1. Ability to understand and the willingness to sign a written informed consent document.
2. Age ≥ 18 years
3. Histologically or cytologically confirmed urothelial carcinoma of the bladder.
Non-urothelial histologies and upper tract disease are excluded.
4. Has clinical stage T2-T4b, N0-3, M0 urothelial carcinoma
5. DECIPHER-Non-basal (Group A) OR DECIPHER-Basal but cisplatin-ineligible (Group B)
a. Cisplatin-ineligible based on ≥1 of the following:
i. CrCl <60 ml/min
ii. Grade 2 hearing loss or peripheral neuropathy
iii. ECOG performance status of 2
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
7. Life expectancy of at least 12 weeks
8. Body weight >30kg
9. Adequate normal organ and marrow function as defined below:
1. Hemoglobin ≥ 8.0 g/dL and asymptomatic
2. Absolute neutrophil count (ANC ≥1.5 x 109/L)
3. Platelet count ≥100 x 109/L
4. Serum bilirubin ≤ 1.5 x Institutional Upper Limit of Normal (ULN) (Note: This
will not apply to patients with confirmed Gilbert's syndrome (persistent or
recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of
hemolysis or hepatic pathology), who will be allowed only in consultation with
5. AST/SGOT and ALT/SGPT ≤ 2.5 x ULN
6. Measured creatinine clearance (CL) >30 mL/min
10. Evidence of post-menopausal status or negative serum pregnancy test for female
pre-menopausal patients. Women will be considered post-menopausal if they meet the
1. Women < 45 years of age would be considered post-menopausal if they underwent
surgical sterilization (bilateral oophorectomy or hysterectomy.
2. Women 45 to <50 years of age would be considered post-menopausal if they have
been amenorrheic for 18 months or more following cessation of exogenous hormonal
treatments, if they have a documented follicle-stimulating hormone levels in the
post-menopausal range (> 40 mlU/mL) or underwent surgical sterilization
(bilateral oophorectomy or hysterectomy).
3. Women ≥50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, if they have a
documented follicle-stimulating hormone levels in the post-menopausal range (> 40
mlU/mL) or underwent surgical sterilization (bilateral oophorecomy, bilateral
salpingectomy or hysterectomy).
11. Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
Subjects must not have any of the following:
1. Prior systemic chemotherapy for bladder cancer
2. Any prior treatment with CTLA-4, including tremelimumab PD-1 or PD-L1 including
durvalumab checkpoint inhibitors
3. Administration of an investigational therapeutic within 28 days prior to Cycle 1, Day
4. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine
therapy, targeted therapy, biologic therapy, tumour embolization, monoclonal
antibodies) ≤28 days prior to the first dose of study drug.
5. Prior pelvic radiation that precludes bladder radiation
6. Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
7. Prior cystectomy
8. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Duke Principal Investigator.
2. Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab or tremelimumab may be included only after consultation
with the Duke Principal Investigator.
9. Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy
for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related
conditions (e.g., hormone replacement therapy) is acceptable.
10. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
radiation within 4 weeks of the first dose of study drug
11. 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
12. Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab or tremelimumab. The following are exceptions to this criterion:
1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent
3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
13. 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
1. Patients with vitiligo or alopecia
2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
3. Any chronic skin condition that does not require systemic therapy
4. Patients without active disease in the last 5 years may be included but only
after consultation with the study physician
5. Patients with celiac disease controlled by diet alone
14. 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
15. History of another primary malignancy except for:
1. 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
2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
3. Adequately treated carcinoma in situ without evidence of disease
16. History of allogenic stem cell transplant
17. History of active primary immunodeficiency
18. Active infection including, clinical evidence of active tuberculosis (cough >2 weeks'
duration, fevers, night sweats, weight loss, and/or abnormal lung imaging), hepatitis
B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human
immunodeficiency virus (positive HIV 1/2 antibodies). 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. Patients positive for hepatitis C (HCV) antibody are
eligible only if polymerase chain reaction is negative for HCV RNA.
19. Receipt of live attenuated vaccine within 30 days prior to Cycle 1 Day 1. Note:
Patients, if enrolled, should not receive live vaccine whilst receiving durvalumab or
tremelimumab and up to 30 days after the last dose of durvalumab or tremelimumab.
20. 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 monotherapy or 180 days after
the last dose of durvalumab + tremelimumab combination therapy.
21. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
22. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical
study regardless of treatment arm assignment.
23. Any condition which, in the opinion of the investigator, would preclude participation
in this trial