AzTrials
AzTrials

Advanced Solid MalignanciesPhase 1/2CERTIS1NCT05417594

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

A Phase 1/2 study testing AZD9574, Temozolomide (TMZ) and [11C]AZ1419 3391 in people with Advanced Solid Malignancies, run by AstraZeneca at 32 sites in 7 countries.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial summary

This study will assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of AZD9574 individually and in combination with anti-cancer agents in participants with advanced cancer that has recurred/progressed. Read more about this study

Who is it for?
Ages 18 to 130 years
Conditions the study is for
Advanced Solid Malignancies
What is being tested?
AZD9574, Temozolomide (TMZ) and [11C]AZ1419 3391
Could I receive a placebo?
No, everyone receives an active treatment
How many people
695 participants
Where
32 sitesin 7 countries
Study dates
24 Jun 2022to 7 Feb 2028
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 130 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

32 sites in 7 countries. Contact the study team or a site near you to ask about taking part.

AstraZeneca Clinical Study Information Center contact

1-877-240-9479

information.center@astrazeneca.com

AstraZeneca Breast Cancer Study Locator Service contact

1-877-400-4656

az-bcsl@careboxhealth.com

32 sites in 7 countries

United States11 sites, 8 recruiting

  • Research Site

    Boston, Massachusetts, 02215

    Recruiting

  • Research Site

    Chicago, Illinois, 60611

    Recruiting

  • Research Site

    Houston, Texas, 77030

    Recruiting

  • Research Site

    La Jolla, California, 92093

    Withdrawn

  • Research Site

    Los Angeles, California, 90095

    Recruiting

  • Research Site

    New York, New York, 10040

    Recruiting

  • Research Site

    New York, New York, 10065

    Recruiting

  • Research Site

    Portland, Oregon, 97239

    Withdrawn

  • Research Site

    Richmond, Virginia, 23298

    Withdrawn

  • Research Site

    San Antonio, Texas, 78229

    Recruiting

  • Research Site

    San Francisco, California, 94143

    Recruiting

Other trials in United States

Spain6 sites, 6 recruiting

  • Research Site

    A Coruña, 15006

    Recruiting

  • Research Site

    Barcelona, 8035

    Recruiting

  • Research Site

    Málaga, 29010

    Recruiting

  • Research Site

    Pozuelo de Alarcón, 28223

    Recruiting

  • Research Site

    Sant Cugat del Vallès, 08195

    Recruiting

  • Research Site

    Seville, 41013

    Recruiting

Other trials in Spain

Germany4 sites

  • Research Site

    Bayern, 80337

    Withdrawn

  • Research Site

    Berlin, 13353

    Withdrawn

  • Research Site

    Heidelberg, 69120

    Withdrawn

  • Research Site

    Mainz, 55131

    Withdrawn

Other trials in Germany

Australia3 sites, 3 recruiting

  • Research Site

    Darlinghurst, 2010

    Recruiting

  • Research Site

    Melbourne, 3000

    Recruiting

  • Research Site

    Randwick, 2031

    Recruiting

Other trials in Australia

South Korea3 sites, 3 recruiting

  • Research Site

    Seoul, 03080

    Recruiting

  • Research Site

    Seoul, 03722

    Recruiting

  • Research Site

    Seoul, 06351

    Recruiting

Other trials in South Korea

United Kingdom3 sites, 3 recruiting

  • Research Site

    Glasgow, Scotland, G12 0YN

    Recruiting

  • Research Site

    London, EC1M 6BQ

    Recruiting

  • Research Site

    Newcastle upon Tyne, NE7 7DN

    Recruiting

Other trials in United Kingdom

Sweden2 sites, 2 recruiting

  • Research Site

    Lund, 22185

    Recruiting

  • Research Site

    Stockholm, 118 83

    Recruiting

Other trials in Sweden

About this study

Official title: 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)

This study will assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of AZD9574 individually and in combination with anti-cancer agents in participants with advanced cancer that has recurred/progressed.

Read the detailed description

This is a modular phase I/IIa, multi-centre, multi-part, open-label, dose escalation, and dose expansion study.

Approximately 695 participants will be enrolled and assigned to study treatments.

This study consists of individual modules each evaluating safety and tolerability.

