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.

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.

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.