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

Open to people ages 18-130

• Eastern Cooperative Oncology Group performance status (ECOG PS) with no deterioration over the previous 2 weeks.
• Progressive cancer at the time of study entry.
• Non-sterilised male participants who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to approximately 3 months after the last dose of study intervention.

• Adequate organ and marrow function.

  Module 1: - Female participants of childbearing potential must have a negative pregnancy test result at screening and prior to each cycle administration of AZD9574. 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.

• Participants must have evaluable disease.

• Patients must be suitable for treatment with a PARPi.

  Part B:

• Participants 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.
• Participants 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:

• 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 one prior line of alkylating chemotherapy for their disease.
• Recurrent disease must be evaluable by MRI.
• Female participants of childbearing potential must have a negative pregnancy test result at screening and prior to each cycle administration of AZD9574 and TMZ.
• Adequate organ and marrow function.

• 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:

• Participants that 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 LMD unless the LMD is of low volume or is previously irradiated and the participant is asymptomatic from the LMD.

  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:

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