A Modular Phase I/IIa, Open-label, Multi-center Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of AZD0516 as Monotherapy and in Combination with Anti-cancer Agents in Participants with Metastatic Prostate Cancer.
- Trial ID
- 2024-520026-11-00
- Protocol
- D9520C00001
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
This modular Phase I/IIa study evaluates AZD0516, an antibody-drug conjugate, as monotherapy and in combination with other anti-cancer agents in participants with metastatic prostate cancer. The primary objectives are multifaceted across the study parts. In the dose escalation phase (Part A), the primary objective is to assess the safety and tolerability and to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of AZD0516 as monotherapy and in combination with anti-cancer agents. In the dose optimisation phase (Part B), the primary objectives include assessing the preliminary anti-tumour activity as well as the safety and tolerability of AZD0516 as monotherapy and in combination with anti-cancer agents. In the efficacy expansion phase (Part C), the primary objective is to assess the anti-tumour activity of AZD0516 as monotherapy and/or in combination with other anti-cancer agents. These objectives are clinically relevant for establishing the therapeutic potential and optimal dosing regimen of AZD0516 in this patient population.
The secondary objectives include:
• Assessment of preliminary anti-tumour activity of AZD0516 as monotherapy and/or in combination with other anti-cancer agents across dose escalation (Part A), dose optimisation (Part B), and efficacy expansion (Part C) phases.
• Characterisation of the pharmacokinetics (PK) of AZD0516 when administered as monotherapy and in combination with anti-cancer agents during dose escalation (Part A) and dose optimisation (Part B) phases.
• Investigation of STEAP2 expression and its relationship to response to AZD0516 as a biomarker assessment during dose escalation (Part A) and dose optimisation (Part B) phases.
• Determination of the immunogenicity of AZD0516 as monotherapy and in combination with anti-cancer agents during dose escalation (Part A) and dose optimisation (Part B) phases.
• Further assessment of safety and tolerability of AZD0516 as monotherapy and in combination with anti-cancer agents during the efficacy expansion phase (Part C).
Participants
This clinical trial enrolled a total of **294 participants**, all of whom were **male** individuals as assigned at birth. The study population consisted of **adults** aged 18 years and older, or the legal age of consent in the participating jurisdiction. Participants had a confirmed diagnosis of **metastatic adenocarcinoma of the prostate** with documented evidence of metastatic disease on imaging studies. All participants were required to be surgically or medically **castrated** with serum **testosterone** levels at or below 50 ng/dL, and those who had not undergone bilateral **orchiectomy** were required to continue ongoing **androgen deprivation therapy** with a **GnRH modulator** throughout the study. The trial population was selected based on having received and progressed on standard therapy, being refractory or intolerant to such therapy, or having contraindications to standard of care treatment. Participants were required to have an **ECOG performance status** of 0 or 1, a life expectancy of at least 12 weeks, and adequate organ and marrow function. Measurable **prostate-specific antigen** levels of at least 1 ng/mL were required for inclusion. Participants were required to use appropriate contraceptive methods during the study and refrain from sperm donation. The study excluded individuals with disease spread limited to regional pelvic lymph nodes or local recurrence only.
Plans and Procedures
This clinical trial is a modular Phase I/IIa, open-label, multi-center study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of AZD0516 administered as monotherapy and in combination with anti-cancer agents in participants with metastatic prostate cancer. The study is structured in three distinct parts: Dose Escalation (Part A), Dose Optimisation (Part B), and Efficacy Expansion (Part C). The trial is non-randomized and follows an open-label design, meaning that both participants and investigators are aware of the treatment being administered. The estimated recruitment start date is January 15, 2026, with the study expected to conclude on October 16, 2028.
The investigational medicinal products include AZD0516, an antibody-drug conjugate administered as a solution for injection/infusion via the intravenous route, and AZD9574, a novel brain penetrant PARP inhibitor that selectively inhibits and traps PARP1, administered as a film-coated tablet via the oral route. AZD0516 contains the active substance AZD0516 of protein origin, while AZD9574 contains the chemical active substance 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4h-quinoxalin-6-yl)methyl]piperazin-1-yl]-n-methylpyridine-2-carboxamide.
