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DURvalumab in Combination With S-488210/S-488211 vAccine in Non-muscle Invasive Bladder CancEr (DURANCE)

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ClinicalTrials.gov Identifier: NCT04106115
Recruitment Status : Not yet recruiting
First Posted : September 26, 2019
Last Update Posted : September 26, 2019
Sponsor:
Collaborators:
AstraZeneca
Shionogi
Information provided by (Responsible Party):
University College, London

Brief Summary:
DURANCE is a two part, phase Ib/II, multi-centre study to assess the safety and activity of S-488210/S-488211 in combination with durvalumab, in patients with non-muscle invasive bladder cancer (NMIBC).

Condition or disease Intervention/treatment Phase
Bladder Cancer Drug: Durvalumab Biological: S-488210/S-488211 Phase 1 Phase 2

Detailed Description:

DURANCE is a registered, phase Ib/II study in patients with surgically debulked bacillus Calmette-Guerin (BCG) unresponsive (resistant or relapsing) non-muscle invasive bladder cancer (NIMBC). Patients will receive up to 24 weeks of durvalumab (a PD-L1 immune checkpoint inhibitor) in combination with S-488210/S-488211 (a 5-peptide cancer vaccine).

Durvalumab will be given as 1500 mg IV infusion every 4 weeks for up to 7 doses, in combination with S-488210/S-S488211 which will be administered as two subcutaneous injections of S-488210/Montanide and S-488211/Montanide starting the day after the first durvalumab dose, then weekly for 6 doses and every 2 weeks for a further 9 doses (up to a maximum of 16 doses).

The phase Ib part of the DURANCE study will look to assess the safety and tolerability of the treatment combination of durvalumab + S-488210/S-488211 by reviewing Dose Limiting Toxicities (DLTs) which have at least a reasonable possibility of being related to the trial treatments (durvalumab and/or S-488210/S-488211). Up to 14 patients will be registered into the phase Ib and provided the DLTs do not exceed the DLT thresholds defined in the trial protocol, the trial will process to the expansion phase of the study (phase 2). In phase 2 the trial will look to assess the disease free survival rate at 1 year following start of treatment.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : December 2019
Estimated Primary Completion Date : February 2023
Estimated Study Completion Date : February 2027

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer
Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: Durvalumab + S-488210/S-488211
Trial treatment for up to 24 weeks of Durvalumab (1500 mg IV infusion every 4 weeks for up to 7 doses) in combination with S-488210/S-488211 vaccine (given as 2 subcutaneous injections of S-488210/Montanide and S-488211/Montanide starting day after first durvalumab dose, then weekly for the first 6 weeks, and then every 2 weeks for a further 9 doses).
Drug: Durvalumab
1500 mg IV infusion every 4 weeks for up to 7 doses
Other Name: MEDI 4736

Biological: S-488210/S-488211
S-488210/S-488211 is given as a 1 mL subcutaneous (SC) injection of S-488210/Montanide emulsion and a 1 mL SC injection of S-488211/Montanide emulsion starting the day after first dose of durvalumab and continuing weekly for 6 doses and then every 2 weeks for a further 9 doses
Other Names:
  • S-488210/Montanide
  • S-488211/Montanide




Primary Outcome Measures :
  1. Occurrence of Dose Limiting Toxicity (Phase 1b) [ Time Frame: At the end of cycle 1 (cycle 1 is 29 days) ]
    Detailed adverse event monitoring will be conducted, assessed using CTCAE v5. Dose Limiting Toxicity (DLT) is defined as any adverse event or laboratory abnormality detailed in the trial protocol, that has a reasonable possibility of being related to trial treatment and occurring at anytime during the DLT evaluation period (28 days from the first administration of S-488210/S-488211 on cycle 1 day 2).

  2. Pathological Disease Free Survival Rate (DFSR) (Phase 2) [ Time Frame: 1 year after start of treatment ]
    Disease Free Survival will be calculated from start of trial treatment (cycle 1 day 1) until the time at which either primary disease is confirmed to have recurred, any secondary cancer is confirmed or death from any cause. The primary endpoint of Disease Free Survival Rate will be assessed at 1 year from start of treatment (and include patients that start trial treatment and receive combination treatment on cycle 2 day 1) and compared to the historical control rate of 20%.


