Metastatic Castration-Resistant Prostate Cancer
Conditions
Keywords
Dose Escalation Study, Metastatic Prostate Cancer, Radiopharmaceutical, Radiotheranostics, Castration-Resistant Prostate Cancer, Radiotherapy, Six Transmembrane Epithelial Antigen of the Prostate 2 (STEAP2), Actinium, Radioconjugate, Radioligand
Brief summary
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
Sponsors
AstraZeneca
Parexel
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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 - 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 |
| 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 |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
| 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 |
| Time to PSA50 response | 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 |
| 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 |
Countries
Australia, South Africa, United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
Outcome results
None listed