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Trial Details
Trial status:
Recruitment start date:
01/07/2021
Funder:
AstraZeneca and Shionogi & Co. Ltd
Sponsor:
UCL
Chief Investigator:
Dr Mark Linch
Recruitment target:
64 (Phase Ib: 14; Phase II: 50)
EudraCT number:
2019-002312-50
Contact details:
ctc.durance@ucl.ac.uk
Lay summary:
DURANCE
A phase Ib/II study to assess the safety and activity of DURvalumab (MEDI4736) in combination with S-488210/S-488211 vAccine in Non-muscle invasive bladder CancEr
Description
Design:
DURANCE is a multi-centre, phase Ib/II, single-arm study looking at the safety and activity of combining durvalumab (a checkpoint inhibitor) with S-488210/S-488211 (a novel cancer peptide vaccine) in patients with non-muscle invasive bladder cancer (NMIBC). 

The study will be conducted in two parts:
  • Phase Ib: 14 patients will be registered to assess the safety of the combined durvalumab and S-488210/S-488211 treatment by evaluating dose limiting toxicities (DLTs)
  • Phase II: further 50 patients will be recruited to assess the efficacy of the combination treatment (patients recruited to the phase Ib will also included in the evaluation of efficacy) 

Treatment:
A total of 64 patients will be registered to receive the following treatment: 
  • Durvalumab, 1500 mg IV infusion every 4 weeks for up to 7 doses
  • S-488210/S-488211 as two 1mL subcutaneous injections of S-488210/Montanide and S-488211/Montanide for up to 16 doses - starting on cycle 1 day 2 (the day after the first dose of durvalumab), then once weekly for 6 week, and then once every 2 weeks for a further 9 doses
All patients must have a cystoscopy examination at the end of week 12 after starting treatment to visualise the tumour. If the cystoscopy reveals incomplete response to trial treatment or disease progression, patients will be withdrawn from further treatment and followed up as per protocol. All patients with confirmed complete response at week 12 will continue onto receive a further 12 weeks of treatment (up to 24 weeks of treatment in total).

