Phase Ib/II Study of AMO959 with Lutetium (177Lu) Vipivotide Tetraxetan and Combination Therapy in Patients with PSMA-Positive Metastatic Castration-Resistant Prostate Cancer

The primary objectives of this study are to characterize the safety and tolerability of AMO959 in combination with lutetium (177Lu) vipivotide tetraxetan and an androgen receptor pathway inhibitor (ARPI) to determine the recommended dose for expansion (RDE) during Phase Ib, and to evaluate the preliminary efficacy of this combination in Phase II for patients with metastatic castration-resistant prostate cancer. Secondary objectives include:

• Evaluation of antitumor activity and preliminary efficacy of the combination therapies.
• Assessment of pharmacokinetics for AMO959 and AAA617.
• Measurement of radiation dosimetry in tumors and organs during Phase Ib.
• Evaluation of radiographic progression-free survival via PSMA PET/CT imaging in Phase II.
• Assessment of health-related quality of life (HRQoL) and other patient-reported outcomes.
• Evaluation of the time to first symptomatic skeletal event (TTSSE).

This study involves 50 male participants diagnosed with metastatic castration-resistant prostate cancer (mCRPC). The study population consists of adults who exhibit PSMA-positive disease confirmed via PSMA-PET imaging. Eligible participants must have histologically confirmed adenocarcinoma of the prostate and demonstrate castration-level testosterone levels or be receiving androgen deprivation therapy (ADT). Selection requires documented disease progression while on an androgen receptor pathway inhibitor (ARPI). In the escalation phase, up to one line of taxane-based chemotherapy is permitted, whereas the expansion phase excludes those previously treated with such agents in the mCRPC setting. Participants must maintain an ECOG performance status of 0 to 2.

This phase Ib/II, open-label, multi-center study evaluates the safety and efficacy of the DNA protein kinase inhibitor AMO959 in combination with lutetium (177Lu) vipivotide tetraxetan and an androgen receptor pathway inhibitor. The research is conducted in adults with PSMA-positive metastatic castration-resistant prostate cancer. The phase Ib component focuses on dose escalation to characterize safety, tolerability, and to determine the recommended dose for expansion. The phase II component aims to assess preliminary efficacy. Primary endpoints include the incidence of dose-limiting toxicities and biochemical response, specifically a 50% decrease in prostate-specific antigen. Secondary endpoints include radiographic progression-free survival and overall survival. The study involves a screening process to confirm histological diagnosis and PSMA-PET positivity. Participation continues through treatment cycles and follow-up assessments until the end-of-study visit or until early termination occurs due to disease progression or clinical necessity.

The experimental treatment includes AMO959, administered in capsule form via an unspecified route. This DNA protein kinase inhibitor is evaluated in combination with lutetium (177Lu) vipivotide tetraxetan, provided as a solution for injection/infusion for intravenous administration. Additionally, an androgen receptor pathway inhibitor is utilized, which may consist of enzalutamide, administered as a soft capsule or oral medication, or abiraterone, administered as an oral tablet.

Background therapies and auxiliary substances used in the study include prednisone, administered as an oral tablet. Other auxiliary agents include degarelix, relugolix, gozetotide, and piflufolastat (18F). Certain treatments may involve gonadotropin releasing hormone analogues.

The assessment of efficacy in this study of metastatic castration-resistant prostate cancer involves several clinical and biochemical parameters. The primary efficacy endpoint is the biochemical response, specifically PSA50, which is defined as the proportion of participants achieving a prostate-specific antigen decrease of 50% or more from baseline at any time during the treatment period before starting new anti-cancer therapy, confirmed by a second measurement at least 4 weeks later.

Secondary efficacy assessments include:

• PSA90, representing the proportion of participants achieving a 90% or greater decrease from baseline, confirmed by a second measurement at least 4 weeks later.
• Radiographic progression-free survival, measured from the start of study treatment to radiographic progressive disease or death.
• Objective response rate, characterized by the proportion of participants achieving complete response or partial response.
• Disease control rate, which includes participants achieving complete response, partial response, or stable disease.
• Duration of response, measured from the time of complete response or partial response to progressive disease or death.
• Time to soft tissue progression, measured from randomization to soft tissue progressive disease.
• Overall survival, defined as the time from the start of study treatment to death.
• rPFS-PET, determined by PSMA PET/CT imaging as the time from randomization to the first documented increase in PSMA-positive tumor volume of 20% or more from baseline, or death.
• FACT-P Prostate Cancer Subscale, evaluating the change from baseline in this specific scale.
• Time to worsening on the Worst Pain, measured using the Brief Pain Inventory – Short Form as the time to a 30% increase from baseline, a minimum 2-point increase, or death.
• Time to symptomatic skeletal event, defined as the time from randomization to the first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, or requirement for radiation therapy for bone pain.
• Pharmacokinetic parameters, including plasma concentrations of AMO959 and blood concentrations of lutetium (177Lu) vipivotide tetraxetan.
• Time activity curves and absorbed radiation doses in selected organs and tumor lesions.