The purpose of this phase Ib/II study is to (a) in Phase Ib evaluate the safety, tolerability, and pharmacokinetics (PK) of AMO959 when given in combination with lutetium (177Lu) vipivotide tetraxetan (also known as \[177Lu\]Lu-PSMA-617 or 177Lu-PSMA-617 and hereafter referred to as AAA617) with an androgen receptor pathway inhibitor (ARPI) in participants with metastatic castration resistant prostate cancer (mCRPC) who have failed one prior ARPI and with or without prior taxane exposure, and (b) in Phase II evaluate the preliminary efficacy of AMO959 in combination with AAA617 and ARPI in participants with mCRPC who have failed one prior ARPI, but who have not yet been exposed to taxane treatment.
This study will consist of two phases: 1. The escalation phase (Ib) will consist of provisionally three dose level cohorts of 3-6 participants investigating the safety, tolerability, and to determine the recommended dose for expansion (RDE) of AMO959 with standard dose of AAA617 +/- ARPI (abiraterone or enzalutamide). Initially AMO959 monotherapy will be administered, and then AMO959 will be given along with AAA617 in the same participants. Dose escalation meetings (DEMs) will occur when all participants in a dose level cohort have completed the DLT evaluation period or have experienced a DLT prior to the end of the evaluation period. 2. The Phase II will follow with 25 participants per arm randomized in a 1:1:1 ratio treated at the RDE(s) of AMO959 along with AAA617 and ARPI (abiraterone or enzalutamide) and AAA617 and ARPI (abiraterone or enzalutamide).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
123
DNA Damage Response inhibitor
PSMA-targeted radiopharmaceutical
Androgen receptor pathway inhibitor
Androgen receptor pathway inhibitor
Novartis Investigative Site
Murdoch, Western Australia, Australia
RECRUITINGPhase Ib: Incidence rate of Dose-limiting toxicities (DLTs)
Incidence of dose limiting toxicities (DLTs) with AMO959 in combination with AAA617 +/- ARPI A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness/injury, or concomitant medications that occurs within the evaluation period and meets any of the criteria specified in the protocol. The National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 5.0 will be used for all grading.
Time frame: Up to 42 days after the first AAA617 dose administration
Phase Ib: Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Incidence of adverse events by type, frequency, and severity, as graded by the NCI CTCAE version 5.0.
Time frame: From date of start of study treatment, assessed up to approximately 45 months
Phase Ib: Number of Participants with dose adjustments
The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation).
Time frame: From date of start of study treatment, assessed up to approximately 24 months
Phase Ib: Dose Intensity
Dose intensity (computed as the ratio of actual cumulative dose received and actual duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity).
Time frame: From date of start of study treatment, assessed up to approximately 24 months
Phase Ib: Duration of exposure to each study drug
Duration of exposure (in months) to each study drug.
Time frame: From date of start of study treatment, assessed up to approximately 24 months
Phase II: Biochemical Response (PSA50)
Biochemical response (PSA50), defined as the proportion of participants who achieved a ≥ 50% decrease in PSA from baseline at any time during the treatment period prior to start of new anti-cancer therapy that is confirmed by a second PSA measurement ≥ 4 weeks later.
Time frame: From date of start of study treatment, assessed up to approximately 24 months
Prostate Specific Antigen 90 (PSA90) response
PSA90 response is defined as the proportion of participants who have achieved a ≥ 90% decrease in PSA from baseline at any time during the treatment period prior to start of new anti-cancer therapy that is confirmed by a second PSA measurement ≥4 weeks later.
Time frame: From date of start of study treatment, assessed up to approximately 24 months
Phase Ib: Prostate Specific Antigen 50 (PSA50) response
PSA50 response is defined as the proportion of participants who have achieved a ≥ 50% decrease in PSA from baseline at any time during the treatment period prior to the start of new anti-cancer therapy, confirmed by a second PSA measurement ≥4 weeks later.
Time frame: From date of start of study treatment, assessed up to approximately 24 months
Phase Ib and Phase II: Radiographic progression-free survival (rPFS)
Radiographic progression- free survival (rPFS) is defined as the time from the date of start of study treatment (Phase Ib) / randomization (Phase II) to the date of first documented radiographic disease progression using conventional imaging and Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 criteria (Scher et al 2016) or death due to any cause, whichever occurs first.
Time frame: From date of start of study treatment (Phase Ib) / randomization (Phase II), assessed up to approximately 24 months
Phase Ib and Phase II: Overall Response Rate (ORR)
Overall Response Rate (ORR) is defined as the proportion of participants with best overall response (BOR) of confirmed complete response (CR) or partial response (PR) in soft tissue based on tumor response data and according to PCWG3-modified RECIST v1.1, in the absence of bone progression as per PCWG3.
Time frame: From date of start of study treatment (Phase Ib) / randomization (Phase II), assessed up to approximately 24 months
Phase Ib and Phase II: Disease control rate (DCR)
Disease control rate (DCR) is defined as the proportion of participants with a BOR of confirmed CR or PR, stable disease (SD) or Non-CR/Non- progressive disease (PD) in soft tissue based on tumor response data and according to PCWG3-modified RECIST v1.1, in the absence of bone progression as per PCWG3.
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Time frame: From date of start of study treatment (Phase Ib) / randomization (Phase II), assessed up to approximately 24 months
Phase Ib and Phase II: Duration of Response (DoR)
Duration of Response (DoR) is defined as the duration of time between the date of first documented response (CR or PR) according to PCWG3- modified RECIST v1.1, in the absence of bone progression as per PCWG3, based on tumor response data and the date of first documented radiographic progression in soft tissue or death due to any cause, whichever occurs first.
Time frame: From date of start of study treatment (Phase Ib) / randomization (Phase II), assessed up to approximately 24 months
Overall Survival (OS)
Overall Survival (OS) is defined as the time from the date of start of study treatment (Phase Ib) / randomization (Phase II) to the date of death due to any cause.
Time frame: From date of start of study, assessed up to approximately 45 months
Phase II: Time to soft tissue progression (TTSTP)
Time to soft tissue progression (TTSTP) is defined as time from randomization to the date of first documented radiographic soft tissue progression per PCWG3-modified RECIST v1.1.
Time frame: From date of start of study randomization, assessed up to approximately 24 months
Phase Ib: Plasma concentrations of AMO959
AMO959 pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms
Time frame: Throughout run-in periods and first cycle with AAA617, assessed up to 6 months
Phase Ib: Plasma concentrations of AAA617
AAA617 pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms
Time frame: Throughout treatment periods with AAA617, assessed up to 6 months
Phase Ib: Time activity curves (TACs) for AAA617
Time Activity Curves (TAC) will be generated by plotting concentrations against time.
Time frame: Throughout treatment periods with AAA617, assessed up to 6 months
Phase Ib: Absorbed radiation doses in selected organs and tumor lesions for AAA617
The organ absorbed radiation dose and effective radiation dose will be evaluated.
Time frame: Throughout treatment periods with AAA617, assessed up to 6 months
Phase II: Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Incidence of adverse events by type, frequency, and severity, as graded by the NCI CTCAE version 5.0.
Time frame: From date of start of study treatment, assessed up to approximately 45 months
Phase II: Number of Participants with dose adjustments
The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation).
Time frame: From date of start of study treatment, assessed up to approximately 24 months
Phase II: Dose Intensity
Dose intensity (computed as the ratio of actual cumulative dose received and actual duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity).
Time frame: From date of start of study treatment, assessed up to approximately 24 months
Phase II: Duration of exposure to each study drug
Duration of exposure (in months) to each study drug.
Time frame: From date of start of study treatment, assessed up to approximately 24 months
Phase II: Radiographic Progression Free Survival (rPFS) by Positron Emission Tomography (PET) (rPFS-PET)
Radiographic Progression Free Survival (rPFS) by Positron Emission Tomography (PET) (rPFS- PET) is defined as the time from the date of randomization to first documented radiographic disease progression (an increase in PSMA-positive tumor volume ≥ 20% from baseline and new PSMA-positive malignant lesions) using PSMA PET/CT imaging (Seifert et al 2023, Gafita et al 2023) or death due to any cause, whichever occurs first.
Time frame: From date of start of study randomization, assessed up to approximately 24 months
Phase II: Change from baseline in FACT-P Prostate Cancer Subscale (PCS)
Change from baseline in FACT-P PCS refers to the difference in a patient's score on the Prostate Cancer Subscale (PCS) of the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire between the start of a study (baseline) and subsequent time points.
Time frame: From date of start of study, assessed up to approximately 45 months.
Phase II: Time to worsening on the Brief Pain Inventory - Short Form (BPI-SF)
Time to worsening on the Worst Pain defined as the time from the date of randomization to the first occurrence of worsening on the Brief Pain Inventory - Short Form (BPI-SF) Worst Pain item of at least 30% increase from baseline or a minimum of 2 points increase from baseline or death due to any cause, whichever occurs first.
Time frame: From date of start of study, assessed up to approximately 45 months.
Phase II: Time to first symptomatic skeletal event (TTSSE)
Time to first symptomatic skeletal event (TTSSE) is defined as the time from the date of randomization to the date of first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, or requirement for radiation therapy to relieve bone pain, or death due to any cause, whichever occurs first.
Time frame: From date of start of study randomization, assessed up to approximately 24 months.