Study of AZD9574 as monotherapy and in combination with anti-cancer agents in patients with advanced solid malignancies

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 Oct 2022 → ongoing

Decision date (initial)

2024-06-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB, 151 85 Södertälje, Sweden

External identifiers

EU CT number

2023-504984-17-00

EudraCT number

2021-006227-17

ClinicalTrials.gov

NCT05417594

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacodynamic, Safety, Efficacy, Others, Pharmacogenomic, Dose response, Pharmacokinetic

To assess the safety and tolerability of AZD9574 as monotherapy and in combination with anti-cancer agents in participants with advanced malignancies

Secondary objectives 20

1. To characterise the PK of AZD9574, following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents.
2. Module 1: To evaluate PD of AZD9574 in tumour tissue when given orally as monotherapy
3. Module 1 : To assess the preliminary antitumour activity of AZD9574 as monotherapy
4. Module 1: To investigate the effect of a high-fat meal on the PK of AZD9574
5. Module 1: To assess the effect of famotidine on the PK of AZD9574
6. Module 2: To assess the preliminary anti-tumour activity of AZD9574 in combination with temozolomide
7. Module 3: To characterise the PK of AZD9574, following single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with TMZ
8. Module 3: To determine PARP1 occupancy in brain by AZD9574 at examined doses and plasma concentration
9. Module 3: To assess the preliminary anti-tumour activity of AZD9574 as monotherapy
10. Module 3: To assess the preliminary anti-tumour activity of AZD9574 in combination with TMZ
11. Module 4: To characterise the PK of AZD9574, T-DXd following a single dose and at steady state after multiple dosing, when given in combination with T-DXd
12. Module 4: To characterise the PD of AZD9574 in tumour tissue, following a single dose and at steady state after multiple dosing, when given orally in combination with T-DXd
13. Module 4: To investigate the immunogenicity of T-DXd
14. Module 4: Monitor risks associated with T-DXd (AESIs) in study participants
15. Module 4: To assess the preliminary anti-tumour activity of AZD9574 in combination with T-DXd
16. Module 5: To assess the PK of AZD9574 and Dato-DXd
17. Module 5: To characterise the PD of AZD9574 in tumour tissue, following a single dose and at steady state after multiple dosing, when given orally in combination with Dato-DXd
18. Module 5: To investigate the immunogenicity of Dato-DXd
19. Module 5: To assess the preliminary anti- tumour activity of AZD9574 in combination with Dato-DXd
20. Module 5: To describe the prevalence (or incidence/frequency, etc) of Dato-DXd AESIs in study participants

Conditions and MedDRA coding

Module 3: advanced/relapsed HER2-negative breast, ovarian, prostate, or pancreatic cancer and expressing BRCA1m, BRCA2m, PALB2m, RAD51Cm or RAD51Dm, IDH-mutant recurrent glioma, breast cancer (without BM)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Provision of signed and dated, written informed consent prior to any study-specific procedures, sampling and analyses.
2. Age ≥ 18 years at the time of screening.
3. Eastern Cooperative Oncology Group performance status (ECOG PS: 0-2) with no deterioration over the previous 2 weeks.
4. Life expectancy ≥ 12 weeks.
5. Progressive cancer at the time of study entry.
6. Female subjects of childbearing potential: Must have negative pregnancy test result at screening and prior to each cycle administration of study treatment and must use at least one highly effective method of birth control
7. Female subjects 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 intervention.
8. 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
9. Female partners of male participants must also 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
10. 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
11. Adequate organ and marrow function as defined by the protocol
12. Participants should be capable of self-administering oral formulations
13. Provision of archival formalin-fixed and paraffin-embedded (FFPE) tumour specimen is mandatory, where available, except if stated that it is optional in a specific module. An archival tissue specimen is preferred but a new tissue sample may be used

Exclusion criteria 24

1. Treatment with any of the following: (a) Any investigational agents or study drugs from a previous clinical study within 5 half-lives or 3 weeks (whichever is shorter) of the first dose of study intervention (b) Any other anti-cancer treatment within 5 half-lives or 3 weeks for cytotoxic and non-cytotoxic treatment or 4 weeks before enrollment for biological products
2. Uncontrolled intercurrent illness within the last 12 months, including but not limited to, active interstitial lung disease, serious chronic GI conditions associated with diarrhoea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the participant to give written informed consent.
3. Any known predisposition to bleeding
4. Any of the following cardiac criteria: (a) Mean resting corrected QT interval (QTcF) >450 milliseconds (b) Any factors that increase the risk of QT prolongation or risk of arrhythmic events (c) Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG and clinically significant sinus node dysfunction not treated with pacemaker
5. Other cardiovascular diseases as defined by any of the following: (a) Symptomatic heart failure (b) Uncontrolled hypertension (c) Hypertensive heart disease with significant left ventricular hypertrophy (d) Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention or coronary artery bypass grafting or cardiac valve replacement/repairment within 6 months (e) Cardiomyopathy of any aetiology (f) Presence of clinically significant valvular heart disease (g) History of atrial or ventricular arrhythmia requiring treatment (h) Transient ischaemic attack, or stroke within 6 months prior to screening (i) Patients with symptomatic hypotension at screening
6. Patients with myelodysplastic syndrome/acute myeloid leukaemia
7. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of the investigational product(s) (IP).
8. Known allergy or hypersensitivity to IP(s) or any of the excipients of the IP(s)
9. Known contra-indication to gadolinium-enhanced MRI imaging or, if applicable, not able to be maintained on a stable or decreasing dose of corticosteroid regimen prior to the baseline MRI.
10. Any concurrent anti-cancer therapy or concurrent use of prohibited medications
11. Judgement by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements
12. Major surgery within 4 weeks of the first dose of study intervention
13. Any condition that, in the opinion of the Investigator, would interfere with evaluation of the study intervention or interpretation of participant safety or study results
14. Concurrent enrolment in another clinical study unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study. Exception to this criterion for imaging studies (eg, PET) may be allowed after discussion with the Sponsor.
15. Involvement in the planning and/or conduct of the study
16. Previous study intervention assignment in the present study Other module specific criteria may apply.
17. 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
18. 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
19. Any known history of persisting (> 2 weeks) severe pancytopenia due to any cause
20. 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
21. 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
22. History of severe brain injury or stroke
23. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required
24. Any live virus or bacterial cancer vaccine within 4 weeks of the first dose of study intervention

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Incidence of AEs/SAEs; DLTs; MTD; Changes from baseline in laboratory findings, ECOG PS, ECGs and vital signs.

Secondary endpoints 23

1. Plasma concentrations of AZD9574 and plasma PK parameters including but not limited to • Area under the curve after a single dose and after multiple doses • Maximum plasma concentration after a single dose and after multiple doses • Time to reach maximum plasma concentration • Minimum plasma concentration at steady state • Half-life • Accumulation ratio • Dose proportionality
2. Module 1: Assessment of pH2AX PD biomarker modulations at baseline and during treatment or pre-treatment in PD biomarkers
3. Module 1: Radiological response evaluated according to response evaluation criteria in solid tumours (RECIST v1.1) − Percentage change in target lesion size − ORR, DoR, TTR, PFS/rPFS. For ovarian cancer participants: CA125 response evaluated according to the GCIG criteria.
4. Module 1: For prostate cancer participants: • Proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later (PSA50 response) • Radiological response evaluated according to RECIST v1.1 + PCWG3 response evaluation criteria
5. Module 1: PK parameters, including but not limited to AUC and/or AUC(0-t), Cmax, Tmax, AUC(0-t) and Cmax ratio, with and without a high fat meal.
6. Module 1: PK parameters, including but not limited to AUC and/or AUC(0-t), Cmax, Tmax, AUC(0-t) and Cmax ratio, with and without famotidine.
7. Module 2: Radiological response evaluated according to RANO-HGG or RANO-LGG • Percentage change in target lesions size • ORR, DoR, TTR, PFS
8. Module 3: Plasma concentrations of AZD9574 and plasma PK parameters including but not limited to • Area under the curve (AUC) after a single dose and after multiple doses • Maximum plasma concentration (Cmax) after a single dose and after multiple doses • Time to reach maximum plasma concentration (tmax) • Minimum plasma concentration at steady state (Cmin,ss) • Half-life (t1/2) • Accumulation ratio
9. Module 3: Difference in radioligand binding to PARP1 from baseline to study intervention administration (occupancy [%])
10. Module 3: Radiological response evaluated according to RECIST v1.1 − Percentage change in target lesion size − ORR, DoR, TTR, PFS/rPFS • For ovarian cancer participants: CA125 response evaluated according to the GCIG criteria
11. Module 3: For prostate cancer participants: − Participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later (PSA50 response) − Radiological response evaluated according to RECIST v1.1 (soft tissue) + PCWG3 (bone) response evaluation criteria
12. Module 3: Radiological response evaluated according to RANO-HGG or RANO-LGG • Percentage change in target lesions size • ORR, DoR, TTR, PFS
13. Module 4: Measurement of plasma concentrations AZD9574 and serum concentrations of T-DXd after administration of a single dose and multiple doses; and derivation of the following PK parameters including, but not limited to (as data allow): • AUC • Cmax • Tmax
14. Module 4: Assessment of modulation from baseline (Visit 1) or pre-treatment in PD biomarkers from (optional) tumour samples; including, but not limited to assessment of pH2AX (Ser139)
15. Module 4: Presence of ADAs for T-DXd
16. Module 4: Incidence of: • ILD/pneumonitis • LVEF • ≥ Grade 3 Neutropenia (Part B only)
17. Module 4: Radiological response evaluated according to response evaluation criteria in solid tumours (RECIST v1.1) percentage change in target lesion size • ORR, DoR, PFS, TTR • Where appropriate, tumour marker response data will be summarized depending on the cancer type, eg, CA125 for ovarian cancer • PFS6 (Part B only)
18. Module 5: Measurement of plasma concentrations of AZD9574 and Dato-DXd after a single dose and multiple doses; and derivation of the following PK parameters, including, but not limited to (as data allow): − AUC − Cmax − Tmax
19. Module 5: Assessment of modulation from baseline (Visit 1) or pre-treatment in PD biomarkers from (optional) tumour samples; includes, but is not limited to assessment of pH2AX (Ser139)
20. Module 5: Presence of ADAs for Dato-DXd
21. Module 5: Radiological response evaluated according to response evaluation criteria in solid tumours (RECIST v1.1) − percentage change in target lesion size − ORR, DoR, PFS, TTR • Where appropriate, tumour marker response data will be summarized depending on the cancer type, eg, CA125 for ovarian cancer.
22. Module 5 : • For participants with prostate cancer: − ORR and rPFS according to RECIST v1.1 (soft tissue) + PCWG3 (bone) response evaluation criteria − Proportion of patients achieving a ≥ 50% decrease in PSA from baseline to the post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later (PSA50 response)
23. Module 5: Incidence of: • Interstitial Lung Disease/Pneumonitis • Infusion-related Reactions • Oral Mucositis/Stomatitis • Mucosal Inflammation Other than Oral Mucositis/Stomatitis • Ocular Surface Events

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 13

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

Clinical Study Information Center

Third parties 1

Locations

2 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 102 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications