidence of a predicted loss of function germline or tumour mutation in one of the following homologous recombination repair genes: BRCA1, BRCA2, PALB2, RAD51C, or RAD51D. (iii) Histologically or cytologically confirmed advanced/metastatic castration-resistant prostate cancer (CRPC) and evidence of a predicted loss of function germline or tumour mutation in one of the following homologous recombination repair genes:BRCA1, BRCA2, PALB2, RAD51C, or RAD51D (d) Histologically or cytologically confirmed advanced/metastatic pancreatic cancer and evidence of a predicted loss of function germline or tumour mutation in one of the following homologous recombination repair genes: BRCA1, BRCA2, PALB2, RAD51C, or RAD51D. * Must have evaluable disease. * Must be suitable for treatment with a PARPi. * Must be capable of eating a high fat meal and adhering to fasting restrictions. Part B: * Must have metastatic or recurrent locally advanced histologically or cytologically confirmed Human Epidermal growth factor Receptor 2 (HER2)-negative carcinoma of the breast and evidence of a predicted loss of function germline or tumour mutation. * Must have at least one lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter. * Participants who have received platinum chemotherapy for advanced breast cancer are eligible to enter the study provided there has been no evidence of disease progression during the platinum chemotherapy. * Participants who have received prior platinum-based chemotherapy as neo-adjuvant/adjuvant treatment are eligible provided at least 12 months have elapsed between the last dose of platinum-based treatment and first dose of study intervention. Module 2: * Must be suitable for treatment with TMZ and have IDH1/2-mutant glioma. * Should have progressive disease after prior radiation therapy and one prior line of alkylating chemotherapy for their disease. * Recurrent disease must be evaluable by MRI. * Female participants of childbearing potential (CBP) must have a negative pregnancy test result at screening and prior to each cycle administration of AZD9574 and TMZ. * Adequate organ and marrow function. Module 3: Panel 1 * Must consent to provide mandated blood samples and archival/fresh tumour tissue for confirmatory tests of their cancer using central laboratory. * Participants must have one of the following: 1. Histologically or cytologically confirmed HER2-negative carcinoma of the breast with recurrent locally advanced or metastatic disease and evidence of a predicted loss of function germline or tumour mutation in BRCA1, BRCA2, PALB2, RAD51C, or RAD51D, 2. Histologically or cytologically confirmed relapsed advanced ovarian, fallopian tube or primary peritoneal cancer and evidence of a predicted loss of function germline or tumour mutation in BRCA1, BRCA2, PALB2, RAD51C, or RAD51D 3. Histologically or cytologically confirmed advanced/metastatic castration-resistant prostate cancer (CRPC) and evidence of a predicted loss of function germline or tumour mutation in in BRCA1, BRCA2, PALB2, RAD51C or RAD51D. 4. Histologically or cytologically confirmed advanced/metastatic pancreatic cancer and evidence of a predicted loss of function germline or tumour mutation in in BRCA1, BRCA2, PALB2, RAD51C, or RAD51D. * Participants must have evaluable disease: at least one measurable and/or non-measurable lesions per RECIST 1.1 * Must be refractory to standard therapy or for which no standard therapy exists. * Any 2 participants in this panel must meet the following CNS criteria: 1. Must have previously treated and progressing or untreated brain metastases confirmed by brain MRI at screening that do not need immediate local therapy. 2. Should have stable neurological function for ≥ 14 days prior to signing the main study ICF. 3. If receiving steroids, the dose should be stable or decreasing for ≥ 14 days prior to signing the main study ICF. Panel 2 * Must be suitable for treatment with TMZ and have IDH1/2-mutant glioma. * Should have progressive disease after prior radiation therapy and one prior line of alkylating chemotherapy for their disease. * Recurrent disease must be evaluable by MRI and at least 1 tumour of \> 1cm diameter detected on MRI. * Formalin-fixed, paraffin-embedded (FFPE) tumour sample from the primary cancer must be available for central testing * Adequate organ and marrow function (in the absence of transfusions or growth factor support within 14 days prior to enrolment) Panel 3 * Must consent to provide mandated blood samples and archival/fresh tumour tissue for confirmatory tests of their cancer using central laboratory. * Must have histologically