Clinical trial NCT05417594: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Malignancies
Keywords: Poly ADP-ribose Polymerase inhibitor (PARPi)
Anti-tumour
Breast cancer
Ovarian cancer
Fallopian tube cancer
Prostate cancer
Pancreatic cancer
Soft tissue disease
Glioma
Astrocytoma
Oliogodendroglioma
Solid tumours
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2022-06-14
Enrollment: 535
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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

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

Approximately 535 participants will be enrolled and assigned to study treatments.

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

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

This module will include 235 participants:

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

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

* Cohort B1 will include participants with advanced/relapsed Human Epidermal Growth Factor Receptor 2 (HER2)-negative breast cancer participants with breast cancer gene (BRCA) mutated (BRCA1m, and BRCA2m), partner and localiser of the BRCA2 gene (PALB2) mutation (PALB2m), RAD51Cm or RAD51Dm, without evidence of untreated brain metastasis at baseline Magnetic Resonance Imaging (MRI) scan.
* Cohort B2 will include participants with advanced/relapsed HER2-negative breast cancer participants with BRCA1m, BRCA2m, PALB2m, RAD51Cm or RAD51Dm, who have either untreated or treated brain metastases that are not requiring immediate local therapy.

  * Up to of 20 participants may be required to get 12 evaluable participants in each cohort for food effect and Acid Reducing Agent (ARA) investigations.

    • Module 2 (AZD9574 in combination with temozolomide (TMZ): This module will include 75 participants for up to 12 cycles.
  * Part A (dose-escalation cohorts) will include participants with Isocitrate Dehydrogenase (IDH)-mutant glioma.

    • Module 3 (PET Sub-study: AZD9574 monotherapy \[Panels 1 and 3\], AZD9574 in combination with TMZ (Panel 2). This module will include 12 participants and is only applicable for Sweden.
  * Panel 1 (AZD9574 monotherapy) will include up to 8 participants with advanced/relapsed HER2-negative breast, ovarian, prostate, or pancreatic cancer and expressing BRCA1m, BRCA2m, PALB2m, RAD51Cm or RAD51Dm.
  * Panel 2 (AZD9574 + TMZ) will include up to 2 participants with IDH-mutant recurrent glioma.
  * Panel 3 (AZD9574 monotherapy) will include up to 2 participants with breast cancer (without BM).

    * Module 4 (AZD9574 in combination with Trastuzumab deruxtecan \[T-DXd\])

This module will include 105 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 105 participants (including backfills):

* Part A (dose escalation cohorts) will include participants with advanced, unresectable, or metastatic solid tumours in different types of cancers.
* Part B (dose expansion cohorts) may be added in the future amendment.

Eligibility criteria: Inclusion Criteria:

* Eastern Cooperative Oncology Group performance status (ECOG PS) with no deterioration over the previous 2 weeks.
* Progressive cancer at the time of 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:

* Must be suitable for treatment with TMZ.
* 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

* Must be suitable for treatment with TMZ.
* 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. 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. 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 approximately 4 months after the last dose of study.
* Male participants must refrain from fathering a child or donating sperm during the study and for approximately 4 months after the last dose of study intervention.
* Adequate organ and marrow function (in the absence of transfusions or growth factor support) within 14 days prior to the first dose of study intervention.

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 approximately 7 months after the last dose of study intervention.
* Female participants must not breastfeed and must not donate or retrieve ova for any use from screening to approximately 7 months after the last dose of study intervention.
* Participants must provide an existing FFPE tumour sample for retrospective, tissue-based IHC testing in a central laboratory to determine HER2 expression and other correlatives.
* ECOG performance status of 0 or 1.
* Participants recruited specifically for PD evaluation must have at least 1 tumour suitable for paired biopsies and be willing to consent to pre-treatment and on-treatment biopsies.

Exclusion Criteria:

* Major surgery within 4 weeks of the first dose of study intervention.
* Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks of the first dose of study intervention.
* With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study intervention.
* Any known history of persisting severe pancytopenia due to any cause.
* Spinal cord compression unless asymptomatic, treated and stable and not requiring continuous corticosteroids at a dose of \> 10 mg prednisone/day or equivalent for at least 4 weeks prior to start of study intervention.
* History of uncontrolled seizures or with need for concurrent administration of more than 2 antiepileptic drugs, or history of epileptic disorder or any seizure history unrelated to tumour.
* History of severe brain injury or stroke.
* Any evidence of severe or uncontrolled systemic diseases including active bleeding diatheses, active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV).
* Uncontrolled intercurrent illness within the last 12 months.
* Any known predisposition to bleeding.
* Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML.
* Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD9574.
* Known allergy or hypersensitivity to investigational product(s) or any of the excipients of the investigational product(s).
* Known contra-indication to gadolinium-enhanced Magnetic Resonance Imaging (MRI) or, if applicable, not able to be maintained on a stable or decreasing dose of corticosteroid regimen (no increase for 7 days) prior to the baseline MRI.
* Any concurrent anti-cancer therapy or concurrent use of prohibited medications.

