Inclusion criteria, exclusion criteria and study summary
Inclusion criteria for registration: 1. Age ≥ 18 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 this protocol) 3. Confirmation of a pure or mixed urothelial (transitional cell) carcinoma (UC) tumour histology based on local institutional pathology reporting 4. ECOG performance status 0 or 1 5. Estimated glomerular filtration rate of ≥ 60 ml/min according to local institutional standard methods for estimation (For patients with impaired GFR (40-60 ml/min) a split dose cisplatin 35 mg/m2 on days 1 and 8 is permitted.) 6. Adequate haematological parameters a. Haemoglobin ≥ 90 g/L b. Neutrophil count ≥ 1.0 x109 /L c. Platelets ≥ 100 x109 /L 7. Adequate biochemical parameters a. Bilirubin ≤ 1.5 x ULN unless due to Gilbert’s syndrome b. 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
Exclusion criteria for randomisation 1. A bladder tumour where a gene expression subtype classification cannot be made 2. A delay in TURBT sample processing such that it is > 4 weeks from receipt of TURBT sample at central laboratory 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 this protocol 4. Active infection likely to impact safety of treatment delivery for any of the treatment groups in this 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 (RNA) 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. The following are exceptions to this criterion: vitiligo,alopecia,hypothyroidism that is stable on hormone replacement and any chronic skin condition that does not require systemic therapy 6. Major surgical procedure (as defined by the treating clinician) within 28 days prior to randomisation 7. Coronary artery bypass graft,angioplasty,vascular stent,myocardial infarction,unstable angina pectoris or congestive cardiac failure (New York Heart Association > 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 the 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 the inclusion criteria a. Patients with Grade ≥2 neuropathy must be evaluated on a case-by-case basis after consultation with the Chief Investigator (or delegate). b. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab,tremelimumab,cisplatin or gemcitabine may be included only after consultation with the Chief Investigator (or delegate). 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-α 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 more than 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 the GUSTO trial would be given with curative intent in the view of the principal investigator and the local multi-disciplinary team 14. Any concurrent chemotherapy,biologic,or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g.,hormone replacement therapy) is acceptable 15. Women who are breastfeeding 16. History of allogenic organ transplantation 17. History of leptomeningeal carcinomatosis 18. History of primary immunodeficiency 19. Receipt of live attenuated vaccine within 30 days prior to randomisation. 20. Prior randomisation or treatment in a previous durvalumab clinical study regardless of treatment arm assignment. 21. Patients who have received prior anti–PD-1 (including durvalumab),anti PD-L1 or anti CTLA-4 (including tremelimumab): a. Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy. b. All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study. c. Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of ≤Grade 2 are eligible if they are stably maintained on appropriate replacement therapy and are asymptomatic. d. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE,not have experienced recurrence of an AE if re-challenged,and not currently require maintenance doses of > 10 mg prednisone or equivalent per day.
GUSTO is a multicentre,prospective,open-label,individually randomised,controlled,parallel-group,multi-stage phase II trial of patients with T2-4a N0 M0 MIBC or T(any) N1 M0 MIBC who are suitable for NAC with cisplatin and gemcitabine prior to radical cystectomy. The trial will assess whether the use of gene expression subtype stratified care using the GUSTO Classifier (Decipher Bladder platform and TCGA 2 classification system),to assign patients to whether they receive NAC and/or immunotherapy (durvalumab / tremelimumab),demonstrates sufficiently improved treatment activity to warrant a phase III trial. Stage 1 will assess the feasibility of both recruitment and the embedding of gene expression subtype stratification into the clinical pathway; 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. Movement between trial stages will be dependent upon the meeting of pre-defined progression criteria. The trial plans to recruit 320 participants over a 3-year period and the total sample size will be confirmed or re-estimated at the end of stage 2. The final sample size will depend on whether the frequencies of gene expression subtype and pathological complete response (pCR) rate in the standard care arm are as assumed based on available evidence,and whether the trial continues to stage 3. The sample size proposed (320) is based on a single-arm assessment within the gene expression subtype-guided arm,where the randomisation to the standard care arm will enable the correct design parameters to be estimated and a secondary unpowered randomised comparison to be carried out. Conducting a larger phase II study with powered randomised comparisons is considered infeasible in a reasonable timeframe. Eligible participants will be randomised via minimisation in a 1:1 ratio to receive either neoadjuvant chemotherapy (cisplatin and gemcitabine) prior to radical cystectomy (standard treatment) or to have radical cystectomy with neoadjuvant and adjuvant chemo/immunotherapy treatment (cisplatin,gemcitabine,durvalumab and tremelimumab) determined based on the gene expression subtype assigned by the GUSTO Classifier. Participants in the standard care arm (and local investigators) will remain blinded to gene expression subtype category. Outcomes will be collected at cystectomy and at 3,6,and 12 months post-cystectomy.
