A Modular Phase I/IIa, Open-label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of Ascending Doses of AZD5305 as Monotherapy and in Combination with Anti-cancer Agents in Patients with Advanced Solid Malignancies (PETRA)
- Trial ID
- 2022-502856-29-00
- Protocol
- D9720C00001
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **safety** and **tolerability** of AZD5305, both as a monotherapy and in combination with anti-cancer agents, in patients with advanced solid tumors. This is clinically relevant as it aims to determine the potential of AZD5305 to be safely administered to patients, which is a critical step in the development of new therapeutic options for advanced malignancies.
Secondary objectives include:
- Characterizing the **pharmacokinetics** (PK) of AZD5305 in plasma following a single dose and at steady state after multiple dosing, both as monotherapy and in combination with anti-cancer agents.
- Assessing the preliminary anti-tumor activity of AZD5305 as monotherapy and in combination with anti-cancer agents.
- Evaluating the **pharmacodynamics** (PD) of AZD5305 in tumor tissue when administered orally as monotherapy.
- Characterizing the PK of AZD5305 in plasma and urine, following a single dose and at steady state after multiple dosing, when given orally as monotherapy.
- Characterizing the PK of AZD5305 and paclitaxel, following a single dose and at steady state after multiple dosing in plasma, when given in combination.
- Characterizing the PK of AZD5305, carboplatin +/- paclitaxel.
- Characterizing the PK of AZD5305 and T-DXd.
- Characterizing the PK of AZD5305 and Dato-DXd.
- Characterizing the PK of AZD5305 and Camizestrant.
Participants
The clinical trial involves a total of **640 participants** diagnosed with **advanced solid tumors**. The study population includes both male and female subjects, aged **18 years and older**, who have been confirmed to have advanced malignancies suitable for the study treatment. Participants were selected based on their ability to provide informed consent and meet specific health criteria, including adequate organ and marrow function, a life expectancy of at least 12 weeks, and an Eastern Cooperative Oncology Group Performance status of 0-2. The trial does not include vulnerable populations. Lifestyle considerations such as the use of effective birth control methods and abstaining from breastfeeding are required for female participants of childbearing potential. Male participants are required to use condoms with spermicide during the study period and for a specified duration after the last dose of the investigational medicinal product. The trial aims to assess the safety and tolerability of AZD5305, both as a monotherapy and in combination with other anti-cancer agents.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and tolerability of AZD5305, both as a monotherapy and in combination with other anti-cancer agents, in patients with advanced solid tumors. This study is structured as a modular Phase I/IIa, open-label, multicenter trial. The trial employs a randomized, controlled design to ensure robust data collection and analysis. The estimated duration of the trial is from April 2024 to December 2026, with participant involvement expected to last approximately 6 months, depending on individual response and treatment tolerability.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, organ function, and disease status. Following successful screening, participants will enter the treatment phase, where they will receive AZD5305 orally in the form of a **film-coated tablet**. The trial includes multiple follow-up visits to monitor safety, pharmacokinetics, and pharmacodynamics, as well as to assess preliminary efficacy. These visits will involve physical examinations, laboratory tests, and imaging studies to evaluate disease progression according to RECIST v1.1 criteria.
The end-of-study visit will occur after the final dose of the investigational product, where comprehensive assessments will be conducted to gather data on the primary and secondary endpoints. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they choose to withdraw consent. Additionally, any significant protocol deviations may also result in early termination from the study. The trial aims to provide valuable insights into the potential therapeutic benefits and safety profile of AZD5305 in treating advanced solid malignancies.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific characteristics. **AZD5305** is a synthetic compound provided in the form of a **film-coated tablet**. It is administered orally. The active substance in AZD5305 is **5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methylpyridine-2-carboxamide**. The dosing schedule and frequency of administration are determined based on the study protocol, and participant compliance is monitored throughout the trial.
**DS-8201a**, also known as **trastuzumab deruxtecan**, is an **antibody-drug conjugate** provided as a **solution for infusion**. It is administered intravenously. The administration schedule is designed to optimize therapeutic outcomes while ensuring patient safety. Compliance with the infusion protocol is closely monitored by the clinical team.
**Camizestrant** is another synthetic compound used in the trial, available as a **film-coated tablet**. It is administered orally. The active substance is **camizestrant**, and the dosing regimen is tailored to the study's objectives. Participant adherence to the oral administration schedule is tracked to ensure accurate data collection.
**Datopotamab deruxtecan** is an **antibody-drug conjugate** provided as a **solution for infusion**. It is administered intravenously. The infusion protocol is carefully followed to maintain consistency across all study sites, and compliance is monitored by the research staff.
