Efficacy of Durvalumab in Non-muscle-invasive Bladder Cancer

NCT03759496 | Unknown Phase 2

• 2 other identifiers: ESR-16-126112018-002100-13
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

Brief Summary

Research Hypothesis Approximately 75% of patients with bladder cancer (BC) present with a disease confined to the mucosa (stage Ta, CIS) or submucosa (stage T1) (non-muscle invasive BC \[NMIBC\]). For high grade NMIBC, i.e. TaG3, T1G3 and CIS, intravesical bacillus Calmette-Guérin (BCG) immunotherapy is the treatment of choice, given that it prevents recurrence and reduces the odds of progression to MIBC. However, since initial BCG therapy fails in approximately 40% of patients over a 2-year period, new treatment options for these patients are of utmost importance. In that field of research durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), demonstrated meaningful clinical activity as well as manageable safety profile in PD-L1-positive patients with BC, many of whom were heavily pretreated. Certain studies using systemic administration of anti-PD1 agents for BCG refractory NMIBC are ongoing. Nevertheless, intravesical administration may be advantageous, since selective bladder tumor uptake of monoclonal antibodies following intravesical administration, while this method results in negligible absorption in the circulation and, therefore, minimal risk of systemic toxicity. This notion is supported by the findings of a recent study of intravesical administration of recombinant adenovirus-mediated interferon-α2b gene therapy (rAd-IFNα), No rAd-IFNα DNA was detected in the blood. Furthermore, no systemic toxicity was reported in a phase II study using the same agent. The investigators, therefore, propose a phase II study of intravesical administration of durvalumab in patients with BCG refractory NMIBC. Since no safety or efficacy data specifically on intravesical administration of durvalumab exist, a run-in part will precede the main phase II, in order to confirm safety of the procedure and to reject a futility hypothesis, as described in the following sections of the protocol. Correlative studies of potential biomarkers in tumor tissue before and after durvalumab instillation are also proposed.

Conditions

Bladder Cancer

Keywords

bladder; durvalumab; cancer

Outcome Measures

Primary Outcomes (3)

• The maximum tolerated dose (MTD) of Durvalumab among 500mg, 750mg and 1000mg that will be given intravesically to patients with BCG-refractory NMIBC

  6 months after trial initiation

• The possibility of a rate of high-grade relapse free (HGFR) that it is defined as the development of TaG3, T1G3, CIS or muscle-invasive disease after the initiation of durvalumab therapy.

  6 months after trial initiation

• Efficacy of intravesical administration of Durvalumab at MTD in patients with BCG-refractory NMIBC assessed by 1-year high-grade-relapse-free (HGRF)-rate

  1 year after patient enrollment

Secondary Outcomes (4)

• Toxicity of the MTD of intravesical Durvalumab administration assessed according to the NCI CTC version 4.03 except from local irritation.

  6 months after trial initiation

• Efficacy assessed by the high-grade progression-free rate at 30 days after the last durvalumab instillation and 6 months following durvalumab therapy.

  30 days and 6 month after last durvalumab instillation

• PD-L1 and VEGF expression assessed in tumor tissue obtained before and after durvalumab instillation

  33 months after FPFV

• Assessment of PD-L1 and VEGF protein levels in urine samples obtained before and after durvalumab instillation

  33 months after FPFV

Study Arms (1)

Durvalumab treated patients

EXPERIMENTAL

Subjects will receive up to 1000mg durvalumab (MEDI4736) via weekly intravesical administration, for up to a maximum of 6 weeks or until confirmed progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.

Biological: Durvalumab

Interventions

Durvalumab BIOLOGICAL

Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass

Also known as: MEDI4736

Durvalumab treated patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Age \> 18 years at time of study entry
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Body weight \>30kg
• Diagnosis of high grade, non-muscle invasive urothelial carcinoma. High-grade carcinoma includes the following types
• TaG3
• T1G3
• CIS
• Tumors with combinations of the above types or containing low grade components in addition to the high-grade component are acceptable. 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 (with or 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. Μaintenance or re-induction can be used according to local practice but are not mandatory for the definition of adequate exposure.
• High grade recurrence after an initial response to BCG therapy.
• Patients intolerant to adequate BCG exposure, defined as
• fewer than 5 instillations of BCG induction therapy

You may not qualify if:

• Disease of the upper urinary tract or prostatic urethra
• ECG with QTcF value \>470 ms
• Participation in another clinical study with an investigational product during the last 4 weeks
• 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
• 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.
• 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.
• 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.
• History of allogenic organ transplantation.
• 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.
• 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
• History of another primary malignancy with exceptions described in protocol
• History of leptomeningeal carcinomatosis
• History of active primary immunodeficiency
• 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)
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab with exceptions described in protocol

Sponsors & Collaborators

• Hellenic GenitoUrinary Cancer Group: lead

Study Sites (1)

Hellenic GenitoUrinary Cancer Group

Athens, Attica, 11527, Greece

Location

Related Publications (1)

• Fragkoulis C, Bamias A, Gavalas N, Tzannis K, Fragiadis E, Pinitas A, Stamatakos PV, Papadopoulos G, Stathouros G, Grammatoglou X, Korkolopoulou P, Zoubouli C, Stravodimos K, Ntoumas K, Mitropoulos D, Skolarikos A, Papatsoris A. Intravesical Administration of Durvalumab for High-risk Non-muscle-invasive Bladder Cancer: A Phase 2 Study by the Hellenic GU Cancer Group. Eur Urol. 2025 Mar;87(3):281-284. doi: 10.1016/j.eururo.2024.12.018. Epub 2025 Jan 17.

  PMID: 39827021 DERIVED

MeSH Terms

Conditions

Urinary Bladder Neoplasms; Neoplasms

Interventions

durvalumab

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 26, 2018
• First Posted: November 30, 2018
• Study Start: November 15, 2018
• Primary Completion: May 31, 2022
• Study Completion: December 31, 2022
• Last Updated: March 23, 2022

Record last verified: 2022-03

Locations

GR (1)