BL13 - Ripple

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 body weight of > 30kg.

7) Patients must have adequate haematologic reserve: Platelet count ≥ 75 x 109/L, Absolute neutrophils ≥ 1.0 x 109/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 hospital/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.

*Patients should begin protocol treatment within 42 days after completion of TMT.

12) 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 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.

13) 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.

14) Patients must be accessible for treatment and follow-up. Patients registered on this trial must be treated and

followed at the participating centre. This implies there must be reasonable geographical limits (for example: 1 ½

hour's driving distance) placed on patients being considered for this trial.

15) Protocol treatment is to begin within 2 working days of patient enrollment.

16) Women/men of childbearing potential must have agreed to use a highly effective contraceptive method during and

for 3 months following treatment. A woman is considered to be of “childbearing potential” if she has had menses at

any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, “effective

contraception” also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of

pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or

vasectomy/vasectomized partner. However, if at any point a previously celibate patient chooses to become

heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is

responsible for beginning contraceptive measures.

Women of childbearing potential will have a pregnancy test to determine eligibility as part of the Pre-Study Evaluation;

this may include an ultrasound to rule-out pregnancy if a false-positive is suspected. For example, when beta-human

chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumour production of hCG, as

seen with some cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy.

17) Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to

interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. 

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:

• Patients with alopecia;

• Patients with Grave’s disease, vitiligo or psoriasis not requiring systemic treatment (within the last 2 years);

• Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement;

• Any chronic skin condition that does not require systemic therapy.

5) Patients with active or uncontrolled intercurrent illness including, but not limited to:

• cardiac dysfunction (symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris,

cardiac arrhythmia);

• active peptic ulcer disease or gastritis;

• active bleeding diatheses;

• psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of

the subject to give written informed consent;

• known history of previous clinical diagnosis of tuberculosis;

• known human immunodeficiency virus infection (positive HIV 1/2 antibodies);

• known active hepatitis B infection (positive HBV surface

antigen(HBsAg).Patients with a past or resolved HBV infection (defined as

presence of hepatitis B core antibody (anti-HBc) and absence of HBsAg) are

eligible;

• 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 hypersensitivity reactions to any study drug or their excipients.

10) Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥ 470 msec in screening ECG

measured using standard institutional method or history of familial long QT syndrome.

11) History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on

baseline CT scan.

12) Any active disease condition which would render the protocol treatment dangerous or impair the ability of the

patient to receive protocol therapy.

13) Any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol.

14) Live attenuated vaccination administered within 30 days prior to randomization. 

Research Nurse: Sirjana Devkota (x3977) Sirjana.Devkota@LTHTR.nhs.uk