A Phase I/II Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of AZD9750 as Monotherapy and in Combination Therapy in Participants with Metastatic Prostate Cancer

Trial ID: 2024-516976-14-00
Protocol: D7270C00001
Sponsor: AstraZeneca AB

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Diseases & Conditions

Prostate cancer metastatic

Objectives

The primary objective is to evaluate the safety and tolerability of AZD9750, administered as monotherapy or in combination with other anticancer agents, to determine the maximum tolerated dose (MTD) and the recommended dose for expansion (RDE) or recommended phase 2 dose (RP2D) in participants with metastatic castration-resistant prostate cancer (mCRPC). Part B focuses on assessing preliminary antitumour efficacy. Secondary objectives include:

Evaluation of preliminary antitumour efficacy for both Part A and Part B.
Characterization of the pharmacokinetics (PK) of AZD9750 as monotherapy or in combination with other anticancer agents.

Participants

This clinical trial involves 250 participants diagnosed with metastatic castration-resistant prostate cancer. The study population consists of males who are at least 18 years of age. Inclusion requires a histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate with documented metastatic disease evidenced by bone or soft tissue lesions. Participants must have undergone surgical or medical castration with serum testosterone levels ≤ 50 ng/dL. Eligible individuals must have experienced disease progression during continuous androgen deprivation therapy as defined by prostate cancer working group 3 guidance. Further requirements include an ECOG performance status of 0 or 1, a life expectancy of at least 12 weeks, and adequate bone marrow and organ function.

Plans and Procedures

This Phase I/II, modular, open-label, multi-centre study is designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of AZD9750 as a monotherapy and in combination with other anticancer agents in participants with metastatic prostate cancer. Part A and B aim to determine the maximum tolerated dose and the recommended dose for phase II, while Part B specifically assesses preliminary antitumour efficacy. The research methodology involves assessing the incidence of dose-limiting toxicities, adverse events, and serious adverse events. Efficacy is measured by the proportion of participants achieving a significant decrease in prostate-specific antigen levels and radiographic responses according to RECIST v1.1 and PCWG3 criteria. Study procedures include a screening process to confirm diagnosis, documentation of metastatic disease, and verification of castrate status via serum testosterone levels. Participants will undergo various clinical assessments, including physical examinations, electrocardiograms, and laboratory parameter monitoring, to identify clinically significant changes from baseline. The study is expected to conclude by November 2028.

Treatment

The experimental treatment AZD9750 is administered as a film-coated tablet via the oral route. This agent is evaluated as a monotherapy and in combination with other anticancer agents for the treatment of metastatic prostate cancer.

The experimental treatment Saruparib is administered in tablet form through oral administration. This substance is utilized as part of the combination therapy regimens within the study protocol.

Efficacy

The preliminary efficacy of AZD9750 in participants with metastatic prostate cancer is assessed through several parameters. In Part B, the evaluation focuses on the proportion of participants achieving a prostate-specific antigen (PSA) decrease of 50% or greater from baseline. For both Part A and Part B, efficacy is further measured by the proportion of participants achieving a 50% or greater decrease in PSA, as well as a 90% or greater decrease in PSA from baseline.

Additional efficacy assessments include:

Objective response rate (ORR), duration of response (DoR), time to response (TTR), and radiographic progression-free survival (rPFS), which are evaluated by the investigator using RECIST v1.1 for soft tissue and PCWG3 criteria for bone.
The best percentage change in tumor lesion (TL) size from baseline, measured via RECIST v1.1.
Time to PSA response and time to PSA progression according to PCWG3 criteria.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participant must be ≥ 18 years at the time of signing the informed consent form.
Histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate.
Documented metastatic disease by conventional imaging by clear evidence of at least one bone lesion and/or at least one soft tissue lesion.
Surgically or medically castrated, with serum testosterone levels ≤ 50 ng/dL (≤ 1.75 nmol/L) within (≤) 28 days before first dose of study intervention.
Participants who have had disease progression while undergoing continuous ADT following standard treatment of metastatic prostate cancer, per PCWG3 guidance. (a) PSA progression defined by a minimum of 3 rising PSA levels with an interval of ≥ 1 week between each determination. (b) Radiographic progression of soft tissue disease by RECIST v1.1 (Eisenhauer et al 2009) with or without PSA progression. (c) Radiographic progression of bone metastasis with 2 or more documented new bone lesions on a bone scan with or without PSA progression.
ECOG performance status score of 0 or 1.
Adequate bone marrow and organ function as defined by the protocol.
Participant must be male (as assigned at birth), inclusive of all gender identities.
Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Life expectancy of ≥ 12 weeks.

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Exclusion Criteria

Participants with pathological finding consistent with any presence of small cell carcinoma, predominant neuroendocrine carcinoma, or any predominant histology other than prostate adenocarcinoma.
Brain metastases, or spinal cord compression.
Participants with any of the following cardiac criteria: (a) Mean resting QTcF > 450 milliseconds obtained from triplicate ECGs and averaged, recorded within 5 minutes. (b) Any factors that increase the risk of QTc prolongation such as the congenital long QTc syndrome or family history of long QTc syndrome, or unexplained sudden death under 40 years of age in first-degree relatives, or any concomitant medication known to prolong the QTc interval within 5 half-lives of the first dose of study intervention (see Appendix H 1), as well as factors that increase the risk of arrhythmic events such as uncorrected abnormalities in serum electrolytes (ie, sodium, potassium, calcium, magnesium). (c) Resting heart rate > 90 bpm or < 45 bpm. (d) Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, or QRS duration > 120 ms, PR interval > 220 ms, second- or third-degree atrioventricular block), and clinically significant sinus node dysfunction not treated with pacemaker. (e) Baseline LVEF < 50%, or clinically significant diastolic dysfunction/LVEDP increase/pulmonary hypertension.
Participants with other cardiovascular diseases as defined by any of the following: (a) Symptomatic heart failure (as defined by New York Heart Association class ≥ 2) or recent hospitalisation for heart failure (< 6 months). (b) Uncontrolled hypertension > 160/90 mmHg. (c) Acute coronary syndrome /acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention, or coronary artery bypass grafting within 6 months, symptomatic angina pectoris. (d) Cardiomyopathy of any aetiology. (e) Presence of clinically significant valvular heart disease. (f) History of atrial or ventricular arrhythmia requiring treatment; subjects with atrial fibrillation and optimally controlled ventricular rate (mean HR < 90 bpm over 24 hours or mean HR < 90 bpm on resting ECG) are permitted. (g) Transient ischaemic attack, or stroke within 6 months prior to screening. (h) Participants with symptomatic hypotension at screening.
Unresolved treatment-related toxicities from previous anticancer therapy of CTCAE Grade ≥ 2 (with exception of vitiligo, alopecia).
Prior treatment with an AR-PROTAC.