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 metastatic castration-resistant prostate cancer (mCRPC).

mCRPC is a cancer of the prostate (male reproductive gland found below the bladder) that has spread to other parts of the body. This type of prostate cancer does not respond to hormone treatment used to lower the level of testosterone, a male sex hormone, to prevent cancer from growing.

The study treatment 225Ac-PSMA-Trillium, also called BAY3563254, is under development to treat advanced metastatic castration-resistant prostate cancer. 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 is BAY3563254 in participants.
• What is the recommended dose of BAY3563254 that is safe and works well that will be further tested in Part 2 of the study.
• How well does BAY3563254 work in participants.

To answer this, the researchers will look at:
• The number and severity of medical problems including serious medical problems that participants experience after taking BAY3563254
• The number of dose-limiting toxicities (DLT) at each dose level. A DLT is a medical problem caused by a drug that is too severe to continue the use of that specific dose.
• The number of participants whose cancer completely disappears (complete response) or reduces by at least 30% (partial response) after taking the treatment (also known as objective response rate (ORR))
• The number of participants who have a decrease in the levels of PSA* by at least 50% in their blood (also known as PSA50). PSA is a protein made by the prostate gland. High levels of PSA may indicate the presence of prostate cancer.
• Participants’ best response to treatment based on their PSA levels (also known as the best overall PSA response).

The study will have two parts. The first part, called dose escalation, is done to find the most appropriate dose of BAY3563254 for use in the second part of the study. For this, each participant will receive one of different increasing amounts of BAY3563254. They will take BAY3563254 as an injection into a vein. All participants in the second part of the study, called dose expansion, will receive the most appropriate dose of BAY3563254 that was identified from the first part of the study.

Participants in this study will take the study treatment once every 6 weeks, which is known as a treatment cycle. Each participant will have up to 4 of these treatment cycles, if the participant benefits from the treatment. Each participant will be in the study for approximately 6 years, including a screening phase of up to 30 days, 6 months of treatment depending on the participant’s benefit, and a follow up phase of 60 months after the end of treatment.

In addition, substudies performed during both dose escalation and dose expansion parts of the study will evaluate:
• the clearance of radioactivity from the body over time
• the doses of radiation that are delivered to normal organs and tumors

During the study, the doctors and their study team will:
• take blood and urine samples
• check vital signs such as blood pressure, heart rate, and body temperature
• examine heart health using electrocardiogram (ECG)
• take tumor samples if required
• check if the participants’ cancer has grown and/or spread using CT (computed tomography) or MRI (magnetic resonance imaging) and bone scan
• check the tumor status using PET (positron emission tomography)
• check the amount of radiation absorbed by tumors and normal organs using SPECT/CT (single-photon emission tomography and computed tomography scan)
• ask the participants questions about how they are feeling and what adverse events they are having.

An adverse event is any medical problem that a participant has during a study. Doctors keep track of all adverse events, irrespective if they think it is related or not to the study treatments. In addition, the participants will be asked to complete a questionnaire on quality of life at certain time points during the study.

The treatment period ends with a visit in 6-12 weeks after the last BAY3563254 dose. About 6-12 weeks after the last dose and every 6 weeks thereafter, the study doctors and their team will check the participants’ health and any changes in their cancer. This active follow-up period ends after 18 months. The long-term follow-up period will start after the end of the active follow-up visit and will continue for up to 60 months after the the last BAY3563254 dose. Participants will be contacted, typically by phone call or clinic visit, approximately every 12 weeks after the end of active follow-up.

Key Participants Requirements

Sex

All

Age

18 - N/A

Inclusion Criteria
- mCRPC with pathological confirmation of adenocarcinoma without small-cell or neuroendocrine features.
- Previous treatment with at least 1 novel androgen axis drug (NAAD) (e.g., enzalutamide, apalutamide, darolutamide and/or abiraterone).
- 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: 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: 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. Radiological 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, NAAD, 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.
- 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 177 Lu PSMA more than 6 weeks before the start of study intervention is required. Note: Participants who have discontinued 177 Lu-PSMA treatment due to intolerance are excluded from Group C.
- 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

235

Trial Dates

March 2024 - May 2031

Phase

Phase 1

Could I Receive a placebo

Products

N/A

Accepts Healthy Volunteer

Where to participate

Status	Institution	Location
Recruiting	Institut Jules Bordet / Nuclear Medicine	Anderlecht, 1070, Belgium
Recruiting	AZ Groeninge Campus Kennedylaan - Urology	Kortrijk, 8500, Belgium
Recruiting	Centre Hospitalier de l'Universite de Montreal (CHUM) - Hopi	Montreal, H2X 3E4, Canada
Recruiting	BC Cancer - Vancouver Site	Vancouver, V5Z 4E6, Canada
Recruiting	The Royal Marsden NHS Foundation Trust \| Sutton - Oak Foundation Drug Development Unit	Sutton, SM2 5PT, United Kingdom
Recruiting	University College London Hospitals NHS Foundation Trust \| University College Hospital - NIHR UCLH Clinical Research Facility	London, W1T 7HA, United Kingdom
Recruiting	Juravinski Cancer Centre - Clinical Trials Department	Hamilton, L8V 5C2, Canada
Recruiting	McGill University Health Centre (MUHC) - Research Institute (RI) - McConnell Centre for Innovative Medicine (CIM)	Montreal, H4A 3J1, Canada
Not yet recruiting	Centre Hospitalier Universitaire de Sherbrooke (CHUS) - Hopital Fleurimont	Sherbrooke, J1H 5N4, Canada
Not yet recruiting	Princess Margaret Cancer Centre – University Health Network - Department of Medical Oncology and Hematology	Toronto, M5G 2C4, Canada
Suspended	Cross Cancer Institute, Clinical Trials Unit	Edmonton, T6G 1Z2, Canada
Suspended	Helsinki University Hospital, Comprehensive Cancer Center	Helsinki, FIN-00029, Finland
Suspended	Turku University Hospital	Turku, 20520, Finland
Suspended	Kuopio University Hospital	Kuopio, 70210, Finland
Suspended	Docrates Mehiläinen Syöpäsairaala	Helsinki, FIN-00180, Finland
Not yet recruiting	Kantonsspital Baden	Baden, 5404, Switzerland
Not yet recruiting	The Newcastle upon Tyne Hospitals NHS Foundation Trust \| Freeman Hospital - Cancer Trials Research Centre	Newcastle upon Tyne, NE7 7DN, United Kingdom
Not yet 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
Not yet recruiting	Sahlgrenska Universitetssjukhuset - Klinisk prövningsenhet Fas I/FIH	Göteborg, 41346, Sweden
Suspended	Akademiska Sjukhuset - Fas-I-enheten	Uppsala, 75185, Sweden
Not yet recruiting	Skånes Universitetssjukhus Lund - Onkologens kliniska forskningsenhet	Lund, 22185, Sweden
Not yet recruiting	Karolinska Universitetssjukhuset - Fas I-enheten Solna CKC	Stockholm, 17176, Sweden
Suspended	Tampere University Hospital	Tampere, 33520, Finland
Not yet recruiting	Universitair Medisch Centrum Groningen (UMCG) - UMC Groningen Comprehensive Cancer Center	Groningen, 9713 GZ, Netherlands
Not yet recruiting	Erasmus Medisch Centrum	Rotterdam, 3015 CE, Netherlands
Not yet recruiting	M Health Fairview Masonic Cancer Clinic - Clinics and Surgery Center	Minneapolis, 55455, United States
Not yet recruiting	XCancer Omaha	Omaha, 68130, United States
Not yet recruiting	The University of Texas MD Anderson Cancer Center - Texas Medical Center	Houston, 77030, United States
Not yet recruiting	City of Hope - Duarte Cancer Center	Duarte, 91010, United States
Not yet recruiting	Universitätsspital Basel	Basel, 4056, Switzerland
Not yet recruiting	Univestitätsspital Zürich (USZ)	Zürich, 8091, Switzerland

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: Incidence of DLTs
DLT: Dose-Limiting Toxicities
Time Frame:
Up to and including Cycle 3 (each cycle is 42 days)
Dose Escalation and 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 Escalation and 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: Radiologic 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
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
Time Frame:
Cycle 1, cycle 2 (From pre-dose up to Day 36 post-dose for each cycle)
Dose Escalation and Dose Expansion: Cmax of PSMA-Trillium-macropa peptide
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 PSMA-Trillium-macropa peptide
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

N/A

Assignment

Sequential Assignment

Trial Arms

Additional Information

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