Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000063910
Ethics application status
Approved
Date submitted
6/12/2019
Date registered
24/01/2020
Date last updated
1/05/2023
Date data sharing statement initially provided
24/01/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
SUBurothelial DUrvalumab injEction-1 (SUBDUE-1)
Scientific title
A phase 1 open label dose-escalation study to evaluate the tolerability, safety, and immunological efficacy of sub-urothelial durvalumab injection in adult subjects with muscle invasive bladder cancer or high-risk non-muscle invasive bladder tumours.
Secondary ID [1] 300015 0
Nil known
Universal Trial Number (UTN)
Trial acronym
SUBDUE-1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Muscle invasive or high risk non muscle invasive bladder cancer 315504 0
Condition category
Condition code
Cancer 313792 313792 0 0
Bladder

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Dose: Three possible doses of durvalumab (25mg, 75mg, 150mg) will be studied to identify the recommended phase II dose. The selected dose will be diluted in 25mls of normal saline.

Duration: Single administration of prescribed dose as per dose escalation schedule. The prescribed dose is administered during flexible cystoscopy two weeks prior to cystectomy.

Mode: Multiple sub-urothelial 1ml injections distributed evenly across the bladder, including the trigone. Residual tumour, if present will be included.

Dose will be determined using a 3x3 dose-escalation technique, up to a maximum dose of 150mg. A minimum of 3 subjects will be enrolled in each dose-level cohort, commencing at 25mg. If no dose-limiting toxicities (DLTs) are observed in the first 3 subjects during the DLT-evaluation period, dose-escalation will continue to the next higher dose cohort.
Formal histopathology review of cystectomy specimens will be undertaken prior to dose escalation.

If 1 of 3 patients in a dose-level cohort experiences a DLT, that dose-level cohort will be expanded to a total of 6 patients. If no more than 1 of 6 subjects in the dose-level cohort experiences a DLT, dose-escalation will continue to the next higher dose-level cohort.

If greater than or equal to 2 subjects in the first dose cohort experience a DLT during the DLT evaluation period, the maximum tolerated dose (MTD) will be exceeded and no further subjects will be enrolled into that dose-level cohort. If this occurs, the preceding dose-level cohort will be evaluated for the MTD and a total of 6 subjects will be treated at the preceding dose level.

If the highest dose-level is reached and no more than 1 of the initial 3 subjects experiences a DLT, that dose-level cohort will be expanded to a total of 6 subjects.

Determination of the recommended phase 2 dose (RP2D) will be the dose level where less than or equal to 1 out of 6 patients experience DLT at the highest dose level below the maximally administered dose.
Intervention code [1] 316284 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 322200 0
To establish whether sub-urothelial administration of durvalumab is tolerable according to the following patient reported outcome measure (PROM):
American Urological Association (AUA) Symptom Index
Timepoint [1] 322200 0
The AUA Symptom Index PROM will be measured at the following intervals:
- Screening (28 to 1 day pre-cystoscopy and durvalumab injection)
- Day of cystoscopy + durvalumab injection
- 24 hours post injection
- 48 hours post-injection
- 2 weeks post-injection
- Fortnightly thereafter until date of cystectomy
- Day of cystectomy
- 2 weeks post cystectomy
Primary outcome [2] 322506 0
To establish whether sub-urothelial administration of durvalumab is tolerable according to the following patient reported outcome measure (PROM):

O'Leary Interstitial Cystitis Symptom Index.
Timepoint [2] 322506 0
The O'Leary Interstitial Cystitis Symptom Index PROM will be measured at the following intervals:
- Screening (28 to 1 day pre-cystoscopy and durvalumab injection)
- Day of cystoscopy + durvalumab injection
- 24 hours post injection
- 48 hours post-injection
- 2 weeks post-injection
- Fortnightly thereafter until date of cystectomy
- Day of cystectomy
- 2 weeks post cystectomy
Primary outcome [3] 322507 0
To identify any composite of local or systemic adverse events associated with sub-urothelial administration of durvalumab.
Timepoint [3] 322507 0
- Screening (28 to 1 day pre-cystoscopy and durvalumab injection): Hepatitis B and C and HIV serology, CMP, FBP, UEC, LDH, TFTs, LFTs, glucose, cortisol, coagulation profile.

- 2 weeks post-injection: CMP, FBP, UEC, LDH, TFTs, LFTs, glucose, cortisol, translational research blood sample, translational research urine sample.

- Fortnightly thereafter until date of cystectomy: CMP, FBP, UEC, LDH, TFTs, LFTs, glucose, cortisol.

- Day of cystectomy: CMP, FBP, UEC, LDH, TFTs, LFTs, glucose, cortisol.

- 2 weeks post cystectomy: CMP, FBP, UEC, LDH, TFTs, LFTs, glucose, cortisol.