or cytologically confirmed HER2-negative carcinoma of the breast with recurrent locally advanced or metastatic disease and evidence of a predicted loss of function germline or tumour mutation in in BRCA1, BRCA2, PALB2, RAD51C or RAD51D . * Must have evaluable disease: at least one measurable and/or non-measurable lesions per RECIST 1.1 . * Must be refractory to standard therapy or for which no standard therapy exists. Module 4: Part A: * Must have the following HER2 status: 1. Breast cancer must be IHC 3+ or IHC 2+/ISH-positive or IHC 2+/ISH-negative or IHC 1+ as determined by local testing using current American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) guidelines for scoring HER2 + breast cancer. 2. Gastric cancer should be IHC 3+ or IHC 2+/ISH-positive based on local tissue testing results. 3. Participants with non-breast and non-gastric cancers must have HER2-overexpression (IHC 3+ or IHC 2+; as determined by local testing using current ASCO-CAP guidelines for gastric IHC scoring). 4. Participants with NSCLC will also be eligible based on the presence of a HER2activating mutation. * Must have progressed following at least one prior systemic treatment and not more than 2 prior lines of cytotoxic therapy for metastatic or advanced disease and have no satisfactory alternative treatment option. * Should have unresectable, or metastatic disease based on most recent imaging. The following tumour types are eligible for this study: Breast cancer, Non-Small Cell Lung Cancer, Colorectal Cancer, Bladder Cancer, Ovarian Cancer, Gastric Cancer, and Other tumour types ( unresectable or metastatic biliary tract cancer, cervical cancer, endometrial cancer, and pancreatic adenocarcinoma). * Adequate organ and marrow function (in the absence of transfusions or growth factor support) within 14 days prior to the first dose of study intervention. * Left ventricular ejection fraction (LVEF) ≥ 50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before start of treatment. * Must have at least one lesion not previously irradiated (or with evidence of disease progression following radiation). * Non-sterilised male participants who are sexually active with a female partner of CBP must use a condom with spermicide from screening to approximately 6 months after the last dose of study intervention. * Male participants must refrain from fathering a child or donating sperm during the study and for approximately 6 months after the last dose of study intervention. Part B - All participants: * Histologically documented unresectable or metastatic breast cancer. * Metastatic or recurrent locally advanced unresectable histologically or cytologically confirmed HER2-low or HER2-ultralow breast carcinoma. * No prior chemotherapy for locally advanced unresectable or metastatic breast cancer. Part B - Participants with brain metastases: * Stable neurological function for ≥ 14 days prior to signing the main study ICF. * If receiving steroids, the dose should be stable or decreasing for ≥ 14 days prior to signing the main study ICF. * Must not have progressing or untreated (stable or progressing) brain metastases. Part B - Participants in CNS cohort: \- Untreated brain metastases, previously treated and stable or progressing brain metastases on screening contrast brain MRI/CT scan, not needing immediate local therapy. Module 5 : * Should have unresectable, or metastatic disease based on most recent imaging. The following tumour types are eligible for this study: TNBC, Endometrial cancer, Ovarian Cancer and CRPC. * Must have progressed following at least one prior systemic treatment for metastatic or advanced disease and have no satisfactory alternative treatment option. * Must have at least one lesion, not previously irradiated that can be accurately measured at baseline as ≥ 10 mm in the longest diameter. * Non-sterilised male participants who are sexually active with a female partner of CBP must use a condom with spermicide from screening to approximately 4 months after the last dose of study. * Male participants must refrain from fathering a child or donating sperm during the study and for approximately 4 months after the last dose of study intervention. * Adequate organ and marrow function (in the absence of transfusions or growth factor support) within 14 days prior to the first dose of study intervention. Modules 1, 2 and 3: * Female participants of CBP: 1. Must have a negative pregnancy test result at screening and prior to each cycle of study treatment. 2. If sexually active with a non-sterilised male partner, must use at least one highly effective method of birth control plus a barrier method from screening to approximately 6 months after the last dose of study treatment. * Female participants must not breastfeed and must not donate or retrieve ova for their own use from screening to approximately 6 months after the last dose of study treatment. * Non-sterilised male participants who are sexually active with a female partner of CBP must use a condom with spermicide from screening to approximately 3 months after the last dose of study intervention. * Female partners of male participants should use at least one highly effective method of contraception from screening to approximately 3 months after the last dose of study intervention of the male participant. * Male participants must refrain from fathering a child or donating sperm from the start of study intervention and for approximately 3 months after the last dose of study intervention. Modules 4 and 5: * Female participants of CBP: 1. Must have a negative pregnancy test result at screening and prior to each cycle of study intervention. 2. If sexually active with a non-sterilised male partner, must use at least one highly effective method of birth control in combination with one effective method (male condom plus spermicide) from screening until approximately 7 months after the last dose of study intervention. * Female participants must not breastfeed and must not donate or retrieve ova for any use from screening to approximately 7 months after the last dose of study intervention. * Participants must provide an existing FFPE tumour sample for retrospective, tissue-based IHC testing in a central laboratory to determine HER2 expression and other correlatives. * ECOG performance status of 0 or 1. * Participants recruited specifically for PD evaluation must have at least 1 tumour suitable for paired biopsies and be willing to consent to pre-treatment and on-treatment biopsies. Exclusion Criteria: * Major surgery within 4 weeks of the first dose of study intervention. * Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks of the first dose of study intervention. * With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study intervention. * Any known history of persisting severe pancytopenia due to any cause. * Spinal cord compression unless asymptomatic, treated and stable and not requiring continuous corticosteroids at a dose of \> 10 mg prednisone/day or equivalent for at least 4 weeks prior to start of study intervention. * History of uncontrolled seizures or with need for concurrent administration of more than 2 antiepileptic drugs, or history of epileptic disorder or any seizure history unrelated to tumour. * History of severe brain injury or stroke. * Any evidence of severe or uncontrolled systemic diseases including active bleeding diatheses, active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). * Uncontrolled intercurrent illness within the last 12 months. * Any known predisposition to bleeding. * Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML. * Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD9574. * Known allergy or hypersensitivity to investigational product(s) or any of the excipients of the investigational product(s). * Known contra-indication to gadolinium-enhanced Magnetic Resonance Imaging (MRI) or, if applicable, not able to be maintained on a stable or decreasing dose of corticosteroid regimen (no increase for 7 days) prior to the baseline MRI. * Any concurrent anti-cancer therapy or concurrent use of prohibited medications. Module 1: Part A: * Have received \> one prior line of therapy in any setting with a PARPi-based regimen. * Participants with an INR \>1.5 unless the patient is receiving non-vitamin K antagonist oral anticoagulants. * Participants with leptomeningeal disease (LMD) unless the LMD is of low volume or is previously treated and the participant is asymptomatic or minimal symptoms. * Participants with insulin-dependent diabetes. * Currently on ARA treatment. Part B: * Participants with an International Normalised Ratio (INR) \>1.5 unless the patient is receiving non-vitamin K antagonist oral anticoagulants. * Participants with LMD are excluded unless the LMD is of low volume or is previously irradiated and the participant is asymptomatic from the LMD. Module 2: * Received a PARPi previously. * Known hypersensitivity to TMZ or dacarbazine or known history of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD9574. * Have received \> 1 prior line of alkylating chemotherapy regimen. Participants who have received procarbazine, lomustine (CCNU), vincristine (PCV) as a prior line of treatment are