GSK5764227 for Advanced solid tumors|Colorectal cancer|Metastatic prostate cancer

Inclusion criteria

• {"criterion_text":"- Is at least 18 years of age or the legal age of consent in the jurisdiction in which the study is taking place at the time of signing the ICF."}
• {"criterion_text":"- Cohort B: PSA ≥ 1 ng/mL during the screening period."}
• {"criterion_text":"- Cohort B: Serum testosterone level ≤ 50 ng/dL or 1.7 nmol/L during the screening period. 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."}
• {"criterion_text":"- Cohort B: Progression on or intolerance to SoC lines of therapy in the mCRPC stage [including, but not limited to, docetaxel, ARPI/ novel hormone therapies (such as enzalutamide, apalutamide, darolutamide), and radio-ligand therapy, etc.]. Participants who have experienced disease progression while receiving NHA in mHSPC are allowed. •\tIf the participant is intolerant to NHA, refuses it, or cannot receive it for other reasons, they may be eligible if they have experienced disease progression after receiving at least one systemic chemotherapy regimen. •\tFirst-generation antiandrogen therapy (i.e., bicalutamide, flutamide, nilutamide) are not considered a novel hormonal agent or a chemotherapy regimen. Participants who have taken first-generation antiandrogen therapeutic drugs must have a washout period of at least 28 days before enrolment. •\tProgressive disease is defined as (at least one of the following): •\tPSA progression: PSA > 1 ng/mL and 2 consecutive increases in PSA at least 1 week apart (compared to current treatment baseline or the nadir during the treatment period) per PCWG3 criteria; and/or •\tProgression of soft tissue lesions according to RECIST 1.1 criteria; and/or •\tBone lesion progression according to PCWG3 criteria."}
• {"criterion_text":"- Cohort B: Has metastatic prostate cancer that includes: ≥1 measurable soft tissue per RECIST 1.1 (not including regional Lymph Nodes) and/or ≥1 metastatic bone lesion per PCWG3 criteria (not a superscan) on bone scintigraphy, at screening."}
• {"criterion_text":"- Cohort B: Where available, participants should provide an archival tumor sample from the most recent biopsy (FFPE block preferred) of primary cancer or from a metastatic site at screening (preferably taken after the completion of the participant’s last line of therapy prior to the first dose of study drug)."}
• {"criterion_text":"- Has an ECOG performance status of 0 or 1, with no deterioration in the 2 weeks before first dose."}
• {"criterion_text":"- Has adequate organ function."}
• {"criterion_text":"- Cohort A: Has histologically confirmed unresectable adenocarcinoma or unresectable metastatic adenocarcinoma of the colon or rectum (histology defined by WHO classification)."}
• {"criterion_text":"- Cohort A: Must have received at least 1 and no more than 2 lines of systemic treatment for advanced CRC, with documented progression on most recent prior line of therapy Prior lines of therapy must have included treatment with either a fluoropyrimidine, oxaliplatin and/or irinotecan, an anti-VEGF monoclonal antibody and/or an anti-EGFR monoclonal antibody, if the approved biologic therapy(ies) is available. In addition, per local practice guidelines, qualifies for treatment with Bevacizumab and/or 5-FU/LV. •\tParticipants with dMMR/MSI-H status may be eligible if they have received prior ICI therapy (if an approved ICI(s) is available) and also meet all other criteria related to prior therapies as listed above. •\tParticipants with known targetable genomic aberrations may be eligible if they meet all other criteria related to prior therapies as listed above and have received the following (if the approved biomarker-directed therapy/-ies is/are available): •\tKRAS G12C mutation, e.g., adagrasib or sotorasib •\tBRAF V600E mutation, e.g., encorafenib •\tHER2 amplification, e.g., trastuzumab with another agent (NOTE: participants who received treatment with T-DX1 are excluded) •\tParticipants who received neoadjuvant or adjuvant chemotherapy and experienced disease progression during treatment or within 6 months of the EOT may count this therapy as a line of treatment."}
• {"criterion_text":"- Cohort A: Has at least 1 target lesion per RECIST 1.1, as determined by the investigator. Measurable lesions that have been previously irradiated and have been shown to be progressing following irradiation may be considered as target lesions. NOTE: It is preferable not to have a pathological lymph node as a singular target lesion."}
• {"criterion_text":"- Cohort A: Participants must provide tissue from a biopsy taken from primary cancer or metastatic site. Fresh biopsy is preferred. If a fresh biopsy is not feasible, archival FFPE blocks (preferred) or slides from the most recent biopsy are acceptable (preferably taken after the completion of the participant’s last line of therapy prior to the first dose of study drug). Tissue is required for retrospective B7-H3 expression analysis by IHC and other biomarker evaluations. Exceptions may be granted by the medical monitor if tissue is unavailable."}
• {"criterion_text":"- Cohort B: Histologically or cytologically confirmed adenocarcinoma of the prostate."}

Exclusion criteria

• {"criterion_text":"- Has a malignancy (except disease under study) that has progressed or required active treatment within the past 24 months except for basal cell or squamous cell carcinomas of the skin or in-situ carcinomas [e.g., breast, cervix, bladder] that have been resected with no evidence of disease."}
• {"criterion_text":"- Cohort A: Serious non-healing wound, non-healing ulcer or non-healing bone fracture. Note: If the participant has had surgery, the wound must be fully healed prior to first dosing."}
• {"criterion_text":"- Cohort A: Confirmed uncontrolled arterial hypertension (defined as systolic blood pressure ≥ 150 mm Hg and/or diastolic blood pressure ≥ 100 mm Hg) or uncontrolled or symptomatic arrhythmia."}
• {"criterion_text":"- Cohort A: Has a history of nephrotic syndrome or Grade 3 proteinuria. Participants discovered to have ≥2 proteinuria on at screening should undergo a 24 hour urine collection and must demonstrate ≤1 g of protein in 24 hours to be eligible."}
• {"criterion_text":"- Cohort A: Known coagulopathy that increases risk of bleeding, bleeding diatheses. Any other hemorrhage/bleeding event CTCAE grade ≥ 3 within 4 weeks prior to first dosing."}
• {"criterion_text":"- Cohort A: Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to first dosing."}
• {"criterion_text":"- Cohort A: Deep venous thromboembolic event within 3 months prior to first dosing or any previous NCI CTCAE grade 4 venous thromboembolism."}
• {"criterion_text":"- Has known complete DPD deficiency (Cohort A2 only)."}
• {"criterion_text":"- Principal Exclusion Criteria Cohort A: Has received treatment with any of the following within the specified timeframe prior to the first dose of study drug: •\tStrong or moderate inhibitors of CYP3A4, CYP2D6, or inhibitors of P-gp or BCRP, within 7 days prior to the first dose of study drug. •\tStrong or moderate inducers of CYP3A4 or inducers of P-gp, within 14 days prior to the first dose of study drug."}
• {"criterion_text":"- Cohort B: Has serious arteriovenous thromboembolic events (such as deep vein thrombosis, pulmonary embolism, etc.) within 3 months prior to the first dose (except for implantable venous port, catheter-related thrombosis, or superficial vein thrombosis, which are not considered \"serious\" (thromboembolism)."}
• {"criterion_text":"- Cohort B: Has serious or poorly controlled hypertension, including: history of hypertensive crisis, hypertensive encephalopathy; adjustment of antihypertensive medications due to poor blood pressure control within 2 weeks prior to the first dose; or recurrent systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg during Screening period"}
• {"criterion_text":"- Has had any major surgery within 28 days prior to first dose."}
• {"criterion_text":"- Cohort B: Has a history of nephrotic syndrome or Grade 3 proteinuria. Participants discovered to have ≥2 proteinuria on dipstick at screening should undergo a 24 hour urine collection and must demonstrate <2 g of protein in 24 hours to be eligible."}
• {"criterion_text":"- Cohort B: Has received treatment with any of the following within the specified timeframe prior to the first dose of study drug: •\tStrong or moderate inhibitors of CYP3A4, CYP2D6, or strong inhibitors of CYP2C8, or inhibitors of P-gp or BCRP, within 7 days prior to the first dose of study drug. •\tStrong or moderate inducers of CYP3A4 (except enzalutamide) or inducers of P-gp, within 14 days prior to the first dose of study drug. •\tCYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, within 7 days prior to the first dose of enzalutamide."}
• {"criterion_text":"- Has clinically significant bleeding symptoms or significant bleeding tendency within 1 month prior to the first dose."}
• {"criterion_text":"- Has serious infection 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. Participants who are receiving or have received prophylactic antibiotics (e.g., prophylaxis against urinary infections) are allowed."}
• {"criterion_text":"- Has untreated brain or CNS metastases or brain/CNS metastases that have progressed [e.g., evidence of new or enlarging brain metastasis or new neurologic symptoms attributable to brain/CNS metastases]. Participants with previously treated and clinically stable brain/CNS metastases and who have completed all corticosteroid therapy for at least 4 weeks prior to dosing are not excluded from participation."}
• {"criterion_text":"- Any evidence of current ILD or pneumonitis OR a prior history of ILD requiring high-dose glucocorticoids or non infectious pneumonitis requiring high-dose glucocorticoids."}
• {"criterion_text":"- Has a history of 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)."}
• {"criterion_text":"- Has received any prior therapy with an ADC with a TOPO1-inhibitor payload."}
• {"criterion_text":"- Cohort A: History of abdominal or gastrointestinal fistula, tracheoesophageal fistula or any Grade 4 fistula, gastrointestinal perforation, or intra‑abdominal abscess or active clinical concern for bowel obstruction."}

Primary endpoints

• {"endpoint_text":"- Incidence of AEs using NCI-CTCAE v5.0, including DLTs and change in safety parameters: •\tIncidence and severity of AEs/SAEs/AESIs and AEs leading to dose modifications •\tVital signs, body weight, laboratory tests (hematology, clinical chemistry, urinalysis), cardiac function (ECG), and ECOG performance status changes","definition_or_measurement_approach":"Assessed using NCI-CTCAE v5.0 including recording DLTs; includes incidence and severity of AEs/SAEs/AESIs and AEs leading to dose modifications, and monitoring of vital signs, body weight, laboratory tests (hematology, clinical chemistry, urinalysis), ECG and ECOG performance status changes."}

Secondary endpoints

• {"endpoint_text":"- Observed PK concentrations of GSK5764227 (conjugated antibody) and GSK5757810 (payload).","definition_or_measurement_approach":"Pharmacokinetic sampling to measure concentrations of conjugated antibody (GSK5764227) and payload (GSK5757810)."}
• {"endpoint_text":"- ADA and NAb incidence and ADA titers against GSK5764227","definition_or_measurement_approach":"Assessment of anti-drug antibodies (ADA), neutralizing antibodies (NAb) incidence and ADA titers to GSK5764227."}
• {"endpoint_text":"- ORR, defined as the proportion of participants who have achieved BOR of confirmed CR or PR as assessed by investigator, according to RECIST 1.1 (Cohort A) or per PCWG3 (Cohort B).","definition_or_measurement_approach":"Objective Response Rate measured as proportion achieving best overall response (confirmed CR or PR) per investigator assessment using RECIST 1.1 (Cohort A) or PCWG3 (Cohort B)."}
• {"endpoint_text":"- DCR18, defined as the proportion of participants who have achieved CR or PR, or SD of ≥17 weeks as assessed by investigator according to PCWG3 (Cohort B).","definition_or_measurement_approach":"Disease control rate at 18 weeks: proportion with CR or PR or stable disease ≥17 weeks per PCWG3 (Cohort B) as assessed by investigator."}
• {"endpoint_text":"- DoR, defined as the time from the date of the first documented objective response (CR/PR) as assessed by investigator according to RECIST 1.1 (Cohort A) or PCWG3 (Cohort B), until the date of the first documented PD or death due to any cause, whichever is earlier","definition_or_measurement_approach":"Duration of Response measured from first documented CR/PR to first documented progression or death, per RECIST 1.1 (Cohort A) or PCWG3 (Cohort B)."}
• {"endpoint_text":"- PFS defined as the time from the date of first dose until the earliest date of documented disease progression as assessed by investigator according to RECIST 1.1 (Cohort A)","definition_or_measurement_approach":"Progression-free survival measured from first dose to earliest documented disease progression per RECIST 1.1 (Cohort A)."}
• {"endpoint_text":"- rPFS (Cohort B): defined as the time from the date of first dose until the earliest date of documented PD per PCWG3-modified RECIST 1.1 (soft tissue lesion assessment) and/or PCWG3 bone lesion assessment (Cohort B)] or death due to any cause.","definition_or_measurement_approach":"Radiographic PFS for Cohort B measured from first dose to documented progression per PCWG3-modified RECIST 1.1 and/or PCWG3 bone lesion assessment, or death."}
• {"endpoint_text":"- PSA50 response defined as a ≥50% decline in PSA levels from baseline (Cohort B)","definition_or_measurement_approach":"PSA50 defined as ≥50% decline from baseline PSA (Cohort B)."}

Spain

Earliest CTIS Part Ii Submission Date

12-11-2025

Latest Decision Or Authorization Date

21-11-2025

Processing Time Days

9

Number Of Sites

5

Number Of Participants

15

Primary sponsor

Full Name

Glaxosmithkline Research & Development Limited

Organisation Type

Pharmaceutical company

Country Of Registered Address

United Kingdom

Third parties

• {"country":"Spain","full_name":"Sermes CRO","duties_or_roles":"patient fee reimbursement","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Azenta Germany GmbH","duties_or_roles":"Sample storage","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Infinity Biologix LLC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Azenta US Inc.","duties_or_roles":"sample storage","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Iqvia Rds Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Ventana Medical Systems Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Primera Analytical Solutions Corp.","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Ireland","full_name":"Teckro Limited","duties_or_roles":"site engagement platform","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Alcura Health Espana S.A.","duties_or_roles":"medicine product destruction","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Guardant Health Inc.","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}