A Modular Phase I/IIa, Open-label, Multi-centre 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

Study Identifier:
D9520C00001
CT.gov Identifier:
NCT07181161
EudraCT Identifier:
2.02452E+11
EU Trial (CTIS) Number:
2024-520026-11-00
Study Contact Information:
(210) 593-5651 or [email protected]
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Study Summary

The main purpose of this study is to assess the safety and tolerability of AZD0516 as monotherapy and/or in combination with other anti-cancer agents for treatment of metastatic prostate cancer.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Prostate
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase I/II
Sex
Male
Age
18 - 130 Years
Study Drug
N/A
Study Status
Indicates the current recruitment status or the expanded access status
Recruiting

Requirements information
Inclusion criteria
  • * Histologically or cytologically confirmed diagnosis of metastatic adenocarcinoma of the prostate. Focal high grade neuroendocrine features are permitted. * Measurable PSA ≥ 1 μg/L (≥ 1 ng/mL). * 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 (ADT) with a gonadotropin releasing hormone (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. * Eastern cooperative oncology group (ECOG) performance status of 0 or 1. * 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). * Provision of baseline archival or newly obtained formalin-fixed paraffin-embedded (FFPE) tumour sample is mandatory. * Documented current evidence of metastatic prostate cancer * Life expectancy of at least 12 weeks in the opinion of the investigator * Documented mCRPC progression at screening as assessed by the investigator with at least one of the following criteria: 1. PSA progression defined by a minimum of 3 rising PSA levels with an interval of ≥ 1 week between each determination. The PSA value at the screening visit should be ≥ 1 μg/L (1 ng/mL). 2. Radiographic disease progression in soft tissue based on response evaluation criteria in solid tumors (RECIST) v1.1 criteria with or without PSA progression as per prostate cancer working group 3 (PCWG3). 3. Radiographic disease progression in bone defined as the appearance of 2 or more new bone lesions on a bone scan as per PCWG3 with or without PSA progression. Main Able to sign informed consent forms (as described in the research protocol), including compliance with the requirements and limitations set forth in the ICF and this protocol.
  • Based on module-specific criteria, it is agreed that sufficient baseline tumor samples (if applicable) shall be provided prior to the commencement of treatment.
  • When signing the ICF, participants must be 18 years of age or older (or the legal Age of informed consent in the jurisdiction where the study is being conducted).
  • A baseline archived tumor sample or a newly acquired FFPE tumor sample must be provided.
  • The diagnosis is metastatic prostate adenocarcinoma confirmed by histology or cytology. Focal high-grade neuroendocrine features are permissible.
  • Within 28 days prior to treatment allocation, subjects must undergo surgical or medical castration to achieve a serum testosterone level ≤50 ng/dL (≤1.75 nmol/L). For subjects who have not previously undergone bilateral orchiectomy and are currently receiving continuous ADT with GnRH modulators, this treatment must begin at least 2 weeks prior to obtaining informed consent and must continue throughout the study period.
  • Measurable PSA ≥ 1 μg/L (≥ 1 ng/mL).
  • The current evidence documented confirms metastatic prostate cancer, with metastatic status defined as the presence of at least one clearly defined metastatic lesion on CT/MRI or bone scan. Subjects with disease extension to local pelvic lymph nodes or localized recurrent disease (e.g., bladder, rectum) are ineligible for the study.
  • The physical condition score of the Eastern Oncology Collaborative Group is 0 or 1.
  • Researchers believe the subjects' life expectancy is at least 12 weeks.
  • Within 21 days prior to the first dose of the planned study intervention, organ and bone marrow function were in good condition (without receiving blood transfusions or growth factor support therapy), as per the study protocol.
  • Subjects must have already received standard treatment but have experienced disease progression, be refractory to standard treatment, or be intolerant to standard treatment. Standard treatment must be consistent with local clinical practice for their disease stage, or the investigator must believe that, based on the effects and/or tolerability of previous treatments, the clinical trial is the best option for the subject's next treatment step. Subjects with contraindications to standard treatment may also be considered, provided they have documentation indicating they are aware of all treatment options.
  • For subjects born male, including all Gender identities: (a) Contraception used by the subject or their partner should comply with local regulations regarding contraception for subjects in clinical studies. (b) For male subjects who are sexually active with a female partner of childbearing potential (including a pregnant partner), male condoms (with spermicide, if available) must be used for contraception during the study and for an appropriate period after the last dose of the study intervention. (i) Investigators should advise subjects on sperm preservation prior to administration of AZD0516. (ii) It is strongly recommended that female partners of male subjects also use highly effective contraceptive methods during this period, as described below: Highly effective contraceptive methods include: complete abstinence is an acceptable method, but it must be part of the subject's daily routine (defined as avoiding heterosexual intercourse throughout the entire risk period associated with the study intervention) (regular abstinence [e.g., calendar method, ovulation method, sympathobasal body method, post-ovulation method], statements that abstinence during exposure to the study intervention drug and withdrawal are unacceptable contraceptive methods), partner vasectomy, ependymide, bilateral tubal obstruction, intrauterine device/ levonorgestrel intrauterine system, Depo-Provera injection, oral contraceptives, and Evra Patch, Xulane, or Muyo.