not allowed. * Previously experienced Grade 4 haematological toxicities or Grade 3 neutropenia associated with infections, or Grade 3 thrombocytopenia with clinically significant bleeding during prior alkylating chemotherapy. * Received bevacizumab within the last 6 months. * Not requiring continuous corticosteroids at a dose of \>10 mg prednisone/day or equivalent for at least 4 weeks prior to start of study intervention. Module 3: All Panels * Positive Allen's test * BMI \> 30.0 kg/m2 or body weight \> 100.0 kg * Suffer from claustrophobia. * Implanted metal devices or implants containing metal. * An INR \>1.5 * Taking acid-reducing agents. Panel 1 * Received \> 1 prior line of therapy in any setting with a PARPi-based regimen * Participants with LMD Panel 2 * Received a PARPi previously. * Known hypersensitivity to TMZ. * Received \> 1 prior line of alkylating chemotherapy regimen. * Previously experienced Grade 4 haematological toxicities or Grade 3 neutropenia associated with infections, or Grade 3 thrombocytopenia with clinically significant bleeding during prior alkylating chemotherapy. * Received bevacizumab within the last 6 months. Panel 3 * Received \> one prior line of therapy in any setting with a PARPi-based regimen. * Participants with LMD. Module 4: All participants: * Current or prior use of immunosuppressive medication within 14 days before the first dose of T-DXd and within 4 weeks for continuous corticosteroids at a dose of approximately \> 10 mg prednisone/day or equivalent. * Should not have received more than 2 prior lines of systemic cytotoxic therapy. * Prior treatment with HER2 directed TOPO1i ADCs and prior AZD9574 is not permitted. * Must not enter the study if they received chloroquine/hydroxychloroquine \< 14 days prior to the first dose. * Presence of unresolved toxicities from previous anti-cancer therapy, defined as toxicities not yet resolved to Grade ≤ 1 or baseline. * Known history of prior platelet transfusion(s) or febrile neutropenia in the advanced disease treatment setting. * Medical history of myocardial infarction. Participants with troponin levels above ULN at screening and without any myocardial related symptoms. * History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or suspected ILD/pneumonitis. * Additional lung-related exclusion criteria: (a) Lung-specific intercurrent clinically significant illnesses (b) Any autoimmune, connective tissue or inflammatory disorders (c) Prior pneumonectomy. * Pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy. * Known hypersensitivity to T-DXd, any of the excipients or other mAbs. * History of another primary malignancy. * An uncontrolled infection requiring IV antibiotics, antivirals, or antifungals. * Active primary immunodeficiency, known uncontrolled active HIV infection or active hepatitis B or hepatitis C infection. Part A (dose escalation): \- Participants with brain metastases are excluded unless asymptomatic, treated, and participant is clinically stable and not requiring continuous corticosteroids at a dose of \> 10 mg prednisone/day or equivalent for at least 4 weeks prior to study intervention. Part B (dose expansion): \- Prior systemic cytotoxic-containing treatment in the metastatic/locally advanced unresectable setting. Part B (dose expansion) - Participants with Brain Metastases: * Known and symptomatic leptomeningeal disease. * Spinal cord compression. Module 5: * Current or prior use of immunosuppressive medication within 14 days before the first dose of Dato-DXd and within 4 weeks for continuous corticosteroids at a dose of approximately \> 10 mg prednisone/day or equivalent. * Corticosteroid mouthwash formulations are permitted to prevent and manage certain AEs. * Prior anti-cancer treatments: 1. Should not have received more than 2 prior lines of systemic cytotoxic therapy 2. Prior treatment with PARPi is permitted 3. Prior TOPO1 inhibitor therapy is NOT permitted 4. Prior treatment with TROP2-directed ADCs is NOT permitted. 5. Prior radiation therapy requires the washout periods. * Must not enter the study if they received chloroquine / hydroxychloroquine \< 14 days prior to the first dose. * History of another primary malignancy. * History of non-infectious ILD/pneumonitis including radiation pneumonitis that required steroids, has current or suspected ILD/pneumonitis. * Clinically severe pulmonary function compromise. * Clinically significant corneal disease. * History of severe hypersensitivity reactions to Dato-DXd, any of the excipients or to other mabs. * Participant is pregnant or breastfeeding or planning to become pregnant.