* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
* Histologically confirmed diagnosis of adenocarcinoma of the prostate or neuroendocrine differentiated prostate cancer.
* 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
Exclusion Criteria
* Treatment with any radiopharmaceutical within 6 weeks of the first dose of Investigational Medicinal Product (IMP).
* Radiation therapy (RT) 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
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Design Details
AllocationNon-Randomized
Intervention ModelSequential Assignment
MaskingNone (Open Label)
Number to Enroll95
Arms & Interventions
Arms
Interventions
Type: Experimental
Description: Participants will receive 1 dose of AZD2287. If eligible for treatment, will receive low dose of AZD2284.
Interventions:
AZD2287
AZD2275
AZD2284
Outcome Measures
Primary Outcome Measures
Number of participants with adverse event (AEs)Part A: From Screening (Day -28) to Day 28; Part B: Screening (Day -42 to Day -14) up to 5 years
Number of participants with Dose Limiting Toxicities (DLTs)Part B: Screening (Day -42 to Day -14) up to 2 cycles (84 days) of AZD2284
Estimates of residence timePart A: Up to Day 8 after dosing with AZD2287 on Day 1
Absorbed radiation doses for AZD2287 and AZD2284Part A: Up to Day 8 after dosing with AZD2287 on Day 1; Part B: Up to Day 8 after dosing with AZD2287 on Day -14
Compare organ uptake of AZD2287 with and without pre-dose administration of AZD2275Part A: Up to Day 8 after dosing with AZD2287 on Day 1; Part B: Up to Day 8 after dosing with AZD2287 on Day -14
Tumor uptake of AZD2287 in selected regions of interest on SPECT/CT and/or planar imagesPart A: Up to Day 8 after dosing with AZD2287 on Day 1; Part B: Up to Day 8 after dosing with AZD2287 on Day -14
Secondary Outcome Measures
Overall Response Rate (ORR)Up to 12 months after the last dose of AZD2284
Proportion of participants with Prostate-Specific Antigen (PSA) 50Up to 12 months after the last dose of AZD2284
Proportion of participants with PSA90Up to 12 months after the last dose of AZD2284
Time to maximum PSA % declineUp 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
Pharmacokinetic ClearancePart A: Up to Day 28; Part B: Up to Cycle 2 (each cycle is 42 days)
Area under concentration-curve from time 0 to the last quantifiable concentration (AUClast)Part A: Up to Day 28; Part B: Up to Cycle 2 (each cycle is 42 days)
Maximum observed drug concentration (Cmax)Part A: Up to Day 28; Part B: Up to Cycle 2 (each cycle is 42 days)
Half-life (t1/2)Part A: Up to Day 28; Part B: Up to Cycle 2 (each cycle is 42 days)
Changes in plasma concentrations of AZD2287 and AZD2284 following AZD2275 pre-administration compared to AZD2287 and AZD2284 alonePart A: Up to Day 28; Part B: Up to Cycle 2 (each cycle is 42 days)
Number of participants with positive antidrug antibodies (ADAs)Part A dose exploration: Up to Day 28; Part B: Up to End of Trial (approximately 1 year)