Study of AZD9574 as monotherapy and in combination with anti-cancer agents in participants with advanced solid malignancies - CERTIS1

Inclusion Criteria

• 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:
• (a) 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,
• (b) 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
• (c) 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.
• (d) 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:
• (a) Must have previously treated and progressing or untreated brain metastases confirmed by brain MRI at screening that do not need immediate local therapy.
• (b) Should have stable neurological function for ≥ 14 days prior to signing the main study ICF.
• (c) 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:
• (a) 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.
• (b) Gastric cancer should be IHC 3+ or IHC 2+/ISH-positive based on local tissue testing results.
• (c) 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).
• (d) 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:
• (a) Must have a negative pregnancy test result at screening and prior to each cycle of study treatment.
• (b) 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:
• (a) Must have a negative pregnancy test result at screening and prior to each cycle of study intervention.
• (b) 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:
• (a) Should not have received more than 2 prior lines of systemic cytotoxic therapy
• (b) Prior treatment with PARPi is permitted
• (c) Prior TOPO1 inhibitor therapy is NOT permitted
• (d) Prior treatment with TROP2-directed ADCs is NOT permitted.
• (e) 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.