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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05417594




Registration number
NCT05417594
Ethics application status
Date submitted
20/05/2022
Date registered
14/06/2022
Date last updated
26/06/2024

Titles & IDs
Public title
Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies
Scientific 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)
Secondary ID [1] 0 0
2021-006227-17
Secondary ID [2] 0 0
D8410C00001
Universal Trial Number (UTN)
Trial acronym
CERTIS1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Solid Malignancies 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - AZD9574
Treatment: Drugs - Temozolomide
Treatment: Drugs - [11C]AZ1419 3391
Treatment: Drugs - Datopotamab Deruxtecan (Dato-DXd)
Treatment: Drugs - Trastuzumab Deruxtecan (T-DXd)

Experimental: Module 1 Part A: Dose escalation - Participants with advanced/relapsed ovarian, breast, pancreatic, or prostate cancer who are deemed suitable for a PARPi will receive AZD9574 monotherapy at escalating cohorts.

Experimental: Module 1 Part B: Dose expansion - Participants with breast cancer who are PARPi naive at doses determined in dose-escalation.

Experimental: Module 2 Part A: Dose escalation - Participants with IDH 1/2-mutant glioma who are PARPi naive will receive AZD9574 and TMZ at escalating cohorts.

Experimental: Module 3 Panel 1: AZD9574 monotherapy (Sweden only) - Participants with advanced/relapsed HER2-negative breast, ovarian, prostate, or pancreatic cancer and expressing BRCA1m, BRCA2m, PALB2m, RAD51Cm or RAD51Dm.

Experimental: Module 3 Panel 2: AZD9574 + TMZ (Sweden only) - Participants with IDH 1/2-mutant glioma who are PARPi naive will receive AZD9574 and TMZ at escalating cohorts.

Experimental: Module 3 Panel 3: AZD9574 monotherapy (Sweden only) - Participants with breast cancer (without BM).

Experimental: Module 4 Part A: Dose escalation (AZD9574 + T-DXdat) - Participants with advanced, unresectable, or metastatic solid tumours that are HER2-positive will receive a combination of AZD9574 and T-DXdat at escalating cohorts.

Experimental: Module 5 Part A : Dose escalation (AZD9574 + Dato-DXd) - 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.


Treatment: Drugs: AZD9574
Participants will receive AZD9574 orally.

Treatment: Drugs: Temozolomide
Participants will receive temozolomide orally.

Treatment: Drugs: [11C]AZ1419 3391
Participants will receive \[11C\]AZ1419 3391 intravenously.

Treatment: Drugs: Datopotamab Deruxtecan (Dato-DXd)
Participants will receive Dato-DXd intravenously.

Treatment: Drugs: Trastuzumab Deruxtecan (T-DXd)
Participants will receive T-DXd intravenously.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Incidence of Adverse Events (AEs), and Serious Adverse Events (SAEs)
Timepoint [1] 0 0
From first dose to post-treatment follow-up (approximately three years)
Primary outcome [2] 0 0
Changes from baseline in laboratory findings, electrocardiograms (ECGs), and vital signs
Timepoint [2] 0 0
From last assessment prior to first dose to post-treatment follow up visit (approximately three years)
Primary outcome [3] 0 0
Change from baseline Eastern Cooperative Oncology Group performance status (ECOG PS)
Timepoint [3] 0 0
From last assessment prior to first dose to post-treatment follow up visit (approximately three years)
Primary outcome [4] 0 0
Incidence of Dose Limiting Toxicities (DLTs)
Timepoint [4] 0 0
Cycle 0 and Cycle 1 (Day 1 to Day 35)
Secondary outcome [1] 0 0
Area Under the Curve (AUC)
Timepoint [1] 0 0
Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary outcome [2] 0 0
Maximum plasma concentration (Cmax)
Timepoint [2] 0 0
Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary outcome [3] 0 0
Time to reach maximum plasma concentration (tmax)
Timepoint [3] 0 0
Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary outcome [4] 0 0
Minimum plasma concentration at steady state (Cmin,ss)
Timepoint [4] 0 0
Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary outcome [5] 0 0
Half-life (t1/2)
Timepoint [5] 0 0
Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary outcome [6] 0 0
Accumulation ratio
Timepoint [6] 0 0
Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary outcome [7] 0 0
Dose proportionality
Timepoint [7] 0 0
Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary outcome [8] 0 0
Module 1: Assessment of pH2AX (phospho-histone 2AX) (Ser139) PD biomarker modulations
Timepoint [8] 0 0
Screening, Cycle 0 Day 1, Cycle 1 Day 8, and Cycle 1 day 15 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary outcome [9] 0 0
Module 1: Percentage change in target lesion (TL) size
Timepoint [9] 0 0
From Baseline to every 8 weeks until disease progression (approximately three years)
Secondary outcome [10] 0 0
Module 1: Objective Response Rate (ORR)
Timepoint [10] 0 0
From Baseline to every 8 weeks until disease progression (approximately three years)
Secondary outcome [11] 0 0
Module 1: Duration of Response (DoR)
Timepoint [11] 0 0
First documented response until the date of documented progression or end of study (approximately three years)
Secondary outcome [12] 0 0
Module 1: Time To Response (TTR)
Timepoint [12] 0 0
From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)
Secondary outcome [13] 0 0
Module 1: Progression Free Survival (PFS)/radiographic Progression-Free Survival (rPFS)
Timepoint [13] 0 0
From the start of first treatment until the date of objective disease progression or death (approximately three years)
Secondary outcome [14] 0 0
Module 1: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)
Timepoint [14] 0 0
From Screening until disease progression or death (approximately three years)
Secondary outcome [15] 0 0
Module 1: Proportion of participants achieving a = 50% decrease in PSA from baseline to the lowest post-baseline PSA result (for prostate cancer only)
Timepoint [15] 0 0
From screening until disease progression or death (approximately three years)
Secondary outcome [16] 0 0
Module 1: Radiological response evaluated according to RECIST v1.1 + Prostate Cancer Working Group 3 (PCWG3) response evaluation criteria (for prostate cancer only)
Timepoint [16] 0 0
Up to the End Of Trial (EOT) [approximately three years]
Secondary outcome [17] 0 0
Module 2: Percentage change in TL size
Timepoint [17] 0 0
From Baseline to every 8 weeks until objective disease progression (approximately three years)
Secondary outcome [18] 0 0
Module 2: ORR
Timepoint [18] 0 0
From Baseline to every 8 weeks until objective disease progression (approximately three years)
Secondary outcome [19] 0 0
Module 2: DoR
Timepoint [19] 0 0
First documented response until the date of documented progression or end of study (approximately three years)
Secondary outcome [20] 0 0
Module 2: TTR
Timepoint [20] 0 0
First dose until the first documentation of a subsequently confirmed objective response (approximately three years)
Secondary outcome [21] 0 0
Module 2: PFS
Timepoint [21] 0 0
From the start of first treatment until the date of objective disease progression or death (approximately three years)
Secondary outcome [22] 0 0
Module 3: Occupancy
Timepoint [22] 0 0
From Screening to Cycle 2 Day 1
Secondary outcome [23] 0 0
Module 3: Adverse Events (AEs) and Serious Adverse Events (SAEs)
Timepoint [23] 0 0
From first dose to post-treatment follow-up (approximately three years)
Secondary outcome [24] 0 0
Module 1 (Food effect): AUC
Timepoint [24] 0 0
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 outcome [25] 0 0
Module 1 (Food effect) : Area under the curve from 0 to t [AUC (0-t)]
Timepoint [25] 0 0
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 outcome [26] 0 0
Module 1 (Food effect): Cmax
Timepoint [26] 0 0
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 outcome [27] 0 0
Module 1 (Food effect): Tmax
Timepoint [27] 0 0
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 outcome [28] 0 0
Module 1 (Food effect) : Maximum plasma concentration (Cmax) ratio (with /without a high fat meal)
Timepoint [28] 0 0
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 outcome [29] 0 0
Module 1 (ARA effect): AUC
Timepoint [29] 0 0
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 outcome [30] 0 0
Module 1 (ARA effect): AUC (0-t)
Timepoint [30] 0 0
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 outcome [31] 0 0
Module 1 (ARA effect): Cmax
Timepoint [31] 0 0
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 outcome [32] 0 0
Module 1 (ARA effect): Tmax
Timepoint [32] 0 0
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 outcome [33] 0 0
Module 1 (ARA effect) : Cmax ratio (with /without famotidine)
Timepoint [33] 0 0
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 outcome [34] 0 0
Module 4 : AUC
Timepoint [34] 0 0
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 outcome [35] 0 0
Module 4 : Cmax
Timepoint [35] 0 0
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 outcome [36] 0 0
Module 4 : Tmax
Timepoint [36] 0 0
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 outcome [37] 0 0
Module 4 : Assessment of pH2AX (phospho-histone 2AX) (Ser139) PD biomarker modulations
Timepoint [37] 0 0
Screening, Cycle 1 Day X2 [last of AZD9574 dosing] (Cycle 1 = 28 days)
Secondary outcome [38] 0 0
Module 4 : Presence of ADAs for T-DXd
Timepoint [38] 0 0
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 outcome [39] 0 0
Module 4 : Incidence of Adverse event of special interest (AESI)
Timepoint [39] 0 0
From first dose until the safety FU (40 [+ 7] days) after discontinuation
Secondary outcome [40] 0 0
Module 4: ORR
Timepoint [40] 0 0
From Baseline to every 6 weeks until disease progression (approximately three years)
Secondary outcome [41] 0 0
Module 4: DoR
Timepoint [41] 0 0
First documented response until the date of documented progression or end of study (approximately three years)
Secondary outcome [42] 0 0
Module 4: PFS
Timepoint [42] 0 0
From the start of first treatment until the date of objective disease progression or death (approximately three years)
Secondary outcome [43] 0 0
Module 4: TTR
Timepoint [43] 0 0
From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)
Secondary outcome [44] 0 0
Module 5 : AUC
Timepoint [44] 0 0
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 outcome [45] 0 0
Module 5 : Cmax
Timepoint [45] 0 0
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 outcome [46] 0 0
Module 5 : Tmax
Timepoint [46] 0 0
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 outcome [47] 0 0
Module 5 : Assessment of pH2AX (phospho-histone 2AX) (Ser139) PD biomarker modulations
Timepoint [47] 0 0
Screening, Cycle 1 Day X2 [last of AZD9574 dosing] (Cycle 1 = 28 days)
Secondary outcome [48] 0 0
Module 5 : Presence of positive ADAs for Dato-DXd
Timepoint [48] 0 0
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 outcome [49] 0 0
Module 5: ORR
Timepoint [49] 0 0
From Baseline to every 6 weeks until disease progression (approximately three years)
Secondary outcome [50] 0 0
Module 5: DoR
Timepoint [50] 0 0
First documented response until the date of documented progression or end of study (approximately three years)
Secondary outcome [51] 0 0
Module 5: TTR
Timepoint [51] 0 0
From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)
Secondary outcome [52] 0 0
Module 5: Progression Free Survival (PFS)/radiographic Progression-Free Survival (rPFS)
Timepoint [52] 0 0
From the start of first treatment until the date of objective disease progression or death (approximately three years)
Secondary outcome [53] 0 0
Module 5 : Incidence of AESIs
Timepoint [53] 0 0
From first dose until the safety FU (40 [+ 7] days) after discontinuation
Secondary outcome [54] 0 0
Module 3: AUC
Timepoint [54] 0 0
Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary outcome [55] 0 0
Module 3: Cmax
Timepoint [55] 0 0
Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary outcome [56] 0 0
Module 3: tmax
Timepoint [56] 0 0
Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary outcome [57] 0 0
Module 3: Cmin,ss
Timepoint [57] 0 0
Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary outcome [58] 0 0
Module 3: t1/2
Timepoint [58] 0 0
Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary outcome [59] 0 0
Module 3: Accumulation ratio
Timepoint [59] 0 0
Cycle 0 Day 1 & 5, Cycle 1 Day 5 (Cycle 0 = 7 days; Cycle 1 = 28 days)
Secondary outcome [60] 0 0
Module 3: Percentage change in target lesion (TL) size
Timepoint [60] 0 0
From Baseline to every 8 weeks until disease progression (approximately three years)
Secondary outcome [61] 0 0
Module 3: ORR
Timepoint [61] 0 0
From Baseline to every 8 weeks until disease progression (approximately three years)
Secondary outcome [62] 0 0
Module 3: DoR
Timepoint [62] 0 0
First documented response until the date of documented progression or end of study (approximately three years)
Secondary outcome [63] 0 0
Module 3: TTR
Timepoint [63] 0 0
From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years)
Secondary outcome [64] 0 0
Module 3: Progression Free Survival (PFS)/radiographic Progression-Free Survival (rPFS)
Timepoint [64] 0 0
From the start of first treatment until the date of objective disease progression or death (approximately three years)
Secondary outcome [65] 0 0
Module 3: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)
Timepoint [65] 0 0
From Screening until disease progression or death (approximately three years)
Secondary outcome [66] 0 0
Module 3: Proportion of participants achieving a = 50% decrease in PSA from baseline to the lowest post-baseline PSA result (for prostate cancer only)
Timepoint [66] 0 0
From screening until disease progression or death (approximately three years)
Secondary outcome [67] 0 0
Module 3: Radiological response evaluated according to RECIST v1.1 + Prostate Cancer Working Group 3 (PCWG3) response evaluation criteria (for prostate cancer only)
Timepoint [67] 0 0
Up to the End Of Trial (EOT) [approximately three years]
Secondary outcome [68] 0 0
Module 4: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)
Timepoint [68] 0 0
From Screening until disease progression or death (approximately three years)
Secondary outcome [69] 0 0
Module 5: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria (for ovarian patients only)
Timepoint [69] 0 0
From Screening until disease progression or death (approximately three years)
Secondary outcome [70] 0 0
Module 5: Proportion of participants achieving a = 50% decrease in PSA from baseline to the post-baseline PSA result (for prostate cancer only)
Timepoint [70] 0 0
From screening until disease progression or death (approximately three years)

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
130 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
4/08/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
12/01/2026
Actual
Sample size
Target
490
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Research Site - Camperdown
Recruitment hospital [2] 0 0
Research Site - Darlinghurst
Recruitment hospital [3] 0 0
Research Site - Melbourne
Recruitment hospital [4] 0 0
Research Site - Randwick
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [3] 0 0
3000 - Melbourne
Recruitment postcode(s) [4] 0 0
2031 - Randwick
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Illinois
Country [3] 0 0
United States of America
State/province [3] 0 0
Massachusetts
Country [4] 0 0
United States of America
State/province [4] 0 0
New York
Country [5] 0 0
United States of America
State/province [5] 0 0
Oregon
Country [6] 0 0
United States of America
State/province [6] 0 0
Texas
Country [7] 0 0
United States of America
State/province [7] 0 0
Virginia
Country [8] 0 0
Germany
State/province [8] 0 0
Bayern
Country [9] 0 0
Germany
State/province [9] 0 0
Berlin
Country [10] 0 0
Germany
State/province [10] 0 0
Heidelberg
Country [11] 0 0
Germany
State/province [11] 0 0
Mainz
Country [12] 0 0
Korea, Republic of
State/province [12] 0 0
Seoul
Country [13] 0 0
Spain
State/province [13] 0 0
A Coruña
Country [14] 0 0
Spain
State/province [14] 0 0
Barcelona
Country [15] 0 0
Spain
State/province [15] 0 0
Pozuelo de Alarcon
Country [16] 0 0
Spain
State/province [16] 0 0
Sant Cugat del Valles
Country [17] 0 0
Spain
State/province [17] 0 0
Sevilla
Country [18] 0 0
Sweden
State/province [18] 0 0
Lund
Country [19] 0 0
Sweden
State/province [19] 0 0
Stockholm
Country [20] 0 0
United Kingdom
State/province [20] 0 0
Glasgow, Scotland
Country [21] 0 0
United Kingdom
State/province [21] 0 0
London
Country [22] 0 0
United Kingdom
State/province [22] 0 0
Newcastle Upon Tyne

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
AstraZeneca
Address
Country

Ethics approval
Ethics application status

Summary
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 490 participants with advanced cancer that has recurred/progressed.
Trial website
https://clinicaltrials.gov/study/NCT05417594
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
AstraZeneca Clinical Study Information Center
Address 0 0
Country 0 0
Phone 0 0
1-877-240-9479
Fax 0 0
Email 0 0
information.center@astrazeneca.com
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT05417594