AZD5305 hADME in Patients With Advanced Solid Malignancies

AstraZeneca

Status and phase: Enrolling; Phase 1

Conditions: Locally Advanced or Metastatic Solid Tumor

Treatments: Drug: [14C]-AZD5305 (therapeutic dose); Drug: Saruparib (AZD5305); Drug: [14C]-AZD5305 microtracer

Study type: Interventional

Funder types: Industry

Identifiers

NCT06713369

D9723C00004

Details and patient eligibility

About

This Phase I, open-label study aims to study to absolute bioavailability of Saruparib (AZD5305) and the absorption, distribution, metabolism and excretion (ADME) of [14C]-Saruparib in patients with advanced solid malignancies.

This will be done on an inpatient basis in 2 parts (single-dose oral administration with radiolabeled microtracer in Part A, single-dose IV radiolabeled administration in Part B) during which samples will be obtained of plasma, urine, feces and vomitus (where applicable).

Full description

This is an open-label, 2-part study in participants with advanced solid malignancies and will be conducted at multiple study sites.

Participants will be assessed for study eligibility prior to admission to the study site during a 28-day screening period. Participants will take part in both Parts A and B of the study.

Part A will assess the absolute bioavailability and evaluate the PK parameters of oral Saruparib and a radiolabelled IV microdose of [14C]-Saruparib

Participants will be admitted to the study site pre-dose of Part A and will remain resident at the study site for PK sampling and safety assessments.

A washout period will be observed between doses of Saruparib in Parts A and B.

Part B will assess the ADME of oral [14C]-Saruparib. Participants will be readmitted to the study site for Part B and will remain resident at the study site for excreta (urine, faeces, and any vomitus) collections, PK sampling, and safety assessments. Participants may be discharged from the study site prior to the last indicated day if both the following discharge criteria are met:

1. ≥ 90% mass balance recovery, and
2. < 1% of the total radioactive dose is recovered in combined excreta (urine and faeces) in 2 consecutive 24-hour periods.

Participants will return to the study site for a Follow-up Visit after the last dose of Saruparib which will include routine safety assessments. After the completion of Parts A and B, and following the Follow-up Visit, participants may be allowed further access to Saruparib.

Additional safety data collection will be conducted.

Enrollment: 8 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Male or female ≥ 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place), at the time of signing the ICF.
2. Histologically or cytologically documented, locally advanced or metastatic solid tumour, excluding lymphoma, for which standard therapy does not exist or has proven ineffective or intolerable.
3. ECOG performance status of 0 or 1 with no deterioration over the 2 weeks prior to dosing.
4. Predicted life expectancy ≥ 12 weeks.
5. Adequate organ and marrow function as defined in the protocol
6. Willingness and ability to comply with study and follow-up procedures.
7. Able and willing to stay in hospital for specified residential periods following administration of Saruparib/[14C]-Saruparib
8. Regular bowel movements
9. Body weight within normal range specified in protocol
10. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies Reproduction
11. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in the protocol

Exclusion criteria

1. Participants with a history of MDS/AML or with features suggestive of MDS/AML (as determined by prior diagnostic investigation). Specific screening for MDS/AML is not required.
2. Participants with any known predisposition to bleeding
3. Any history of persisting severe cytopenia due to any cause
4. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of Saruparib.
5. History of another primary malignancy, with some exceptions
6. Persistent toxicities (CTCAE Grade ≥ 2), excluding alopecia, caused by previous anticancer therapy.
7. Spinal cord compression or brain metastases for at least 4 weeks prior to start of study intervention unless asymptomatic and stable
8. Abnormal cardiac function exclusions or cardiovascular disease
9. History of arrhythmia
10. Active HBV (positive HBsAg result) or HCV.
11. Evidence of active and uncontrolled HIV infection.
12. Active tuberculosis infection
13. Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.
14. As judged by the investigator, any other evidence of diseases (such as severe or uncontrolled systemic diseases or active uncontrolled infections which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or would jeopardise compliance with the protocol.
15. Any prior treatment with a PARP inhibitor or platinum chemotherapy.
16. Other anticancer therapy (chemotherapy, immunotherapy, hormonal anticancer therapy, radiotherapy [except for palliative local radiotherapy]), biological therapy or other novel agent is not permitted until the last PK sampling is completed.
17. Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation or to more than 30% of the bone marrow within 4 weeks before the first dose of study intervention
18. Concomitant use of medications or herbal supplements known to be CYP3A4 strong and moderate inhibitors or inducers
19. Concomitant use of drugs that are known to prolong or shorten QT and have a known risk of Torsades de Pointes
20. Participants who have participated in another absorption, distribution, metabolism, and excretion study within 1 year prior to screening.
21. Participation in another clinical study with a study intervention administered in the last 3 months or 5 half-lives prior to dosing, whichever is longer.
22. Participants with a known hypersensitivity to Saruparib or any of the excipients of the product.
23. Participants who have been administered any amount of a [14C]-labelled compound within the last 12 months.
24. Use of tobacco- or nicotine-containing products or alcohol may be exclusionary
25. Poor peripheral venous access (venous access via a port will be permitted).
26. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
27. Judgment 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.
28. Previous enrolment in the present study.
29. For female participants only: currently pregnant (confirmed with positive pregnancy test) or planning to become pregnant, breast-feeding, or intending to donate/retrieve ova before 6 months after the last dose of Saruparib.

Trial design

Primary purpose: Basic Science

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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8 participants in 1 patient group

Primary Treatment Arm - AZD5305

Experimental group

Description:

Part A will assess absolute bioavailability via oral administration of Saruparib (AZD5305) and IV \[14C\]-saruparib microtracer. Part B will assess ADME via IV \[14C\]-saruparib administration

Treatment:

Drug: [14C]-AZD5305 microtracer

Drug: Saruparib (AZD5305)

Drug: [14C]-AZD5305 (therapeutic dose)