  • Core protocol which contains information applicable to all modules.
  • Module 1 (AZD9574 monotherapy):

This module will include 235 participants:

  • Part A (dose-escalation cohorts) will include participants with advanced/relapsed ovarian, breast, pancreatic or prostate cancer that are deemed suitable for a Poly ADP-Ribose Polymerase (PARPi) by the Investigator.
  • Part B (dose-expansion cohorts):

This module will include up to 3 expansion cohorts with 30 participants in each:

  • Cohort B1 will include participants with advanced/relapsed Human Epidermal Growth Factor Receptor 2 (HER2)-negative breast cancer participants with breast cancer gene (BRCA) mutated (BRCA1m, and BRCA2m), partner and localiser of the BRCA2 gene (PALB2) mutation (PALB2m), RAD51Cm or RAD51Dm, without evidence of untreated brain metastasis at baseline Magnetic Resonance Imaging (MRI) scan.
  • Cohort B2 will include participants with advanced/relapsed HER2-negative breast cancer participants with BRCA1m, BRCA2m, PALB2m, RAD51Cm or RAD51Dm, who have either untreated or treated brain metastases that are not requiring immediate local therapy.
  • Up to of 20 participants may be required to get 12 evaluable participants in each cohort for food effect and Acid Reducing Agent (ARA) investigations.
  • Module 2 (AZD9574 in combination with temozolomide (TMZ): This module will include 75 participants for up to 12 cycles.
  • Part A (dose-escalation cohorts) will include participants with Isocitrate Dehydrogenase (IDH)-mutant glioma.
  • Module 3 (PET Sub-study: AZD9574 monotherapy [Panels 1 and 3], AZD9574 in combination with TMZ (Panel 2). This module will include 12 participants and is only applicable for Sweden.
  • Panel 1 (AZD9574 monotherapy) will include up to 8 participants with advanced/relapsed HER2-negative breast, ovarian, prostate, or pancreatic cancer and expressing BRCA1m, BRCA2m, PALB2m, RAD51Cm or RAD51Dm.
  • Panel 2 (AZD9574 + TMZ) will include up to 2 participants with IDH-mutant recurrent glioma.
  • Panel 3 (AZD9574 monotherapy) will include up to 2 participants with breast cancer (without BM).
  • Module 4 (AZD9574 in combination with Trastuzumab deruxtecan [T-DXd])

This module will include 265 participants (including backfills):

  • Part A (dose escalation cohorts) will include participants with advanced, unresectable, or metastatic solid tumours that are HER2-positive.
  • Part B (dose expansion cohorts) will include up to 4 cohorts with participants with HER2-low/ultralow, HR positive breast cancer. Approximately 30 response evaluable participants without brain metastases or with treated and stable brain metastasis will be enrolled in each cohort and up to 10 additional participants with brain metastases (CNS cohort) may be enrolled in each cohort.
  • Module 5 (AZD9574 in combination with Datopotamab deruxtecan [Dato-DXd])

This module will include 105 participants (including backfills):

  • Part A (dose escalation cohorts) will include participants with advanced, unresectable, or metastatic solid tumours in different types of cancers.
  • Part B (dose expansion cohorts) may be added in the future amendment.
Being tested
AZD9574, Temozolomide (TMZ), [11C]AZ1419 3391, Trastuzumab Deruxtecan (T-DXd), Datopotamab Deruxtecan (Dato-DXd)
Keywords
Poly ADP-ribose Polymerase inhibitor (PARPi), Anti-tumour, Breast cancer, Ovarian cancer, Fallopian tube cancer, Prostate cancer, Pancreatic cancer, Soft tissue disease, Glioma, Astrocytoma, Oliogodendroglioma, Solid tumours
Medical subject headings
Breast Neoplasms, Ovarian Neoplasms, Fallopian Tube Neoplasms, Prostatic Neoplasms, Pancreatic Neoplasms, Glioma, Astrocytoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AZD9574Drug

    Participants will receive AZD9574 orally.

  • Temozolomide (TMZ)Drug

    Participants will receive temozolomide orally.

  • [11C]AZ1419 3391Drug

    Participants will receive [11C]AZ1419 3391 intravenously.

  • Trastuzumab Deruxtecan (T-DXd)Drug

    Participants will receive T-DXd intravenously.

  • Datopotamab Deruxtecan (Dato-DXd)Drug

    Participants will receive Dato-DXd intravenously.

Study groups in NCT05417594
Study groupRoleWhat they receive
Module 1 Part A: Dose escalationExperimentalParticipants with advanced/relapsed ovarian, breast, pancreatic, or prostate cancer who are deemed suitable for a PARPi will receive AZD9574 monotherapy at escalating cohorts.
Receives: Drug: AZD9574
Module 1 Part B: Dose expansionExperimentalParticipants with breast cancer who are PARPi naive at doses determined in dose-escalation.
Receives: Drug: AZD9574
Module 2 Part A: Dose escalationExperimentalParticipants with IDH 1/2-mutant glioma who are PARPi naive will receive AZD9574 and TMZ at escalating cohorts.
Receives: Drug: AZD9574; Drug: Temozolomide (TMZ)
Module 3 Panel 1: AZD9574 monotherapy (Sweden only)ExperimentalParticipants with advanced/relapsed HER2-negative breast, ovarian, prostate, or pancreatic cancer and expressing BRCA1m, BRCA2m, PALB2m, RAD51Cm or RAD51Dm.
Receives: Drug: AZD9574; Drug: [11C]AZ1419 3391
Module 3 Panel 2: AZD9574 + TMZ (Sweden only)ExperimentalParticipants with IDH 1/2-mutant glioma who are PARPi naive will receive AZD9574 and TMZ at escalating cohorts.
Receives: Drug: AZD9574; Drug: Temozolomide (TMZ); Drug: [11C]AZ1419 3391
Module 3 Panel 3: AZD9574 monotherapy (Sweden only)ExperimentalParticipants with breast cancer (without BM).
Receives: Drug: AZD9574; Drug: [11C]AZ1419 3391
Module 4 Part A: Dose escalation (AZD9574 + T-DXd)ExperimentalParticipants with advanced, unresectable, or metastatic solid tumours that are HER2-positive will receive a combination of AZD9574 and T-DXd at at escalating cohorts.
Receives: Drug: AZD9574; Drug: Trastuzumab Deruxtecan (T-DXd)
Module 4 Part B : Dose expansion (AZD9574 + T-DXd)ExperimentalParticipants with HER2-low/ultralow, HR positive breast cancer will receive a combination of different doses of AZD9574 and T-DXd at expanding cohorts.
Receives: Drug: AZD9574; Drug: Trastuzumab Deruxtecan (T-DXd)
Module 5 Part A : Dose escalation (AZD9574 + Dato-DXd)ExperimentalParticipants with advanced, unresectable, or metastatic solid tumours in different types of cancers will receive a combination of AZD9574 and Dato-DXd at escalating cohorts.
Receives: Drug: AZD9574; Drug: Datopotamab Deruxtecan (Dato-DXd)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence of Adverse Events (AEs), and Serious Adverse Events (SAEs)

    The safety and tolerability of AZD9574 as monotherapy and in combination with anti-cancer agents and TMZ in participants with advanced malignancies will be assessed.

    Measured: From first dose to post-treatment follow-up (approximately three years)

  2. Changes from baseline in laboratory findings, electrocardiograms (ECGs), and vital signs

    The safety and tolerability of AZD9574 as monotherapy and in combination with anti-cancer agents and TMZ in participants with advanced malignancies will be assessed.

    Measured: From last assessment prior to first dose to post-treatment follow up visit (approximately three years)

  3. Change from baseline Eastern Cooperative Oncology Group performance status (ECOG PS)

    The performance status of ECOG will be assessed based on an ECOG grade of 0 to 4 where '0' is a high grade while '4' is a low grade. An ECOG grade of '0' means that the participant is fully active, able to carry on all pre-disease performance without restriction. An ECOG grade of '4' means that the participant is completely disabled, cannot carry on any self-care, and is totally confined to a bed or chair.

    Measured: From last assessment prior to first dose to post-treatment follow up visit (approximately three years)

  4. Incidence of Dose Limiting Toxicities (DLTs)

    The safety and tolerability of AZD9574 as monotherapy and in combination with anti-cancer agents in participants with advanced malignancies will be assessed at each dose level.

    Measured: Cycle 0 and Cycle 1 (Day 1 to Day 35)

Secondary outcomes (76)

  1. Area Under the Curve (AUC)

    The AUC of AZD9574 following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents will be evaluated.

    Measured: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  2. Maximum plasma concentration (Cmax)

    The Cmax of AZD9574 following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents will be evaluated.

    Measured: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  3. Time taken to reach maximum plasma concentration (tmax)

    The tmax of AZD9574 following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents will be evaluated.

    Measured: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  4. Minimum plasma concentration at steady state (Cmin,ss)

    The Cmin,ss of AZD9574 following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents will be evaluated.

    Measured: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  5. Half-life (t1/2)

    The t1/2 of AZD9574 following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents will be evaluated.

    Measured: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  6. Accumulation ratio

    The accumulation ratio of AZD9574 following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents will be evaluated.

    Measured: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  7. Dose proportionality

    The dose proportionality of AZD9574 following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents will be evaluated.

    Measured: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  8. Module 1: Assessment of pH2AX (phospho-histone 2AX) (Ser139) PD biomarker modulations

    The PD biomarker modulations of pH2AX (Ser139) at baseline and during treatment or pre-treatment will be assessed in tumour tissue when given orally as monotherapy.

    Measured: Screening, Cycle 0 Day 1, Cycle 1 Day 8, and Cycle 1 day 15 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  9. Module 1: Percentage change in target lesion (TL) size

    The percentage change in TL size will be determined for participants with measurable disease at baseline and is derived at each visit.

