Trial of Local Cystoscopic Injection of Tremelimumab Plus Systemic Durvalumab for High Risk Non-Muscle Invasive Bladder Cancer

NCT05120622 | Withdrawn Phase 1 FDA Drug

• 1 other identifier: H20-03454
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

We will conduct a Phase I trial testing whether local cystoscopic injection of tremelimumab into the bladder wall in combination with systemic administration of durvalumab in localized bladder cancer will stimulate an effective anti-tumour immune response with minimal systemic immune response and clinical toxicity.

Conditions

Bladder Cancer; High-Risk Cancer; Tremelimumab; Durvalumab; Non-muscle Invasive

Outcome Measures

Primary Outcomes (2)

• Number of participants with grade 3 adverse events related to tremelimumab

  The safety of local cystoscopic injection of tremelimumab into the bladder wall in combination with systemic durvalumab in subjects with bladder cancer as measured by the number of participants developing grade 3 adverse events

  60 months

• Maximal tremelimumab dose that produces grade 3 adverse events in less than 2 participants

  60 months

Secondary Outcomes (1)

• Complete pathological response

  6 months

Other Outcomes (3)

• Immune cell analysis from whole blood sample

  60 months

• Cytokine profiling

  60 months

• Sequencing of cell free DNA

  60 months

Study Arms (1)

Tremelimumab

EXPERIMENTAL

Patients who will receive local cystoscopic injection of tremelimumab into the bladder wall in combination with systemic administration of durvalumab

Drug: Tremelimumab

Interventions

Tremelimumab DRUG

Tremelimumab 25 mg / 50 mg / 75 mg local cystoscopic injection into bladder wall at or adjacent to site of prior tumour resection (dose divided into 4 injection sites), administered 6 and 3 weeks before radical cystectomy. Durvalumab 1500mg via IV infusion administered 6 and 3 weeks before radical cystectomy.

Tremelimumab

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• \- 1. Disease Related Criteria
• Dose Escalation Phase
• Subjects must have histologically proven bladder cancer of any histology and any stage or grade confirmed by biopsy or transurethral bladder tumour resection (TURBT) within 120 days of study registration (defined as date of signing informed consent).
• Subjects must be scheduled for radical cystectomy at the trial hospital.
• Dose Expansion Phase
• Subjects must have histologically proven, recurrent, urothelial carcinoma in situ of the bladder within 60 days prior to registration.
• Pure squamous carcinoma in situ will be excluded.
• Subjects may have concomitant Ta or T1 bladder tumours that have undergone visible complete resection within 60 days prior to registration. CIS disease is not expected to be completely excised.
• All patient tumour tissue from the histologic diagnosis of recurrence is available for central review by the study pathologist at Vancouver General Hospital. This does not need to be completed before starting study treatment.
• Subjects must have had cystoscopy confirming no visible papillary tumour within 21 days prior to registration. (CIS disease is not expected to have been completely excised). If the TURBT or bladder biopsy falls within 21 days of registration it will fulfil this criterion.
• Subjects must have had urine cytology within 21 days prior to registration. Cytology for subjects with CIS component is not expected to be negative for malignant cells.
• All subjects with T1 urothelial carcinoma at study entry must undergo re-TURBT within 60 days prior to registration, and must have evidence of uninvolved muscularis propria in the pathologic specimen from either the first or the second TURBT. Tissue from the re-resection must be submitted for central review in addition to the tissue from the first TURBT (see Section 8.2). The TURBT that identified the recurrent T1 disease may have taken place more than 60 days prior to registration but not more than 120 days. Subjects with high-grade Ta or CIS do not require a re-TURBT, but if this is performed at the discretion of the treating physician, the second TURBT must be within 60 days of registration. There is no requirement for muscularis propria in the specimen of Ta/CIS subjects, but the tissue from the first and second TURBTs must be submitted for central review. If a patient with Ta/T1 disease undergoes repeat TURBT, the patient can be included as having CIS if there is CIS on either TURBT.
• Subjects with prior urothelial carcinoma in the upper urinary tract within the previous 24 months will only be eligible if they had ≤ T1 carcinoma and were treated with nephroureterectomy.
• Subjects must have a CT or MRI (including CT-IVP, CT-urogram or MR-urogram) of the abdomen and pelvis to rule out upper tract malignancy and intra-abdominal metastases within 90 days prior to registration. If a patient cannot tolerate intravenous contrast, a retrograde pyelogram should be performed within 90 days prior to registration.
• Subjects must be deemed unfit for radical cystectomy by the treating physician, or the patient must refuse radical cystectomy, which is considered standard of care for these subjects. The reason for subjects not to undergo cystectomy will be clearly documented.

You may not qualify if:

• \- 1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) 2. Subjects must not have had urothelial carcinoma in the prostatic urethra within the previous 24 months.
• \. Subjects must not have had muscle invasive (stage T2 or greater) or lymph node positive (N1-3) urothelial carcinoma of the bladder or upper tract (ureter, renal pelvis, renal calyx) at any time.
• \. Participation in another clinical study with an investigational product during the last 28 days 5. 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 6. Subjects must not have had prior systemic chemotherapy for bladder cancer or systemic immunotherapy, including, but not limited to interferon alfa-2b, high dose IL-2, PEG-IFN, anti-PD-1, anti-PD-L1, or anti-CTLA4.
• \- Subjects with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the QI.
• \- Subjects with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the QI.
• \. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable. Subjects must not require treatment with a RANKL inhibitor (e.g. denosumab) who cannot discontinue it before treatment with durvalumab/tremelimumab.
• \. Subjects must not have received any prior radiation to the bladder for bladder cancer.
• \. Major surgical procedure (as defined by the QI) within 28 days prior to the first dose of IP. Note: Local surgery including bladder biopsy or transurethral bladder tumour resection is acceptable.
• \. History of allogenic bone marrow or solid organ transplantation. 10. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion:
• \- Subjects with vitiligo or alopecia
• \- Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• \- Any chronic skin condition that does not require systemic therapy
• \- Subjects without active disease in the last 5 years may be included but only after consultation with the study physician
• \- Subjects with celiac disease controlled by diet alone 11. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection (requiring oral or IV antibiotics within 14 days prior to registration), 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 except for
• \- Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence

Sponsors & Collaborators

• University of British Columbia: lead

Study Sites (1)

Vancouver General Hospital

Vancouver, British Columbia, V6H3Z6, Canada

Location

MeSH Terms

Conditions

Urinary Bladder Neoplasms

Interventions

tremelimumab

Condition Hierarchy (Ancestors)

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

Study Officials

• Peter Black

  University of British Columbia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: September 20, 2021
• First Posted: November 15, 2021
• Study Start: September 1, 2021
• Primary Completion: May 1, 2022
• Study Completion: May 1, 2022
• Last Updated: October 31, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)