The primary objective of Dose Escalation (Part A) is to assess the safety and tolerability of AZD0516 and to determine the maximum tolerated dose and/or recommended dose for expansion as monotherapy and in combination with anti-cancer agents. Safety endpoints include the incidence of adverse events, adverse events of special interest, serious adverse events, dose-limiting toxicities, and the rate of AZD0516 discontinuation due to toxicity. Clinically significant changes from baseline in laboratory parameters, vital signs, electrocardiograms, ECOG performance status, and physical examination are also assessed. In Dose Optimisation (Part B), the primary objectives are to evaluate the preliminary antitumour activity of AZD0516 as measured by PSA50 response rate (the proportion of participants achieving at least a 50% reduction in prostate-specific antigen levels), as well as to assess safety and tolerability. Efficacy Expansion (Part C) focuses on evaluating the anti-tumour activity of AZD0516 as monotherapy and/or in combination with other anti-cancer agents, with PSA50 response rate as the primary efficacy endpoint.
Secondary efficacy endpoints across all study parts include PSA-related parameters such as PSA90 response rate, time to PSA50 and PSA90 response, duration of PSA50 and PSA90 response, durable PSA50 and PSA90 response rates, time to PSA progression, and PSA levels over time. Radiological response endpoints are assessed by the investigator according to RECIST v1.1 criteria for soft tissue and PCWG3 criteria for bone, including objective response rate, best overall response, duration of response, durable response rate, disease control rate, time to response, percentage change in tumour size, and radiographic progression-free survival. Overall survival is also evaluated as a secondary efficacy endpoint. In Parts A and B, secondary objectives include pharmacokinetic assessments of plasma concentrations and pharmacokinetic parameters of AZD0516, total antibody (conjugated and unconjugated), and total unconjugated warhead, including but not limited to area under the curve, maximum plasma concentration, time to maximum concentration, clearance, and half-life. Biomarker analyses include evaluation of STEAP2 expression via immunohistochemistry on treatment versus at baseline in paired biopsy cohorts and assessment of the association between STEAP2 expression and AZD0516 response. Immunogenicity is assessed by evaluating the number and percentage of participants who develop anti-drug antibodies. In Efficacy Expansion (Part C), secondary objectives focus on safety parameters similar to those assessed in Part A.
Eligible participants must be male, as assigned at birth, aged 18 years or older, with histologically or cytologically confirmed diagnosis of metastatic adenocarcinoma of the prostate. Focal high-grade neuroendocrine features are permitted. Participants must be surgically or medically castrated with serum testosterone levels ≤ 50 ng/dL (≤ 1.75 nmol/L) within 28 days before treatment allocation. Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone modulator is required for participants who have not undergone bilateral orchiectomy, initiated at least 2 weeks prior to consent and continued throughout the study. Participants must have measurable PSA ≥ 1 µg/L (≥ 1 ng/mL) and documented current evidence of metastatic prostate cancer, defined as at least one documented metastatic lesion on either computed tomography/magnetic resonance imaging or bone scan. Participants whose disease spread is limited to regional pelvic lymph nodes or local recurrence are not eligible. Additional inclusion criteria include ECOG performance status of 0 or 1, life expectancy of at least 12 weeks, and adequate organ and marrow function in the absence of blood transfusion or growth factor support within 21 days prior to the scheduled first dose of study intervention. Participants must have received and progressed on, are refractory to, or are intolerant to standard therapy in accordance with local practice for their stage of disease, or a clinical study is considered the best option for the participant's next treatment. Provision of a baseline archival or newly obtained formalin-fixed paraffin-embedded tumour sample is mandatory. Male participants who are sexually active with a female partner of childbearing potential must use a male condom (and add spermicide, if available) while on study and for an appropriate period after the final dose of study intervention, and must refrain from sperm donation during this period.
The trial involves a screening visit to assess eligibility, followed by treatment visits during which study interventions are administered and safety and efficacy assessments are conducted. Follow-up visits are scheduled to monitor ongoing response, disease progression, and long-term safety. The end-of-study visit occurs upon completion of the study or upon early termination. Participant involvement duration varies depending on the study part and individual response to treatment, extending from the time of enrollment until disease progression, unacceptable toxicity, withdrawal of consent, or study completion. Conditions that may lead to early termination from the study include the occurrence of dose-limiting toxicities, unacceptable adverse events, disease progression, participant request, investigator decision, or non-compliance with study procedures.
Treatment
The experimental medication AZD9574 is administered as a film-coated tablet via the oral route. The active substance is 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4h-quinoxalin-6-yl)methyl]piperazin-1-yl]-n-methylpyridine-2-carboxamide, which is a chemical compound. AZD9574 represents a novel brain penetrant PARP inhibitor that potently and selectively inhibits and traps PARP1. The investigational product is supplied in multiple formulations as film-coated tablets for oral administration.