Module 1:

Part A:

* 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:

* 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 have received procarbazine, lomustine (CCNU), vincristine (PCV) as a prior line of treatment are not allowed.
* Previously experienced Grade 4 haematological toxicities or Grade 3 neutropenia associated with infections, or Grade 3 thrombocytopenia with clinically significant bleeding during prior alkylating chemotherapy.
* Received bevacizumab within the last 6 months.
* Not requiring continuous corticosteroids at a dose of \>10 mg prednisone/day or equivalent for at least 4 weeks prior to start of study intervention.

Module 3:

All Panels

* Positive Allen's test
* 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

* Received \> 1 prior line of therapy in any setting with a PARPi-based regimen
* Participants with LMD

Panel 2

* Received a PARPi previously.
* Known hypersensitivity to TMZ.
* Received \> 1 prior line of alkylating chemotherapy regimen.
* Previously experienced Grade 4 haematological toxicities or Grade 3 neutropenia associated with infections, or Grade 3 thrombocytopenia with clinically significant bleeding during prior alkylating chemotherapy.
* Received bevacizumab within the last 6 months.

Panel 3

* Received \> one prior line of therapy in any setting with a PARPi-based regimen.
* Participants with LMD.

Module 4:

* 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.

Primary outcomes:
measure: Incidence of Adverse Events (AEs), and Serious Adverse Events (SAEs)
timeFrame: From first dose to post-treatment follow-up (approximately three years)
measure: Changes from baseline in laboratory findings, electrocardiograms (ECGs), and vital signs
timeFrame: From last assessment prior to first dose to post-treatment follow up visit (approximately three years)
measure: Change from baseline Eastern Cooperative Oncology Group performance status (ECOG PS)
timeFrame: From last assessment prior to first dose to post-treatment follow up visit (approximately three years)
measure: Incidence of Dose Limiting Toxicities (DLTs)
timeFrame: Cycle 0 and Cycle 1 (Day 1 to Day 35)
Secondary outcomes:
measure: Area Under the Curve (AUC)
timeFrame: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
measure: Maximum plasma concentration (Cmax)
timeFrame: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
measure: Time to reach maximum plasma concentration (tmax)
timeFrame: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
measure: Minimum plasma concentration at steady state (Cmin,ss)
timeFrame: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
measure: Half-life (t1/2)
timeFrame: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
measure: Accumulation ratio
timeFrame: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
measure: Dose proportionality
timeFrame: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
measure: Module 1: Assessment of pH2AX (phospho-histone 2AX) (Ser139) PD biomarker modulations
timeFrame: Screening, Cycle 0 Day 1, Cycle 1 Day 8, and Cycle 1 day 15 (Cycle 0 = 7 days; Cycle 1 = 28 days)
measure: Module 1: Percentage change in target lesion (TL) size
timeFrame: From Baseline to every 8 weeks until disease progression (approximately three years)
measure: Module 1: Objective Response Rate (ORR)
timeFrame: From Baseline to every 8 weeks until disease progression (approximately three years)
measure: Module 1: Duration of Response (DoR)
timeFrame: First documented response until the date of documented progression or end of study (approximately three years)
measure: Module 1: Time To Response (TTR)
timeFrame: From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)
measure: Module 1: Progression Free Survival (PFS)/radiographic Progression-Free Survival (rPFS)
timeFrame: From the start of first treatment until the date of objective disease progression or death (approximately three years)
measure: Module 1: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)
timeFrame: From Screening until disease progression or death (approximately three years)
measure: Module 1: Proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result (for prostate cancer only)
timeFrame: From screening until disease progression or death (approximately three years)
measure: Module 1: Radiological response evaluated according to RECIST v1.1 + Prostate Cancer Working Group 3 (PCWG3) response evaluation criteria (for prostate cancer only)
timeFrame: Up to the End Of Trial (EOT) [approximately three years]
measure: Module 2: Percentage change in TL size
timeFrame: From Baseline to every 8 weeks until objective disease progression (approximately three years)
measure: Module 2: ORR
timeFrame: From Baseline to every 8 weeks until objective disease progression (approximately three years)
measure: Module 2: DoR
timeFrame: First documented response until the date of documented progression or end of study (approximately three years)
measure: Module 2: TTR
timeFrame: First dose until the first documentation of a subsequently confirmed objective response (approximately three years)
measure: Module 2: PFS
timeFrame: From the start of first treatment until the date of objective disease progression or death (approximately three years)
measure: Module 3: Occupancy
timeFrame: From Screening to Cycle 2 Day 1
measure: Module 3: Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose to post-treatment follow-up (approximately three years)
measure: Module 1 (Food effect): AUC
timeFrame: 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)
measure: Module 1 (Food effect) : Area under the curve from 0 to t [AUC (0-t)]
timeFrame: 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)
measure: Module 1 (Food effect): Cmax
timeFrame: 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)
measure: Module 1 (Food effect): Tmax
timeFrame: 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)
measure: Module 1 (Food effect) : Maximum plasma concentration (Cmax) ratio (with /without a high fat meal)
timeFrame: 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)
measure: Module 1 (ARA effect): AUC
timeFrame: 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)
measure: Module 1 (ARA effect): AUC (0-t)
timeFrame: 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)
measure: Module 1 (ARA effect): Cmax
timeFrame: 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)
measure: Module 1 (ARA effect): Tmax
timeFrame: 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)
measure: Module 1 (ARA effect) : Cmax ratio (with /without famotidine)
timeFrame: 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)
measure: Module 4 : AUC
timeFrame: 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
measure: Module 4 : Cmax
timeFrame: 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
measure: Module 4 : Tmax
timeFrame: 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
measure: Module 4 : Assessment of pH2AX (phospho-histone 2AX) (Ser139) PD biomarker modulations
timeFrame: Screening, Cycle 1 Day X2 [last of AZD9574 dosing] (Cycle 1 = 28 days)
measure: Module 4 : Presence of ADAs for T-DXd
timeFrame: 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
measure: Module 4 : Incidence of Adverse event of special interest (AESI)
timeFrame: From first dose until the safety FU (40 [+ 7] days) after discontinuation
measure: Module 4: ORR
timeFrame: From Baseline to every 6 weeks until disease progression (approximately three years)
measure: Module 4: DoR
timeFrame: First documented response until the date of documented progression or end of study (approximately three years)
measure: Module 4: PFS
timeFrame: From the start of first treatment until the date of objective disease progression or death (approximately three years)
measure: Module 4: TTR
timeFrame: From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)
measure: Module 5 : AUC
timeFrame: 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
measure: Module 5 : Cmax
timeFrame: 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
measure: Module 5 : Tmax
timeFrame: 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
measure: Module 5 : Assessment of pH2AX (phospho-histone 2AX) (Ser139) PD biomarker modulations
timeFrame: Screening, Cycle 1 Day X2 [last of AZD9574 dosing] (Cycle 1 = 28 days)
measure: Module 5 : Presence of positive ADAs for Dato-DXd
timeFrame: 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
measure: Module 5: ORR
timeFrame: From Baseline to every 6 weeks until disease progression (approximately three years)
measure: Module 5: DoR
timeFrame: First documented response until the date of documented progression or end of study (approximately three years)
measure: Module 5: TTR
timeFrame: From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)
measure: Module 5: Progression Free Survival (PFS)/radiographic Progression-Free Survival (rPFS)
timeFrame: From the start of first treatment until the date of objective disease progression or death (approximately three years)
measure: Module 5 : Incidence of AESIs
timeFrame: From first dose until the safety FU (40 [+ 7] days) after discontinuation
measure: Module 3: AUC
timeFrame: Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
measure: Module 3: Cmax
timeFrame: Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
measure: Module 3: tmax
timeFrame: Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
measure: Module 3: Cmin,ss
timeFrame: Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
measure: Module 3: t1/2
timeFrame: Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
measure: Module 3: Accumulation ratio
timeFrame: Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
measure: Module 3: Percentage change in target lesion (TL) size
timeFrame: From Baseline to every 8 weeks until disease progression (approximately three years)
measure: Module 3: ORR
timeFrame: From Baseline to every 8 weeks until disease progression (approximately three years)
measure: Module 3: DoR
timeFrame: First documented response until the date of documented progression or end of study (approximately three years)
measure: Module 3: TTR
timeFrame: From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)
measure: Module 3: Progression Free Survival (PFS)/radiographic Progression-Free Survival (rPFS)
timeFrame: From the start of first treatment until the date of objective disease progression or death (approximately three years)
measure: Module 3: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)
timeFrame: From Screening until disease progression or death (approximately three years)
measure: Module 3: Proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result (for prostate cancer only)
timeFrame: From screening until disease progression or death (approximately three years)
measure: Module 3: Radiological response evaluated according to RECIST v1.1 + Prostate Cancer Working Group 3 (PCWG3) response evaluation criteria (for prostate cancer only)
timeFrame: Up to the End Of Trial (EOT) [approximately three years]
measure: Module 4: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)
timeFrame: From Screening until disease progression or death (approximately three years)
measure: Module 5: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)
timeFrame: From Screening until disease progression or death (approximately three years)
measure: Module 5: Proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the post-baseline PSA result (for prostate cancer only)
timeFrame: From screening until disease progression or death (approximately three years)
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: San Francisco
country: United States
facility: Research Site
state: California
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: New York
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: Portland
country: United States
facility: Research Site
state: Oregon
city: Houston
country: United States
facility: Research Site
state: Texas
city: Richmond
country: United States
facility: Research Site
state: Virginia
city: Camperdown
country: Australia
facility: Research Site
city: Darlinghurst
country: Australia
facility: Research Site
city: Melbourne
country: Australia
facility: Research Site
city: Randwick
country: Australia
facility: Research Site
city: Bayern
country: Germany
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Heidelberg
country: Germany
facility: Research Site
city: Mainz
country: Germany
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: A Coruña
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Pozuelo de Alarcon
country: Spain
facility: Research Site
city: Sant Cugat del Valles
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Lund
country: Sweden
facility: Research Site
city: Stockholm
country: Sweden
facility: Research Site
city: Glasgow, Scotland
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Newcastle Upon Tyne
country: United Kingdom
facility: Research Site
Study officials:
References: