Recruiting

Advanced metastatic castration-resistant prostate cancer, Prostate specific membrane antigen (PSMA) expression

Bayer Identifier:

22049

ClinicalTrials.gov Identifier:

NCT06217822

EudraCT Number:

Not Available

EU CT Number:

2023-507486-26-00

First-in-human study of 225Ac-PSMA-Trillium (BAY 3563254) in participants with advanced metastatic castration-resistant prostate cancer (mCRPC)

Trial purpose

Researchers are looking for a better way to treat participants who have advanced metastatic castration-resistant prostate cancer (mCRPC).

mCRPC is a cancer of the prostate (a male reproductive gland located below the bladder) that has spread to other parts of the body. This type of prostate cancer no longer responds to hormone treatment used to lower testosterone levels, a male sex hormone that can promote cancer growth. Prostate-specific membrane antigen (PSMA) is a protein found at higher levels on prostate cancer cells than on healthy cells. Researchers believe that targeting PSMA may help treat prostate cancer.

The study treatment 225Ac-PSMA-Trillium, also called BAY3563254, is being developed to treat advanced mCRPC. It works by binding to PSMA and giving off radiation that can damage cancer cells and stop them from growing.

The main purpose of this first-in-human study is to learn:

• How safe BAY3563254 is in participants.
• What the most suitable dose and treatment schedule of BAY3563254 are for further study.
• How well BAY3563254 works when given alone or together with other cancer treatments in participants with mCRPC.

To answer this, researchers will assess:

• The number and severity of medical problems, including serious medical problems, experienced after treatment.
• The number of dose-limiting toxicities (DLTs) at each dose level. A DLT is a side effect that is too severe to continue treatment at a specific dose.
• The number of participants whose cancer completely disappears or shrinks by at least 30% after treatment (objective response rate, ORR).
• The number of participants whose prostate-specific antigen (PSA*) level decreases by at least 50% (PSA50).
• Participants’ best response based on PSA levels (best overall PSA response).
• How long participants respond to treatment and how long their cancer remains under control.

*PSA is a protein made by the prostate gland. High levels may indicate the presence of prostate cancer.

The study has two parts. In the first part (dose escalation), participants will receive increasing doses of BAY3563254 to identify the most suitable dose and treatment schedule.

In the second part (dose expansion), participants will receive the dose and schedule selected in Part 1. Depending on the study group, participants may receive BAY3563254 alone or together with another cancer treatment, either an androgen receptor pathway inhibitor (ARPI), which blocks signals that help prostate cancer grow, or an immune checkpoint inhibitor (ICI), which helps the immune system recognize and attack cancer cells. Participants will be assigned to study groups based on their previous prostate cancer treatments.

Participants will receive BAY3563254 as an injection into a vein. Depending on the study part and treatment group, treatment may be given every 6 or 8 weeks for up to 4 treatment cycles. Each participant will be in the study for approximately 6 years, including screening, treatment, and follow-up.

A substudy conducted at selected sites will evaluate:

• How radioactivity is cleared from the body over time.
• The amount of radiation delivered to tumors and healthy organs.

During the study, doctors and study staff will:

• Collect blood and urine samples.
• Review medical history and medications.
• Measure vital signs such as blood pressure, heart rate, and body temperature.
• Examine heart health using electrocardiograms (ECGs).
• Collect tumor samples if required.
• Monitor cancer using CT, MRI, bone scans, and PET scans.
• Assess radiation absorbed by tumors and healthy organs in participants taking part in the imaging substudy.
• Ask participants about their health and any adverse events.

An adverse event is any medical problem that occurs during a study, whether or not it is related to the study treatment. Participants may also complete questionnaires about their symptoms and quality of life.

After treatment ends, participants will continue to be monitored to assess their health and any changes in their cancer. Follow-up may include clinic visits or telephone contacts. The long-term follow-up period will continue for up to approximately 60 months after treatment ends.

Key Participants Requirements

Sex

All

Age

18 - N/A (No Limit)

