A Study to Learn How Safe the Study Treatment Actinium-225-macropa-pelgifatamab (BAY3546828) is, How it Affects the Body, How it Moves Into, Through and Out of the Body, and About Its Anticancer Activity in Participants With Advanced Metastatic Castration-resistant Prostate Cancer (mCRPC)

NCT06052306 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: 221432022-502623-22-00
• Study Type: interventional
• Target: 232
• Locations: 8 countries
• Sites: 28

Brief Summary

Researchers are looking for a better way to treat people who have advanced metastatic castration-resistant prostate cancer (mCRPC). In participants with metastatic castration-resistant prostate cancer (mCRPC), the cancer of the prostate has spread to other parts of the body (metastatic) and does not respond to the lowering of testosterone levels in the body (castration resistant). The cancer is 'advanced' and is unlikely to be cured or controlled with currently available treatments. Despite new treatment options for participant(s) with prostate cancer in recent years, the cancer often returns and worsens. The study treatment actinium-225-macropa-pelgifatamab (also called 225Ac-pelgi or BAY3546828) is a new type of treatment under development for participants with mCRPC who have already received available treatments or have few treatment options available. It works by binding to a protein on the surface of the cancer cells called prostate specific membrane antigen (PSMA). As it gives off a type of radioactivity that travels a very short distance, it kills the nearby (cancer) cells that express PSMA. The main purpose of this first-in-human study in participants with mCRPC is to learn:

• How safe different doses of 225Ac-pelgi are.
• To what degree medical problems caused by 225Ac-pelgi can be tolerated by the participants?
• Which dose of 225Ac-pelgi is optimal for treatment (safe and working well)?
• How good is 225Ac-pelgi's anticancer activity? To answer this, the researchers will look at:
• The number and severity of medical problems that the participants have after treatment with 225Ac-pelgi (per dose level).
• The ratio of medical problems and anticancer activity per dose.
• Anticancer activity of the optimal 225Ac-pelgi dose as proportion of participants who have at least halved prostate-specific antigen (PSA) levels after 12 weeks of treatment or later and/or shrunken or no longer detectable tumors.
• The lowest PSA level reached after treatment start. Doctors keep track of all medical problems (also called adverse events) that participants have during the study, even if they do not think that they might be related to the study treatment. Anticancer activity is measured using cancer imaging techniques and change in blood level of a protein called PSA. PSA is made by normal and by cancerous cells in the body. The PSA level is taken as a marker for prostate cancer development and is usually elevated in participants with mCRPC. In addition, researchers want to find out how 225Ac-pelgi moves into, through and out of the body. The study will have two parts. The first part, called dose escalation, is done to find the most appropriate dose and schedule that can be given in the second part of the study. For this, each participant will receive one of the predefined increasing doses of 225Ac-pelgi as an infusion into the vein. All participants in part 2, called dose expansion, will receive the most appropriate dose and schedule identified from the first part of the study. More than one dose level or schedule from part 1 may be tested. Both the participants and the study team know what treatment the participants will take. Participants in this study will take the study treatment 225Ac-pelgi once in a period of 6 weeks called a cycle. Each participant will have 4 of these treatment cycles, if the participant benefits from the treatment. Each participant will be in the study for up to nearly six years, including a first test (screening) phase of a maximum of 30 days, up to 12 months of treatment depending on the participant's benefit, and a follow-up phase of 60 months after the end of treatment. The following visits to the study site are planned: 2 during the screening phase, 8 in the first treatment cycle, 7 in subsequent cycles, and a visit 6 to 12 weeks after the last dose. In the following 12 months, visits are planned every 6 weeks and during the next 48 months phone calls or clinic visits are planned approximately every 12 weeks. In addition, a sub study during the dose escalation part will gather information on the distribution of the study treatment in the body, the proportion that binds to the cancer cells, and the resulting radiation at the tumor site. During the study, the study team will:
• Do physical examinations
• Check vital signs such as blood pressure, heart rate, and body temperature
• Take blood, and urine samples
• Examine heart health using echocardiogram and electrocardiogram (ECG)
• Take tumor samples
• Track 225Ac-pelgi in the body using gamma imaging (generally available at all study sites)
• Check the tumor status using PET (positron emission tomography), CT (computed tomography) or MRI (magnetic resonance imaging) and bone scan
• Ask questions about the impact of the disease on the participants' wellbeing and activities of daily life (Eastern Cooperative Oncology Group Performance status (ECOG PS)).

Conditions

Metastatic Castration-resistant Prostate Cancer

Outcome Measures

Primary Outcomes (8)

• Dose escalation & Dose expansion: The Incidence of treatment-emergent adverse events (TEAEs) including treatment-emergent serious adverse events (TESAEs)

  After first administration of study treatment up to 42 days after the last dose of study treatment

• Dose escalation & Dose expansion: The Severity of TEAEs including TESAEs

  After first administration of study treatment up to 42 days after the last dose of study treatment

• Dose escalation: Incidence of dose limiting toxicities (DLTs) at each 225Ac dose level during the DLT observation period

  DLTs will be summarized by MedDRA system organ class, preferred term and worst CTCAE grade.

  Up to Cycle 3 (each cycle is 42 days)

• Dose escalation: Objective response rate (ORR) at each 225Ac dose level during the DLT observation period

  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.

  Up to Cycle 3 (each cycle is 42 days)

• Dose escalation: ≥50% decline in Prostate-specific antigen value from baseline (Cycle 1, Day 1) (PSA50) response at each 225Ac dose level during the DLT observation period

  PSA partial response is defined as a ≥50% decline in PSA value from Cycle 1 Day 1 (baseline). This PSA decline must be confirmed to be sustained by a second PSA value obtained 3 to 4 or more weeks later.

  Up to Cycle 3 (each cycle is 42 days)

• Dose expansion: Objective response rate (ORR) by Prostate Cancer Working Group 3 (PCWG3) guidelines based on investigator review

  Up to 12 months after End of treatment

• Dose expansion: ≥50% decline in Prostate-specific antigen value from baseline (Cycle 1, Day 1) (PSA50) response at 12 weeks or later

  At 12 weeks or later (up to 12 months after End of treatment)

• Dose expansion: Best overall Prostate-specific antigen (PSA) response

  Up to 12 months after End of treatment

Secondary Outcomes (11)

• Dose escalation & Dose expansion: Radiologic progression-free survival (rPFS ) by PCWG3 based on investigator review

  Up to 12 months after end of treatment

• Dose escalation & Dose expansion: Duration of PSA50 response

  Up to 12 months after end of treatment

• Dose escalation & Dose expansion: Duration of response (DOR) by PCWG3 based on investigator review

  Up to 12 months after end of treatment

• Dose escalation: Recommended dose level(s) of 225Ac-pelgi for dose expansion

  Up to 4 cycles (each cycle is 42 days)

• Dose escalation: Recommended dose schedule of 225Ac-pelgi for dose expansion

  Up to 4 cycles (each cycle is 42 days)

Study Arms (4)

Dose escalation of BAY3546828

EXPERIMENTAL

Participants with advanced metastatic castration-resistant prostate cancer (mCRPC) will receive 225Ac-pelgi dose in a stepwise fashion, according to a predefined dose escalation scheme

Drug: BAY3546828

Dose expansion group A of BAY3546828

EXPERIMENTAL

Participants with advanced mCRPC with at least 1 but no more than 2 prior taxane regimens. No prior radionuclide therapy

Drug: BAY3546828

Dose expansion group B of BAY3546828

EXPERIMENTAL

Participants with advanced mCRPC who have not received taxane chemotherapy since becoming castration-resistant. No prior radionuclide therapy.

Drug: BAY3546828

Dose expansion group C of BAY3546828

EXPERIMENTAL

Participants with advanced mCRPC after prior Lutetium-177 labeled PSMA ligand (177Lu-PSMA) treatment.

Drug: BAY3546828

Interventions

BAY3546828 DRUG

Intravenous (IV) infusion on Day 1 of each cycle.

Dose escalation of BAY3546828; Dose expansion group A of BAY3546828; Dose expansion group B of BAY3546828; Dose expansion group C of BAY3546828

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 taxane therapy 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 \*A taxane regimen consists of a minimum of 2 treatment cycles (maximum number of cycles as per local guidelines). A treatment break within a taxane regimen may be given provided that another anticancer therapy is not administered during that time
• Prior treatment with an established 177Lu-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 tratment 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:
• 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).

You may not qualify if:

• 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) ≥2.5cm 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 ≥ 1cm 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 1cm of enhancing tissue on contrast-enhanced Computer 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 intervention, except luteinizing hormone-releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH). Start of study intervention 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 177Lu PSMA more than 6 weeks before the start of study intervention is required.
• Note: Participants who have discontinued 177Lu-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.
• Dose Expansion (Groups A, B and C): Presence of \>3 liver metastases, any diffuse liver metastasis, or PSMA-non-avid liver metastasis (uptake is lower or equal compared to healthy liver tissue).

Sponsors & Collaborators

• Bayer: lead

Study Sites (28)

City of Hope - Duarte Cancer Center

Duarte, California, 91010, United States

Location

M Health Fairview Masonic Cancer Clinic - Clinics and Surgery Center

Minneapolis, Minnesota, 55455, United States

Location

XCancer Omaha

Omaha, Nebraska, 68130, United States

Location

The University of Texas MD Anderson Cancer Center - Texas Medical Center

Houston, Texas, 77030, United States

Location

Utah Cancer Specialists Cancer Center - Medical Oncology

Salt Lake City, Utah, 84106, United States

Location

Centre Hospitalier de l'Universite de Montreal (CHUM) | Oncology

Montreal, Quebec, H2X 0C1, Canada

Location

McGill University Health Centre (MUHC) - Research Institute (RI) - McConnell Centre for Innovative Medicine (CIM)

Montreal, Quebec, H4A 3J1, Canada

Location

Centre hospitalier universitaire de Sherbrooke (CHUS) | Oncology

Sherbrooke, Quebec, J1H 5N4, Canada

Location

Kuopio University Hospital, Kuopion yliopistollinen sairaala (KYS) - Syövänhoitokeskus

Kuopio, Northern Savonia, 70210, Finland

Location

Tampere University Hospital, Tampereen yliopistollinen sairaala (TAYS) - Syöpäkeskus

Tampere, Pirkanmaa, 33520, Finland

Location

CRST Oy - Clinical Research Services Turku

Turku, Southwest Finland, 20520, Finland

Location

HUS-Yhtymä, Helsingin yliopistollinen sairaala (HUS) - Syöpäkeskus

Helsinki, Uusimaa, 00029, Finland

Location

Docrates Mehiläinen Syöpäsairaala

Helsinki, Uusimaa, 00180, Finland

Location

Istituto Europeo di Oncologia s.r.l - Medicina Nucleare

Milan, 20141, Italy

Location

IRCCS Istituto Nazionale Tumori Fondazione Pascale - S. C. Medicina Nucleare e Terapia Metabolica

Naples, 80131, Italy

Location

Erasmus Medisch Centrum

Rotterdam, South Holland, 3015 CE, Netherlands

Location

Universitair Medisch Centrum Groningen

Groningen, 9713 GZ, Netherlands

Location

Skånes Universitetssjukhus Lund - Onkologens kliniska forskningsenhet

Lund, Skåne County, 221 85, Sweden

Location

Karolinska Universitetssjukhuset - Fas I-enheten Solna CKC

Stockholm, Stockholm County, 171 76, Sweden

Location

Akademiska sjukhuset i Uppsala - Fas 1-enheten

Uppsala, Uppsala County, 751 85, Sweden

Location

Sahlgrenska Universitetssjukhuset - Klinisk prövningsenhet Fas I/FIH

Gothenburg, Västra Götaland County, 413 46, Sweden

Location

Kantonsspital Baden

Baden, Canton of Aargau, 5404, Switzerland

Location

Universitätsspital Basel

Basel, Canton of Basel-City, 4056, Switzerland

Location

Univestitätsspital Zürich (USZ)

Zurich, 8091, Switzerland

Location

Cambridge University Hospitals NHS Foundation Trust | Addenbrookes Hospital - Clinical Research Centre

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

Location

University College London Hospitals NHS Foundation Trust | University College Hospital - NIHR UCLH Clinical Research Facility

London, Greater London, W1T 7HA, United Kingdom

Location

The Royal Marsden NHS Foundation Trust | Sutton - Oak Foundation Drug Development Unit

Sutton, Surrey, SM2 5PT, United Kingdom

Location

The Newcastle upon Tyne Hospitals NHS Foundation Trust | Freeman Hospital - Cancer Trials Research Centre

Newcastle upon Tyne, Tyne and Wear, NE7 7DN, United Kingdom

Location

Related Publications (1)

• Schatz CA, Zitzmann-Kolbe S, Moen I, Klotz M, Nair S, Stargard S, Bjerke RM, Wickstrom Biseth K, Feng YZ, Indrevoll B, Cruciani V, Karlsson J, Haendler B, Nielsen CH, Alfsen MZ, Hammer S, Hennekes H, Cuthbertson A, Hagemann UB, Larsen A. Preclinical Efficacy of a PSMA-Targeted Actinium-225 Conjugate (225Ac-Macropa-Pelgifatamab): A Targeted Alpha Therapy for Prostate Cancer. Clin Cancer Res. 2024 Jun 3;30(11):2531-2544. doi: 10.1158/1078-0432.CCR-23-3746.

  PMID: 38593212 DERIVED

Related Links

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 7, 2023
• First Posted: September 25, 2023
• Study Start: September 20, 2023
• Primary Completion (Estimated): June 8, 2027
• Study Completion (Estimated): August 10, 2031
• Last Updated: April 17, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

IT (2); FI (5); NL (2); CA (3); US (5); CH (3); GB (4); SE (4)