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

Advanced Solid Malignancies Clinical Trial

— CERTIS1  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05417594
• Other study ID #: D8410C00001
• Secondary ID: 2021-006227-17
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: June 24, 2022
• Est. completion date: January 12, 2026

Study information

• Verified date: June 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 490 participants with advanced cancer that has recurred/progressed.

Description:

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

Approximately 490 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 220 participants:

• Part A (dose-escalation cohorts) will include 130 participants (including backfills) 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 BRCA mutated (BRCA1m, and BRCA2m), PALB2 mutation (PALB2m), RAD51Cm or RAD51Dm, without evidence of 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):

• Part A (dose-escalation cohorts) will include 75 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 90 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) may be added in the future following a protocol amendment.

• Module 5 (AZD9574 in combination with Datopotamab deruxtecan [Dato-DXd])

This module will include 90 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 490
• Est. completion date: January 12, 2026
• Est. primary completion date: January 12, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

Inclusion Criteria:

• Eastern Cooperative Oncology Group performance status (ECOG PS) with no deterioration over the previous 2 weeks.

• Progressive cancer at the time of study entry.

• Adequate organ and marrow function.

Module 1:

• Female participants of childbearing potential:

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

2. 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 childbearing potential 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.

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.

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

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.

Module 3:

All Panels:

• Female participants of childbearing potential:

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

2. 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.

Panel 1

• Participants 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:

1. 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,

2. 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

3. 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

4. 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

• Participants 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:

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

2. Participants should have stable neurological function for = 14 days prior to signing the main study ICF.

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

Panel 2

• Participants must be suitable for treatment with TMZ.

• Participants must have IDH1/2-mutant glioma.

• Participants should have progressive disease after prior radiation therapy and 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

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

• Participants 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 .

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

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

Module 4:

• Participants must have the following HER2 status:

1. Participants with breast cancer must be IHC 3+ or IHC 2+/ISH-positive or IHC 2+/ISH-negative or IHC 1+ as determined by local testing using current American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) guidelines for scoring HER2 + breast cancer.

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

3. 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).

4. Participants with NSCLC will also be eligible based on the presence of a HER2activating mutation.

• Participants 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.

• Participants 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.

• Participants 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 childbearing potential 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.

Module 5 :

• Participants 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.

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

• Participants 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 childbearing potential must use a condom with spermicide from screening to at least 4 months after the last dose of study.

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

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

Module 4 & 5:

• Female participants of childbearing potential:

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

2. 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 at least 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 at least 7 months after the last dose of study intervention.

• Participants must provide an existing FFPE tumour sample for retrospective, tissue-based IHC testing in a central laboratory to determine HER2 expression 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:

• 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 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.

• Participants 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:

• 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.

Module 3:

All Panels

• Positive Allen's test

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

• Participants who suffer from claustrophobia.

• Participants with implanted metal devices or implants containing metal

• Participants with an INR >1.5

• Participants taking acid-reducing agents.

Panel 1

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

• Participants with leptomeningeal disease (LMD)

Panel 2

• Participants who have received a PARPi previously.

• Known hypersensitivity to TMZ.

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

• Participants who had previously experienced Grade 4 haematological toxicities 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.

Panel 3

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

• Participants with LMD

Module 4:

• 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.

• Participants 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.

• Participants 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.

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

• Participants with 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.

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

• History of another primary malignancy.

• Participants with 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.

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:

(d) Participants should not have received more than 2 prior lines of systemic cytotoxic therapy (e) Prior treatment with PARPi is permitted (f) Prior TOPO1 inhibitor therapy is NOT permitted (g) Prior treatment with TROP2-directed ADCs is NOT permitted. (h) Prior radiation therapy requires the washout periods.

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

• History of another primary malignancy.

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

• History of severe hypersensitivity reactions to other monoclonal antibodies.

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

Related Conditions & MeSH terms

• Advanced Solid Malignancies
• Neoplasms

Intervention

Drug:
• AZD9574
Participants will receive AZD9574 orally.
• Temozolomide
Participants will receive temozolomide orally.
• [11C]AZ1419 3391
Participants will receive [11C]AZ1419 3391 intravenously.
• Datopotamab Deruxtecan (Dato-DXd)
Participants will receive Dato-DXd intravenously.
• Trastuzumab Deruxtecan (T-DXd)
Participants will receive T-DXd intravenously.