  • Subjects are not allowed to donate sperm during the study period and for an appropriate period after the last dose of the study intervention.
Exclusion criteria
  • 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. * History of leptomeningeal carcinomatosis. * Unresolved toxicities of Grade ≥ 2 (National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) from prior therapy (excluding vitiligo, alopecia, and endocrine disorders that are controlled with replacement hormone therapy). * Uncontrolled intercurrent illness within the last 12 months. * Cardiovascular disorder (History of arrhythmia, uncontrolled hypertension, symptomatic hypotension, history of brain perfusion problems, symptomatic heart failure, prior or current cardiomyopathy, severe valvular heart disease) * History of malignancy * History of non-infectious interstitial lung disease (ILD)/pneumonitis * Active infection exclusions, including tuberculosis and infections with Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or Human Immunodeficiency Virus (HIV). * Any known predisposition to bleeding * Clinically severe pulmonary compromise * Participants with Myelodysplastic syndrome (MDS)/Acute Myeloid Leukemia (AML) or with features suggestive of MDS/AML. * Previous treatment with a STEAP2 targeting modality, chemotherapeutic agent that inhibits topoisomerase activity or metabolic enzymes. Cancer-related spinal cord compression or brain metastases are not considered for enrollment unless the patient has been asymptomatic, treated, and stable for at least 4 weeks prior to study enrollment, and does not require continuous corticosteroid therapy at >10 mg prednisone/day or an equivalent dose. If any subject is identified as having a high risk of spinal cord compression based on imaging at screening, appropriate treatment for the bone lesion should be administered prior to study enrollment. Confirmation of the absence of brain metastases via scan is not required.
  • There is a history of leptomeningeal carcinoma.
  • Subjects with ≥ Grade 2 toxicity that has not been relieved by prior treatment (NCI CTCAE v5.0) (excluding vitiligo, alopecia, and endocrine disorders controllable by alternative hormone therapy). Subjects with chemotherapy-induced Grade 2 neuropathy may be eligible for inclusion based on the investigator's judgment and after consultation with the AstraZeneca study physician.
  • Having uncontrolled comorbidities within the past 12 months, including but not limited to uncontrolled diabetes, substance abuse, severe chronic gastrointestinal disorders associated with diarrhea, or mental illness/social conditions that limit compliance with study requirements, significantly increases the risk of adverse events (AEs) or affects the participant's ability to provide written informed consent.
  • Cardiovascular disease is defined as: (a) a history of: symptomatic or treatment-required arrhythmias (e.g., multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia) (NCI CTCAE v5.0 grade 3); symptomatic or uncontrolled atrial fibrillation despite treatment; or asymptomatic persistent ventricular tachycardia. Note: Serum electrolyte abnormalities (e.g., sodium, potassium, calcium, magnesium) that may increase the risk of arrhythmic events should be corrected before starting the study intervention. (b) Uncontrolled hypertension as determined by the investigator. Hypertensive subjects may be eligible, but BP must be adequately controlled at baseline. Subjects may be re-screened for BP requirements. (c) Symptomatic hypotension detected at screening. (d) Acute coronary syndrome/acute myocardial infarction, unstable angina, percutaneous coronary intervention, or coronary artery bypass grafting within the past 6 months. (e) History of cerebral perfusion problems (e.g., carotid artery stenosis) or stroke or transient ischemic attack within the 6 months prior to screening. (f) Presentation of symptomatic heart failure (defined as New York Heart Association functional class ≥2). (g) History of or current cardiomyopathy. (h) Severe valvular heart disease. (i) Mean resting QTcF >470 ms obtained from three ECG examinations (recorded and averaged over 5 minutes). (j) Any factors that increase the risk of QTc interval prolongation or arrhythmic events, such as heart failure, congenital long QT syndrome, a family history of long QT syndrome, or unexplained sudden death of a first-degree relative before age 40.
  • A history of malignancy is not required, except in the following cases: (a) malignant tumors that have undergone radical treatment, have no known active disease for at least 2 years prior to the first administration of the study intervention, and have a low potential risk of recurrence; (b) well-treated non-melanoma skin cancer or malignant freckle-like nevus with no evidence of disease; (c) well-treated carcinoma in situ with no evidence of disease; and (d) locally non-invasive primary disease under surveillance.
