Clinical Trials /

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

NCT04106115

Description:

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).

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: DURvalumab in Combination With S-488210/S-488211 vAccine in Non-muscle Invasive Bladder CancEr
  • 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

Clinical Trial IDs

  • ORG STUDY ID: UCL/121881
  • NCT ID: NCT04106115

Conditions

  • Bladder Cancer

Interventions

DrugSynonymsArms
DurvalumabMEDI 4736Durvalumab + S-488210/S-488211
S-488210/S-488211S-488210/Montanide, S-488211/MontanideDurvalumab + S-488210/S-488211

Purpose

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).

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.
    

Trial Arms

NameTypeDescriptionInterventions
Durvalumab + S-488210/S-488211ExperimentalTrial 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).
  • Durvalumab
  • S-488210/S-488211

Eligibility 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 planned start of treatment)

          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) and demonstration of no
                  muscle invasive disease in the resected specimens (muscle must be present in the
                  tumour sample)

               -  Bladder 'Mapping biopsies' taken

               -  CT of the chest

               -  CT Urogram or MRI of the abdomen and pelvis (if CT is not possible)

         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 patient information sheet (PIS) 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 (SLE)

               -  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 patients
             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 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 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 enrolment to, or treatment in a previous durvalumab clinical study, regardless
             of treatment arm assignment

         30. Patients must not donate blood while participating in this study and for at least 90
             days following the last dose of trial treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Occurrence of Dose Limiting Toxicity (Phase 1b)
Time Frame:At the end of cycle 1 (cycle 1 is 29 days)
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:1 year DFSR stratified by HLA-A*02:01
Time Frame:1 year after start of treatment
Safety Issue:
Description: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.
Measure:5 year Overall Survival rate
Time Frame:5 years from start of treatment to date of death, if applicable.
Safety Issue:
Description:Overall survival will be assessed from time of starting treatment to time of death from any cause.
Measure:5 year Overall Survival rate stratified by HLA-A*02:01
Time Frame:5 years from start of treatment to date of death, if applicable.
Safety Issue:
Description:Overall survival will be assessed from time of starting treatment to time of death from any cause, stratified by HLA-A*02:01 positive or negative.
Measure: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.
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University College, London

Trial Keywords

  • Non-Muscle Invasive Bladder Cancer (NMIBC)
  • Durvalumab
  • S-488210/S-488211
  • Immunotherapy
  • Vaccine
  • PD-L1 Inhibitor
  • BCG unresponsive

Last Updated

December 16, 2019