Phase I/II Study of [225Ac]Ac-PSMA-R2 in Metastatic Hormone-Sensitive and Castration-Resistant Prostate Cancer with/without Prior 177Lu-PSMA Therapy
- Trial ID
- 2023-507672-52-00
- Protocol
- CAAA802A12101
- Sponsor
- Novartis Pharma AG
Trial statistics
Objectives
The primary objective of this study is to characterize the **safety** and tolerability of 225Ac-PSMA-R2, as well as to determine the Recommended Dose for Expansion (RDE) and corresponding regimen for 225Ac-PSMA-R2 monotherapy. This is evaluated in three groups: Group 1 includes PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) participants previously treated with 177Lu-labelled PSMA-targeted radioligand therapy (RLT), Group 2 includes PSMA-positive mCRPC participants not previously treated with 177Lu-labelled PSMA-targeted RLT, and Group 3 includes PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC) participants not previously treated with 177Lu-labelled PSMA-targeted RLT. Additionally, the study aims to evaluate the anti-tumor activity of 225Ac-PSMA-R2 in mCRPC post-177Lu and pre-177Lu treatment (naïve) and mHSPC (pre-177Lu treatment) participants. The clinical relevance of these objectives lies in optimizing the therapeutic regimen for patients with advanced prostate cancer, potentially improving treatment outcomes and patient management.
Secondary objectives include:
- For dose escalation: Assessing the clinical anti-tumor activity of 225Ac-PSMA-R2 in Groups 1, 2, and 3, and characterizing the pharmacokinetics (PK) of 225Ac-PSMA-R2 post-secular equilibrium.
- For dose expansion in pre-177Lu and post-177Lu-labelled PSMA-targeted RLTs: Assessing the clinical anti-tumor activity, characterizing the safety and tolerability, and evaluating the impact of treatment on health-related quality of life (HRQoL).
- For dose expansion in post-177Lu-labelled PSMA-targeted RLTs: Characterizing the PK of 225Ac-PSMA-R2 pre- and post-secular equilibrium.
Participants
The clinical trial involves a total of **9 participants** diagnosed with **PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC)** and **metastatic castration-resistant prostate cancer (mCRPC)**, with or without prior 177Lu-PSMA radioligand therapy. The study population consists exclusively of **male subjects** aged **18 years and older**, who are not considered part of a vulnerable population. Participants were selected based on their ability to understand and sign an informed consent form, evidence of PSMA-positive disease, and a documented progressive form of prostate cancer. They must have adequate organ function and, for mCRPC patients, a castrate level of serum or plasma testosterone. Lifestyle considerations such as diet and physical activity are not specified. The trial does not include female subjects, and the selection criteria ensure that participants have a stable health status, with specific requirements for previous treatments and disease progression. The sponsor has not provided additional information regarding lifestyle factors or other demographic details.
Plans and Procedures
The clinical trial is designed as an open-label, multi-center study focusing on the evaluation of **225Ac-PSMA-R2** in men with **metastatic hormone-sensitive prostate cancer (mHSPC)** and **metastatic castration-resistant prostate cancer (mCRPC)**. The trial is structured into two phases: dose escalation and dose expansion. The primary objective during the dose escalation phase is to assess the safety and tolerability of **225Ac-PSMA-R2** and determine the recommended dose for expansion. The dose expansion phase aims to evaluate the anti-tumor activity of the treatment in different participant groups, including those with prior exposure to **177Lu-labelled PSMA-targeted radioligand therapy** and those without.
The trial is expected to commence recruitment on November 7, 2023, and is projected to conclude by August 1, 2026. Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as evidence of **PSMA-positive disease** and adequate organ function. Following the screening, participants will be enrolled into the study and will attend regular follow-up visits to monitor treatment effects, adverse events, and overall health status. The end-of-study visit will mark the completion of the participant's involvement, where final assessments will be conducted.
Participant involvement is anticipated to last throughout the trial duration, with specific timelines dependent on individual response and treatment schedules. Conditions that may lead to early termination from the study include the occurrence of dose-limiting toxicities, significant adverse events, or withdrawal of consent. The trial's methodology ensures rigorous monitoring and assessment to maintain participant safety and data integrity.
Treatment
The clinical trial involves the administration of several experimental and non-experimental treatments. **ABIRATERONE** is utilized in the study as an androgen receptor inhibitor. It is administered in the form of a tablet via oral use. The specific dosage and frequency of administration are not detailed in the provided data. Participant compliance with the administration of ABIRATERONE is monitored throughout the trial.
**GALLIUM (68GA) PSMA-R2**, marketed as AAA502, is another experimental treatment used in the trial. It is provided as a kit for radiopharmaceutical preparation and administered intravenously. This compound is a chemical substance, and its role in the trial is to target PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) and metastatic hormone-sensitive prostate cancer (mHSPC).
**AAA802** is administered as a solution for injection or infusion. This experimental treatment is delivered intravenously, and its active substance is also referred to as AAA802. The specific dosing schedule and participant compliance measures are not specified in the available data.
**RELUGOLIX** is included in the trial as a gonadotropin-releasing antagonist. It is administered orally in tablet form. The trial does not provide specific information regarding the dosage or frequency of administration for RELUGOLIX.
**ENZALUTAMIDE** is another androgen receptor inhibitor used in the study. It is available in both tablet and capsule forms and is administered orally. The trial documentation does not specify the exact dosage or administration frequency for ENZALUTAMIDE.
**APALUTAMIDE** is administered as a film-coated tablet via oral use. It functions as an androgen receptor inhibitor. The trial does not provide detailed information on the dosage or frequency of administration for APALUTAMIDE.
**DEGARELIX ACETATE** and **DEGARELIX** are both administered as solutions for injection. They are delivered subcutaneously and act as gonadotropin-releasing antagonists. The trial does not specify the dosing schedule or participant compliance measures for these treatments.
**DAROLUTAMIDE** is included in the trial as an androgen receptor inhibitor. It is administered orally in the form of a film-coated tablet. The specific dosage and frequency of administration are not detailed in the provided data.
**GOZETOTIDE**, marketed as Locametz 25 micrograms kit for radiopharmaceutical preparation, is administered intravenously as a solution for injection. It is used in the trial to target PSMA-positive cancer cells. The trial does not provide specific information regarding the dosage or frequency of administration for GOZETOTIDE.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for dose escalation include the incidence and severity of dose-limiting toxicities (DLTs) during the first 42 days of treatment, as well as the incidence and severity of adverse events (AEs) and serious adverse events (SAEs), including changes in laboratory values, electrocardiograms (ECGs), and vital signs. For dose expansion, the primary endpoint is the Overall Response Rate (ORR) in soft tissue according to PCWG3 modified RECIST v1.1, in the absence of bone progression, as assessed by central evaluation, along with the PSA50 response rate.
Secondary endpoints for dose escalation and expansion include safety assessments, such as the incidence and severity of AEs and SAEs, and tolerability measures, including the frequency of dose interruptions, reductions, and dose intensity. Additional secondary endpoints involve the evaluation of response rates, such as ORR, Disease Control Rate (DCR), Best Overall Response (BOR), radiographic progression-free survival (rPFS), overall survival (OS), and duration of response (DoR) per PCWG3 criteria. The trial will also measure changes from baseline in alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels, as well as radioactivity measurements in blood during Cycle 1 to derive pharmacokinetic parameters of 225Ac-PSMA-R2.
Furthermore, the trial will assess changes from baseline in health-related quality of life (HRQoL) using instruments such as XeQoL, EQ-5D-5L, FACT-P, and BPI-SF, with the exception of XeQoL, which will be evaluated only in the dose expansion phase. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the therapeutic impact of the investigational product on participants with metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Ability to understand and sign an approved Informed Consent Form (ICF), and to understand and comply with all protocol requirements
- 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: • Group 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. • Group 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.
- Adequate organ function: • Bone marrow reserve: • White blood cell (WBC) count ≥ 3.0 x 109/L and absolute neutrophil count (ANC) ≥ 1.5 x 109/L. • Platelets ≥ 75 x 109/L. • Hemoglobin ≥ 8 g/dL (8 g/dL is equivalent to 80 g/L. • Hepatic function: • Total bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN). For participants with known Gilbert’s Syndrome ≤ 3 x ULN is permitted. • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN OR ≤ 5.0 x ULN for patients with liver metastases. • Albumin > 3.0 g/dL (3.0 g/dL is equivalent to 30 g/L. • Renal function: • Creatinine clearance ≥ 60 mL/min. Note that participants with hydronephrosis or findings indicating blockage of urinary outflow are not eligible
- Human immunodeficiency virus (HIV)-infected participants who are healthy and have a low risk of acquired immune deficiency syndrome (AIDS)-related outcomes are eligible.
- 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.
- Adults ≥ 18 years of age
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) : ECOG 0-1 for participants in dose escalation ECOG 0-2 for participants in dose expansion
- Histological, pathological, and/or cytological confirmation of prostate cancer
- 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.
- Evidence of PSMA-positive disease by 68Ga-PSMA-R11 PET/CT and eligible as determined by central reading
- 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
- 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).
- 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.
- For mHSPC participants: treatment naïve OR minimally treated after metastatic prostate cancer diagnosis (whether de novo or progressive (metachronous) XX
Exclusion Criteria
- 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.
- 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: • NYHA 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. • History 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). • Mobitz 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).
- 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
- A superscan as seen in the baseline bone scan
- 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
- Previous treatment with PSMA-targeted RLT for Group 2 and Group 3
- Any other investigational agents within 28 days of the anticipated C1D1 of 225Ac-PSMA-R2 therapy.
- 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).
- Uncontrolled pain or incompatibility that may result in participant’s lack of ability to comply with imaging procedures
- Transfusion for the sole purpose of eligibility into the study.
- History of CNS metastases and symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression are NOT eligible, except: • Previous therapy (surgery, radiotherapy, gamma knife) and are neurologically stable, asymptomatic, and are not receiving corticosteroids for the purposes of maintaining neurologic integrity. • Epidural disease, canal disease and prior cord involvement if those areas have been treated, are stable, and not neurologically impaired.
- 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
- Current severe urinary incontinence, hydronephrosis, severe voiding dysfunction, any level of urinary obstruction requiring indwelling/condom catheters
- Known hypersensitivity to components of the imaging product or investigational therapy or its analogues.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 07 Nov 2023 | 32 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ENZALUTAMIDE | Other | — | ORAL USE | — | — | SUB77412 |
ABIRATERONE | Other | — | ORAL USE | — | — | SUB07361MIG |
APALUTAMIDE | Other | — | ORAL USE | — | — | SUB189031 |
DEGARELIX ACETATE | Other | — | SUBCUTANEOUS | — | — | SUB27749 |
DEGARELIX | Other | — | SUBCUTANEOUS | — | — | SUB27748 |
DAROLUTAMIDE | Other | — | ORAL USE | — | — | SUB185326 |
ENZALUTAMIDE | Other | — | ORAL USE | — | — | SUB77412 |
RELUGOLIX | Other | — | ORAL USE | — | — | SUB189168 |
ABIRATERONE | Other | — | ORAL USE | — | — | SUB07361MIG |
AAA802 | Test | SOLUTION FOR INJECTION/INFUSION | INTRAVENOUS | — | — | PRD10889250 |