AAA802 for PSMA-positive metastatic hormone-sensitive prostate cancer | PSMA-positive metastatic castration-resistant prostate cancer

Inclusion criteria

• {"criterion_text":"- Ability to understand and sign an approved Informed Consent Form (ICF), and to understand and comply with all protocol requirements\n- Evidence of PSMA-positive disease by 68Ga-PSMA-R11 PET/CT and eligible as determined by central reading\n- Recovered or stabilized to ≤ Grade 1 from all clinically significant toxicities related to prior PCa therapy with an exception for neuropathy to ≤ Grade 2 and alopecia any grade\n- A documented progressive mHSPC or mCRPC based on at least 1 of the following criteria: • Serum or plasma PSA progression defined as an increase in in PSA ≥ 25% and > 2 ng/mL above nadir, confirmed by progression at 2 time points at least 3 weeks apart over a previous reference value measured at least 1 week prior. The minimal start value is 2.0 ng/mL. • Soft-tissue progression defined as an increase ≥ 20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or more new lesions. • Progression of bone disease defined as evaluable disease or new bone lesions(s) by bone scan (2 + 2 PCWG3 criteria, Scher et al 2016).\n- A castrate level of serum or plasma testosterone (<50 ng/dL or < 1.7 nmol/L) for mCRPC patients at screening. Monitoring of testosterone level is not mandated for participants with mHSPC who are receiving SoC treatment.\n- For mHSPC participants: treatment naïve OR minimally treated with: •\tUp to 45 days of luteinizing hormone-releasing hormone (LHRH) agonist/antagonists or bilateral orchiectomy with or without first generation antiandrogen (e.g. bicalutamide, flutamide) for metastatic prostate cancer is allowed prior to ICF signature. If given, first generation anti-androgen must be discontinued prior to start of study therapy or after 45 days, whichever happens first. If received, prior LHRH agonist/antagonist with or without first generation antiandrogen use in the adjuvant/neo-adjuvant setting must have been discontinued > 12 months prior to ICF signature AND must not have exceeded 24 months of therapy AND must not have shown disease progression within 12 months of completing adjuvant/neo-adjuvant therapy. Temporarily ADT adjuvant to EBRT in the curative setting is allowed; however, this must have been discontinued > 3 months prior to inclusion. •\tUp to 45 days of CYP17 inhibitor or ARDT exposure for metastatic prostate cancer is allowed prior to ICF signature. •\tPrior chemotherapy is not required.\n- For mCRPC participants: Prior orchiectomy or ongoing ADT and meet the following criteria in terms of previous 177Lu-labelled PSMA-targeted RLTs in both dose escalation and dose expansion: •\tGroup 1 (dose escalation) and Group 1 (dose expansion): (post-ARPI, post-taxane-based chemotherapy, post-177Lu-PSMA-RLT): participants must have received previous treatment with 177Lu-labelled PSMA-targeted RLTs. •\tGroup 2 (dose escalation) and Group 2 (dose expansion): (post ARPI, pre-177Lu-PSMA-RLT): participants must have never received previous treatment with 177Lu-labelled PSMA-targeted RLTs. Prior taxane-based chemotherapy is not required.\n- Adequate organ function: •\tBone marrow reserve: • White blood cell (WBC) count ≥ 3.0 x 109/L and absolute neutrophil count (ANC) ≥ 1.5 x 109/L. •\tPlatelets ≥ 75 x 109/L. •\tHemoglobin ≥ 8 g/dL (8 g/dL is equivalent to 80 g/L. •\tHepatic function: •\tTotal bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN). For participants with known Gilbert’s Syndrome ≤ 3 x ULN is permitted. •\tAlanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN OR ≤ 5.0 x ULN for patients with liver metastases. •\tAlbumin > 3.0 g/dL (3.0 g/dL is equivalent to 30 g/L. •\tRenal function: •\tCreatinine clearance ≥ 60 mL/min. Note that participants with hydronephrosis or findings indicating blockage of urinary outflow are not eligible\n- Human immunodeficiency virus (HIV)-infected participants who are healthy and have a low risk of acquired immune deficiency syndrome (AIDS)-related outcomes are eligible.\n- For participants who have partners of childbearing potential, the use a method of birth control with adequate barrier protection, deemed acceptable by the Investigator during the study and for 6 months after last study drug administration.\n- Adults ≥ 18 years of age\n- Eastern Cooperative Oncology Group Performance Status (ECOG PS) : ECOG 0-1 for participants in dose escalation ECOG 0-2 for participants in dose expansion\n- Histological, pathological, and/or cytological confirmation of prostate cancer\n- Have ≥ 1 metastatic lesion that is present on a baseline CT, Magnetic Resonance Imaging (MRI), or bone scan imaging according to baseline scan imaging as defined in protocol Section 8.3.1."}

Exclusion criteria

• {"criterion_text":"- Previous treatment with any of the following within 6 weeks of IRT cohort enrollment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 or hemi-body irradiation.\n- Transfusion for the sole purpose of eligibility into the study.\n- History of CNS metastases and symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression are NOT eligible, except: •\tPrevious therapy (surgery, radiotherapy, gamma knife) and are neurologically stable, asymptomatic, and are not receiving corticosteroids for the purposes of maintaining neurologic integrity. •\tEpidural disease, canal disease and prior cord involvement if those areas have been treated, are stable, and not neurologically impaired.\n- Concurrent serious (as determined by investigator) medical conditions, including, but not limited to, uncontrolled infection, active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation\n- Current severe urinary incontinence, hydronephrosis, severe voiding dysfunction, any level of urinary obstruction requiring indwelling/condom catheters\n- Known hypersensitivity to components of the imaging product or investigational therapy or its analogues.\n- History of myocardial infarction, angina pectoris, or coronary artery bypass graft within 6 months prior to ICF signature and/or clinically active significant cardiac disease defined as any of the following: •\tNYHA class 3/4 congestive heart failure within 6 months prior to ICF signature unless treated with improvement and echocardiogram or MUGA demonstrates EF > 45% with improvement in symptoms to class < 3, left ventricular ejection fraction (LVEF) < 50% as determined by echocardiogram (ECHO), uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mmHg and/or Diastolic Blood Pressure (DBP) ≥ 100 mmHg with or without antihypertensive medication. •\tHistory or current diagnosis of ECG abnormalities indicating significant risk of safety for participants in the study, primarily mean resting corrected QT interval (QTc) > 470 millisecond (msec), obtained from average value 3 ECG recordings taken approximately 2-3 minutes apart as per Investigator assessment and/or others such as: concomitant clinically significant cardiac arrhythmias e.g. sustained ventricular tachycardia, complete left bundle branch block, or high-grade atrioventricular (AV) block (e.g. bifascicular block). •\tMobitz type II, long AT syndrome, known family history and/or current condition of Torsade de Pointes and third-degree AV block, or any factor increasing the risk of QTc prolongation(e.g. hypokalemia).\n- Diagnosis of other malignancies expected to alter life expectancy or may interfere with disease assessment. Prior history of malignancy who have been disease free for more than 3 years are eligible\n- A superscan as seen in the baseline bone scan\n- Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 6 months after stopping study treatment. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time specified above. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF\n- Previous treatment with PSMA-targeted RLT for Group 2 and Group 3\n- Any other investigational agents within 28 days of the anticipated C1D1 of 225Ac-PSMA-R2 therapy.\n- Any systemic anti-cancer therapy (e.g. other concurrent chemotherapy, radioligand therapy, immunotherapy or biological therapy including monoclonal antibodies) within 28 days of the anticipated C1D1 of 225Ac-PSMA-R2 therapy. Patients on stable bisphosphonate or denosumab for ≥ 15 days prior to study start are not excluded (with the exception of the drugs listed on inclusion criteria #14 for mHSPC patients).\n- Uncontrolled pain or incompatibility that may result in participant’s lack of ability to comply with imaging procedures"}

Primary endpoints

• {"endpoint_text":"- Primary endpoint for dose escalation: Incidence and severity of DLTs during the DLT observation period (first 42 days of treatment).Incidence and severity of AEs and SAEs including changes in laboratory values, ECGs and vital signs by group and frequency schedule (Q6W and Q4W).Primary endpoint for dose expansion: Overall Response Rate (ORR) per in soft tissue according to PCWG3 modified RECIST v1.1 in absence of bone progression (as per PCWG3), by central assessment and (PSA50) response rate.","definition_or_measurement_approach":"DLTs measured during the DLT observation period (first 42 days). Incidence and severity of AEs/SAEs assessed including lab changes, ECGs and vital signs by group and schedule (Q6W and Q4W). ORR assessed in soft tissue per PCWG3 modified RECIST v1.1 by central assessment in absence of bone progression; PSA50 response rate also measured."}
• {"endpoint_text":"- Primary endpoint for dose escalation: Tolerability: Frequency of dose interruptions, reductions, discontinuations, and dose intensity by group.","definition_or_measurement_approach":"Tolerability assessed by counting frequency of dose interruptions, dose reductions, treatment discontinuations and calculation of dose intensity by treatment group."}

