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

Official title

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

Overview

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

Interventions

• Drug AZD2287
  Participants will receive AZD2287
• Drug AZD2275
  Participants will receive AZD2275
• Drug AZD2284
  Participants will receive AZD2284

Primary outcome measures

• Number of participants with adverse event (AEs) [Time frame: Part A: Up to Day 28; Part B: Up to 5 years]
• Number of participants with Dose Limiting Toxicities (DLTs) [Time frame: Part B: Up to 84 days of receiving AZD2284]
• Estimates of residence time [Time frame: Part A: Up to 8 days after a dose of AZD2287]
• Absorbed radiation doses for AZD2287 and AZD2284 [Time frame: 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 [Time frame: 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 [Time frame: 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 (12)

• Overall Response Rate (ORR) [Time frame: Up to 12 months after the last dose of AZD2284]
• Proportion of participants with Prostate-Specific Antigen (PSA) 50 [Time frame: Up to 12 months after the last dose of AZD2284]
• Proportion of participants with PSA90 [Time frame: Up to 12 months after the last dose of AZD2284]
• Time to PSA50 response [Time frame: Up to 12 months after the last dose of AZD2284]
• Duration of Response (DoR) [Time frame: Up to 12 months after the last dose of AZD2284]
• Radiographic Progression Free Survival (rPFS) [Time frame: Up to 12 months after the last dose of AZD2284]
• Overall Survival (OS) [Time frame: Part A: Up to Day 28; Part B: Up to 5 years]
• Pharmacokinetic Clearance [Time frame: 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) [Time frame: Part A: Up to Day 28; Part B: Up to 84 days]
• Maximum observed drug concentration (Cmax) [Time frame: Part A: Up to Day 28; Part B: Up to 84 days]
• Half-life (t1/2) [Time frame: 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 [Time frame: Part A: Up to Day 28; Part B: Up to 84 days]

Eligibility criteria

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 -

• Serum/plasma PSA progression
• Soft-tissue progression
• 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:

• At least 1 androgen receptor pathway inhibitor (ARPI)
• A poly (adp-ribose) polymerase (PARP) inhibitor for participants with known BRCA mutation
• 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:

• At least 1 ARPI
• A PARP inhibitor for participants with known BRCA mutation per local practice, unless ineligible per Investigator decision.
• A checkpoint inhibitor for participants with known MSI-H, dMMR, or TMB ≥ 10 mut/Mb.
• 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.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 12 centers

• Research Site — Palo Alto
• Research Site — San Diego
• Research Site — Miami
• Research Site — Tampa
• Research Site — Chicago
• Research Site — Metairie
• Research Site — Boston
• Research Site — Rochester
• … and 4 more centers

South Africa · 3 centers

• Research Site — CapeTown
• Research Site — Durban
• Research Site — Pretoria

Australia · 1 center

• Research Site — East Melbourne

Identifiers

NCT: NCT06879041 · D7580C00001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