Inclusion Criteria

- mCRPC with pathological confirmation of adenocarcinoma without small-cell or neuroendocrine features.
- Previous treatment and progression/relapse on at least 1ARPI (e.g., enzalutamide, apalutamide, darolutamide and/or abiraterone). Group D: Specific prior treatment with abiraterone is required. Group E: Prior treatment with enzalutamide, apalutamide or darolutamide is required.
- Prior orchiectomy and/or ongoing androgen deprivation therapy and a castrate level of serum testosterone (<50 ng/dL or <1.7 nmol/L).
- Prior taxane treatment:
-- Dose Escalation: Participants must either have had prior treatment with at least 1 but no more than 2 taxane regimens, or been deemed ineligible for or refused taxane therapy on consultation with their physician
-- Dose Expansion Group A, Group F: Participants must have had prior treatment with at least 1 but no more than 2 taxane regimens, in the castration-resistant setting
- Dose Expansion Group B, Group D, and Group F: Participants must not have received any taxane regimens since becoming castration-resistant
-- Dose Expansion Group C: Participants must either have had prior treatment with at least 1 but no more than 2 taxane regimens, or been deemed ineligible for or refused taxane therapy on consultation with their physician
- Prior treatment with an established Lu-PSMA therapy (i.e., dose activity and cycles comparable to approved treatments) is required for participants in Dose Expansion Group C only. More specifically, to qualify for this expansion group, participants must not have discontinued 177Lu-PSMA treatment due to intolerance.
- Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
- Adequate bone marrow, hepatic, and renal function, as assessed by the following laboratory requirements within 30 days before start of study intervention, as indicated below. Note that blood transfusions (red blood cells or platelets) and administration of G-CSF or GM-CSF are prohibited within 21 days prior to screening for the below bone marrow-related parameters.
-- Hemoglobin ≥9.0 g/dL
-- Absolute neutrophil count (ANC) ≥1500/mm^3
-- Platelet count ≥100,000/mm^3
-- Total bilirubin ≤1.5 x the Upper limit of normal (ULN), or ≤3×ULN if the participant has a confirmed history of Gilbert’s syndrome (note that participants with Gilbert's syndrome should be carefully evaluated for other liver-related disorders that may impact their suitability for this study).
-- Alanine transaminase (ALT) and Aspartate transaminase (AST) ˂2.5 x ULN (≤5 x ULN for participants with liver involvement)
-- Participants on a stable dose of anticoagulation therapy are allowed to participate if they have no sign of bleeding or clotting, and prothrombin time international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT) test results are acceptable at the Investigator’s discretion
-- Estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m^2, according to the Modified Diet in Renal Disease (MDRD) abbreviated formula and serum creatinine ≤1.5 x ULN
- Participants must have at least one PSMA-positive (prostate-specific membrane antigen) distant metastatic lesion on the screening PSMA PET/CT scan using the study-designated PSMA PET tracers, as determined by the site Investigator. For eligibility purposes, a PSMA-positive lesion must have activity greater than the liver by visual assessment of the screening PSMA PET/CT. A PSMA-positive metastatic lesion should not correspond to a normal tissue structure or benign lesion.
- Documented progressive mCRPC per PCWG3, and a minimum starting PSA value of 2.0 ng/mL is mandatory. Progressive mCRPC is defined as meeting at least one of the following criteria:
a. PSA progression (defined as 2 consecutive increases over a previous reference value obtained at a minimum of 1-week
b. Radiographic progression in soft-tissue lesions according to PCWG3 modification of RECIST v1.1 criteria
c. Progression of bone disease (defined as ≥ 2 new bone lesions according to PCWG3 bone scan criteria)

Exclusion Criteria

- Participants who have any of the following tumor lesions which are PSMA negative AND meet the size criteria below are excluded as determined by the site Investigator. A PSMA-negative lesion for eligibility purposes must have activity equal to or less than the liver by visual assessment of the screening PSMA PET/CT scan using the study-designated PSMA PET/CT tracers. A PSMA-negative metastatic lesion should not correspond to a normal tissue structure or benign lesion.
-- a. Any single or multiple lymph node(s) ≥2.5 cm in the short axis.
-- b. Any solid organ metastasis (e.g., lung, liver, adrenal glands, etc.) that is ≥1 cm in the short axis.
-- c. Any bone metastasis with a soft tissue component ≥ 1 cm in short axis with the soft tissue component being PSMA-negative. PSMA-negative osseous metastases without a soft tissue component do not exclude a participant.
-- d. Predominantly necrotic lesions with greater than 1 cm of enhancing tissue on contrast-enhanced computed tomography / magnetic resonance imaging (CT/MRI).
- Prior systemic anticancer therapy including chemotherapy, ARPI, biologic therapy, immunotherapy, or investigational therapies within 4 weeks of the start of study treatment, except luteinizing hormone-releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH). Start of study treatment is allowed in shorter timeframes if 5 half-lives of the prior drug(s) have elapsed.
- Prior radiopharmaceutical treatment using actinium-225.
Other prior radiopharmaceutical treatments:
• Dose escalation and Dose expansion Groups A and B: Prior treatment with a radiopharmaceutical is prohibited, with the exception of prior treatment with radium-223 dichloride more than 3 months before the start of study intervention. Note: Participants who have discontinued radium-223 dichloride treatment due to intolerance are excluded from Groups A and B.
• Dose expansion Group C: Prior treatment with a radiopharmaceutical is prohibited with the following exceptions: Prior treatment with radium-223 dichloride more than 3 months before the start of study intervention is permitted; and prior treatment with 177Lu-PSMA more than 6 weeks before the start of study intervention is required. Note: Participants who have discontinued 177Lu-PSMA or radium-223 dichloride treatment due to intolerance are excluded from Group C.
- Dose expansion Group D, Group E and Group F: Prior treatment with a radiopharmaceutical is prohibited.
- Prior definitive therapy (radiotherapy or surgery) completed less than 6 weeks before the start of study intervention. Note that palliative radiotherapy completed less than 6 weeks before the start of study intervention will be allowed if: (i) no more than 10% of the participants’ bone marrow is irradiated, (ii) it does not encompass all potential target/measurable lesions for participants in dose expansion.
- Toxic effects of Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grade ≥2 from prior anticancer therapy not yet stabilized or where significant post-treatment toxicities have been observed. Chronic toxic effects of CTCAE Grade ≤2 from prior anticancer therapy where no further resolution is expected do not require exclusion with agreement between the Investigator and Sponsor (e.g., chemotherapy-induced neuropathy, fatigue, alopecia, anorexia, etc.).

Trial summary

Enrollment Goal

353

Trial Dates

March 2024 - May 2032

Phase

Phase I

Could I Receive a placebo

Products

Actinium (225Ac) Felivotide Mopaxetan, BAY 3563254

Accepts Healthy Volunteer

Where to participate

Status	Institution	Location
Active, not recruiting	The Royal Marsden (Surrey) \| Oak Foundation Drug Development Unit	Sutton, SM2 5PT, United Kingdom
Recruiting	University College Hospital \| NIHR UCLH Clinical Research Facility	London, W1T 7HA, United Kingdom
Recruiting	Freeman Hospital \| Northern Centre for Cancer Care	Newcastle-Upon-Tyne, NE7 7DN, United Kingdom
Withdrawn	M Health Fairview Masonic Cancer Clinic - Clinics and Surgery Center	Minneapolis, 55455, United States
Not Yet Recruiting	XCancer Omaha	Omaha, 68130, United States
Withdrawn	The University of Texas MD Anderson Cancer Center - Texas Medical Center	Houston, 77030, United States
Withdrawn	City of Hope - Duarte Cancer Center	Duarte, 91010, United States
Withdrawn	Utah Cancer Specialists Cancer Center - Medical Oncology	Salt Lake City, 84106, United States
Not Yet Recruiting	Yokohama City University Hospital	Yokohama, 236-0004, Japan
Not Yet Recruiting	The Cancer Institute Hospital of JFCR	Koto-ku, 135-8550, Japan
Recruiting	Istituto Europeo di Oncologia s.r.l - Medicina Nucleare	Milano, 20141, Italy
Not Yet Recruiting	IRCCS Istituto Nazionale Tumori Fondazione Pascale - S. C. Medicina Nucleare e Terapia Metabolica	Napoli, 80131, Italy
Recruiting	BC Cancer \| Vancouver	Vancouver, V5Z 4E6, Canada
Recruiting	Centre Hospitalier de l'Universite de Montreal (CHUM) \| Oncology	Montreal, H2X 0C1, Canada
Recruiting	Juravinski Cancer Centre \| Clinical Trials	Hamilton, L8V 5C2, Canada
Recruiting	Princess Margaret Cancer Centre \| Medical Oncology and Hematology	Toronto, M5G 2C4, Canada
Recruiting	Research Institute of the McGill University Health Centre \| McConnell Centre for Innovative Medicine	Montreal, H4A 3J1, Canada
Recruiting	Centre hospitalier universitaire de Sherbrooke (CHUS) \| Oncology	Sherbrooke, J1H 5N4, Canada
Recruiting	AZ Groeninge Campus Kennedylaan - Urology	Kortrijk, 8500, Belgium
Recruiting	Institut Jules Bordet / Nuclear Medicine	Anderlecht, 1070, Belgium
Recruiting	UZ Leuven - Campus Gasthuisberg - Nuclear Medicine	Leuven, 3000, Belgium
Recruiting	Universitair Medisch Centrum Groningen (UMCG) - UMC Groningen Comprehensive Cancer Center	Groningen, 9713 GZ, Netherlands
Withdrawn	Erasmus Medisch Centrum	Rotterdam, 3015 CE, Netherlands
Recruiting	Karolinska Universitetssjukhuset - Solna - Fas I-enheten Solna CKC	Stockholm, 171 76, Sweden
Recruiting	Sahlgrenska Universitetssjukhuset - Sahlgrenska Sjukhuset - Klinisk prövningsenhet Fas I/FIH	Göteborg, 413 46, Sweden
Not Yet Recruiting	Akademiska sjukhuset i Uppsala - Fas 1-enheten	Uppsala, 751 85, Sweden
Recruiting	Skånes Universitetssjukhus - Lund - Onkologens kliniska forskningsenhet	Lund, 221 85, Sweden
Withdrawn	Kantonsspital Baden	Baden, 5404, Switzerland
Recruiting	Universitätsspital Basel	Basel, 4056, Switzerland
Recruiting	UniversitätsSpital Zürich (USZ) - Klinik für Medizinische Onkologie und Hämatologie	Zürich, 8091, Switzerland
Recruiting	HUS-Yhtymä, Helsingin yliopistollinen sairaala (HUS) - Syöpäkeskus	Helsinki, 00029, Finland
Recruiting	Turku University Hospital, Turun yliopistollinen sairaala (TYKS) - Syöpäkeskus	Turku, 20540, Finland
Recruiting	Kuopio University Hospital, Kuopion yliopistollinen sairaala (KYS) - Syövänhoitokeskus	Kuopio, 70210, Finland
Recruiting	Docrates Mehiläinen Syöpäsairaala	Helsinki, 00180, Finland
Not Yet Recruiting	Tampere University Hospital, Tampereen yliopistollinen sairaala (TAYS) - Syöpäkeskus	Tampere, 33520, Finland

Primary Outcome

Dose Escalation and Dose Expansion: Incidence of TEAEs (including TESAEs)
TEAE: Treatment-emergent adverse event TESAE: Treatment-emergent serious adverse event
Time Frame:
After the first administration of study intervention up to 42 days after the last dose of study intervention
Dose Escalation and Dose Expansion: Severity of TEAEs (including TESAEs)
Time Frame:
After the first administration of study intervention up to 42 days after the last dose of study intervention
Dose Escalation and Dose Expansion: Incidence of DLTs and preliminary activity (OPR, PSA50) informed by joint TITE-CRM
DLT: Dose-Limiting Toxicities
Time Frame:
Up to and including Cycle 3 (each cycle is 42 days)
Dose Expansion: ORR by PCWG3 guideline based on Investigator review
ORR is defined as the proportion of participants who have a confirmed complete response (CR) or partial response (PR) per PCWG3 guidelines as assessed by the Investigator.
Time Frame:
Up to 18 months after end of treatment
Dose Expansion: PSA50 response
PSA50 response is defined as a ≥50% decline in PSA value from baseline (Cycle 1 Day 1).
Time Frame:
At 12 weeks or later (up to 18 months after end of treatment)
Dose Expansion: Best overall PSA response
Best overall PSA response corresponds to the maximum percentage decline or the minimum percentage increase (if no decline) in PSA value from baseline (Cycle 1 Day 1).
Time Frame:
Up to 18 months after end of treatment

Secondary Outcome

Dose Expansion: Recommended dose for further clinical development
Time Frame:
Up to 18 months after end of treatment
Dose Expansion: Recommended dose regimen for further clinical development
Time Frame:
Up to 18 months after end of treatment
Dose Escalation and Dose Expansion: Radiographic progression-free survival (rPFS) by PCWG3 based on Investigator review
rPFS is defined as the time from the start of study treatment to the date of first observed disease progression (Investigator’s radiological assessment by PCWG3) or death due to any cause, if death occurs without progression is documented.
Time Frame:
Up to 18 months after end of treatment
Dose Escalation and Dose Expansion: Duration of response (DOR) by PCWG3 based on Investigator review
DOR is defined as the time from the first documented objective response of PR or CR by PCWG3, whichever occurs earlier, to disease progression or death (if death occurs without progression is documented).
Time Frame:
Up to 18 months after end of treatment
Dose Escalation and Dose Expansion: Duration of PSA50 response
Duration of PSA50 response is defined as the time from the first documented PSA50 response to PSA progression by PCWG3 or death (if death occurs without progression is documented).
Time Frame:
Up to 18 months after end of treatment
Dose Escalation and Dose Expansion: Cmax of 225Ac
Blood activity and plasma concentration of 225Ac-PSMA-Trillium PK parameters
Time Frame:
Cycle 1, cycle 2 (From pre-dose up to Day 36 post-dose for each cycle)
Dose Escalation and Dose Expansion: AUC and AUC(0-tlast) of 225Ac
Blood activity and plasma concentration of 225Ac-PSMA-Trillium PK parameters
Time Frame:
Cycle 1, cycle 2 (From pre-dose up to Day 36 post-dose for each cycle)

Trial design

A Phase 1 open-label, first-in-human, multi-center study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of 225Ac-PSMA-Trillium in participants with advanced metastatic castration-resistant prostate cancer (mCRPC)

Trial Type

Interventional

Intervention Type

Drug

Trial Purpose

Treatment

Allocation

Non-Randomized

Blinding

Open Label

Assignment

Sequential

Trial Arms

Additional Information

Click here to find further information and, after study completion, the study results according to Bayer's transparency standards.