Locations

Country	Name	City	State
Australia	Research Site	Camperdown
Australia	Research Site	Darlinghurst
Australia	Research Site	Melbourne
Australia	Research Site	Randwick
Germany	Research Site	Bayern
Germany	Research Site	Berlin
Germany	Research Site	Heidelberg
Germany	Research Site	Mainz
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Spain	Research Site	A Coruña
Spain	Research Site	Barcelona
Spain	Research Site	Pozuelo de Alarcon
Spain	Research Site	Sant Cugat del Valles
Spain	Research Site	Sevilla
Sweden	Research Site	Lund
Sweden	Research Site	Stockholm
United Kingdom	Research Site	Glasgow, Scotland
United Kingdom	Research Site	London
United Kingdom	Research Site	Newcastle Upon Tyne
United States	Research Site	Boston	Massachusetts
United States	Research Site	Chicago	Illinois
United States	Research Site	Houston	Texas
United States	Research Site	La Jolla	California
United States	Research Site	Los Angeles	California
United States	Research Site	New York	New York
United States	Research Site	New York	New York
United States	Research Site	Portland	Oregon
United States	Research Site	Richmond	Virginia
United States	Research Site	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Australia,  Germany,  Korea, Republic of,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	From first dose to post-treatment follow-up (approximately three years)
Primary	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.	From last assessment prior to first dose to post-treatment follow up visit (approximately three years)
Primary	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.	From last assessment prior to first dose to post-treatment follow up visit (approximately three years)
Primary	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.	Cycle 0 and Cycle 1 (Day 1 to Day 35)
Secondary	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.	Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary	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.	Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary	Time 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.	Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary	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.	Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary	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.	Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary	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.	Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary	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.	Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary	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.	Screening, Cycle 0 Day 1, Cycle 1 Day 8, and Cycle 1 day 15 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary	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.	From Baseline to every 8 weeks until disease progression (approximately three years)
Secondary	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.	From Baseline to every 8 weeks until disease progression (approximately three years)
Secondary	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.	First documented response until the date of documented progression or end of study (approximately three years)
Secondary	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.	From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)
Secondary	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.	From the start of first treatment until the date of objective disease progression or death (approximately three years)
Secondary	Module 1: 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.	From Screening until disease progression or death (approximately three years)
Secondary	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.	From screening until disease progression or death (approximately three years)
Secondary	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.	Up to the End Of Trial (EOT) [approximately three years]
Secondary	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).	From Baseline to every 8 weeks until objective disease progression (approximately three years)
Secondary	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.	From Baseline to every 8 weeks until objective disease progression (approximately three years)
Secondary	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.	First documented response until the date of documented progression or end of study (approximately three years)
Secondary	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.	First dose until the first documentation of a subsequently confirmed objective response (approximately three years)
Secondary	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.	From the start of first treatment until the date of objective disease progression or death (approximately three years)
Secondary	Module 3: Occupancy	Occupancy (%) is defined as the estimated difference in radioligand binding to PARP1 from baseline to PET examination after drug administration.	From Screening to Cycle 2 Day 1
Secondary	Module 3: Adverse Events (AEs) and Serious Adverse Events (SAEs)	The safety of radioligand [11C]AZ14193391 will be assessed.	From first dose to post-treatment follow-up (approximately three years)
Secondary	Module 1 (Food effect): AUC	To investigate the effect of a high-fat meal on the AUC of AZD9574 (Fasted and fed state).	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)
Secondary	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).	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)
Secondary	Module 1 (Food effect): Cmax	To investigate the effect of a high-fat meal on the Cmax of AZD9574 (Fasted and fed state).	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)
Secondary	Module 1 (Food effect): Tmax	To investigate the effect of a high-fat meal on the Tmax of AZD9574 (Fasted and fed state).	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)
Secondary	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).	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)
Secondary	Module 1 (ARA effect): AUC	To assess the effect of famotidine on the AUC of AZD9574 (with and without famotidine).	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)
Secondary	Module 1 (ARA effect): AUC (0-t)	To assess the effect of famotidine on the AUC (0-t) of AZD9574 (with and without famotidine).	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)
Secondary	Module 1 (ARA effect): Cmax	To assess the effect of famotidine on the Cmax of AZD9574 (with and without famotidine).	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)
Secondary	Module 1 (ARA effect): Tmax	To assess the effect of famotidine on the Tmax of AZD9574 (with and without famotidine).	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)
Secondary	Module 1 (ARA effect) : Cmax ratio (with /without famotidine)	To assess the effect of famotidine on the Cmax ratio of AZD9574 (with and without famotidine).	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)
Secondary	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.	AZD9574: Cycle 1 Day X1 (first AZD9574 dosing), 15, X2 (last of AZD9574 dosing), Cycle 2 Day 1, X1 (first AZD9574 dosing), X2 (last of AZD9574 dosing),15 and Cycle 3 Day 1 T-DXd: Cycle 1 Day X1 (pre-dose AZD9574), 1, 15, Cycle 2 Day 1, and Cycle 4 Day 1
Secondary	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.	AZD9574: Cycle 1 Day X1 (first AZD9574 dosing), 15, X2 (last of AZD9574 dosing), Cycle 2 Day 1, X1 (first AZD9574 dosing), X2 (last of AZD9574 dosing),15 and Cycle 3 Day 1 T-DXd: Cycle 1 Day X1 (pre-dose AZD9574), 1, 15, Cycle 2 Day 1, and Cycle 4 Day 1
Secondary	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.	AZD9574: Cycle 1 Day X1 (first AZD9574 dosing), 15, X2 (last of AZD9574 dosing), Cycle 2 Day 1, X1 (first AZD9574 dosing), X2 (last of AZD9574 dosing),15 and Cycle 3 Day 1 T-DXd: Cycle 1 Day X1 (pre-dose AZD9574), 1, 15, Cycle 2 Day 1, and Cycle 4 Day 1
Secondary	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.	Screening, Cycle 1 Day X2 [last of AZD9574 dosing] (Cycle 1 = 28 days)
Secondary	Module 4 : Presence of ADAs for T-DXd	To investigate the immunogenicity of T-DXd.	Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, EoT(End of treatment) ± 7 days, Safety follow up (FU) 40 [+ 7] days after last dose
Secondary	Module 4 : Incidence of Adverse event of special interest (AESI)	To monitor risks associated with T-DXd (AESI) in study participants.	From first dose until the safety FU (40 [+ 7] days) after discontinuation
Secondary	Module 4: 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).	From Baseline to every 6 weeks until disease progression (approximately three years)
Secondary	Module 4: 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.	First documented response until the date of documented progression or end of study (approximately three years)
Secondary	Module 4: 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.	From the start of first treatment until the date of objective disease progression or death (approximately three years)
Secondary	Module 4: 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.	From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)
Secondary	Module 5 : AUC	To assess the AUC of AZD9574 and Dato-DXd.	AZD9574: Cycle 1 Day X1 (first AZD9574 dosing), 15, X2 (last of AZD9574 dosing), Cycle 2 Day 1, X1 (first AZD9574 dosing), 15, Cycle 3 Day 1 Dato-DXd: Cycle 1 Day 1, X1 (pre-dose AZD9574), 15, X2 (pre-dose AZD9574), Cycle 2 Day 1, Cycle 3 Day 1
Secondary	Module 5 : Cmax	To assess the Cmax of AZD9574 and Dato-DXd.	AZD9574: Cycle 1 Day X1 (first AZD9574 dosing), 15, X2 (last of AZD9574 dosing), Cycle 2 Day 1, X1 (first AZD9574 dosing), 15, Cycle 3 Day 1 Dato-DXd: Cycle 1 Day 1, X1 (pre-dose AZD9574), 15, X2 (pre-dose AZD9574), Cycle 2 Day 1, Cycle 3 Day 1
Secondary	Module 5 : Tmax	To assess the Tmax of AZD9574 and Dato-DXd.	AZD9574: Cycle 1 Day X1 (first AZD9574 dosing), 15, X2 (last of AZD9574 dosing), Cycle 2 Day 1, X1 (first AZD9574 dosing), 15, Cycle 3 Day 1 Dato-DXd: Cycle 1 Day 1, X1 (pre-dose AZD9574), 15, X2 (pre-dose AZD9574), Cycle 2 Day 1, Cycle 3 Day 1
Secondary	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.	Screening, Cycle 1 Day X2 [last of AZD9574 dosing] (Cycle 1 = 28 days)
Secondary	Module 5 : Presence of positive ADAs for Dato-DXd	To investigate the immunogenicity of Dato-DXd.	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
Secondary	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.	From Baseline to every 6 weeks until disease progression (approximately three years)
Secondary	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.	First documented response until the date of documented progression or end of study (approximately three years)
Secondary	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.	From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)
Secondary	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.	From the start of first treatment until the date of objective disease progression or death (approximately three years)
Secondary	Module 5 : Incidence of AESIs	To describe the prevalence (or incidence/frequency, etc) of Dato-DXd AESIs in study participants.	From first dose until the safety FU (40 [+ 7] days) after discontinuation
Secondary	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.	Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary	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.	Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary	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.	Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary	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.	Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary	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.	Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary	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.	Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary	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.	From Baseline to every 8 weeks until disease progression (approximately three years)
Secondary	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).	From Baseline to every 8 weeks until disease progression (approximately three years)
Secondary	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.	First documented response until the date of documented progression or end of study (approximately three years)
Secondary	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.	From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)
Secondary	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.	From the start of first treatment until the date of objective disease progression or death (approximately three years)
Secondary	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.	From Screening until disease progression or death (approximately three years)
Secondary	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.	From screening until disease progression or death (approximately three years)
Secondary	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.	Up to the End Of Trial (EOT) [approximately three years]
Secondary	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.	From Screening until disease progression or death (approximately three years)
Secondary	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.	From Screening until disease progression or death (approximately three years)
Secondary	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.	From screening until disease progression or death (approximately three years)