The experimental medication AZD0516 is administered as a solution for injection/infusion via the intravenous route. The active substance is AZD0516, which is classified as a protein of other origin. AZD0516 is characterized as an antibody-drug conjugate/biologic. This investigational agent is evaluated both as monotherapy and in combination with other anti-cancer agents in participants with metastatic prostate cancer.
Efficacy
Efficacy will be assessed using multiple parameters across different study parts. In Dose Optimisation (Part B) and Efficacy Expansion (Part C), the primary efficacy endpoint is PSA50 response rate. Secondary efficacy endpoints include additional PSA-related parameters such as PSA90 response rate, time to PSA50 response, time to PSA90 response, duration of PSA50 response, duration of PSA90 response, durable PSA50 response rate, durable PSA90 response rate, time to PSA progression, and PSA over time. Radiological response endpoints will be evaluated by the investigator according to RECIST v1.1 criteria for soft tissue and PCWG3 criteria for bone, including overall response rate, best overall response, duration of response, durable response rate, disease control rate, time to response, percentage change in tumour size, and radiographic progression-free survival. Overall survival will also be assessed as a secondary efficacy endpoint.
Biomarker analysis will include evaluation of target expression via STEAP2 immunohistochemistry on treatment versus at baseline in paired biopsy cohorts, and assessment of the association between STEAP2 expression and AZD0516 response. Baseline PSA levels of at least 1 µg/L will be required for study entry, and serum testosterone levels must be documented at 50 ng/dL or below within 28 days before treatment allocation.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Informed Consent - Capable of giving signed informed consent as described in the study protocol which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
- Informed Consent - Consent to provide adequate baseline tumour sample prior to start of treatment, as applicable per module-specific criteria.
- Informed Consent - Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional Genomics Initiative research that supports the Genomic Initiative (see study protocol). Participants who do not provide informed consent for Optional Genetic Research may still be enrolled in the study.
- Age - Participant must be ≥ 18 years of age inclusive, or the legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the ICF.
- Tissue sample - Provision of baseline archival or newly obtained FFPE tumour sample is mandatory.
- Type of Participant and Disease Characteristics - Histologically or cytologically confirmed diagnosis of metastatic adenocarcinoma of the prostate. Focal high grade neuroendocrine features are permitted.
- Type of Participant and Disease Characteristics - Surgically or medically castrated with serum testosterone levels ≤ 50 ng/dL (≤ 1.75 nmol/L) within ≤ 28 days before treatment allocation. Ongoing ADT with a GnRH modulator for participants who have not undergone bilateral orchiectomy must be initiated at least 2 weeks prior to consent and must continue throughout the study.
- Type of Participant and Disease Characteristics - Measurable PSA ≥ 1 µg/L (≥ 1 ng/mL).
- Type of Participant and Disease Characteristics - Documented current evidence of metastatic prostate cancer, where metastatic status is defined as at least one documented metastatic lesion on either CT/MRI or bone scan. Participants whose disease spread is limited to regional pelvic lymph nodes or local recurrence (eg, bladder, rectum) are not eligible.
- Type of Participant and Disease Characteristics - ECOG performance status of 0 or 1.
- Type of Participant and Disease Characteristics - Life expectancy of at least 12 weeks in the opinion of the investigator.
- Type of Participant and Disease Characteristics - Adequate organ and marrow function in the absence of blood transfusion or growth factor support (within 21 days prior to the scheduled first dose of study intervention as indicated in the study protocol).
- Type of Participant and Disease Characteristics - Participants must have received and progressed on, are refractory or are intolerant to standard therapy in accordance with local practice for their stage of disease or, in the opinion of the investigator, a clinical study is the best option for the participant’s next treatment based on response and/or tolerability to prior therapy. Participants with contraindications, to standard of care therapy, may also be considered if it is documented, and they have been informed about all therapeutic options.
- Sex and Contraceptive/Barrier Requirements - Male, as assigned at birth, inclusive of all gender identities: (a) Contraceptive use by participants or participant partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. (b) Participants who are sexually active with a female partner of childbearing potential, including a pregnant partner, must use a male condom (and add spermicide, if available) while on study and for an appropriate period after final dose of study intervention. (i) Investigators are to advise participants about the preservation of sperm prior to AZD0516. (ii) It is strongly recommended for the female partner of a male participant to also use a highly effective method of contraception throughout this period, as described below: Highly effective birth control methods include: Total sexual abstinence is an acceptable method provided it is the usual lifestyle of the participant (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study interventions [periodic abstinence eg, calendar, ovulation, symptothermal, post-ovulation methods, declaration of abstinence for the duration of exposure to study intervention, and withdrawal are not acceptable methods of contraception]), a vasectomised partner, Implanon®, bilateral tubal occlusion, intrauterine device/levonorgestrel intrauterine system, Depo-Provera™ injections, oral contraceptive, and Evra Patch™, Xulane™, or NuvaRing®.
- Sex and Contraceptive/Barrier Requirements - Participants must refrain from sperm donation while on study and for an appropriate period following the last dose of study intervention.
Exclusion Criteria
- Medical Conditions - Cancer related spinal cord compression, or brain metastases 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 study enrolment. Any participant at high risk of cord compression based on imaging at screening should have the bone lesions treated prior to study enrolment. A scan to confirm the absence of brain metastases is not required.
- Medical Conditions - History of leptomeningeal carcinomatosis.
- Medical Conditions - Unresolved toxicities of Grade ≥ 2 (NCI CTCAE v5.0) from prior therapy (excluding vitiligo, alopecia, and endocrine disorders that are controlled with replacement hormone therapy). Participants with chemotherapy-induced Grade 2 neuropathy may be eligible at discretion of the investigator and after consultation with the AstraZeneca Study Physician.
- Medical Conditions - Uncontrolled intercurrent illness within the last 12 months, including but not limited to, uncontrolled diabetes mellitus, substance abuse, serious chronic gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of experiencing AEs or compromise the ability of the participant to give written informed consent.
- Medical Conditions - Cardiovascular disorder defined as: (a) History of arrhythmia (such as multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (NCI CTCAE v5.0 Grade 3); symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Note: Abnormalities in serum electrolytes that can increase the risk of arrhythmic events (ie, sodium, potassium, calcium, magnesium) should be corrected before starting the study intervention. (b) Uncontrolled hypertension, defined as systolic BP > 160 mmHg or diastolic BP > 90 mmHg despite optimal medical management, as determined by the investigator. Hypertensive participants may be eligible, but BP must be adequately controlled at baseline. Participants may be re-screened regarding the BP requirement. (c) Symptomatic hypotension at screening. (d) Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention, or coronary artery bypass grafting within 6 months. (e) History of brain perfusion problems (eg, carotid stenosis) or stroke, or transient ischaemic attack in the last 6 months prior to screening. (f) Symptomatic heart failure (as defined by New York Heart Association class ≥ 2). (g) Prior or current cardiomyopathy. (h) Severe valvular heart disease. (i) Mean resting QTcF > 470 ms obtained from triplicate ECGs and averaged, recorded within 5 minutes. (j) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in a first degree relative.
- Medical Conditions - History of malignancy, except for: (a) Malignancy treated with curative intent and with no known active disease for at least 2 years before the first dose of study intervention and with low potential risk for recurrence. (b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. (c) Adequately treated carcinoma in situ without evidence of disease. (d) Localised non-invasive primary disease under surveillance.
- Medical Conditions - Active infection exclusions, including tuberculosis and infections with HBV (verified by known positive HBsAg result), HCV, or HIV (verified by positive HIV-1 or HIV-2 antibodies). (a) Known uncontrolled hepatitis B and/or chronic or active hepatitis B with HBV DNA ≥ 100 IU/mL, refer to the protocol for screening tests and eligibility algorithm. (i) Participants with HBsAg positive are eligible if HBV DNA < 100 IU/mL and agrees to start or maintain antiviral treatment. (ii) Participants with HBsAg negative and HBV viral load ‘detectable’ are eligible if HBV DNA < 100 IU/mL and agrees to start or maintain antiviral treatment. (iii) Participants with HBsAg negative, anti-HBc positive, and HBV DNA ‘undetectable’ are eligible. (iv) Participants with HBsAg negative, anti-HBc negative, and anti-HBs positive are eligible. (v) Participants with HBsAg positive or HBV DNA detectable should receive antiviral prophylactic therapy for the duration of anti-cancer therapy, as well as for at least 12 months after the last dose of anti-cancer therapy. Participants should have at least 2 weeks of antiviral prophylaxis before starting study drug. Refer to the protocol for additional management guidelines. (b) Known chronic, active, or uncontrolled hepatitis C, defined as anti-HCV IgM/IgG positive and HCV RNA detectable by polymerase chain reaction. Participants with a history of HCV infection are eligible if they have been treated and cured with an undetectable HCV viral load at least 12 weeks post antiviral treatment of HCV.