Secondary Outcome Measures :
  1. 1 year DFSR stratified by HLA-A*02:01 [ Time Frame: 1 year after start of treatment ]
    If the primary endpoint (DFSR) is statistically signification, comparison of DFSR at 1 year will be conducted between patients that are human leukocyte antigen-A (HLA-A*02:01) positive versus negative.

  2. 1 year DFSR stratified by PD-L1 status [ Time Frame: 1 year after start of treatment ]
    DFSR at 1 year stratified by PD-L1 status will be performed.

  3. 1 year DFSR stratified by baseline Tumour Infiltrating Lymphocyte (TIL) status [ Time Frame: 1 year after start of treatment ]
    DFSR at 1 year stratified by TIL status (high, intermediate and low) to assess the distribution of a three-category variable (TIL status) over survival status.

  4. 5 year Overall Survival rate [ Time Frame: 5 years from start of treatment to date of death, if applicable. ]
    Overall survival will be assessed from time of starting treatment to time of death from any cause.

  5. Assessment of Quality of Life using EORTC QLQ-C30 questionnaire [ Time Frame: Assessments will be performed at baseline (prior to starting treatment on cycle 1 days 1), every 12 weeks up to 12 months after start of treatment and 24 months after start of treatment. ]
    Quality of Life assessments will be undertaken using EORTC QLQ-C30 (version 3) questionnaire using Likert score (26 questions scored: 1=not at all, 2=a little, 3=quite a bit, 4=very much; 2 questions scored: 1-7, 1=very poor, 7=excellent) . Descriptions of mean change in EORTC QLQ-C30 scores will be presented and compared to baseline values from pre-treatment.

  6. Assessment of Quality of Life using EQ-5D-5L questionnaire [ Time Frame: Assessments will be performed at baseline (prior to starting treatment on cycle 1 days 1), every 12 weeks up to 12 months after start of treatment and 24 months after start of treatment. ]
    Quality of Life assessments will be undertaken using EQ-5D-5L (self-reported) questionnaire using a combination of Likert score (5 questions with 5 dimensions of abilities) and visual analogue score (scored 0-100, 0=worst, 100=best). Descriptions of mean change in EQ-5D-5L scores will be presented and compared to baseline values from pre-treatment.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically proven high risk non-muscle invasive bladder cancer (NMIBC)
  2. Adequate archival tissue sample available for histological assessment (date sample taken must be within 3 months of registration)
  3. Predominant histologic component (> 50%) must be urothelial (transitional cell) carcinoma
  4. Bacillus Calmette-Guerin (BCG) unresponsive disease
  5. Refused or deemed clinically inappropriate for radical cystectomy
  6. ≥18 years of age
  7. Body weight >30 kg
  8. World Health Organisation (WHO) performance status 0-1
  9. Must have undergone each of the following procedures within 8 weeks of registration:

    • Complete excision of all papillary disease (T1/TaHG). For participants with T1 lesions, restaging trans-urethral resection of bladder tumour (TURBT) must be performed within 4 weeks of the initial TURBT to confirm histologically that there is no muscle invasive disease.
    • Resection of all detectable carcinoma in situ (CIS), where feasible. Fluorescence-guided cystoscopy is encouraged but not mandated.
    • Bladder 'Mapping biopsies' taken.
    • CT of the chest and CT or MRI of the abdomen and pelvis.
  10. Adequate haematological status:

    • Haemoglobin ≥9.0 g/dL
    • Absolute neutrophil count ≥1.5 x 10^9/L (≥150,000 per mm3)
    • Platelet count ≥100 x 10^9/L (≥100,000 per mm3)
    • International Normalised Ratio (INR) ≤1.5 and Activated Partial Thromoplastin Time (APTT) ≤1.5 x Upper Limit Normal (ULN). NB: This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
  11. Adequate liver function:

    • Total bilirubin ≤1.5 X ULN (<3.0 x ULN for patients with Gilbert's syndrome)
    • Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≤2.5 x ULN
  12. Adequate renal function: Measured creatinine clearance ≥40 mL/min or calculated creatinine clearance ≥40 mL/min using Cockcroft-Gault formula 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 informed consent form (ICF) and in this protocol). NB: Consent must be obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
  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 visits, treatment plan, laboratory tests and any other study procedures.