**PACLITAXEL** is used as a comparator treatment in the study. It is a synthetic compound administered as a **solution for infusion** via the intravenous route. The administration schedule is based on standard clinical practice, and adherence to the protocol is ensured through regular monitoring.
Throughout the trial, all medications are administered according to the specified routes and forms, with compliance monitoring in place to ensure adherence to the study protocol. The trial aims to assess the safety, tolerability, and preliminary efficacy of these treatments in patients with advanced solid malignancies.
Efficacy
The efficacy of the investigational product AZD5305 in the clinical trial will be assessed through a series of secondary endpoints. These include radiological response evaluations according to the Response Evaluation Criteria in Solid Tumours (RECIST v1.1), which will measure the best percentage change in target lesions, overall response rate (ORR), duration of response (DoR), progression-free survival (PFS), and time to response (TTR). For patients with ovarian cancer, the CA125 response will be evaluated according to the Gynecologic Cancer InterGroup (GCIG) criteria. In prostate cancer patients, the PSA50 response, ORR, and radiographic PFS (rPFS) will be assessed using RECIST 1.1 and Prostate Cancer Working Group 3 (PCWG3) criteria.
Additional efficacy assessments will include the evaluation of **biomarker** modulations, such as pH2AX (Ser139), at baseline and during treatment. Pharmacokinetic (PK) parameters, including plasma concentrations of AZD5305 and other agents, will be measured after single and multiple doses. These parameters include area under the curve (AUC), maximum concentration (Cmax), and time to maximum concentration (Tmax). The effect of a high-fat meal on the PK of AZD5305 will also be investigated. The schedule for these assessments will be aligned with the study protocol, ensuring comprehensive data collection and analysis throughout the trial duration.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.
- Age ≥ 18 at the time of screening.
- Patients must have histological or cytological confirmation of advanced malignancy considered to be suitable for study treatment and meeting module specific eligibility criteria.
- Eastern Cooperative Oncology Group Performance status (ECOG) PS: 0-2 with no deterioration in the previous 2 weeks.
- Life expectancy ≥ 12 weeks.
- Progressive cancer at the time of study entry.
- Patients must have evaluable disease as defined in module-specific criteria for Part A and Part B.
- 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.
- 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.
- 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.
- Adequate organ and marrow function as defined by the protocol.
- 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.
- Other module specific criteria may apply.
Exclusion Criteria
- 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.
- Concomitant use of medications or herbal supplements known to be cytochrome P450 3A4 (CYP3A4) strong inhibitors or inducers.
- Concomitant use of drugs that are known to prolong or shorten QT and have a known risk of Torsades de Pointes.
- 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.
- Major surgery within 4 weeks of the first dose of study treatment.
- 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.
- 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.
- Any history of persisting (> 2 weeks) severe pancytopenia due to any cause.
- 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.
- Patients with any known predisposition to bleeding.
- 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.
- 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.
- Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (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 AZD5305.
- Known allergy or hypersensitivity to investigational product(s) or any of the excipients of the investigational product(s).
- Any concurrent therapy anti-cancer therapy or concurrent use of prohibited medications.
- 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.
- Any condition that, in the investigator's opinion, would interfere with evaluation of the study treatment or interpretation of subject safety or study results.
- 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.
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site.
- Previous study treatment assignment in the present study.
- Uncontrolled intercurrent illness within the last 12 months.
- Prior malignancy whose natural history has the potential to interfere with safety and efficacy assessments of the investigational regimen.
- Other module specific criteria may apply.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 15 Apr 2024 | 50 |
 Hungary | Not Recruiting | 15 Apr 2024 | 76 |
 Italy | Not Recruiting | 15 Apr 2024 | 65 |
 Poland | Not Recruiting | 15 Apr 2024 | 47 |
 Spain | Not Recruiting | 15 Apr 2024 | 189 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Saruparib | Test | FILM-COATED TABLET | ORAL | — | — | PRD10813424 |
Saruparib | Test | FILM-COATED TABLET | ORAL | — | — | PRD11223671 |
Saruparib | Test | TABLET | ORAL | — | — | PRD10197822 |
PACLITAXEL | Test | PHF00230MIG | INTRAVENOUS USE | — | — | SCP129816 |
DS-8201a | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | — | — | PRD5308994 |
Saruparib | Test | FILM-COATED TABLET | ORAL | — | — | PRD10813387 |
Datopotamab deruxtecan | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | — | — | PRD9684738 |
Camizestrant | Test | FILM-COATED TABLET | ORAL | — | — | PRD9916833 |