- Medical Conditions - Active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
- Medical Conditions - Any known predisposition to bleeding (eg, active peptic ulceration, recent [within 6 months] haemorrhagic stroke, proliferative diabetic retinopathy).
- Medical Conditions - History of non-infectious ILD/pneumonitis that has required oral or intravenous steroids, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening (findings from screening CT/HRCT if available).
- Medical Conditions - Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement or prior pneumonectomy or require supplemental oxygen (including intermittent or discretionary use).
- Medical Conditions - Participants with MDS/AML or with features suggestive of MDS/AML.
- Prior/Concomitant Therapy - Previous treatment with a STEAP2 targeting modality.
- Prior/Concomitant Therapy - Previous treatment with a chemotherapeutic agent or ADC that inhibits TOP1 activity.
- Prior/Concomitant Therapy - Any concomitant medications or herbal supplements known to be strong inhibitors of metabolic enzymes. The required washout period prior to starting study intervention is at least 21 days or 5 half-lives, whichever is longer.
- Prior/Concomitant Therapy - Treatment with any of the following agents and interventions: (a) Any other anti-cancer agents within the following time periods prior to the first dose of study intervention (i) Cytotoxic treatment: 21 days. (ii) Non-cytotoxic drugs: 21 days or 5 half-lives (whichever is longer). (iii) Biological products including immuno-oncology agents: 28 days. (iv) Any investigational agents or study interventions from a previous clinical study: 28 days or 5 half-lives (whichever is longer). (b) Radiotherapy: Participants who have received wide field of radiation (including whole brain radiotherapy) within 28 days prior to the first dose of study intervention or limited field radiotherapy (including stereotactic radiotherapy or gamma-knife) for palliative intent within 14 days prior to the first dose of study intervention. Participants who have not recovered from radiotherapy-related toxicity to Grade 1 or baseline will not be eligible. (c) Major surgery (as defined by the investigator): Within 28 days prior to the first dose of study intervention. (d) Chloroquine/hydroxychloroquine: At least 14 days prior to the first dose of study intervention.
- Prior/Concomitant Therapy - Any concurrent anti-cancer treatment except for GnRH modulators, which should be continued throughout the study (unless bilateral orchiectomy). Participants on a stable bisphosphonate or denosumab regimen are eligible.
- Prior/Concomitant Therapy - Any concomitant medications known to prolong QTc and/or have a known risk for TdP should not be combined with AZD0516. The required washout period prior to starting study intervention is at least 7 days or 5 half-lives, whichever is longer. Exception: Anti-emetics known to prolong QTc interval are permitted; ECGs and electrolytes will be closely monitored.
- Prior/Concomitant Therapy - Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Participants, if enrolled, should not receive live vaccine while receiving study intervention and up to 3 months after the last dose of study intervention. Participants can receive COVID-19 vaccines, at the discretion of the investigator, following a benefit/risk evaluation for the individual participant and in accordance with local rules and regulations and vaccination guidelines. Note: If a COVID-19 vaccine is administered it should be done > 72 hours prior to study intervention initiation or after the completion of the DLT period.
- Prior/Concurrent Clinical Study Experience - 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
- Prior/Concurrent Clinical Study Experience - Known hypersensitivity to AZD0516 or any of the excipients of the product.
- Other Exclusions - Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
- Other Exclusions - 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.
- Other Exclusions - Previous enrolment and treatment in the present study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Yet Recruiting | 15 Jan 2026 | 38 |
 Poland | Not Yet Recruiting | 15 Jan 2026 | 26 |
 Spain | Recruiting | 15 Jan 2026 | 43 |
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 |
|---|---|---|---|---|---|---|
AZD0516 | Test | SOLUTION FOR INJECTION/INFUSION | INTRAVENOUS | — | — | PRD12505265 |
AZD9574 | Test | FILM-COATED TABLET | ORAL | — | — | PRD11235681 |
AZD9574 | Test | FILM-COATED TABLET | ORAL | — | — | PRD11235679 |
AZD9574 | Test | FILM-COATED TABLET | ORAL | — | — | PRD11235680 |
AZD9574 | Test | FILM-COATED TABLET | ORAL | — | — | PRD11235682 |