Secondary endpoints

• {"endpoint_text":"- Secondary endpoint for dose escalation: Secondary endpoint for dose expansion : ● Safety: Incidence and severity of AEs and serious adverse events (SAEs) including changes in laboratory values, electrocardiograms (ECGs) and vital signs by group.","definition_or_measurement_approach":"Safety measured by incidence and severity of AEs and SAEs and changes in labs, ECGs and vital signs, reported by group."}
• {"endpoint_text":"- Secondary endpoint for dose escalation: Secondary endpoint for dose expansion : ● Tolerability: Frequency of dose interruptions, reductions, and dose intensity, by group.","definition_or_measurement_approach":"Tolerability measured by frequency counts of dose interruptions, reductions and dose intensity by group."}
• {"endpoint_text":"- Escalation:ORR,DCR,BOR,rPFS,OS,DoR per PCWG3 (investigator), Time to 1st SSE, responses measured by PSA (response rate, duration, time to 1st response, time to progression). Change from baseline in ALP/LDH. Expansion:DCR,BOR,DoR in soft tissue only according to PCWG3 absence of bone progression (central). rPFS per PCWG3 (central) and PFS (local), OS, Time to 1st SSE, responses measured by PSA (response rate, duration, time to 1st response, time to progression), change from baseline in ALP/LDH.","definition_or_measurement_approach":"Efficacy endpoints include ORR, DCR, BOR, rPFS, OS, DoR per PCWG3; time to first SSE; PSA-based response metrics (rate, duration, time to response, time to progression); changes from baseline in ALP and LDH. Assessments per investigator and central review as specified (PCWG3/RECIST)."}
• {"endpoint_text":"- Radioactivity measurements in blood during Cycle 1 and derived PK parameters (i.e., AUC, Cmax, CL, Tmax, Vz, T1/2) of 225Ac-PSMA-R2 at different measurement times (post-secular equilibrium).","definition_or_measurement_approach":"Radioactivity measured in blood during Cycle 1 with PK parameters derived (AUC, Cmax, CL, Tmax, Vz, T1/2) at specified time points post-secular equilibrium."}
• {"endpoint_text":"- Secondary endpoint for dose expansion: Secondary endpoint for dose expansion in pre-177Lu and post-177Lu-labelled PSMA-targeted RLTs:Change from baseline in HRQoL as assessed by XeQoL, EQ-5D-5L, FACT-P and BPI-SF. With the exception of XeQoL, the other HRQoL’s will be assessed in dose expansion only.","definition_or_measurement_approach":"Health-related quality of life measured as change from baseline using XeQoL, EQ-5D-5L, FACT-P and BPI-SF questionnaires; most HRQoL instruments assessed during dose expansion only (except XeQoL)."}

France

Earliest CTIS Part Ii Submission Date

30-10-2023

Latest Decision Or Authorization Date

13-11-2025

Processing Time Days

745

Number Of Sites

6

Number Of Participants

32

Primary sponsor

Full Name

Novartis Pharma AG

Organisation Type

Pharmaceutical company

Country Of Registered Address

Switzerland

Contract research organisations

Name

Icon Clinical Research Limited

Name

IQVIA Limited

Responsibilities

Management of drug supply logistics and dispensing

Name

Syneos Health Inc.

Name

Parexel International (IRL) Limited

Third parties

• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"Database management and quality control","organisation_type":"Non-Pharmaceutical company"}
• {"country":"France","full_name":"Creapharm Clinical Supplies","duties_or_roles":"Drug destruction, storage, distribution","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Medical Equipment Supplies And Management Limited","duties_or_roles":"Supply of 2ml vacutainer heparin tubes","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Invicro LLC","duties_or_roles":"Imaging","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services SARL","duties_or_roles":"Supply of 3ml vacutainer heparin tubes, provision of lab kits and logistics for ctDNA collection","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"RWS Life Sciences Inc.","duties_or_roles":"Patient Reported Outcomes (PRO) & Electronic Patient Reported Outcomes ((e)PRO) formatting, translations, and licensing","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"Cardiac safety, ECG","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"Management of drug supply logistics and dispensing","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Syneos Health Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Kayentis","duties_or_roles":"Coordination of licensing, translation and development of electronic patient reported outcomes (PROs). Data capture and cleaning of completed PROs.","organisation_type":"Non-Pharmaceutical company"}