Evaluation of AZD9574 Monotherapy and Combination Therapy in Advanced Solid Malignancies: A Phase I/IIa Study
- Trial ID
- 2023-504984-17-00
- Protocol
- D8410C00001
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **safety** and tolerability of AZD9574, both as a monotherapy and in combination with anti-cancer agents, in participants with advanced malignancies. This is clinically relevant as it aims to determine the potential of AZD9574 to be safely administered to patients with advanced solid tumors, which could lead to new therapeutic options for these conditions.
Secondary objectives include:
- Characterizing the pharmacokinetics (PK) of AZD9574 following a single dose and at steady state after multiple dosing, both as monotherapy and in combination with anti-cancer agents.
- Evaluating the pharmacodynamics (PD) of AZD9574 in tumor tissue when administered orally as monotherapy.
- Assessing the preliminary antitumor activity of AZD9574 as monotherapy and in combination with agents such as temozolomide (TMZ) and trastuzumab deruxtecan (T-DXd).
- Investigating the effect of a high-fat meal and famotidine on the PK of AZD9574.
- Determining PARP1 occupancy in the brain by AZD9574 at examined doses and plasma concentrations.
- Characterizing the PD of AZD9574 in tumor tissue when given in combination with T-DXd and datopotamab deruxtecan (Dato-DXd).
- Investigating the immunogenicity of T-DXd and Dato-DXd.
- Monitoring risks associated with T-DXd and Dato-DXd in study participants.
- Describing the prevalence or incidence of adverse events of special interest (AESIs) related to Dato-DXd in study participants.
Participants
The clinical trial involves a total of **392 participants** diagnosed with various advanced malignancies, including **unresectable or metastatic solid tumors** in breast, endometrial, ovarian, and prostate cancer, as well as IDH-mutant glioma and HER2-negative breast, ovarian, prostate, or pancreatic cancer. The study population comprises both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group performance status of 0 to 2, indicating a relatively stable health status. Participants were selected based on their progressive cancer status at the time of study entry and their ability to self-administer oral formulations. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific reproductive health guidelines, including the use of effective contraception methods. The trial includes a vulnerable population, and all participants are required to provide informed consent prior to any study-specific procedures.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the investigational drug AZD9574, both as a monotherapy and in combination with other anti-cancer agents. The trial targets patients with advanced solid malignancies, including breast, endometrial, ovarian, and prostate cancers, among others. The study is structured into multiple modules, each focusing on specific cancer types and genetic mutations, such as IDH-mutant glioma and HER2-negative breast cancer. The trial is expected to run until August 29, 2026, with recruitment having commenced on September 30, 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, organ function, and cancer progression. Following successful screening, participants will be randomized into treatment groups. Regular follow-up visits will be scheduled to monitor safety, collect pharmacokinetic data, and assess treatment efficacy through various endpoints, including changes in laboratory findings, radiological responses, and biomarker modulations. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted.
The expected length of participant involvement varies depending on individual response to treatment and the specific module of the trial. Participants may be withdrawn from the study early due to adverse events, lack of efficacy, or withdrawal of consent. The trial's primary endpoints include the incidence of adverse events, dose-limiting toxicities, and changes in vital signs, while secondary endpoints focus on pharmacokinetic parameters and radiological responses. The study aims to provide comprehensive data on the investigational drug's safety and efficacy profile in a diverse patient population.
Treatment
The clinical trial involves the administration of **AZD9574**, a film-coated tablet containing the active substance **6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridine-2-carboxamide**. This experimental medication is administered orally. The specific dosage and frequency of administration are determined based on the study protocol, which aims to assess the safety and tolerability of AZD9574 as monotherapy and in combination with other anti-cancer agents in patients with advanced solid malignancies. Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedule.
**Temozolomide** is used as a comparator treatment in the study. It is available in hard capsule form under the brand name TEMOZO-cell®, with varying dosages of 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg. Temozolomide is administered orally, and its use is guided by standard-of-care protocols for the treatment of certain malignancies. The administration schedule and dosage are tailored to the individual needs of the participants, and compliance is monitored to ensure accurate data collection.
**Trastuzumab deruxtecan**, marketed as DS-8201a, is provided as a solution for infusion. This medication is administered intravenously and is included in the study to evaluate its effects in combination with AZD9574. The infusion schedule is determined by the study protocol, and participant adherence to the treatment regimen is closely monitored.
**Datopotamab deruxtecan** is another investigational agent used in the trial, available as a solution for infusion. It is administered intravenously, and its role in the study is to assess its efficacy and safety in combination with AZD9574. The dosing schedule is specified in the study protocol, and compliance is tracked to ensure the integrity of the trial data.
The study also includes the use of **[11C]AZ14193391**, a solution for injection, administered via intravenous bolus. This compound is utilized as an auxiliary agent in the trial, and its administration is conducted according to the study's specific requirements. Monitoring of participant compliance is integral to the study's success, ensuring that all data collected is reliable and accurate.
Efficacy
The efficacy of the investigational product AZD9574 will be assessed in a clinical trial involving patients with advanced solid malignancies. The primary endpoints for evaluating efficacy include the incidence of adverse events (AEs) and serious adverse events (SAEs), dose-limiting toxicities (DLTs), and maximum tolerated dose (MTD). Changes from baseline in laboratory findings, Eastern Cooperative Oncology Group performance status (ECOG PS), electrocardiograms (ECGs), and vital signs will also be monitored.
Secondary endpoints will focus on pharmacokinetic (PK) parameters such as plasma concentrations of AZD9574, area under the curve (AUC), maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), minimum plasma concentration at steady state (Cmin,ss), half-life, and accumulation ratio. Additionally, the study will evaluate radiological responses according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), including percentage change in target lesion size, overall response rate (ORR), duration of response (DoR), time to response (TTR), and progression-free survival (PFS). For specific cancer types, additional assessments such as CA125 response for ovarian cancer and PSA50 response for prostate cancer will be conducted.
Assessments will be conducted at various timepoints throughout the study, including baseline, during treatment, and at the end of treatment. The study will utilize validated scales and criteria, such as RECIST v1.1, to ensure consistent and reliable measurement of efficacy parameters. The data collected will be analyzed to determine the preliminary efficacy of AZD9574 as a monotherapy and in combination with other anti-cancer agents.
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 years at the time of screening.
- Eastern Cooperative Oncology Group performance status (ECOG PS: 0-2) with no deterioration over the previous 2 weeks.
- Life expectancy ≥ 12 weeks.
- Progressive cancer at the time of study entry.
- 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
- 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.
- 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 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
- 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
- Adequate organ and marrow function as defined by the protocol
- Participants should be capable of self-administering oral formulations
- 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
- 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
- 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.
- Any known predisposition to bleeding
- 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
- 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
- Patients with myelodysplastic syndrome/acute myeloid leukaemia
- 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).
- Known allergy or hypersensitivity to IP(s) or any of the excipients of the IP(s)
- 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.
- Any concurrent anti-cancer therapy or concurrent use of prohibited medications
- 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
- Major surgery within 4 weeks of the first dose of study intervention
- 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
- 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.
- Involvement in the planning and/or conduct of the study
- Previous study intervention assignment in the present study Other module specific criteria may apply.
- 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 (> 2 weeks) 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
- 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
- Any live virus or bacterial cancer vaccine within 4 weeks of the first dose of study intervention
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Recruiting | 30 Sept 2022 | 150 |
 Sweden | Recruiting | 30 Sept 2022 | 26 |
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 |
|---|---|---|---|---|---|---|
AZD9574 | Test | FILM-COATED TABLET | ORAL | — | — | PRD11235679 |
TEMOZO-cell® 20 mg Hartkapseln | Test | HARTKAPSELN | ORAL | — | — | PRD1964941 |
AZD9574 | Test | FILM-COATED TABLET | ORAL | — | — | PRD11235681 |
AZD9574 | Test | FILM-COATED TABLET | ORAL | — | — | PRD13535981 |
TEMOZO-cell® 5 mg Hartkapseln | Test | HARTKAPSELN | ORAL | — | — | PRD1964952 |
TEMOZO-cell® 180 mg Hartkapseln | Test | HARTKAPSELN | ORAL | — | — | PRD2091954 |
AZD9574 | Test | FILM-COATED TABLET | ORAL | — | — | PRD11235680 |
Datopotamab deruxtecan | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | — | — | PRD9684738 |
TEMOZO-cell ®250 mg Hartkapseln | Test | HARTKAPSELN | ORAL | — | — | PRD1964936 |
AZD9574 | Test | FILM-COATED TABLET | ORAL | — | — | PRD11235682 |