NCT05417594招募中1 期
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)
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AstraZeneca
- 入组人数
- 695
- 试验地点
- 33
- 主要终点
- Incidence of Adverse Events (AEs), and Serious Adverse Events (SAEs)
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 130 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •- Participants must have one of the following: (i) Histologically or cytologically confirmed relapsed advanced ovarian, fallopian tube or primary peritoneal cancer and evidence of a predicted loss of function germline or tumour mutation in one of the following homologous recombination repair genes: BRCA1, BRCA2, PALB2, RAD51C or RAD51D (ii) Histologically or cytologically confirmed HER2-negative carcinoma of the breast with recurrent locally advanced or metastatic disease and evidence of a predicted loss of function germline or tumour mutation in one of the following homologous recombination repair genes: BRCA1, BRCA2, PALB2, RAD51C, or RAD51D.
- •(iii) Histologically or cytologically confirmed advanced/metastatic castration-resistant prostate cancer (CRPC) and evidence of a predicted loss of function germline or tumour mutation in one of the following homologous recombination repair genes:BRCA1, BRCA2, PALB2, RAD51C, or RAD51D (d) Histologically or cytologically confirmed advanced/metastatic pancreatic cancer and evidence of a predicted loss of function germline or tumour mutation in one of the following homologous recombination repair genes: BRCA1, BRCA2, PALB2, RAD51C, or RAD51D.
- •Must have evaluable disease.
- •Must be suitable for treatment with a PARPi.
- •Must be capable of eating a high fat meal and adhering to fasting restrictions.
- •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.
- •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.
- •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.
- •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)
- •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.
- •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.
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排除标准
- •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 AZD
- •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.
- •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.
- •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.
- •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 AZD
- •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.
- •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.
- •Received > 1 prior line of therapy in any setting with a PARPi-based regimen
- •Participants with LMD
- •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.
- •Received > one prior line of therapy in any setting with a PARPi-based regimen.
- •Participants with LMD.
- •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.
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研究组 & 干预措施
Module 2 Part A: Dose escalation
Experimental
Participants with IDH 1/2-mutant glioma who are PARPi naive will receive AZD9574 and TMZ at escalating cohorts.
干预措施: AZD9574 (Drug)
Module 1 Part A: Dose escalation
Experimental
Participants with advanced/relapsed ovarian, breast, pancreatic, or prostate cancer who are deemed suitable for a PARPi will receive AZD9574 monotherapy at escalating cohorts.
干预措施: AZD9574 (Drug)
Module 3 Panel 3: AZD9574 monotherapy (Sweden only)
Experimental
Participants with breast cancer (without BM).
干预措施: [11C]AZ1419 3391 (Drug)
Module 5 Part A : Dose escalation (AZD9574 + Dato-DXd)
Experimental
Participants with advanced, unresectable, or metastatic solid tumours in different types of cancers will receive a combination of AZD9574 and Dato-DXd at escalating cohorts.
干预措施: Datopotamab Deruxtecan (Dato-DXd) (Drug)
Module 3 Panel 1: AZD9574 monotherapy (Sweden only)
Experimental
Participants with advanced/relapsed HER2-negative breast, ovarian, prostate, or pancreatic cancer and expressing BRCA1m, BRCA2m, PALB2m, RAD51Cm or RAD51Dm.
干预措施: AZD9574 (Drug)
Module 1 Part B: Dose expansion
Experimental
Participants with breast cancer who are PARPi naive at doses determined in dose-escalation.
干预措施: AZD9574 (Drug)
Module 2 Part A: Dose escalation
Experimental
Participants with IDH 1/2-mutant glioma who are PARPi naive will receive AZD9574 and TMZ at escalating cohorts.
干预措施: Temozolomide (TMZ) (Drug)
Module 3 Panel 2: AZD9574 + TMZ (Sweden only)
Experimental
Participants with IDH 1/2-mutant glioma who are PARPi naive will receive AZD9574 and TMZ at escalating cohorts.
干预措施: Temozolomide (TMZ) (Drug)
Module 4 Part B : Dose expansion (AZD9574 + T-DXd)
Experimental
Participants with HER2-low/ultralow, HR positive breast cancer will receive a combination of different doses of AZD9574 and T-DXd at expanding cohorts.
干预措施: AZD9574 (Drug)
Module 3 Panel 3: AZD9574 monotherapy (Sweden only)
Experimental
Participants with breast cancer (without BM).
干预措施: AZD9574 (Drug)
Module 4 Part A: Dose escalation (AZD9574 + T-DXd)
Experimental
Participants with advanced, unresectable, or metastatic solid tumours that are HER2-positive will receive a combination of AZD9574 and T-DXd at at escalating cohorts.
