Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies

Inclusion Criteria:

• Eastern Cooperative Oncology Group performance status (ECOG PS) with nodeterioration over the previous 2 weeks.

• Progressive cancer at the time of study entry.

• Adequate organ and marrow function.

Module 1:

• Female participants of childbearing potential:

1. Must have a negative pregnancy test result at screening and prior to each cycleof study treatment.

2. If sexually active with a non-sterilised male partner, must use at least onehighly effective method of birth control plus a barrier method from screeningto approximately 6 months after the last dose of study treatment.

• Female participants must not breastfeed and must not donate or retrieve ova fortheir own use from screening to approximately 6 months after the last dose of studytreatment.

• Non-sterilised male participants who are sexually active with a female partner ofchildbearing potential must use a condom with spermicide from screening toapproximately 3 months after the last dose of study intervention.

• Female partners of male participants should use at least one highly effective methodof contraception from screening to approximately 3 months after the last dose ofstudy intervention of the male participant.

• Male participants must refrain from fathering a child or donating sperm from thestart of study intervention and for approximately 3 months after the last dose ofstudy intervention.

Part A:

• Participants must have one of the following: (i) Histologically or cytologicallyconfirmed relapsed advanced ovarian, fallopian tube or primary peritoneal cancer andevidence of a predicted loss of function germline or tumour mutation in one of thefollowing homologous recombination repair genes: BRCA1, BRCA2, PALB2, RAD51C orRAD51D (ii) Histologically or cytologically confirmed HER2-negative carcinoma of thebreast with recurrent locally advanced or metastatic disease and evidence of apredicted loss of function germline or tumour mutation in one of the followinghomologous 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.

• Participants must have evaluable disease.

• Patients must be suitable for treatment with a PARPi.

• Participants must be capable of eating a high fat meal and adhering to fastingrestrictions.

Part B:

• Participants must have metastatic or recurrent locally advanced histologically orcytologically confirmed Human Epidermal growth factor Receptor 2 (HER2)-negativecarcinoma of the breast and evidence of a predicted loss of function germline ortumour mutation.

• Participants must have at least one lesion, not previously irradiated, that can beaccurately measured at baseline as ≥ 10 mm in the longest diameter.

• Participants who have received platinum chemotherapy for advanced breast cancer areeligible to enter the study provided there has been no evidence of diseaseprogression during the platinum chemotherapy.

• Participants who have received prior platinum-based chemotherapy asneo-adjuvant/adjuvant treatment are eligible provided at least 12 months haveelapsed between the last dose of platinum-based treatment and first dose of studyintervention.

Module 2:

• Participants must be suitable for treatment with TMZ.

• Participants must have IDH1/2-mutant glioma.

• Participants should have progressive disease after prior radiation therapy and oneprior line of alkylating chemotherapy for their disease.

• Recurrent disease must be evaluable by MRI.

• Female participants of childbearing potential must have a negative pregnancy testresult at screening and prior to each cycle administration of AZD9574 and TMZ.

• Adequate organ and marrow function.

Module 3:

All Panels:

• Female participants of childbearing potential:

1. Must have a negative pregnancy test result at screening and prior to each cycleof study treatment.

2. If sexually active with a non-sterilised male partner, must use at least onehighly effective method of birth control plus a barrier method from screeningto approximately 6 months after the last dose of study treatment.

• Female participants must not breastfeed and must not donate or retrieve ova fortheir own use from screening to approximately 6 months after the last dose of studytreatment.

Panel 1

• Participants must consent to provide mandated blood samples and archival/freshtumour 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 breastwith recurrent locally advanced or metastatic disease and evidence of apredicted loss of function germline or tumour mutation in BRCA1, BRCA2, PALB2,RAD51C, or RAD51D,

2. Histologically or cytologically confirmed relapsed advanced ovarian, fallopiantube or primary peritoneal cancer and evidence of a predicted loss of functiongermline or tumour mutation in BRCA1, BRCA2, PALB2, RAD51C, or RAD51D

3. Histologically or cytologically confirmed advanced/metastaticcastration-resistant prostate cancer (CRPC) and evidence of a predicted loss offunction germline or tumour mutation in in BRCA1, BRCA2, PALB2, RAD51C orRAD51D

4. Histologically or cytologically confirmed advanced/metastatic pancreatic cancerand evidence of a predicted loss of function germline or tumour mutation in inBRCA1, BRCA2, PALB2, RAD51C, or RAD51D.

• Participants must have evaluable disease: at least one measurable and/ornon-measurable lesions per RECIST 1.1

• Participants must be refractory to standard therapy or for which no standard therapyexists.

• Any 2 participants in this panel must meet the following CNS criteria:

1. Participants must have previously treated and progressing or untreated brainmetastases confirmed by brain MRI at screening that do not need immediate localtherapy.

2. Participants should have stable neurological function for ≥ 14 days prior tosigning the main study ICF.

3. If receiving steroids, the dose should be stable or decreasing for ≥ 14 daysprior to signing the main study ICF.

Panel 2

• Participants must be suitable for treatment with TMZ.

• Participants must have IDH1/2-mutant glioma.

