Muscle invasive bladder cancer with pure or mixed urothelial (transitional) cell carcinoma Cancer
Conditions
Interventions
Current interventions as of 30/06/2025:
GUSTO is a multicentre, prospective, open-label, individually randomised, controlled, parallel-group, multi-stage phase II trial of patients with T2-4a N0 M0
stage 2 will confirm feasibility of recruitment and assess the assumptions for the sample size calculation and stage 3 will involve an assessment of treatment outcomes using this stratified approach.
Sponsors
Sheffield Teaching Hospitals NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Current inclusion criteria as of 30/06/2025: Inclusion criteria for registration: 1. Age =18 years 2. Eastern Co-operative Oncology Group (ECOG) performance status 0 or 1 3. Currently considered for neoadjuvant chemotherapy and radical cystectomy with curative intent and suitable for all protocol defined treatment (chemotherapy and immunotherapy as defined for all treatment groups in this protocol) 4. Confirmation of MIBC (full report not required): - high grade pure or mixed urothelial (transitional) cell carcinoma which is at least T1 on histology AND radiological evidence of T2+ N1 cancer OR - high grade pure or mixed urothelial (transitional) cell carcinoma which is at least T2 on histology 5. Written informed consent for registration (PIS-1 and Participant Supplementary Document) Inclusion criteria for randomisation: 1. Diagnosed with MIBC staged as either T2-4a N0 M0, T (any) N1 M0 or T1 on histology with radiological evidence of T2+ or N1 2. Planned for neoadjuvant chemotherapy and radical cystectomy with curative intent and suitable for all protocol defined treatment (chemotherapy and immunotherapy as defined for all treatment groups in the protocol) 3. Confirmation of a pure or mixed urothelial (transitional cell) carcinoma tumour histology based on local institutional pathology reporting 4. ECOG performance status 0 or 1 5. Estimated creatinine clearance rate (using the Cockcroft-Gault formula) of >40 ml/min according to local institutional standard methods for estimation: patients with creatinine clearance = 60 ml/min are eligible for full dose cisplatin; patients with impaired creatinine clearance (40-60 ml/min) are eligible only if split dose cisplatin 35 mg/m2 is given on days 1 and 8 of neoadjuvant treatment. 6. Adequate haematological parameters 6.1. Haemoglobin =90 g/Lb. 6.3 Neutrophil count =1.5 x109 /L 6.2. Platelets =100 x109 /L 7. Adequate biochemical parameters: 7.1. Bilirubin =1.5 x ULN unless due to Gilbert’s syndrome 7.2. ALT and/or AST =1.5 x ULN (both ALT and AST are recommended) 8. Body weight >30 kg 9. Life expectancy of at least 12 weeks 10. For women of childbearing potential, negative blood serum pregnancy test and adequate contraceptive precautions 11. For men of reproductive potential, effective contraception if the risk of conception exists 12. Written informed consent for randomisation (PIS-2 and Participant Supplementary Document) 13. Patients must be able and willing to comply with the terms of the protocol for the duration of the study including treatment, trial visits and assessments _____ Previous inclusion criteria: Inclusion criteria for registration: 1. Age =18 years 2. Eastern Co-operative Oncology Group (ECOG) performance status 0 or 1 3. Currently considered for neoadjuvant chemotherapy and radical cystectomy with curative intent and suitable for all protocol defined treatment (chemotherapy and immunotherapy as defined for all treatment groups in this protocol) 4. Histological confirmation of MIBC with pure or mixed urothelial (transitional) cell carcinoma (full report not required) 5. Written informed consent for registration (PIS-1 and Participant Supplementary Document) Inclusion criteria for randomisation: 1. Diagnosed with MIBC staged as either T2-4a N0 M0 or T (any) N1 M0 2. Planned for neoadjuvant chemotherapy and radical cystectomy with curative intent and suitable for all protocol defined treatment (chemotherapy and immunotherapy as defined for all treatment groups in the pr
Exclusion criteria
Exclusion criteria: Current exclusion criteria as of 30/06/2025: 1. Bladder tumour where a gene expression subtype classification cannot be made 2.TURBT sample processing delay such that >4 weeks from receipt of TURBT sample (from initial or repeat surgery if relevant) at central lab to receipt of gene expression subtype result at site 3. Known or suspected allergy or hypersensitivity reaction to any of the components of study treatment or their excipients for any of the treatment groups in the protocol 4. Active infection likely to impact safety of treatment delivery for any of the study treatment groups in the protocol or radical cystectomy. This includes known active tuberculosis, hepatitis B (known positive HBsAg result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid 5. Active documented autoimmune or inflammatory disorders, including but not limited to, inflammatory bowel disease (e.g., colitis or Crohn’s disease), systemic lupus erythematosus, sarcoidosis, Wegener syndrome (granulomatosis with polyangiitis), Graves’ disease, rheumatoid arthritis and uveitis. Exceptions: vitiligo, alopecia, hypothyroidism that is stable on hormone replacement and any chronic skin condition not requiring systemic therapy and patients with coeliac disease controlled by diet alone. 6. Major surgical procedure grade 2) within the last 6 months 8. Mean QT interval corrected for heart rate =470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart) 9. Uncontrolled concurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise ability of the patient to give written informed consent 10. Any unresolved toxicity NCI CTCAE Grade =2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in inclusion criteria 11. Current or prior use of immunosuppressive medications within 14 days prior to randomisation including, but not limited to, systemic corticosteroids at doses exceeding 10 mg /day of prednisolone or equivalent, methotrexate, azathioprine, and tumour necrosis factor-a blockers. Permitted exceptions include: use prior to imaging procedures in patients with contrast allergies, use of inhaled, topical, and intranasal corticosteroids 12. Radiotherapy treatment to >30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug 13. A current separate other malignancy. Current non-melanoma skin cancer, cervical carcinoma in situ or incidental localised prostate cancer is permissible. Other prior malignancy is acceptable if treatment within GUSTO is given with curative intent 14. Any concurrent chem
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| GUSTO has been designed with three interim stages and each stage has a separate set of objectives and endpoints: Stage 1 (to be assessed once the trial has been open to recruitment for 6 months): 1. Recruitment, defined as the number of patients randomised within the first 6 months of the trial opening. 2. Time to return of gene expression subtype allocation, defined as the time from the date the sample is received by the Sheffield central laboratory to the date the gene expression subtype allocation is entered onto the lab-specific database. 3. Gene expression subtype allocation success rate, defined as the proportion of samples sent to the Sheffield central laboratory which are successfully allocated a gene expression subtype. Stage 2 (be assessed once the trial has been open to recruitment for 24 months): 1. Recruitment, defined as the number of patients randomised within the first 24 months of the trial opening. 2. Gene expression subtype distribution, defined as the proportion of samples (of those successfully allocated a gene expression subtype) in each gene expression subtype. 3. Pathological complete response rate in the standard care arm by gene expression subtype, defined as the proportion of patients within each gene expression subtype who are defined as having a pathological complete response according to local pathologist report (pT0) at RC. 4. Confirmation/re-estimation of sample size Stage 3: Pathological complete response rate by gene expression subtype in the gene expression subtype-guided arm post-cystectomy An interim assessment of gene-expression subtype pathological response rate will take place once all randomised participants have completed cystectomy or are known not to be proceeding to cystectomy. Final analysis will take place once all randomised participants have been followed up for 12 months post-cystectomy. At this later point, the stage 1 and 2 endpoints will be re-evaluated. | — |
Secondary
| Measure | Time frame |
|---|---|
| Gene expression subtype endpoints (to be assessed once all randomised participants have been followed up for 12 months post-cystectomy): 1. RNA quality and mass/yield, defined as the quality and yield of the samples tested at Sheffield central laboratory. RNA quality will be measured using two measures: the 260:230 ratio and the 260:280 ratio. RNA yield will be measured in nanograms per microlitre (ng/uL). 2. Gene expression subtype allocation re-test rate and repeat assay success rate, defined as the proportion of samples sent to the Sheffield central laboratory which require retesting, and the proportion of those re-tested samples which are successfully allocated a gene expression subtype after re-testing. 3. Time from patient consent to TURBT sample dispatch, defined as the time from a patient consenting to gene expression subtyping to the time their TURBT sample is sent for gene expression profiling. 4. Time to RNA extraction, processing and gene expression subtype allocation, defined as the time from the sample being received in Sheffield to RNA extraction/processing/gene expression subtype allocation, respectively. Clinical secondary endpoints (to be assessed once all randomised participants have been followed up for 12 months post-cystectomy): 1. Disease-free survival (DFS) at 12 months post-cystectomy and at the end of the trial for all consenting patients registered and all patients randomised into the trial. Disease-free survival for randomised participants is defined as the time from the date of RC to the first recurrence of disease post-RC, or death due to any cause or last follow-up. DFS will be assessed in patients who undergo RC and are disease free at adjuvant baseline visit. If a participant has not had disease recurrence or is still alive at the time of analysis or lost to follow-up before disease recurrence/death is documented, they will be censored at the last date known alive. Participants discontinuing protocol treatment or receiving non-proto | — |
Countries
England, Scotland, United Kingdom
Contacts
Public ContactRuby Lister-Whelan
Outcome results
None listed