  • Exclude active infections, including tuberculosis and HBV infection (verified by a known positive HBsAg result), HCV, or HIV (verified by a positive HIV 1 or HIV 2 antibody). (a) For subjects with known uncontrolled hepatitis B and/or chronic or active hepatitis B (HBV DNA ≥ 100 IU/mL), please refer to the study protocol for screening procedures and eligibility criteria. (i) For HBsAg-positive subjects, if their HBV DNA < 100 IU/mL and they agree to start or maintain antiviral therapy, they are eligible to participate in the study. (ii) For HBsAg-negative subjects with a “detectable” HBV viral load, if their HBV DNA < 100 IU/mL and they agree to start or maintain antiviral therapy, they are eligible to participate in the study. (iii) Subjects who are HBsAg-negative, anti-HBc-positive, and have “undetectable” HBV DNA are eligible to participate in the study. (iv) Subjects who are HBsAg-negative, anti-HBc-negative, and anti-HBs-positive are eligible to participate in the study. (v) For subjects who are HBsAg positive or have detectable HBV DNA, antiviral prophylaxis should be continued during anticancer therapy and for at least 12 months after the last dose of anticancer therapy. Subjects should receive antiviral prophylaxis for at least 2 weeks before starting study drug therapy. See the study protocol for other management guidelines. (b) Known chronic, active, or uncontrolled hepatitis C, defined as positive anti-HCV IgM/IgG and detectable HCV RNA by polymerase chain reaction. Subjects with a history of HCV infection who have been treated and cured but whose HCV viral load is undetectable for at least 12 weeks after starting HCV antiviral therapy are eligible to participate in the study.
  • Active tuberculosis infection (clinical evaluation may include clinical history, physical examination and radiological results, or tuberculosis testing according to local treatment guidelines)
  • Known bleeding tendency (e.g., active peptic ulcer, recent [within 6 months] hemorrhagic stroke, proliferative diabetic retinopathy).
  • Patients with a history of non-infectious ILD/non-infectious pneumonia requiring oral or intravenous steroid treatment, or whose screening imaging findings (such as CT/HRCT results at the time of screening) cannot rule out suspected ILD/non-infectious pneumonia.
  • Clinically severe lung damage caused by concurrent lung disease, including but not limited to any underlying lung disease or any autoimmune, connective tissue or inflammatory disease with lung involvement or previous pneumonectomy or supplemental oxygen (including intermittent use or as appropriate).
  • Subjects with MDS/AML or with MDS/AML characteristics.
  • Previously received STEAP2 targeted therapy.
  • Previously received chemotherapy drugs or ADC treatment that inhibit TOP1 activity.
  • Concomitant use of any potent inhibitors of metabolic enzymes or herbal supplements. A washout period of at least 21 days or 5 half-lives (whichever is longer) is required before initiating the study intervention.
  • Subjects who have received any of the following medications and interventions: (a) Any other anticancer medication received within the following timeframes prior to the first dose of the study intervention: (i) Cytotoxic therapy: 21 days. (ii) Non-cytotoxic drugs: 21 days or 5 half-lives (whichever is longer). (iii) Biologics (including immuno-oncology drugs): 28 days. (iv) Use of any investigational drug or study intervention previously studied in a clinical trial: 28 days or 5 half-lives (whichever is longer). (b) Radiation therapy: Subjects who received wide-field radiation therapy (including whole-brain radiation therapy) within 28 days prior to the first dose of the study intervention or narrow-field radiation therapy (including stereotactic radiotherapy or Gamma Knife) as palliative care within 14 days prior to the first dose of the study intervention. Subjects who have not recovered from radiation-related toxicities to Grade 1 or baseline are ineligible for inclusion. (c) Major surgery (as defined by the investigator): within 28 days prior to the first dose of the study intervention. (d) Chloroquine/hydroxychloroquine: at least 14 days prior to the first dose of the study intervention.
  • In addition to GnRH modulators, other anticancer therapies are prohibited from being administered concurrently. GnRH modulators should be continued throughout the study period (unless bilateral orchiectomy is performed). Subjects receiving stable bisphosphonates or denosumab regimens are eligible to participate in the study.
  • Any concomitant medications known to prolong the QTc interval and/or pose a risk of TdP must not be used in combination with AZD0516. A washout period of at least 7 days or 5 half-lives (whichever is longer) is required before initiating the study intervention. Exceptions: Antiemetics known to prolong the QTc interval are permitted; ECG and electrolytes should be closely monitored.
  • Participants must have received a live attenuated vaccine within 30 days prior to the first dose of the study intervention. Note: After enrollment, participants must not receive a live vaccine during treatment with the study intervention or within 3 months of the last dose. After a benefit/risk assessment of individual participants, the investigator will determine at their discretion, in accordance with local regulations and vaccination guidelines, whether a participant is eligible for COVID-19 vaccination. Note: If COVID-19 vaccination is chosen, it should be administered >72 hours before the start of treatment with the study intervention or after the end of the DLT period.
  • Enrollment in another clinical study is permitted, unless that study is an observational (non-interventional) clinical study or is in the follow-up phase of an interventional study.
  • 20
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  • twenty one Known allergy to AZD0516 or any of the excipients in this product.
  • 21
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  • twenty two Personnel involved in the design and/or implementation of this study (applicable to AstraZeneca staff and/or research center staff).
  • 22
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  • twenty three Subjects deemed unlikely to comply with research procedures, limitations, and requirements by the researchers are not eligible to participate in this study.
  • 23
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  • twenty four Students who had previously been enrolled in this study and received treatment.

Clinical Study Information for Healthcare Providers

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Study Locations

Location
Investigator
Status
Condition(s) Treated at Site
Location
START Carolinas
Myrtle Beach, SC, United States, 29572
Investigator
Neal Shore
Status
Recruiting
Condition(s) Treated at Site
Prostate