Non-muscle-invasive bladder cancer MedDRA version: 20.0 Level: PT Classification code 10005003 Term: Bladder cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Durvalumab
Product Code: MEDI14736
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Durvalumab
Other descriptive name: MEDI14736
Concentration unit: mg mil
Sponsors
Hellenic GenitoUrinaty Cancer Group (HGUCG)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Written informed consent and any locally-required authorization (eg, HIPAA in the USA, EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations 2. Age > 18 years at time of study entry 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 4. Body weight >30kg 5. Diagnosis of high grade, non-muscle invasive urothelial carcinoma. High-grade carcinoma includes the following types a) TaG3 b) T1G3 c) CIS 6. Failure in previous intravesical treatment with Bacillus Calmette Guerin (BCG). Failure in BCG defined as: 6a. Disease refractory to Bacillus Calmette Guerin (BCG) therapy to adequate BCG exposure. BCG refractory disease is defined as If high-grade tumor appears during BCG therapy If high-grade, non-muscle-invasive papillary tumor is present at three months If CIS (without concomitant papillary tumor) is present at three and six months Adequate exposure is defined as a minimum of 5 out of 6 BCG induction doses. Maintenance or re-induction can be used according to local practice but are not mandatory for the definition of adequate exposure. 6b High grade recurrence after an initial response to BCG therapy. 6c. Patients intolerant to adequate BCG exposure, defined as: fewer than 5 instillations of BCG induction therapy No more than one cycle of maintenance BCG therapy 7. Subjects may have received other intravesical or systemic therapies for NMIBC or CIS before or after receiving BCG, as long as they meet the aforementioned criteria for BCG refractory disease. 8. Subjects are not candidates for immediate cystectomy or have elected not to undergo the procedure. 9. Adequate normal organ and marrow function as defined below: a) Haemoglobin = 9.0 g/dL b) Absolute neutrophil count (ANC) > 1500 per mm3 c) Platelet count >100,000 per mm3 d) Serum bilirubin = 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician. e) AST (SGOT)/ALT (SGPT) = 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be = 5x ULN f) Serum creatinine Cl>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance 10. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal subjects. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: a) Women 1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or u
Exclusion criteria
Exclusion criteria: 1. Disease of the upper urinary tract or prostatic urethra 2. ECG with QTcF value >470 ms 3 Participation in another clinical study with an investigational product during the last 4 weeks 4. 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 5. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) within 14 days prior to the first dose of study drug. Immediate postoperative intravesical instillation of epirubicin or mitomycin C is allowed if occurred more than 14 days prior to the first dose of the study drug. 6. 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 Subjects with Grade =2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. Subjects with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician. 7. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable. 8. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. 9. History of allogenic organ transplantation. 10. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]) - more details in protocol. 11. Uncontrolled intercurrent 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 diarrhea, 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 12. History of another primary malignancy with exceptions described in protocol 13. History of leptomeningeal carcinomatosis 14. History of active primary immunodeficiency 15. Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus. Subjects with a past or resolved HBV infection are eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA (see details in protocol) 16. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab with exceptions described in protocol 17. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Subjects, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP. 18. Female subjects who are pregnant
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objectives in the Run-in part of the study is: 1. To assess maximum tolerated dose (MTD) of Durvalumab given intravesically to patients with BCG-refractory NMIBC 2. To reject a possibility of a <10% HGRF rate (futility hypothesis) The primary objective in the Phase II of the study is: Efficacy of intravesical administration of Durvalumab at MTD in patients with BCG-refractory NMIBC assessed by 1-year high-grade-relapse-free (HGRF)-rate;Secondary Objective: Secondary Objective(s) (of Phase II): 1. Assessment of toxicity of the MTD of intravesical Durvalumab administration 2. Assessment of secondary efficacy end points a) First post therapy assessment (within 30 days) and 6-month HGRF rate b) muscle-invasive disease at 1-year 3. Assessment of PD-L1 and VEGF expression, lymphocyte subpopulations and tumor mutational load in tumor tissue obtained before and after durvalumab instillation 4. Assessment of PD-L1 and VEGF in urine samples obtained before and after durvalumab instillation 5. Assessment of Durvalumab systemic absorption after intravesical administration;Primary end point(s): Safety Assessments: Adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESI) will be assessed according to NCI CTCAE v4.03. Efficacy Assessments: Efficacy will be assessed by the high-grade progression-free rate at 1 year (primary end point),30 days after the last durvalumab instillation and 6 months following durvalumab therapy. Failure will be defined as the appearance of TaG3, T1G3 or CIS or muscle-invasive disease following durvalumab therapy. Tumor status will be evaluated with simple white-light cystoscopy and/or transurethral biopsy of suspicious lesions. ;Timepoint(s) of evaluation of this end point: Efficacy will be assessed by the high-grade progression-free rate at 1 year (primary end point),30 days after the last durvalumab instillation and 6 months following durvalumab therapy. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): PD-L1 and VEGF expression, lymphocyte subpopulations and tumor mutational load will be assessed in tumor tissue obtained before and after durvalumab instillation. Tissue will be obtained as part of institutional practice. No additional biopsies for the needs of this study will be performed.;Timepoint(s) of evaluation of this end point: PD-L1 and VEGF levels in urine will be assessed prior to and after the 1st instillation and before the last instillation. | — |
Countries
Greece
Contacts
Public ContactAristotelis Bamias
Hellenic GenitoUrinaty Cancer Group (HGUCG)
Outcome results
None listed