A Phase 1/2 First-Time-in-Human study of GSK5458514 administered alone or in combination with other anti-cancer agents in participants with mCRPC

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Glaxosmithkline Research & Development Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

16 Jan 2026 → ongoing

Decision date (initial)

2025-11-03

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2025-521581-10-00

ClinicalTrials.gov

NCT06990880

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Dose response, Pharmacokinetic, Safety, Efficacy

To determine the Maximum tolerated dose (MTD)/ Maximum administered dose (MAD) and evaluate the safety and tolerability of GSK5458514 in participants with mCRPC

Secondary objectives 3

1. To assess the pharmacokinetic (PK) profile of GSK5458514 in serum
2. To assess the immunogenicity against GSK5458514
3. To evaluate the clinical activity of GSK5458514 in participants with mCRPC

Conditions and MedDRA coding

Neoplasms, Prostate

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal. Details on GSK's data sharing criteria can be found at: https://www.gsk.com/en-gb/innovation/trials/data-transparency/

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Provide signed informed consent. Participants must be capable of providing informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol
2. Male participants 18 years of age or older (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of signing the ICF. Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 195 days, after the last dose of study intervention: Refrain from donating sperm PLUS either: Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent. OR Must agree to use contraception as detailed below: Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant.
3. Participants with mCRPC: o Histologically or cytologically confirmed adenocarcinoma of the prostate o Metastatic disease diagnosed either by radiologic imaging (Positron emission tomography [PET]- Computed tomography [CT]) and/or regular CT and/or Magnetic resonance imaging (MRI) and/or bone scan o Castration-resistant status as per PCWG3 criteria
4. Has prior novel anti-androgen receptor therapy failure and had treatment failure with 1-2 taxane-based chemotherapy regimens including for metastatic hormone sensitive prostate cancer
5. Has (1) at least 1 soft tissue Target Lesion per PCWG3-modified RECIST 1.1, OR (2) if Non-Target soft tissue disease only per PCWG3-modified RECIST 1.1, may be included if a rise in PSA on 2 successive determinations at least 1 week apart (the most recent screening measurement must have been ≥ 2 ng/mL) with testosterone levels <50 ng/dL, OR (3) bone disease defined by PCWG3 (2 or more lesions on bone scan at screening), as determined by the investigator
6. Documented disease progression on most recent systemic therapy defined by fulfilling at least 1 of the PCWG3 criteria
7. Have serum testosterone <50 ng/dL (<1.7 nM). Patients must have undergone bilateral orchiectomy or be on continuous androgen-deprivation therapy with a GnRH agonist or antagonist; this therapy must have been initiated at least 4 weeks prior to randomization and treatment must be continued throughout the study
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤1, with no deterioration in the 2 weeks before step-up treatment period Day 1
9. Have supplied tumor tissue from a newly obtained biopsy or archival tumor tissue for retrospective detection of Prostate-specific membrane antigen (PSMA) expression and other biomarker analysis. Tissue from a newly obtained biopsy is preferred. If a newly obtained biopsy is not feasible, archival tumor tissue preferably taken after the completion of the participant’s last line of therapy prior to the first dose of study drug is acceptable
10. Participants must have adequate organ function

Exclusion criteria 21

1. Pathological finding consistent with small cell, neuroendocrine carcinoma of the prostate or any histology different from adenocarcinoma
2. History of central nervous system (CNS) metastases or leptomeningeal disease
3. Diagnosis of invasive malignancy or history of invasive malignancy other than the disease under study within the last 5 years, except as noted below: o History of an invasive malignancy for which the participant was definitively treated, and in which the participant has been disease free for at least 2 years, and which, in the opinion of the principal investigator and medical monitor, is not expected to affect the evaluation of the effects of the study intervention on the currently targeted disease under study o Curatively treated basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, and/or in situ breast cancer may be enrolled
4. Has ongoing adverse reaction(s) from prior therapy that have not recovered to ≤Grade 1 or to the baseline status preceding prior therapy, excluding [e.g., alopecia, hearing loss, vitiligo, endocrinopathy managed with replacement therapy, and Grade 2 neuropathy], or that the investigator, with the agreement of the sponsor, considers to be stable and not clinically relevant for the tolerability of study intervention in the current clinical study
5. Confirmed history or recurrent autoimmune disease that has required systemic treatments in the 2 years prior to screening. Participants with prior history of autoimmune disease must be discussed with the medical monitor. Replacement therapy is not considered a form of systemic therapy (e.g., thyroid hormone for autoimmune thyroiditis or insulin is not exclusionary)
6. Has evidence of interstitial lung disease, non-infectious pneumonitis, and/or a history of interstitial lung disease, non-infectious pneumonitis that required steroid
7. Any anti-cancer therapy or prior systemic biologic therapy, including immunotherapy within 4 weeks of start dose
8. Prior PSMA radionuclide therapy within 2 months prior to GSK5458514 unless participant received <2 cycles
9. Prior PSMA-Chimeric antigen receptor T cell therapy (CAR-T) cell therapy and PSMA (T cell engager) TCE/ Bispecific T cell engagers (BiTE) or other prostate tumor-associated antigens (TAA) specific TCE
10. Has any history of prior allogenic or autologous bone marrow transplant or other solid organ transplant
11. Has known sensitivity to study intervention components or excipients or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study
12. History of severe neurological or psychiatric disorder, including epilepsy, dementia, or major depression deemed to interfere with study assessments
13. Has had any major surgery (such as craniotomy, thoracotomy, or laparotomy, etc.) within 4 weeks prior to first dose of study intervention
14. Serious infections within 4 weeks prior to the first dose, including but not limited to infectious complications, bacteremia, severe pneumonia treated with IV antibiotics for ≥2 weeks; active infections with therapeutic IV antibiotics within 2 weeks prior to the first dose or oral antibiotics within 1 week prior to the first dose. Participants who are receiving or have received prophylactic antibiotics (e.g., prophylaxis against urinary infections) are allowed
15. Has an Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) value >2.5x upper limit of normal (ULN) or >5x ULN if documented history of liver metastases
16. Has a total bilirubin value >1.5x ULN NOTE: Participants with Gilbert’s syndrome can be included with a total bilirubin value >1.5x ULN, provided direct bilirubin is ≤1.5x ULN and participant otherwise meets entry criteria
17. Has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, or persistent jaundice. NOTE: Stable noncirrhotic chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if the participant otherwise meets entry criteria.
18. Has documented presence of Hepatitis B surface antigen (HBsAg), at screening or within 3 months prior to the first dose of study intervention NOTE: Participants who are considered high-risk or from countries with intermediate/high HBV endemicity (per WHO guidelines [WHO, 2017]), and who are negative for HBsAg and HBcAb but positive for HbsAb, will also be tested for HBV DNA to rule out occult HBV.
19. Has a positive Hepatitis C virus (HCV) antibody test result at screening or within 3 months prior to Cycle 1 Day 1 unless the participant can meet the following criteria. NOTE: Participants with a positive HCV antibody test result due to prior resolved disease can be enrolled if a confirmatory negative HCV RNA test is obtained and the participant otherwise meets entry criteria.
20. Has a positive Hepatitis C virus (HCV) RNA test result at screening or within 3 months prior to the first dose of study intervention NOTE: The HCV RNA test is optional, and participants with a negative HCV antibody test are not required to undergo HCV RNA testing as well
21. Is unable to adhere to the protocol defined SoA, including requirements for the Follow-up Period of the study, study procedures, restrictions, and requirements as determined by the investigator

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Number of participants with dose limiting toxicities (DLTs) during DLT observation period
2. Number of participants with adverse events (AEs), serious adverse events (SAEs), by Severity
3. Number of participants with AEs leading to dose modifications

Secondary endpoints 5

1. GSK5458514 PK parameters following IV dose administration, as data permit - Area under concentration from 0 to t (AUC 0‑t) of GSK5458514 - Maximum concentration (Cmax) of GSK5458514
2. Number of participants with Anti-drug antibodies (ADA) against GSK5458514
3. Titers of Anti-drug antibodies (ADA) against GSK5458514
4. Prostate-specific antigen decrease from baseline >=50% (PSA50) Response Rate
5. Objective Response Rate (ORR)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Glaxosmithkline Research & Development Limited

Sponsor organisation

Glaxosmithkline Research & Development Limited

Address

79 New Oxford Street

City

London

Postcode

WC1A 1DG

Country

United Kingdom

Scientific contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Public contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Third parties 6

Locations

2 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 21 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications