A Phase I Study of [225Ac]-AZD2284 in Patients With Metastatic Castration-Resistant Prostate Cancer

A Phase I, First-in-human, Dose Escalation Study Of [225Ac]-AZD2284 in Patients With Metastatic Castration-Resistant Prostate Cancer

The main purpose of the study is to assess the safety and tolerability of AZD2284, AZD2287, and AZD2275.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Castration-Resistant Prostate Cancer
• Intervention / Treatment: Drug: AZD2287; Drug: AZD2284; Drug: AZD2275

Detailed Description

This is a first-in-human, Phase I, non-randomized, open-label clinical trial designed to evaluate AZD2284, AZD2287, and AZD2275.

This trial will consist of 2 Parts:

Part A (Imaging):

- Part A (Cold Antibody Exploration): aims to determine the optimal dosing regimen, with or without unconjugated antibody (AZD2275) pre-administration to improve the biodistribution of AZD2287.

Part B (Therapeutic):

• Part B (Actinium-225 Dose Escalation): aims to assess the safety, tolerability, and efficacy of escalating doses of AZD2284 informed by the optimal dosing regimen identified in Part A.
• Part B Expansion Cohorts 1 and 2: aims to explore efficacy of AZD2284.

• Study Type: Interventional
• Enrollment (Estimated): 136
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• Australia
  • East Melbourne, Australia, 3002
    • Recruiting
    • Research Site
• South Africa
  • CapeTown, South Africa, 7925
    • Not yet recruiting
    • Research Site
  • Durban, South Africa, 4013
    • Withdrawn
    • Research Site
  • Pretoria, South Africa, 181
    • Not yet recruiting
    • Research Site
• United States
  • California
    • Palo Alto, California, United States, 94304
      • Not yet recruiting
      • Research Site
    • San Diego, California, United States, 92103
      • Not yet recruiting
      • Research Site
  • Florida
    • Miami, Florida, United States, 33165
      • Recruiting
      • Research Site
    • Tampa, Florida, United States, 33612
      • Recruiting
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Recruiting
      • Research Site
  • Louisiana
    • Metairie, Louisiana, United States, 70006
      • Not yet recruiting
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Research Site
  • Minnesota
    • Rochester, Minnesota, United States, 55902
      • Not yet recruiting
      • Research Site
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Recruiting
      • Research Site
  • New York
    • New York, New York, United States, 10032
      • Not yet recruiting
      • Research Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Not yet recruiting
      • Research Site
  • Oregon
    • Portland, Oregon, United States, 97239
      • Not yet recruiting
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Main Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Histologically confirmed diagnosis of adenocarcinoma of the prostate without strong clinical suspicion of majority neuroendocrine differentiation.
• Must have had prior bilateral orchiectomy and/or ongoing androgen-deprivation therapy and a castrate level of serum/plasma testosterone (< 50 ng/dL or < 1.7 nmol/L).
• At least one metastatic lesion present on baseline Computed Tomography (CT), Magnetic Resonance Imaging (MRI), or bone scan obtained ≤ 28 days prior to the first dose of Investigational Medicinal Product (IMP). Participants may have non-measurable lesions including bone only metastases.
• Adequate organ function
• Part A only: Metastatic prostate cancer considered to be stable or progressing metastatic castration resistant prostate cancer (mCRPC).

• Part B only: Progressing mCRPC defined as meeting at least one of following documented criteria -

  1. Serum/plasma PSA progression
  2. Soft-tissue progression
  3. Progression of bone disease

• Part B Dose Escalation: Previously treated with at least 2 prior lines of systemic anti-cancer therapy for mCRPC. Prior lines must include:

  1. At least 1 androgen receptor pathway inhibitor (ARPI)
  2. A poly (adp-ribose) polymerase (PARP) inhibitor for participants with known BRCA mutation
  3. A checkpoint inhibitor for participants with known microsatellite instability-high (MSI-H), deficient mismatch pair (dMMR), or tumor mutational burden (TMB) ≥ 10 mut/Mb

• Part B Dose Expansion: Previously treated with at least 1 prior line of systemic anti-cancer therapy for mCRPC. Prior lines must include:

  1. At least 1 ARPI
  2. A PARP inhibitor for participants with known BRCA mutation per local practice, unless ineligible per Investigator decision.
  3. A checkpoint inhibitor for participants with known MSI-H, dMMR, or TMB ≥ 10 mut/Mb.
  4. No previous cytotoxic chemotherapy for CRPC. Taxanes for metastatic hormone sensitive prostate cancer (mHSPC) is acceptable if the last cycle Day 1 was > 12 months before first study treatment.
  5. Previous treatment with prostate specific membrane antigen radioligand therapy (PSMA-RLT) or Radium-223 is allowed but not required. Participants who have had prior radiation therapy, including therapeutic radiopharmaceuticals, external bean radiation therapy (EBRT), and/or brachytherapy are eligible, subject to satisfying all other inclusion/exclusion criteria. Therapeutic radiopharmaceuticals will be considered a prior line of systemic therapy.

Main Exclusion Criteria:

• Treatment with any radiopharmaceutical within 6 weeks of the first dose of Investigational Medicinal Product (IMP).
• Radiation therapy (RT) or external beam radiation therapy (EBRT) within 28 days prior to the first dose and all RT-related events have not recovered to Grade ≤ 1.
• Administration of any systemic cytotoxic or investigational therapy ≤ 28 days of the first dose of IMP or 5 half-lives, whichever is shorter.
• All prior treatment-related adverse events must have resolved to Grade ≤ 1.
• Concurrent severe and/or uncontrolled illness not related to cancer and/or social situation that would limit compliance with study requirements.
• Known or suspected allergies or contraindications to any of the investigational drugs or any component of the investigational drug formulation.
• Clinically relevant proteinuria
• Diffuse and intense osseous radiotracer uptake on bone scintigraphy or PSMA imaging characteristic of a superscan.
• Chronic corticosteroid use greater than 10 mg prednisone equivalent daily.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part B: Cohort E1; Participants will receive dose of AZD2284 determined by the earlier results. Expansion cohort may be opened to further characterize the safety and efficacy of the dose level.	Drug: AZD2287; Participants will receive AZD2287; Drug: AZD2284; Participants will receive AZD2284; Drug: AZD2275; Participants will receive AZD2275
Experimental: Part B: Cohort E2; Participants will receive dose of AZD2284 determined by the earlier results. Expansion cohort may be opened to further characterize the safety and efficacy of the dose level.	Drug: AZD2287; Participants will receive AZD2287; Drug: AZD2284; Participants will receive AZD2284; Drug: AZD2275; Participants will receive AZD2275
Experimental: Part A: Cohort A1: AZD2287 (Hot only); Participants will receive AZD2287. If eligible for treatment, will receive dose level (DL)1 of AZD2284.	Drug: AZD2287; Participants will receive AZD2287; Drug: AZD2284; Participants will receive AZD2284
Experimental: Part A: Cohort A2: AZD2275 + AZD2287 (Cold +Hot); Participants will receive DL1 of AZD2275 followed by AZD2287. If eligible for treatment, will receive DL1 of AZD2284.	Drug: AZD2287; Participants will receive AZD2287; Drug: AZD2284; Participants will receive AZD2284; Drug: AZD2275; Participants will receive AZD2275
Experimental: Part A: Cohort A3: AZD2275 + AZD2287 (Cold +Hot); Participants will receive DL2 of AZD2275 followed by AZD2287. If eligible for treatment, will receive DL1 of AZD2284.	Drug: AZD2287; Participants will receive AZD2287; Drug: AZD2284; Participants will receive AZD2284; Drug: AZD2275; Participants will receive AZD2275
Experimental: Part B (Actinium-225 Dose Escalation): DL1: AZD2284; Participants will receive AZD2287 (± AZD2275 as determined in Part A). If eligible for treatment, will receive DL1 of AZD2284.	Drug: AZD2287; Participants will receive AZD2287; Drug: AZD2284; Participants will receive AZD2284; Drug: AZD2275; Participants will receive AZD2275
Experimental: Part B (Actinium-225 Dose Escalation): DL2: AZD2284; Participants will receive AZD2287 (± AZD2275 as determined in Part A). If eligible for treatment, will receive DL2 of AZD2284.	Drug: AZD2287; Participants will receive AZD2287; Drug: AZD2284; Participants will receive AZD2284; Drug: AZD2275; Participants will receive AZD2275
Experimental: Part B (Actinium-225 Dose Escalation): DL3: AZD2284; Participants will receive AZD2287 (± AZD2275 as determined in Part A). If eligible for treatment, will receive DL3 of AZD2284.	Drug: AZD2287; Participants will receive AZD2287; Drug: AZD2284; Participants will receive AZD2284; Drug: AZD2275; Participants will receive AZD2275
Experimental: Part B (Actinium-225 Dose Escalation): DL4: AZD2284; Participants will receive AZD2287 (± AZD2275 as determined in Part A). If eligible for treatment, will receive DL4 of AZD2284.	Drug: AZD2287; Participants will receive AZD2287; Drug: AZD2284; Participants will receive AZD2284; Drug: AZD2275; Participants will receive AZD2275

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of participants with adverse event (AEs)	Part A: Up to Day 28; Part B: Up to 5 years
Number of participants with Dose Limiting Toxicities (DLTs)	Part B: Up to 84 days of receiving AZD2284
Estimates of residence time	Part A: Up to 8 days after a dose of AZD2287
Absorbed radiation doses for AZD2287 and AZD2284	Part A: Up to 8 days after a dose of AZD2287; Part B: Up to 7 days after a dose of AZD2287
Compare organ uptake of AZD2287 with and without pre-dose administration of AZD2275	Part A: Up to 8 days after a dose of AZD2287; Part B: Up to 7 days after a dose of AZD2287
Tumor uptake of AZD2287 in selected regions of interest on SPECT/CT and/or planar images	Part A: Up to 8 days after a dose of AZD2287; Part B: Up to 7 days after a dose of AZD2287

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall Response Rate (ORR)	Up to 12 months after the last dose of AZD2284
Proportion of participants with Prostate-Specific Antigen (PSA) 50	Up to 12 months after the last dose of AZD2284
Proportion of participants with PSA90	Up to 12 months after the last dose of AZD2284
Duration of Response (DoR)	Up to 12 months after the last dose of AZD2284
Radiographic Progression Free Survival (rPFS)	Up to 12 months after the last dose of AZD2284
Overall Survival (OS)	Part A: Up to Day 28; Part B: Up to 5 years
Time to PSA50 response	Up to 12 months after the last dose of AZD2284
Pharmacokinetic Clearance	Part A: Up to Day 28; Part B: Up to 84 days
Area under concentration-curve from time 0 to the last quantifiable concentration (AUClast)	Part A: Up to Day 28; Part B: Up to 84 days
Maximum observed drug concentration (Cmax)	Part A: Up to Day 28; Part B: Up to 84 days
Half-life (t1/2)	Part A: Up to Day 28; Part B: Up to 84 days
Changes in plasma concentrations of AZD2287 and AZD2284 following AZD2275 pre-administration compared to AZD2287 and AZD2284 alone	Part A: Up to Day 28; Part B: Up to 84 days
Number of participants with positive antidrug antibodies (ADAs)	Part A: Up to Day 28; Part B: Approximately 28 days after End of Treatment (EOT) visit

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2025
• Primary Completion (Estimated): April 16, 2029
• Study Completion (Estimated): April 16, 2029

Study Registration Dates

• First Submitted: March 11, 2025
• First Submitted That Met QC Criteria: March 11, 2025
• First Posted (Actual): March 17, 2025

Study Record Updates

• Last Update Posted (Actual): May 12, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Radiotherapy; Metastatic Prostate Cancer; Radioligand; Castration-Resistant Prostate Cancer; Radiopharmaceutical; Dose Escalation Study; Actinium; Radiotheranostics; Radioconjugate; Six Transmembrane Epithelial Antigen of the Prostate 2 (STEAP2)
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms
• Other Study ID Numbers: D7580C00001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure."Yes",indicatesthat AZ are accepting requests for IPD, but this does not mean all requests will be approved.
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA/PhRMA Data-Sharing Principles. For details of our timelines, please refer to our disclosure commitment athttps://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No