A Phase II trial looking at trimodality therapy with or without durvalumab for patients with muscle-invasive bladder cancer
- Conditions
- Muscle-invasive bladder cancerCancerMalignant neoplasm of bladder
- Registration Number
- ISRCTN65058008
- Lead Sponsor
- niversity Hospital Southampton NHS Foundation Trust
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Ongoing
- Sex
- All
- Target Recruitment
- 82
1. Histologic diagnosis of urothelial carcinoma of the bladder. Patients with mixed histology and focal differentiation are eligible but patients with pure small cell histology will be excluded
2. Stage T2-T4a N0M0 at time of diagnosis (AJCC-TNM version 8) based on trans-urethral resection of bladder tumour (TURBT), imaging, and/or bimanual examination under anesthesia (EUA)
3. CT scan of the chest/abdomen/pelvis within 8 weeks from enrollment, showing no evidence of metastatic disease
4. Patients must be =18 years of age
5. Patients must have a life expectancy greater than 6 months
6. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (see Appendix I) and a bodyweight of >30 kg
7. Patients must have adequate hematologic reserve: Platelet count =75 x 10e9/l, Absolute neutrophils =1.0 x 10e9/l. Anemia will be corrected to minimum hemoglobin of 90 g/l with red cell transfusions, if necessary
8. Patients must have an estimated creatinine clearance (Cockcroft-Gault Equation) =30 ml/min
9. Patients must have adequate liver function with a bilirubin =1.5 ULN (if confirmed Gilbert’s, eligible providing bilirubin =3 x UNL) and AST/ALT (SGOT/SGPT) <2.5 x the upper normal limit
10. All patients must have a tumour block from their primary tumour available and consent to release the block/cores/cut slides for correlative analyses and the centre/pathologist must have agreed to the submission of the specimen(s)
11. Patients have completed prior trimodality therapy (TMT) consisting of surgery, chemotherapy and radiation therapy treatment prior to enrollment on the BL.13 study
12. Patients should begin protocol treatment within 42 days after completion of TMT
13. Prior Surgery: Patients have completed transurethral resection, prior to study enrollment
14. Prior Chemotherapy:
14.1. Patients may have completed up to 4 cycles of cisplatin-based neoadjuvant chemotherapy. Adjuvant chemotherapy is not permitted
14.2. Patients will have received cisplatin, given intravenously during the radiation therapy
OR
14..3. Patients may have received fluorouracil and mitomycin given intravenously once weekly or gemcitabine as an alternative to cisplatin during radiotherapy
15. Prior Radiation Therapy: The patient should have received radiation therapy with curative intent as part of trimodality therapy (TMT) given per institutional standards. These standards should ensure that radiotherapy treatment was delivered using: Dose and fractionation protocol considered as having curative intent; IMRT, VMAT or 4 field conformal techniques; CT-based planning; treatment volume margins specified as per institutional policy; daily imaging for treatment verification
16. Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires in either English or French. The baseline assessment must be completed within the required timelines, prior to registration/randomization. Inability (lack of comprehension in English or French, or other equivalent reason such as cognitive issues or lack of competency) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible
17. Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate
18.
1. Pre-existing medical conditions precluding treatment
2. Pregnancy or lactating mothers
3. Received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-PD-L1, including durvalumab anti-programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB ligand, a member of the Tumour Necrosis Factor Receptor [TNFR] family), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
4. 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, celiac disease (controlled by diet alone) or other serious gastrointestinal chronic conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), rheumatoid arthritis, hypophysitis, uveitis, etc, within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
4.1. Patients with alopecia
4.2. Patients with Grave’s disease, vitiligo or psoriasis not requiring systemic treatment (within the last 2 years)
4.3. Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement
4.4. Any chronic skin condition that does not require systemic therapy
5. Patients with active or uncontrolled intercurrent illness including, but not limited to:
5.1. Cardiac dysfunction (symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia)
5.2. Active peptic ulcer disease or gastritis
5.3. Active bleeding diatheses
5.4. Psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent;
5.5. Known history of previous clinical diagnosis of tuberculosis
5.6. Known human immunodeficiency virus infection (positive HIV 1/2 antibodies)
5.7. Known active hepatitis B infection (positive HBV surface antigen (HBsAg). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody (anti-HBc) and absence of HBsAg) are eligible
5.8. Known active hepatitis C infection. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
6. History of primary immunodeficiency, history of allogenic organ transplant that requires therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of randomization* or a prior history of severe (grade 3 or 4) immune-mediated toxicity from other immune therapy or grade = 3 infusion reaction
* Intranasal/inhaled corticosteroids or systemic steroids that do not to exceed 10 mg/day of prednisone or equivalent dose of an alternative corticosteroid are permissible
7. Current or prior use of immunosuppressive medication within 28 days of study entry, with the exceptions of intranasal and inhaled corticosteroids or systemic chronic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Corticosteroids used on study for anti-emetic purpose are allowed. Corticosteroids as premedication for hypersensitivity reactions (e.g. computed tomography [CT] scan premedication) are allowed.
8. Peripheral neuropathy = grade 2 (CTCAE v5.0)
9. History of allergic or h
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Disease-free survival, which is defined as the time from the randomization to the time of the first event that is either recurrent (local or distant) bladder cancer, a new primary bladder cancer or death from any cause. Measured by:<br>1. Time to death<br>2. Time to recurrence as measured by:<br>2.1. CT scan at baseline, weeks 8, 12, 24, 48. Post treatment/surveillance no recurrence every 3 months for the first 2 years, then at months 30 & 36, then annually. Post recurrence every 6 months until death<br>2.2. Cystoscopy with bladder bioscopy and urine cytology at weeks 12, 24, 48. Post treatment/surveillance no recurrence every 3 months, post recurrence every 6 months until death
- Secondary Outcome Measures
Name Time Method