Patients will be followed up every 3 months from start of treatment up to 1 year, then annually up for 5 years from the start of trial treatment. 
Key inclusion/exclusion criteria:
Inclusion Criteria:
  1. Histologically proven high-risk non-muscle invasive bladder cancer (high-risk tumours include any of the following features: T1 lesions, high-grade disease, tumours larger than 3 cm, multiple or recurrent lesions, and CIS) 
  2. Adequate archival tissue sample available for histological assessment 
  3. Predominant histologic component (>50%) must be urothelial (transitional cell) carcinoma 
  4. BCG unresponsive disease (i. persistent high-risk NMIBC, ii. stage or grade progression, or iii. recurrence of high-risk NMIBC after disease-free period - despite receiving adequate course of BCG) or intolerable to BCG therapy
  5. Refused or deemed clinically inappropriate for radical cystectomy 
  6. ≥18 years of age 
  7. Body weight >30 kg 
  8. WHO performance status 0-1 
  9. Must have undergone each of the following procedures within 8 weeks of registration: (i) Complete excision of all papillary disease (T1/TaHG) and demonstration of no muscle invasive disease in the resected specimen (ii) Bladder ‘Mapping biopsies’ taken (iii) CT of the chest (iv) CT urogram or MRI of the abdomen and pelvis (if CT is not possible) 
  10. Adequate haematological status: (i) Haemoglobin ≥9.0 g/dL (ii) Absolute neutrophil count ≥1.5 x 10^9/L (iii) Platelet count ≥100 x 10^9/L (iv) INR and APTT ≤1.5 x ULN  
  11. Adequate liver function: (i) Total bilirubin ≤1.5 X ULN (ii) AST or ALT ≤2.5 x ULN  
  12. Adequate renal function: Measured creatinine clearance or calculated creatinine clearance using Cockcroft-Gault formula of ≥40 mL/min, or by 24-hour urine collection for determination of creatinine clearance) 
  13. Life expectancy of ≥6 months 
  14. Willing and able to give informed consent (which includes compliance with the requirements and restrictions listed in the patient information sheet and trial protocol) 
  15. Patients of child-bearing potential and male patients with female partners of child-bearing potential must agree to use highly effective contraception methods from date of consent, which must be continued for up to 90 days after last treatment administration. 
  16. Female patients must not be pregnant. There should be sufficient evidence of post-menopausal status or a negative serum pregnancy test for pre-menopausal female patients 
  17. Willingness and ability to comply with scheduled visit, treatment plan, laboratory tests and any other study procedures 
Exclusion Criteria: 
  1. Any history of autoimmune or inflammatory disease including: inflammatory bowel disease, diverticulitis, SLE, sarcoidosis syndrome, wegener syndrome (Exceptions: thyroid disease on stable treatment, any chronic skin condition that does not require systemic corticosteroid therapy)
  2. Prior allogeneic stem cell or solid organ transplantation
  3. Prior treatment with anti- PD-1, PD-L1 or CTLA-4 monoclonal antibody or other novel immune-oncology agent(s)
  4. Active invasive malignancy in the previous 2 years excluding non-melanoma skin cancer
  5. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organising pneumonia or evidence of active pneumonitis on screening chest CT scan
  6. Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
  7. QTcF value of >470 ms. If prolonged, should be confirmed by 2 further ECGs each at least 5 minutes apart
  8. Patients with risk factors for bowel perforation: (i) history of acute diverticulitis or intra-abdominal abcess in the last 3 years (ii) history of mechanical GI obstruction or abdominal carcinomatosis 
  9. Any unresolved toxicity Grade ≥2 from previous anti-cancer therapy with the exception of alopecia, vitiligo and laboratory values defined in the inclusion criteria  
  10. Receipt of last dose of anti-cancer therapy within 30 days prior to first dose of trial treatment 
  11. Treatment with any experimental drug within 30 days or 5 half-lives (whichever is longer) of the first dose of trial treatment
  12. Concurrent enrolment in another clinical study, unless it is an observational/ non-interventional clinical study or during the follow-up period of an interventional study
  13. Any evidence of severe or uncontrolled systemic diseases or laboratory finding that in the view of the investigator makes it undesirable for the patient to participate in the trial
  14. Received therapeutic oral antibiotics that cannot be discontinued at least 14 days prior to starting treatment or received IV antibiotics within 14 days prior to registration 
  15. Any psychiatric or other disorder that impacts the ability to give informed consent or comply with trial treatment and activities
  16. History of leptomeningeal carcinomatosis
  17. Active infection of TB (clinically evaluated in accordance with local guidelines)
  18. Patients must not have had systemic corticosteroid therapy (>10 mg daily prednisone equivalent) within 14 days prior to registration or concomitant use of other immunosuppressive medications 
  19. Administration of a live, attenuated vaccine within 4 weeks prior to planned start of treatment or anticipation that such a live, attenuated vaccine will be required during the study
  20. Evidence of significant uncontrolled concomitant disease that could substantially increase the risk of incurring AEs, affect compliance with the protocol or interpretation of results, including significant liver disease, uncontrolled hypertension, serious chronic GI conditions associated with diarrhoea and uncontrolled major seizure disorder
  21. Major surgical procedure within 28 days prior to first dose of treatment
  22. Significant cardiovascular disease (as outlined in the protocol)
  23. Uncontrolled Type 1 diabetes (eligible if controlled on a stable insulin regimen)
  24. Uncontrolled adrenal insufficiency
  25. Active hepatitis infection or hepatitis C (HCV). Patients with past hepatitis B virus infection or resolved infection are eligible. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA
  26. Known active primary immune deficiency, including uncontrolled HIV (detectable viral load) or AIDS-related illness
  27. Women who are pregnant or breast feeding
  28. Known allergy or hypersensitivity to any of the IMPs or their excipients 
  29. Prior enrollment to, or treatment in a previous durvalumab clinical study
  30. Must not donate blood while participating in this study and for at least 90 days following the last dose of trial treatment
Duration of recruitment: 24 months
Aim
Phase Ib: To evaluation the safety and tolerability of S-488210/S-488211 in combination with durvalumab in patients with NMIBC

Phase Ib & II: To assess the efficacy of S-488210/S-488211 in combination with durvalumab
Trial protocols
Trial protocols must not be applied to patients treated outside trials. UCL CTC can only ensure that approved trial investigators are provided with amendments to protocols.
No protocols have been currently made available for download
Trial documents
No documents have been currently made available for download
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