• Participants should have progressive disease after prior radiation therapy and oneprior line of alkylating chemotherapy for their disease.

• Recurrent disease must be evaluable by MRI and at least 1 tumour of > 1cm diameterdetected on MRI.

• Formalin-fixed, paraffin-embedded (FFPE) tumour sample from the primary cancer mustbe available for central testing

• Adequate organ and marrow function (in the absence of transfusions or growth factorsupport within 14 days prior to enrolment)

Panel 3

• Participants must consent to provide mandated blood samples and archival/freshtumour tissue for confirmatory tests of their cancer using central laboratory.

• Participants must have histologically or cytologically confirmed HER2-negativecarcinoma of the breast with recurrent locally advanced or metastatic disease andevidence 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/ornon-measurable lesions per RECIST 1.1 .

• Participants must be refractory to standard therapy or for which no standard therapyexists.

Module 4:

• Participants must have the following HER2 status:

1. Participants with 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 AmericanSociety of Clinical Oncology-College of American Pathologists (ASCO-CAP)guidelines for scoring HER2 + breast cancer.

2. Participants with gastric cancer should be IHC 3+ or IHC 2+/ISH-positive basedon local tissue testing results.

3. Participants with non-breast and non-gastric cancers must haveHER2-overexpression (IHC 3+ or IHC 2+; as determined by local testing usingcurrent ASCO-CAP guidelines for gastric IHC scoring).

4. Participants with NSCLC will also be eligible based on the presence of aHER2activating mutation.

• Participants must have progressed following at least one prior systemic treatmentand not more than 2 prior lines of cytotoxic therapy for metastatic or advanceddisease and have no satisfactory alternative treatment option.

• Participants should have unresectable, or metastatic disease based on most recentimaging. 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 tractcancer, cervical cancer, endometrial cancer, and pancreatic adenocarcinoma).

• Adequate organ and marrow function (in the absence of transfusions or growth factorsupport) within 14 days prior to the first dose of study intervention.

• Left ventricular ejection fraction (LVEF) ≥ 50% by either echocardiogram (ECHO) ormultigated acquisition (MUGA) scan within 28 days before start of treatment.

• Participants must have at least one lesion not previously irradiated (or withevidence of disease progression following radiation).

• Non-sterilised male participants who are sexually active with a female partner ofchildbearing potential must use a condom with spermicide from screening toapproximately 6 months after the last dose of study intervention.

• Male participants must refrain from fathering a child or donating sperm during thestudy and for approximately 6 months after the last dose of study intervention.

Module 5 :

• Participants should have unresectable, or metastatic disease based on most recentimaging. The following tumour types are eligible for this study: TNBC, Endometrialcancer, Ovarian Cancer and CRPC.

• Participants must have progressed following at least one prior systemic treatmentfor metastatic or advanced disease and have no satisfactory alternative treatmentoption.

• Participants must have at least one lesion, not previously irradiated that can beaccurately measured at baseline as ≥ 10 mm in the longest diameter.

• Non-sterilised male participants who are sexually active with a female partner ofchildbearing potential must use a condom with spermicide from screening to at least 4 months after the last dose of study.

• Male participants must refrain from fathering a child or donating sperm during thestudy and for at least 4 months after the last dose of study intervention.

• Adequate organ and marrow function (in the absence of transfusions or growth factorsupport) within 14 days prior to the first dose of study intervention.

Module 4 & 5:

• Female participants of childbearing potential:

1. Must have a negative pregnancy test result at screening and prior to each cycleof study intervention.

2. If sexually active with a non-sterilised male partner, must use at least onehighly effective method of birth control in combination with one effectivemethod (male condom plus spermicide) from screening until at least 7 monthsafter the last dose of study intervention

• Female participants must not breastfeed and must not donate or retrieve ova for anyuse from screening to at least 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 andother correlatives.

• ECOG performance status of 0 or 1.

• Participants recruited specifically for PD evaluation must have at least 1 tumoursuitable for paired biopsies and be willing to consent to pre-treatment andon-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 alimited field of radiation for palliation within 2 weeks of the first dose of studyintervention.

• With the exception of alopecia, any unresolved toxicities from prior therapy greaterthan Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time ofstarting study intervention.

• Any known history of persisting severe pancytopenia due to any cause.

• Spinal cord compression unless asymptomatic, treated and stable and not requiringcontinuous corticosteroids at a dose of > 10 mg prednisone/day or equivalent for atleast 4 weeks prior to start of study intervention.

• History of uncontrolled seizures or with need for concurrent administration of morethan 2 antiepileptic drugs, or history of epileptic disorder or any seizure historyunrelated to tumour.

• History of severe brain injury or stroke.

• Any evidence of severe or uncontrolled systemic diseases including active bleedingdiatheses, active infection including hepatitis B, hepatitis C and humanimmunodeficiency 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 withfeatures suggestive of MDS/AML.

• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability toswallow the formulated product or previous significant bowel resection that wouldpreclude adequate absorption of AZD9574.

• Known allergy or hypersensitivity to investigational product(s) or any of theexcipients 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 ofcorticosteroid 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:

• Participants that have received > one prior line of therapy in any setting with aPARPi-based regimen.

• Participants with an INR >1.5 unless the patient is receiving non-vitamin Kantagonist oral anticoagulants.

• Participants with leptomeningeal disease (LMD) unless the LMD is of low volume or ispreviously treated and the participant is asymptomatic or minimal symptoms.

• Participants with insulin-dependent diabetes.

• Participants currently on ARA treatment.

Part B:

• Participants with an International Normalised Ratio (INR) >1.5 unless the patient isreceiving non-vitamin K antagonist oral anticoagulants.

• Participants with LMD are excluded unless the LMD is of low volume or is previouslyirradiated and the participant is asymptomatic from the LMD.

Module 2:

• Participants who have received a PARPi previously.

• Known hypersensitivity to TMZ or dacarbazine or known history of allergic reactionsattributed to compounds of similar chemical or biologic composition to AZD9574.

• Participants who have received > 1 prior line of alkylating chemotherapy regimen.

• Participants who had previously experienced Grade 4 haematological toxicities orGrade 3 neutropenia associated with infections, or Grade 3 thrombocytopenia withclinically significant bleeding during prior alkylating chemotherapy.

• Participants who have received bevacizumab within the last 6 months.

• Not requiring continuous corticosteroids at a dose of >10 mg prednisone/day orequivalent for at least 4 weeks prior to start of study intervention.

Module 3:

All Panels

• Positive Allen's test

• Participants with a BMI > 30.0 kg/m2 or body weight > 100.0 kg

• Participants who suffer from claustrophobia.

• Participants with implanted metal devices or implants containing metal

• Participants with an INR >1.5

• Participants taking acid-reducing agents.

Panel 1

• Participants that have received > one prior line of therapy in any setting with aPARPi-based regimen .

• Participants with leptomeningeal disease (LMD)

Panel 2

• Participants who have received a PARPi previously.

• Known hypersensitivity to TMZ.

• Participants who have received > 1 prior line of alkylating chemotherapy regimen.

• Participants who had previously experienced Grade 4 haematological toxicities orGrade 3 neutropenia associated with infections, or Grade 3 thrombocytopenia withclinically significant bleeding during prior alkylating chemotherapy.

• Participants who have received bevacizumab within the last 6 months.

Panel 3

• Participants that have received > one prior line of therapy in any setting with aPARPi-based regimen.

• Participants with LMD

Module 4:

• Current or prior use of immunosuppressive medication within 14 days before the firstdose of T-DXd and within 4 weeks for continuous corticosteroids at a dose ofapproximately > 10 mg prednisone/day or equivalent.

• Participants should not have received more than 2 prior lines of systemic cytotoxictherapy.

• Prior treatment with HER2 directed TOPO1i ADCs and prior AZD9574 is not permitted.

• Participants must not enter the study if they receivedchloroquine/hydroxychloroquine < 14 days prior to the first dose.

• Presence of unresolved toxicities from previous anti-cancer therapy, defined astoxicities not yet resolved to Grade ≤ 1 or baseline.

• Participants with a known history of prior platelet transfusion(s) or febrileneutropenia in the advanced disease treatment setting.

• Participants with medical history of myocardial infarction. Participants withtroponin levels above ULN at screening and without any myocardial related symptoms.

• History of (non-infectious) ILD/pneumonitis that required steroids, has currentILD/pneumonitis, or suspected ILD/pneumonitis.

• Additional lung-related exclusion criteria: (a) Lung-specific intercurrentclinically significant illnesses (b) Any autoimmune, connective tissue orinflammatory disorders (c) Prior pneumonectomy.

• Pleural effusion, ascites or pericardial effusion that requires drainage, peritonealshunt, or Cell-free and Concentrated Ascites Reinfusion Therapy.

• Participants with a known hypersensitivity to T-DXd, any the excipients or othermAbs.

• History of another primary malignancy.

• Participants with an uncontrolled infection requiring IV antibiotics, antivirals, orantifungals.

• Active primary immunodeficiency, known uncontrolled active HIV infection or activehepatitis B or hepatitis C infection.

Module 5:

• Current or prior use of immunosuppressive medication within 14 days before the firstdose of Dato-DXd and within 4 weeks for continuous corticosteroids at a dose ofapproximately > 10 mg prednisone/day or equivalent.

• Corticosteroid mouthwash formulations are permitted to prevent and manage certainAEs.

• Prior anti-cancer treatments:

(d) Participants should not have received more than 2 prior lines of systemiccytotoxic therapy (e) Prior treatment with PARPi is permitted (f) Prior TOPO1inhibitor therapy is NOT permitted (g) Prior treatment with TROP2-directed ADCs isNOT permitted. (h) Prior radiation therapy requires the washout periods.

• Participants must not enter the study if they received chloroquine /hydroxychloroquine < 14 days prior to the first dose.

• History of another primary malignancy.

• Participant has history of non-infectious ILD/pneumonitis including radiationpneumonitis 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, or any of the excipientsof the product.

• History of severe hypersensitivity reactions to other monoclonal antibodies.

• Participant is pregnant or breastfeeding or planning to become pregnant.