    Measured: From Baseline to every 8 weeks until disease progression (approximately three years)

  10. Module 1: Objective Response Rate (ORR)

    ORR is defined as the percentage of participants who have a confirmed response of Complete Response (CR) or Partial Response (PR) prior to any evidence of progression according to Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1) for solid tumours, RECIST v1.1 and/or Prostate Cancer Working Group 3 (PCWG3 [bone]) for prostate cancer, and Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) for brain metastases.

    Measured: From Baseline to every 8 weeks until disease progression (approximately three years)

  11. Module 1: Duration of Response (DoR)

    The DoR is defined as the time from the date of first documented response (which is subsequently confirmed) until date of documented progression or death in the absence of disease progression according to RECIST v1.1 for solid tumours, RECIST v1.1 and/or PCWG3 for prostate cancer, and RANO-BM for brain metastases.

    Measured: First documented response until the date of documented progression or end of study (approximately three years)

  12. Module 1: Time To Response (TTR)

    TTR is defined as the time from first dose until the first documentation of a subsequently confirmed objective response according to RECIST v1.1 for solid tumours, RECIST v1.1 and/or PCWG3 for prostate cancer, and RANO-BM for brain metastases.

    Measured: From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)

  13. Module 1: Progression Free Survival (PFS)/radiographic Progression-Free Survival (rPFS)

    PFS and rPFS are defined as the time from start of first treatment until the date of objective disease progression or death regardless of whether the participant withdraws from study therapy or receives another anti-cancer therapy prior to progression according to RECIST v1.1 for solid tumours, RECIST v1.1 and/or PCWG3 for prostate cancer, and RANO-BM for brain metastases.

    Measured: From the start of first treatment until the date of objective disease progression or death (approximately three years)

  14. Module 1: Cancer Antigen 125 (CA125) response evaluated according to the gynecologic cancer intergroup (GCIG) criteria (for ovarian patients only)

    CA125 response is defined as at least a 50% reduction in CA125 levels from a pre-treatment sample.

    Measured: From Screening until disease progression or death (approximately three years)

  15. Module 1: Proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result (for prostate cancer only)

    PSA50 response is defined as the proportion of participants achieving a ≥ 50% decrease in Prostate Specific Antigen (PSA) from baseline to the lowest post-baseline PSA, confirmed by a consecutive PSA at least 3 weeks later and will be based on PSA evaluable participants.

    Measured: From screening until disease progression or death (approximately three years)

  16. Module 1: Radiological response evaluated according to RECIST v1.1 + Prostate Cancer Working Group 3 (PCWG3) response evaluation criteria (for prostate cancer only)

    In participants with prostate cancer, disease progression will be deemed to have occurred if soft tissue disease progression, bone lesion progression, or death are met.

    Measured: Up to the End Of Trial (EOT) [approximately three years]

  17. Module 1 (Food effect): AUC

    To investigate the effect of a high-fat meal on the AUC of AZD9574 (Fasted and fed state).

    Measured: Cycle 0 Day 1,2,3, Cycle 1 Day 1,2,8 to 15 and Cycle 2 Day 1, and Cycle 3 Day 1 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  18. Module 1 (Food effect) : Area under the curve from 0 to t [AUC (0-t)]

    To investigate the effect of a high-fat meal on the AUC (0-t) of AZD9574 (Fasted and fed state).

    Measured: Cycle 0 Day 1,2,3, Cycle 1 Day 1,2,8 to 15 and Cycle 2 Day 1, and Cycle 3 Day 1 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  19. Module 1 (Food effect): Cmax

    To investigate the effect of a high-fat meal on the Cmax of AZD9574 (Fasted and fed state).

    Measured: Cycle 0 Day 1,2,3, Cycle 1 Day 1,2,8 to 15 and Cycle 2 Day 1, and Cycle 3 Day 1 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  20. Module 1 (Food effect): tmax

    To investigate the effect of a high-fat meal on the tmax of AZD9574 (Fasted and fed state).

    Measured: Cycle 0 Day 1,2,3, Cycle 1 Day 1,2,8 to 15 and Cycle 2 Day 1, and Cycle 3 Day 1 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  21. Module 1 (Food effect) : Maximum plasma concentration (Cmax) ratio (with /without a high fat meal)

    To investigate the effect of a high-fat meal on the Cmax ratio of AZD9574 (Fasted and fed state).

    Measured: Cycle 0 Day 1,2,3, Cycle 1 Day 1,2,8 to 15 and Cycle 2 Day 1, and Cycle 3 Day 1 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  22. Module 1 (ARA effect): AUC

    To assess the effect of rabeprazole on the AUC of AZD9574 (with and without rabeprazole).

