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 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:
• 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,
• 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
• 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.
• 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:
• Must have previously treated and progressing or untreated brain metastases confirmed by brain MRI at screening that do not need immediate local therapy.
• Should have 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.
• 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:
• 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.
• Gastric cancer should be IHC 3+ or IHC 2+/ISH-positive based on local tissue testing results.
• 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).
• 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:
• Must have a negative pregnancy test result at screening and prior to each cycle of study treatment.
• 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:
• Must have a negative pregnancy test result at screening and prior to each cycle of study intervention.
• 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:
• Should not have received more than 2 prior lines of systemic cytotoxic therapy
• Prior treatment with PARPi is permitted
• Prior TOPO1 inhibitor therapy is NOT permitted
• Prior treatment with TROP2-directed ADCs is NOT permitted.
• 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.