干预措施: Trastuzumab Deruxtecan (T-DXd) (Drug)
Module 5 Part A : Dose escalation (AZD9574 + Dato-DXd)
Experimental
Participants with advanced, unresectable, or metastatic solid tumours in different types of cancers will receive a combination of AZD9574 and Dato-DXd at escalating cohorts.
干预措施: AZD9574 (Drug)
Module 3 Panel 1: AZD9574 monotherapy (Sweden only)
Experimental
Participants with advanced/relapsed HER2-negative breast, ovarian, prostate, or pancreatic cancer and expressing BRCA1m, BRCA2m, PALB2m, RAD51Cm or RAD51Dm.
干预措施: [11C]AZ1419 3391 (Drug)
Module 3 Panel 2: AZD9574 + TMZ (Sweden only)
Experimental
Participants with IDH 1/2-mutant glioma who are PARPi naive will receive AZD9574 and TMZ at escalating cohorts.
干预措施: [11C]AZ1419 3391 (Drug)
Module 4 Part B : Dose expansion (AZD9574 + T-DXd)
Experimental
Participants with HER2-low/ultralow, HR positive breast cancer will receive a combination of different doses of AZD9574 and T-DXd at expanding cohorts.
干预措施: Trastuzumab Deruxtecan (T-DXd) (Drug)
Module 4 Part A: Dose escalation (AZD9574 + T-DXd)
Experimental
Participants with advanced, unresectable, or metastatic solid tumours that are HER2-positive will receive a combination of AZD9574 and T-DXd at at escalating cohorts.
干预措施: AZD9574 (Drug)
Module 3 Panel 2: AZD9574 + TMZ (Sweden only)
Experimental
Participants with IDH 1/2-mutant glioma who are PARPi naive will receive AZD9574 and TMZ at escalating cohorts.
干预措施: AZD9574 (Drug)
结局指标
主要结局
Incidence of Adverse Events (AEs), and Serious Adverse Events (SAEs)
时间窗: From first dose to post-treatment follow-up (approximately three years)
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.
Changes from baseline in laboratory findings, electrocardiograms (ECGs), and vital signs
时间窗: From last assessment prior to first dose to post-treatment follow up visit (approximately three years)
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.
Change from baseline Eastern Cooperative Oncology Group performance status (ECOG PS)
时间窗: From last assessment prior to first dose to post-treatment follow up visit (approximately three years)
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.
Incidence of Dose Limiting Toxicities (DLTs)
时间窗: Cycle 0 and Cycle 1 (Day 1 to Day 35)
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.
次要结局
- Module 3: Cmax(Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Half-life (t1/2)(Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Area Under the Curve (AUC)(Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Maximum plasma concentration (Cmax)(Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Time to reach maximum plasma concentration (tmax)(Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Accumulation ratio(Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Dose proportionality(Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Minimum plasma concentration at steady state (Cmin,ss)(Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Module 1: Assessment of pH2AX (phospho-histone 2AX) (Ser139) PD biomarker modulations(Screening, Cycle 0 Day 1, Cycle 1 Day 8, and Cycle 1 day 15 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Module 1: Percentage change in target lesion (TL) size(From Baseline to every 8 weeks until disease progression (approximately three years))
- Module 1: Objective Response Rate (ORR)(From Baseline to every 8 weeks until disease progression (approximately three years))
- Module 1: Duration of Response (DoR)(First documented response until the date of documented progression or end of study (approximately three years))
- Module 1: Time To Response (TTR)(From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years))
- Module 1: Progression Free Survival (PFS)/radiographic Progression-Free Survival (rPFS)(From the start of first treatment until the date of objective disease progression or death (approximately three years))
- Module 1: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)(From Screening until disease progression or death (approximately three years))
- Module 1: Proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result (for prostate cancer only)(From screening until disease progression or death (approximately three years))
- Module 1: Radiological response evaluated according to RECIST v1.1 + Prostate Cancer Working Group 3 (PCWG3) response evaluation criteria (for prostate cancer only)(Up to the End Of Trial (EOT) [approximately three years])
- Module 2: Percentage change in TL size(From Baseline to every 8 weeks until objective disease progression (approximately three years))
- Module 2: ORR(From Baseline to every 8 weeks until objective disease progression (approximately three years))
- Module 2: DoR(First documented response until the date of documented progression or end of study (approximately three years))
- Module 2: TTR(First dose until the first documentation of a subsequently confirmed objective response (approximately three years))
- Module 2: PFS(From the start of first treatment until the date of objective disease progression or death (approximately three years))
- Module 3: Occupancy(From Screening to Cycle 2 Day 1)
- Module 3: Adverse Events (AEs) and Serious Adverse Events (SAEs)(From first dose to post-treatment follow-up (approximately three years))
- Module 1 (Food effect): AUC(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))
- Module 1 (Food effect) : Area under the curve from 0 to t [AUC (0-t)](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))
- Module 1 (Food effect): Cmax(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))
- Module 1 (Food effect): Tmax(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))
- Module 1 (Food effect) : Maximum plasma concentration (Cmax) ratio (with /without a high fat meal)(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))
- Module 1 (ARA effect): AUC(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))
- Module 1 (ARA effect): AUC (0-t)(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))
- Module 1 (ARA effect): Cmax(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))
- Module 1 (ARA effect): Tmax(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))
- Module 1 (ARA effect) : Cmax ratio (with /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))
- Module 4 : Incidence of Adverse event of special interest (AESI)(From first dose until the safety FU (40 [+ 7] days) after discontinuation)
- Module 5 : Presence of positive ADAs for 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)
- Module 5: ORR(From Baseline to every 6 weeks until disease progression (approximately three years))
- Module 5: DoR(First documented response until the date of documented progression or end of study (approximately three years))
- Module 5: TTR(From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years))
- Module 5: Progression Free Survival (PFS)/radiographic Progression-Free Survival (rPFS)(From the start of first treatment until the date of objective disease progression or death (approximately three years))
- Module 5 : Incidence of AESIs(From first dose until the safety FU (40 [+ 7] days) after discontinuation)
- Module 3: AUC(Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Module 3: Cmax(Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Module 3: tmax(Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Module 3: Cmin,ss(Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Module 3: t1/2(Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Module 3: Accumulation ratio(Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Module 3: Percentage change in target lesion (TL) size(From Baseline to every 8 weeks until disease progression (approximately three years))
- Module 3: ORR(From Baseline to every 8 weeks until disease progression (approximately three years))
- Module 3: DoR(First documented response until the date of documented progression or end of study (approximately three years))
- Module 3: TTR(From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years))
- Module 3: Progression Free Survival (PFS)/radiographic Progression-Free Survival (rPFS)(From the start of first treatment until the date of objective disease progression or death (approximately three years))
- Module 3: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)(From Screening until disease progression or death (approximately three years))
- Module 3: Proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result (for prostate cancer only)(From screening until disease progression or death (approximately three years))
- Module 3: Radiological response evaluated according to RECIST v1.1 + Prostate Cancer Working Group 3 (PCWG3) response evaluation criteria (for prostate cancer only)(Up to the End Of Trial (EOT) [approximately three years])
- Module 4: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)(From Screening until disease progression or death (approximately three years))
- Module 5: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)(From Screening until disease progression or death (approximately three years))
- Module 5: Proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the post-baseline PSA result (for prostate cancer only)(From screening until disease progression or death (approximately three years))
- 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)(From the first dose until the end of 12 months or EOT, whichever comes first (approximately three years))
- 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(From the first dose until the end of 12 months or EOT, whichever comes first (approximately three years))
- Area Under the Curve (AUC)(Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Maximum plasma concentration (Cmax)(Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Time to reach maximum plasma concentration (tmax)(Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Minimum plasma concentration at steady state (Cmin,ss)(Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Half-life (t1/2)(Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Accumulation ratio(Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Dose proportionality(Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Module 1: Assessment of pH2AX (phospho-histone 2AX) (Ser139) PD biomarker modulations(Screening, Cycle 0 Day 1, Cycle 1 Day 8, and Cycle 1 day 15 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Module 1: Percentage change in target lesion (TL) size(From Baseline to every 8 weeks until disease progression (approximately three years))
- Module 1: Objective Response Rate (ORR)(From Baseline to every 8 weeks until disease progression (approximately three years))
- Module 1: Duration of Response (DoR)(First documented response until the date of documented progression or end of study (approximately three years))
- Module 1: Time To Response (TTR)(From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years))
- Module 1 (Food effect) : Maximum plasma concentration (Cmax) ratio (with /without a high fat meal)(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))
- Module 1 (ARA effect): AUC(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))
- Module 1 (ARA effect): AUC (0-t)(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))
- Module 1: Progression Free Survival (PFS)/radiographic Progression-Free Survival (rPFS)(From the start of first treatment until the date of objective disease progression or death (approximately three years))
- Module 1: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)(From Screening until disease progression or death (approximately three years))
- Module 1 (ARA effect): Cmax(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))
- Module 1 (ARA effect): Tmax(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))
- Module 1: Proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result (for prostate cancer only)(From screening until disease progression or death (approximately three years))
- Module 1 (ARA effect) : Cmax ratio (with /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))
- Module 1: Radiological response evaluated according to RECIST v1.1 + Prostate Cancer Working Group 3 (PCWG3) response evaluation criteria (for prostate cancer only)(Up to the End Of Trial (EOT) [approximately three years])
- Module 1 (Food effect): AUC(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))
- Module 1 (Food effect) : Area under the curve from 0 to t [AUC (0-t)](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))
- Module 1 (Food effect): Cmax(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))
- Module 1 (Food effect): Tmax(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))
- Module 2: Percentage change in TL size(From Baseline to every 8 weeks until objective disease progression (approximately three years))
- Module 2: ORR(From Baseline to every 8 weeks until objective disease progression (approximately three years))
- Module 2: DoR(First documented response until the date of documented progression or end of study (approximately three years))
- Module 2: TTR(First dose until the first documentation of a subsequently confirmed objective response (approximately three years))
- Module 2: PFS(From the start of first treatment until the date of objective disease progression or death (approximately three years))
- Module 3: Occupancy(From Screening to Cycle 2 Day 1)
- Module 3: Adverse Events (AEs) and Serious Adverse Events (SAEs)(From first dose to post-treatment follow-up (approximately three years))
- Module 3: AUC(Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Module 3: tmax(Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Module 3: Cmin,ss(Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Module 3: t1/2(Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Module 3: Accumulation ratio(Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days))
- Module 3: Percentage change in target lesion (TL) size(From Baseline to every 8 weeks until disease progression (approximately three years))
- Module 3: ORR(From Baseline to every 8 weeks until disease progression (approximately three years))
- Module 3: DoR(First documented response until the date of documented progression or end of study (approximately three years))
- Module 3: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)(From Screening until disease progression or death (approximately three years))
- Module 3: TTR(From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years))
- Module 3: Proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result (for prostate cancer only)(From screening until disease progression or death (approximately three years))
- Module 3: Progression Free Survival (PFS)/radiographic Progression-Free Survival (rPFS)(From the start of first treatment until the date of objective disease progression or death (approximately three years))
- Module 3: Radiological response evaluated according to RECIST v1.1 + Prostate Cancer Working Group 3 (PCWG3) response evaluation criteria (for prostate cancer only)(Up to the End Of Trial (EOT) [approximately three years])
- Module 4 : AUC(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))
- Module 4 : Cmax(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))
- Module 4 : Assessment of pH2AX (phospho-histone 2AX) (Ser139) PD biomarker modulations(Cycle 1 Day X1, Day X2 [last of AZD9574 dosing] (Cycle 1 = 28 days))
- Module 4 : Tmax(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))
- Module 4 : Presence of ADAs for T-DXd(Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Safety follow-up (FU) 40 [+ 7] days after last dose)
- Module 4 : Incidence of Adverse event of special interest (AESI)(From first dose until the safety FU (40 [+ 7] days) after discontinuation)
- Module 4 (Part A): ORR(From Baseline to every 6 weeks until disease progression (approximately three years))
- Module 4 (Part B): ORR(From Baseline to every 6 weeks for the first 24 weeks and then every 9 weeks until disease progression (approximately three years))
- Module 4 (Part A): DoR(First documented response until the date of documented progression or end of study (approximately three years))
- Module 4 (Part B): DoR(First documented response until the date of documented progression or end of study (approximately three years))
- Module 4 (Part A): PFS(From the start of first treatment until the date of objective disease progression or death (approximately three years))
- Module 4 (Part B): PFS(From the start of first treatment until the date of objective disease progression or death (approximately three years))
- Module 4 (Part A): TTR(From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years))
- Module 4 (Part B): TTR(From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years))
- Module 4 (Part B only): Progression-free survival at 6 months (PFS6)(At 6 months after start of first treatment)
- Module 5: Proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the post-baseline PSA result (for prostate cancer only)(From screening until disease progression or death (approximately three years))
- Module 4: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)(From Screening until disease progression or death (approximately three years))
- Module 5 : Cmax(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)
- Module 5 : AUC(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)
- Module 5 : Tmax(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)
- Module 5 : Assessment of pH2AX (phospho-histone 2AX) (Ser139) PD biomarker modulations(Cycle 1 Day X1, Day X2 [last of AZD9574 dosing] (Cycle 1 = 28 days))
- Module 5 : Presence of positive ADAs for 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)
- Module 5: ORR(From Baseline to every 6 weeks until disease progression (approximately three years))
- Module 5: DoR(First documented response until the date of documented progression or end of study (approximately three years))
- Module 5: TTR(From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years))
- Module 5: Progression Free Survival (PFS)/radiographic Progression-Free Survival (rPFS)(From the start of first treatment until the date of objective disease progression or death (approximately three years))
- Module 5 : Incidence of AESIs(From first dose until the safety FU (40 [+ 7] days) after discontinuation)
- Module 5: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)(From Screening until disease progression or death (approximately three years))
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