    Measured: Cycle 0 Day 1,3, Cycle 1 Day 1,2,8 to 15,16, Cycle 2 Day 1, Cycle 3 Day 1 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  23. Module 1 (ARA effect): AUC (0-t)

    To assess the effect of rabeprazole on the AUC (0-t) of AZD9574 (with and without rabeprazole).

    Measured: Cycle 0 Day 1,3, Cycle 1 Day 1,2,8 to 15,16, Cycle 2 Day 1, Cycle 3 Day 1 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  24. Module 1 (ARA effect): Cmax

    To assess the effect of rabeprazole on the Cmax of AZD9574 (with and without rabeprazole).

    Measured: Cycle 0 Day 1,3, Cycle 1 Day 1,2,8 to 15,16, Cycle 2 Day 1, Cycle 3 Day 1 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  25. Module 1 (ARA effect): tmax

    To assess the effect of rabeprazole on the tmax of AZD9574 (with and without rabeprazole).

    Measured: Cycle 0 Day 1,3, Cycle 1 Day 1,2,8 to 15,16, Cycle 2 Day 1, Cycle 3 Day 1 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  26. Module 1 (ARA effect) : Cmax ratio (with /without rabeprazole)

    To assess the effect of rabeprazole on the Cmax ratio of AZD9574 (with and without rabeprazole).

    Measured: Cycle 0 Day 1,3, Cycle 1 Day 1,2,8 to 15,16, Cycle 2 Day 1, Cycle 3 Day 1 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  27. Module 2: Percentage change in TL size

    The percentage change in TL size will be determined for participants with measurable disease at baseline and is derived at each visit by the measurability of TL according to Response Assessment in Neuro-Oncology - high-grade glioma (RANO-HGG) or Response Assessment in Neuro-Oncology - low-grade glioma (RANO-LGG).

    Measured: From Baseline to every 8 weeks until objective disease progression (approximately three years)

  28. Module 2: ORR

    The ORR is defined as the percentage of participant with high- or low-grade gliomas with at least one visit response of CR or PR according to RANO-HGG or RANO-LGG.

    Measured: From Baseline to every 8 weeks until objective disease progression (approximately three years)

  29. Module 2: DoR

    The DoR is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression according to RANO-HGG or RANO-LGG.

    Measured: First documented response until the date of documented progression or end of study (approximately three years)

  30. Module 2: TTR

    TTR is defined as the time from first dose until the first documentation of a subsequently confirmed objective response according to RANO-HGG or RANO-LGG.

    Measured: First dose until the first documentation of a subsequently confirmed objective response (approximately three years)

  31. Module 2: PFS

    The PFS is defined as the time from the start of study intervention until the date of objective disease progression or death regardless of whether the participant withdraws from study intervention or receives another anti-cancer therapy prior to progression according to RANO-HGG or RANO-LGG.

    Measured: From the start of first treatment until the date of objective disease progression or death (approximately three years)

  32. Module 3: Occupancy

    Occupancy (%) is defined as the estimated difference in radioligand binding to PARP1 from baseline to positron emission tomography (PET) examination after drug administration.

    Measured: From Screening to Cycle 2 Day 1

  33. Module 3: AUC

    The AUC of AZD9574 following single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with TMZ will be evaluated.

    Measured: Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  34. Module 3: Cmax

    The Cmax of AZD9574 following single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with TMZ will be evaluated.

    Measured: Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  35. Module 3: tmax

    The tmax of AZD9574 following single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with TMZ will be evaluated.

    Measured: Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  36. Module 3: Cmin,ss

    The Cmin,ss of AZD9574 following single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with TMZ will be evaluated.

    Measured: Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  37. Module 3: t1/2

    The t1/2 of AZD9574 following single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with TMZ will be evaluated.

    Measured: Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  38. Module 3: Accumulation ratio

    The accumulation ratio of AZD9574 following single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with TMZ will be evaluated.

    Measured: Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)

  39. Module 3: Percentage change in target lesion (TL) size

    The percentage change in TL size will be determined for participants with measurable disease at baseline and is derived at each visit.

    Measured: From Baseline to every 8 weeks until disease progression (approximately three years)

  40. Module 3: ORR

    ORR is defined as the percentage of participants who have a confirmed response of Complete Response (CR) or Partial Response (PR) prior to any evidence of progression according to Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1) for solid tumours, RECIST v1.1 and/or Prostate Cancer Working Group 3 (PCWG3 [bone]) for prostate cancer, and Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) for brain metastases and according to Response Assessment in Neuro-Oncology - high-grade glioma (RANO-HGG) or Response Assessment in Neuro-Oncology - low-grade glioma (RANO-LGG).

    Measured: From Baseline to every 8 weeks until disease progression (approximately three years)

  41. Module 3: DoR

    The DoR is defined as the time from the date of first documented response (which is subsequently confirmed) until date of documented progression or death in the absence of disease progression according to RECIST v1.1 for solid tumours, RECIST v1.1 and/or PCWG3 for prostate cancer, RANO-BM for brain metastases and RANO-HGG or RANO-LGG.

    Measured: First documented response until the date of documented progression or end of study (approximately three years)

  42. Module 3: TTR

    TTR is defined as the time from first dose until the first documentation of a subsequently confirmed objective response according to RECIST v1.1 for solid tumours, RECIST v1.1 and/or PCWG3 for prostate cancer, RANO-BM for brain metastases and RANO-HGG or RANO-LGG.

    Measured: From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)

  43. Module 3: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)

    CA125 response is defined as at least a 50% reduction in CA125 levels from a pre-treatment sample.

    Measured: From Screening until disease progression or death (approximately three years)

  44. Module 3: Proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result (for prostate cancer only)

    PSA50 response is defined as the proportion of participants achieving a ≥ 50% decrease in Prostate Specific Antigen (PSA) from baseline to the lowest post-baseline PSA, confirmed by a consecutive PSA at least 3 weeks later and will be based on PSA evaluable participants.

    Measured: From screening until disease progression or death (approximately three years)

  45. Module 3: Progression Free Survival (PFS)/radiographic Progression-Free Survival (rPFS)

    PFS and rPFS are defined as the time from start of first treatment until the date of objective disease progression or death regardless of whether the participant withdraws from study therapy or receives another anti-cancer therapy prior to progression according to RECIST v1.1 for solid tumours, RECIST v1.1 and/or PCWG3 for prostate cancer, RANO-BM for brain metastases and RANO-HGG or RANO-LGG.

    Measured: From the start of first treatment until the date of objective disease progression or death (approximately three years)

  46. Module 3: Radiological response evaluated according to RECIST v1.1 + Prostate Cancer Working Group 3 (PCWG3) response evaluation criteria (for prostate cancer only)

    In participants with prostate cancer, disease progression will be deemed to have occurred if soft tissue disease progression, bone lesion progression, or death are met.

    Measured: Up to the End Of Trial (EOT) [approximately three years]

  47. Module 4 : AUC

    To characterise the AUC of AZD9574, T-DXd following a single dose and at steady state after multiple dosing, when given in combination with T-DXd.

    Measured: AZD9574 (Parts A and B): Cycle (C) 1 Day (D) X1 (first dose), X2 (last dose), C2 D1, X1 (first dose), D15 (part A only), and C3 D1 T DXd: C1 D1, X1 (pre-dose AZD9574), X2, C2 D1, C3 D1, and C4 D1, up to safety follow-up (40-days after last dose)

  48. Module 4 : Cmax

    To characterise the Cmax of AZD9574, T-DXd following a single dose and at steady state after multiple dosing, when given in combination with T-DXd.

    Measured: AZD9574 (Parts A and B): C1 X1 (first dose), X2 (last dose), C2 D1, X1 (first dose), D15 (part A only), and C3 D1 T DXd: C1 D1, X1 (pre-dose AZD9574), X2, C2 D1, C3 D1, and C4 D1, up to safety follow-up (40-days after last dose)

  49. Module 4 : tmax

    To characterise the tmax of AZD9574, T-DXd following a single dose and at steady state after multiple dosing, when given in combination with T-DXd.

    Measured: AZD9574 (Parts A and B): C1 X1 (first dose), X2 (last dose), C2 D1, X1 (first dose), D15 (part A only), and C3 D1 T DXd: C1 D1, X1 (pre-dose AZD9574), X2, C2 D1, C3 D1, and C4 D1, up to safety follow-up (40-days after last dose)

  50. Module 4 : Assessment of pH2AX (phospho-histone 2AX) (Ser139) PD biomarker modulations

    To characterise the PD of AZD9574 in tumour tissue, following a single dose and at steady state after multiple dosing, when given orally in combination with T-DXd.

    Measured: Cycle 1 Day X1, Day X2 [last of AZD9574 dosing] (Cycle 1 = 28 days)

  51. Module 4 : Presence of ADAs for T-DXd

    To investigate the immunogenicity of T-DXd.

    Measured: Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Safety follow-up (FU) 40 [+ 7] days after last dose

  52. Module 4 : Incidence of Adverse event of special interest (AESI)

    To monitor risks associated with T-DXd (AESI) in study participants.

    Measured: From first dose until the safety FU (40 [+ 7] days) after discontinuation

  53. Module 4 (Part A): ORR

    ORR is defined as the percentage of participants who have a confirmed response of Complete Response (CR) or Partial Response (PR) prior to any evidence of progression according to Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1).

    Measured: From Baseline to every 6 weeks until disease progression (approximately three years)

  54. Module 4 (Part B): ORR

    ORR is defined as the percentage of participants who have a confirmed response of CR or PR prior to any evidence of progression according to RECIST v1.1, RECIST v1.1 and RANO-BM for participants with brain metastasis.

    Measured: From Baseline to every 6 weeks for the first 24 weeks and then every 9 weeks until disease progression (approximately three years)

  55. Module 4 (Part A): DoR

    The DoR is defined as the time from the date of first documented response (which is subsequently confirmed) until date of documented progression or death in the absence of disease progression according to RECIST v1.1.

    Measured: First documented response until the date of documented progression or end of study (approximately three years)

  56. Module 4 (Part B): DoR

    The DoR is defined as the time from the date of first documented response (which is subsequently confirmed) until date of documented progression or death in the absence of disease progression according to RECIST v1.1, RECIST v1.1 and RANO-BM for participants with brain metastasis.

    Measured: First documented response until the date of documented progression or end of study (approximately three years)

  57. Module 4 (Part A): PFS

    PFS is defined as the time from start of first treatment until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdraws from study therapy or receives another anti-cancer therapy prior to progression according to RECIST v1.1.

    Measured: From the start of first treatment until the date of objective disease progression or death (approximately three years)

  58. Module 4 (Part B): PFS

    PFS is defined as the time from start of first treatment until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdraws from study therapy or receives another anti-cancer therapy prior to progression according to RECIST v1.1, RECIST v1.1 and RANO-BM for participants with brain metastasis.

    Measured: From the start of first treatment until the date of objective disease progression or death (approximately three years)

  59. Module 4 (Part A): TTR

    TTR is defined as the time from first dose until the first documentation of a subsequently confirmed objective response according to RECIST v1.1.

    Measured: From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)

  60. Module 4 (Part B): TTR

    TTR is defined as the time from first dose until the first documentation of a subsequently confirmed objective response according to RECIST v1.1, RECIST v1.1 and RANO-BM for participants with brain metastasis.

    Measured: From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)

  61. Module 4 (Part B only): Progression-free survival at 6 months (PFS6)

    The PFS is defined as the time from the start of study intervention until the date of objective disease progression or death regardless of whether the participant withdraws from study intervention or receives another anti-cancer therapy prior to progression according to RECIST v1.1, RECIST v1.1 and RANO-BM for participants with brain metastasis.

    Measured: At 6 months after start of first treatment

  62. Module 4 (Part B): Number of participants experiencing each level of symptomatic AEs as measured by the Patient-Reported Outcomes Version of the common terminology criteria for adverse events (PRO-CTCAE)

    The PRO-CTCAE is an item library of symptoms experienced by participants while undergoing treatment of their cancer. It assess the presence/absence, severity, frequency, and interference of treatment-related symptoms from the participant's perspective.

    Measured: From the first dose until the end of 12 months or EOT, whichever comes first (approximately three years)

  63. Module 4 (Part B): Number of participants reporting overall side effect bother on the patient's global impression of treatment tolerability (PGI-TT) while receiving treatment

    The PGI-TT is a single item assessment of the participant's overall level of bother due to treatment-related side effects of cancer treatment over a 1-week period.

    Participants will be asked to choose the response that best describes the severity of their overall cancer symptoms over the past week to aid in the interpretation of other clinical outcomes and explore the cumulative impact of treatment-related side effects. The response options are: "not at all", "a little bit", "somewhat", "quite a bit", and "very much".

    Measured: From the first dose until the end of 12 months or EOT, whichever comes first (approximately three years)

  64. Module 4: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)

    CA125 response is defined as at least a 50% reduction in CA125 levels from a pre-treatment sample.

    Measured: From Screening until disease progression or death (approximately three years)

  65. Module 5 : AUC

    To assess the AUC of AZD9574 and Dato-DXd.

    Measured: AZD9574: Cycle 1 Day X1 (first dose), X2 (last dose), Cycle 2 Day 1, X1 (first dose), Day 15, Cycle 3 Day 1 Dato-DXd: Cycle 1 Day 1, X1 (pre-dose AZD9574), X2, Cycle 2 Day 1, Cycle 4 Day 1, C8D1, every 4 cycles thereafter on Day 1

  66. Module 5 : Cmax

    To assess the Cmax of AZD9574 and Dato-DXd.

    Measured: AZD9574: Cycle 1 Day X1 (first dose), X2 (last dose), Cycle 2 Day 1, X1 (first dose), Day 15, Cycle 3 Day 1 Dato-DXd: Cycle 1 Day 1, X1 (pre-dose AZD9574), X2, Cycle 2 Day 1, Cycle 4 Day 1, C8D1, every 4 cycles thereafter on Day 1

  67. Module 5 : tmax

    To assess the tmax of AZD9574 and Dato-DXd.

    Measured: AZD9574: Cycle 1 Day X1 (first dose), X2 (last dose), Cycle 2 Day 1, X1 (first dose), Day 15, Cycle 3 Day 1 Dato-DXd: Cycle 1 Day 1, X1 (pre-dose AZD9574), X2, Cycle 2 Day 1, Cycle 4 Day 1, C8D1, every 4 cycles thereafter on Day 1

  68. Module 5 : Assessment of pH2AX (phospho-histone 2AX) (Ser139) PD biomarker modulations

    To characterise the PD of AZD9574 in tumour tissue, following a single dose and at steady state after multiple dosing, when given orally in combination with Dato-DXd.

    Measured: Cycle 1 Day X1, Day X2 [last of AZD9574 dosing] (Cycle 1 = 28 days)

  69. Module 5 : Presence of positive ADAs for Dato-DXd

    To investigate the immunogenicity of Dato-DXd.

    Measured: Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, EoT(End of treatment) ± 7 days, Safety follow up (FU) 28 [+ 7] days after last dose

  70. Module 5: ORR

    ORR is defined as the percentage of participants who have a confirmed response of Complete Response (CR) or Partial Response (PR) prior to any evidence of progression according to Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1) and PCWG3 for prostate cancer.

    Measured: From Baseline to every 6 weeks until disease progression (approximately three years)

  71. Module 5: DoR

    The DoR is defined as the time from the date of first documented response (which is subsequently confirmed) until date of documented progression or death in the absence of disease progression according to RECIST v1.1.

    Measured: First documented response until the date of documented progression or end of study (approximately three years)

  72. Module 5: TTR

    TTR is defined as the time from first dose until the first documentation of a subsequently confirmed objective response according to RECIST v1.1.

    Measured: From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)

  73. Module 5: Progression Free Survival (PFS)/radiographic Progression-Free Survival (rPFS)

    PFS and rPFS are defined as the time from start of first treatment until the date of objective disease progression or death regardless of whether the participant withdraws from study therapy or receives another anti-cancer therapy prior to progression according to RECIST v1.1 for solid tumours, RECIST v1.1 and/or PCWG3 for prostate cancer.

    Measured: From the start of first treatment until the date of objective disease progression or death (approximately three years)

  74. Module 5 : Incidence of AESIs

    To describe the prevalence (or incidence/frequency, etc) of Dato-DXd AESIs in study participants.

    Measured: From first dose until the safety FU (40 [+ 7] days) after discontinuation

  75. Module 5: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)

    CA125 response is defined as at least a 50% reduction in CA125 levels from a pre-treatment sample.

    Measured: From Screening until disease progression or death (approximately three years)

  76. Module 5: Proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the post-baseline PSA result (for prostate cancer only)

    PSA50 response is defined as the proportion of participants achieving a ≥ 50% decrease in Prostate Specific Antigen (PSA) from baseline to the lowest post-baseline PSA, confirmed by a consecutive PSA at least 3 weeks later and will be based on PSA evaluable participants.

    Measured: From screening until disease progression or death (approximately three years)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Jun 2022
  2. Study start24 Jun 2022
  3. Primary completion7 Feb 2028 (estimated)
  4. Study completion7 Feb 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
695 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05417594
Sponsor's protocol ID
D8410C00001
Other IDs
2023-504984-17-00, 2021-006227-17, 2023
Acronym
CERTIS1
Status last verified
Sep 2026
First submitted
20 May 2022
Last updated
5 Oct 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Publications

  • Staniszewska AD, Pilger D, Gill SJ, Jamal K, Bohin N, Guzzetti S, Gordon J, Hamm G, Mundin G, Illuzzi G, Pike A, McWilliams L, Maglennon G, Rose J, Hawthorne G, Cortes Gonzalez M, Halldin C, Johnstrom P, Schou M, Critchlow SE, Fawell S, Johannes JW, Leo E, Davies BR, Cosulich S, Sarkaria JN, O'Connor MJ, Hamerlik P. Preclinical Characterization of AZD9574, a Blood-Brain Barrier Penetrant Inhibitor of PARP1. Clin Cancer Res. 2024 Apr 1;30(7):1338-1351. doi: 10.1158/1078-0432.CCR-23-2094.

    PubMed 37967136

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing AZD9574, Temozolomide (TMZ) and [11C]AZ1419 3391 in people with Advanced Solid Malignancies, run by AstraZeneca at 32 sites in 7 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 93 inclusion and 91 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 5 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 32 sites in United States, Spain, Germany, Australia, South Korea and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact AstraZeneca Clinical Study Information Center (1-877-240-9479, information.center@astrazeneca.com), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of Adverse Events (AEs), and Serious Adverse Events (SAEs) (time frame: From first dose to post-treatment follow-up (approximately three years)). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05417594, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Oct 2026.

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