Study of AZD5305 as Monotherapy and 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

27 Jul 2021 → ongoing

Decision date (initial)

2024-05-21

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2022-502856-29-00

EudraCT number

2020-002688-77

ClinicalTrials.gov

NCT04644068

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

To assess the safety and tolerability of AZD5305 as monotherapy and in combination with anti-cancer agents in patients with advanced malignancies.

Secondary objectives 9

1. To characterize the PK of AZD5305 in plasma following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents.
2. To assess the preliminary anti-tumour activity of AZD5305 as monotherapy and in combination with anti-cancer agents.
3. To evaluate PD of AZD5305 in tumour tissue when given orally as monotherapy.
4. Module 1: To characterize the PK of AZD5305 in plasma and urine, following a single dose and at steady state after multiple dosing, when given orally as monotherapy.
5. Module 2: To characterise the PK of AZD5305 and paclitaxel, following a single dose and at steady state after multiple dosing in plasma, when given in combination.
6. Module 3: PK of AZD5305, carboplatin +/- paclitaxel.
7. Module 4: PK of AZD5305 and T-DXd.
8. Module 5: PK of AZD5305 and Dato-DXd.
9. Module 6 :PK of AZD5305 and Camizestrant.

Conditions and MedDRA coding

Advanced Solid Tumors

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 at the time of screening.
3. Patients must have histological or cytological confirmation of advanced malignancy considered to be suitable for study treatment and meeting module specific eligibility criteria.
4. Eastern Cooperative Oncology Group Performance status (ECOG) PS: 0-2 with no deterioration in the previous 2 weeks.
5. Life expectancy ≥ 12 weeks.
6. Progressive cancer at the time of study entry.
7. Patients must have evaluable disease as defined in module-specific criteria for Part A and Part B.
8. 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 plus a barrier method.
9. 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 treatment with IMP.
10. Male patients must use a condom with spermicide with all sexual partners from screening to approximately 6 months after the last dose of AZD5305 IMP.
11. Adequate organ and marrow function as defined by the protocol.
12. For part B expansion cohorts: Provision of formalin-fixed and paraffin embedded (FFPE) tumour specimen is mandatory, where available, except if stated that it is optional in a specific Module.
13. Other module specific criteria may apply.

Exclusion criteria 24

1. Treatment with any of the following: a) Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment b) 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 treatment c) Any other anticancer treatment within the time periods to the first dose of study treatment as indicated in the protocol d) Any live virus or bacterial vaccine within 28 days of the first dose of study treatment.
2. Concomitant use of medications or herbal supplements known to be cytochrome P450 3A4 (CYP3A4) strong inhibitors or inducers.
3. Concomitant use of drugs that are known to prolong or shorten QT and have a known risk of Torsades de Pointes.
4. During the 4 weeks prior to the first dose, receiving continuous corticosteroids at a dose of > 10 mg prednisone/day or equivalent for any reason.
5. Major surgery within 4 weeks of the first dose of study treatment.
6. 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 treatment.
7. 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 treatment.
8. Any history of persisting (> 2 weeks) severe pancytopenia due to any cause.
9. Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring continuous corticosteroids at a dose of >10mg prednisone/day or equivalent for at least 4 weeks prior to start of study treatment. Patients with leptomeningeal carcinomatosis are excluded. Any evidence of severe or uncontrolled systemic diseases, including, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and HIV. Screening for chronic conditions is not required.
10. Patients with any known predisposition to bleeding.
11. Any of the following cardiac criteria; a) Mean resting corrected QT interval (QTcF) > 450 milliseconds or QTcF<340 milliseconds b) Any factors that increase the risk of QT prolongation, shortening or risk of arrhythmic events, congenital long or short QT syndrome, family history of long QT syndrome, familial short QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication c) Known to prolong or shorten the QT interval d) Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG and clinically significant sinus node dysfunction not treated with pacemaker.
12. 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 (ACS)/acute myocardial infarction (AMI), unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) within 6 months e) Cardiomyopathy of any etiology f) Presence of clinically significant valvular heart disease g) History of atrial or ventricular arrhythmia requiring treatment; subjects with atrial fibrillation/flutter and optimally controlled ventricular rate (<100 beats per minute) are permitted h) Transient ischaemic attack, or stroke within 6 months prior to screening i) Patients with symptomatic hypotension at screening.
13. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML).
14. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD5305.
15. Known allergy or hypersensitivity to investigational product(s) or any of the excipients of the investigational product(s).
16. Any concurrent therapy anti-cancer therapy or concurrent use of prohibited medications.
17. Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
18. Any condition that, in the investigator's opinion, would interfere with evaluation of the study treatment or interpretation of subject safety or study results.
19. 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.
20. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site.
21. Previous study treatment assignment in the present study.
22. Uncontrolled intercurrent illness within the last 12 months.
23. Prior malignancy whose natural history has the potential to interfere with safety and efficacy assessments of the investigational regimen.
24. Other module specific criteria may apply.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Safety and tolerability will be assessed by the presence of AEs, SAEs, DLTs, MTD, physical examination changes from baseline, ECOG changes from baseline, and changed from baseline in laboratory findings, vital signs, and ECG results.

Secondary endpoints 11

1. Plasma concentrations of AZD5305 and plasma PK parameters, including but not limited to AUC, Cmax and Tmax as data allow, of AZD5305 after single dose and multiple doses administration.
2. Radiological response evaluated according to response evaluation criteria in solid tumours (RECIST v1.1) a) Best percentage change in target lesion b) ORR, DoR, PFS, TTR.
3. For ovarian cancer patients, CA125 response evaluated according to the GCIG criteria.
4. For prostate cancer patients, PSA50 response and ORR and rPFS using RECIST 1.1 and PCWG3 criteria.
5. Includes, but is not limited to assessment pH2AX (Ser139) PD G58biomarker modulations at baseline visit 1 and during treatment and other module specific biomarker.
6. Plasma and urine concentrations and PK parameters of AZD5305 and paclitaxel after single dose and multiple doses administration, including, but not limited to AUC, Cmax and Tmax, as data allow.
7. To investigate the effect of a high-fat meal on the PK of AZD5305.
8. Total plasma concentration and PK parameters, as data allow, of carboplatin during and after infusion.
9. Plasma concentrations and PK parameters of T-DXd (T-DXd, total anti-HER2 antibody and MAAA-1181a) after single dose and multiple dose administration, including, but not limited to AUC, Cmax and Tmax, as data allow.
10. Plasma concentrations and PK parameters of Dato-DXd, total anti TROP2 antibody, and MAAA-1181a (payload) including, but not limited to AUC, Cmax and Tmax, as data allow.
11. Plasma concentrations and PK parameters of AZD5305 and camizestrant after single dose and multiple dose administration, including, but not Q53limited to: AUC, Cmax, Tmax, as data allow.

Investigational products

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

Test 8

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

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Locations

5 EU/EEA countries · 30 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 84 files

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

Application history

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