Histopathology of the radical cystectomy will be assessed to determine any local adverse events.
Secondary outcome [1] 377683 0
To examine the local immunological efficacy of sub-urothelial administration of durvalumab by assessing the quantity and distribution of associated immune cells composite of both tumour infiltrating lymphocytes (TILs) and tumour activated macrophages (TAMs) in pre-administration biopsies as compared to in the histopathological specimen post cystectomy.
Timepoint [1] 377683 0
The secondary efficacy endpoint will be analysed by histological and immunohistochemical analysis post cystectomy.

Eligibility
Key inclusion criteria
Study population: Participants with either muscle invasive bladder cancer or high-risk non-muscle invasive (T1, high grade Ta, carcinoma in-situ) bladder tumours scheduled for cystectomy, who have refused or are ineligible for systemic neo-adjuvant chemotherapy.

Inclusion criteria;
1. Age equal to or greater than 18 years
2. ECOG performance less than 2
3. Life expectancy equal to or greater than 6 months
4. Adequate organ and marrow function
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients who have received neo-adjuvant chemotherapy
2. Any concurrent cancer therapy of the same biological intent that may interact with durvalumab.
3. Participation in another clinical study with an investigational product during the last 28 days
4. Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade equal to or greater than 2 from previous anticancer therapy
5. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of sub-urothelial durvalumab
6. Major surgical procedure within 28 days prior to administration of durvalumab, excluding trans-urethral resection of bladder tumour
7. History of allogenic organ transplantation
8. Active or prior documented autoimmune or inflammatory disorders
9. History of another primary malignancy within the last 5 years, excluding non-melanomatous skin cancer
10. History of active primary immunodeficiency
11. Active tuberculosis, hepatitis B, hepatitis C
12. Current or prior use of immunosuppressive medication within 14 days before the first dose
of durvalumab
13. Receipt of live attenuated vaccine within 30 days prior to administration of sub-urothelial
durvalumab. Patients should not receive live vaccine up to 30 days after durvalumab
administration
14. Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from screening
to 90 days after the last dose of durvalumab
15. Known allergy or hypersensitivity to durvalumab

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The analysis of the toxicity, patient reported outcome measures (PROMs), TILS, and TAMS data will be primarily descriptive in nature. Changes in the quantities of TILS and TAMS between the pre-administration bladder biopsies and the subsequent cystectomy specimen biopsies will be analyzed using Wilcoxon’s signed-rank test.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
9/12/2019
Date of last participant enrolment
Anticipated
30/09/2022
Actual
10/05/2022
Date of last data collection
Anticipated
31/08/2023
Actual
9/08/2022
Sample size
Target
12
Accrual to date
Final
11
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 15413 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 28734 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 304468 0
Other Collaborative groups
Name [1] 304468 0
Australian and New Zealand Urogential and Prostate (ANZUP) Cancer Trials Group
Country [1] 304468 0
Australia
Funding source category [2] 304483 0
Charities/Societies/Foundations
Name [2] 304483 0
Spinnaker Health Research Foundation
Country [2] 304483 0
Australia
Funding source category [3] 304484 0
Commercial sector/Industry
Name [3] 304484 0
AstraZeneca Pty Ltd (drug only)
Country [3] 304484 0
Australia
Primary sponsor type
Hospital
Name
South Metropolitan Health Service
Address
11 Robin Warren Drive,
Murdoch WA 6150
Country
Australia
Secondary sponsor category [1] 304739 0
None
Name [1] 304739 0
Address [1] 304739 0
Country [1] 304739 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304901 0
South Metropolitan Health Service Human Research Ethics Committee
Ethics committee address [1] 304901 0
Ethics committee country [1] 304901 0
Australia
Date submitted for ethics approval [1] 304901 0
29/10/2019
Approval date [1] 304901 0
02/12/2019
Ethics approval number [1] 304901 0
RGS0000003534

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 98586 0
Prof Dickon Hayne
Address 98586 0
Fiona Stanley Hospital
11 Robin Warren Drive
Murdoch WA 6150
Country 98586 0
Australia
Phone 98586 0
+61 08 6152 2222
Fax 98586 0
Email 98586 0
[email protected]
Contact person for public queries
Name 98587 0
Cynthia Hawks
Address 98587 0
Fiona Stanley Hospital
11 Robin Warren Drive
Murdoch WA 6150
Country 98587 0
Australia
Phone 98587 0
+61 08 6152 6916
Fax 98587 0
Email 98587 0
[email protected]
Contact person for scientific queries
Name 98588 0
Dickon Hayne
Address 98588 0
Fiona Stanley Hospital
11 Robin Warren Drive
Murdoch WA 6150
Country 98588 0
Australia
Phone 98588 0
+61 08 6152 2222
Fax 98588 0
Email 98588 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseImmunotherapy for Bladder Cancer: Latest Advances and Ongoing Clinical Trials.2022https://dx.doi.org/10.1080/08820139.2022.2118606
Dimensions AIThe SUB-urothelial DUrvalumab InjEction-1 (SUBDUE-1) trial: first-in-human trial in patients with bladder cancer2024https://doi.org/10.1111/bju.16325
N.B. These documents automatically identified may not have been verified by the study sponsor.