Exclusion Criteria:

  1. Any history of autoimmune or inflammatory disease including (all patients with a history of an autoimmune condition but without active disease in the last 5 years may be included only after consultation with the CI/TMG):

    • Inflammatory bowel disease (e.g. colitis or Crohn's disease)
    • Diverticulitis (with the exception of diverticulosis)
    • Systemic lupus erythematous
    • Sarcoidosis syndrome
    • Wegener syndrome (granulomatosis with polyangitis, Grave's disease, rheumatoid arthritis, hypophysitis, uveitis, etc.)
  2. Patients with prior allogeneic stem cell or solid organ transplantation
  3. Patients who have had 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, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia) or evidence of active pneumonitis on screening chest CT scan (history of radiation pneumonitis in the radiation field is permitted)
  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, this should be confirmed by 2 further ECGs each separated by at least 5 minutes.
  8. Patients with the following risk factors for bowel perforation:

    • History of acute diverticulitis or intra-abdominal abcess in the last 3 years
    • History of mechanical GI obstruction or abdominal carcinomatosis
  9. Any unresolved toxicity CTCAE Grade ≥2 from previous anti-cancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. Patients with any irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the CI/TMG
  10. Receipt of last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, embolisation, monoclonal antibodies) within 30 days prior to first dose of trial treatment. NB: If sufficient washout time has not occurred due to the schedule or pharmacokinetic (PK) properties of an agent, a longer washout period will be required, as agreed by the Trial Management Group (TMG) and/or Chief Investigator (CI).
  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 intravenous (IV) antibiotics within 14 days prior to registration. NB: Patients receiving prophylactic antibiotics (e.g. for prevention of a urinary tract infection or COPD) are eligible
  15. Any psychiatric or other disorder (e.g. brain metastases) that impacts the ability to give informed consent or comply with trial treatment and activities
  16. History of leptomeningeal carcinomatosis
  17. Active infection of tuberculosis (TB) (clinically evaluated in accordance with local guidelines, e.g. clinical history, examination and radiographic findings with or without TB testing as clinically indicated)
  18. Patients must not have had systemic corticosteroid therapy (>10 mg daily prednisolone equivalent) within 14 days prior to registration or concomitant use of other immunosuppressive medications. NB: The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e. for adrenal insufficiency) and mineralocorticoids (e.g. fludrocortisone) are allowed
  19. Administration of a live, attenuated vaccine within 4 weeks prior to start of planned 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 adverse events (AEs), affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis), uncontrolled hypertension, serious chronic gastrointestinal conditions associated with diarrhoea and uncontrolled major seizure disorder
  21. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of trial treatment. This does not include rigid cystoscopy and biopsies
  22. Significant cardiovascular disease, such as:

    • New York Heart Association cardiac disease (Class II or greater)
    • Myocardial infarction within 3 months prior to registration
    • Unstable arrhythmias
    • Unstable angina
  23. Patients with uncontrolled Type 1 diabetes mellitus. Patients controlled on a stable insulin regimen are eligible
  24. Patients with uncontrolled adrenal insufficiency
  25. Patients with active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
  26. Known active primary immune deficiency, including but not limited to, uncontrolled human immunodeficiency virus (HIV) (detectable viral load) or acquired immunodeficiency syndrome (AIDS)-related illness
  27. Women who are pregnant or breast feeding. Female or male patient of reproductive potential who is not willing to employ highly effective birth control from screening to 90 days after the last dose of trial treatment.
  28. Known allergy or hypersensitivity to any of the investigational products or their excipients
  29. Prior randomisation to, or treatment in a previous durvalumab clinical study, regardless of treatment arm assignment
  30. Patients should not donate blood while participating in this study and for at least 90 days following the last dose of trial treatment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04106115


Contacts
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Contact: Rubina Begum 020 7679 9514 ctc.durance@ucl.ac.uk
Contact: Marian Duggan 020 7679 9883 ctc.durance@ucl.ac.uk

Sponsors and Collaborators
University College, London
AstraZeneca
Shionogi
Investigators
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Principal Investigator: Mark Linch University College London Hospital

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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT04106115     History of Changes
Other Study ID Numbers: UCL/121881
First Posted: September 26, 2019    Key Record Dates
Last Update Posted: September 26, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University College, London:
Non-Muscle Invasive Bladder Cancer (NMIBC)
Durvalumab
S-488210/S-488211
Immunotherapy
Vaccine
PD-L1 Inhibitor
BCG unresponsive
Additional relevant MeSH terms:
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Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Durvalumab
Vaccines
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents