| Eligibility |
Inclusion Criteria:
1. Male and female subjects; age = 18 years at the time of study entry.
2. Subjects must provide written informed consent prior to performance of any
protocol-related procedures, including screening evaluations and must be willing to
comply with treatment and follow up.
3. Subjects must have histologic documentation of transitional cell carcinoma of the
urothelium (including the urinary bladder, ureter, urethra and renal pelvis) of the
urinary tract (cystoscopy and biopsy or positive cytology).
4. Patients must have confirmed cT2-T4 N0-1 M0 (TNM classification).
5. Archival tumour samples for biomarker research in formalin-fixed and paraffin-embedded
blocks.
6. Body weight >30kg
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. Life expectancy of at least 12 weeks
9. Adequate organ function as determined by:
a) Hematological (without growth factor or transfusion support within 28 days prior to
first dose of investigational product)
- Absolute neutrophil count (ANC) = 1500/mm3 (= 1.5 GI/L).
- Platelets = 100,000/mm3 (= 100 GI/L)
- Hemoglobin = 9 g/dL (= 90 g/L)
10. Hepatic:
1. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =2.5 x upper
limit of normal unless liver metastases are present, in which case it must be =5x
ULN.
2. Total bilirubin = 1.5 × the upper limit of normal. For subjects with Gilbert's
disease = 3 mg/dL (= 51.3 µmol/L).
11. Renal:
a) Calculated CrCl or 24-hour urine CrCl>40 mL/min or Calculated creatinine clearance
CL>40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for
determination of creatinine clearance
12. Fasting serum triglycerides = 2.5 × upper limit of normal AND total cholesterol = 300
mg/dL (= 7.75 mmol/L). Lipid-lowering medication is allowed.
13. HbA1c = 8%.
14. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have
been amenorrheic for 12 months without an alternative medical cause.
Exclusion Criteria:
1. Histology of pure adenocarcinoma, pure squamous cell carcinoma, or predominant small
cell carcinoma or sarcomatoid features in the tumor sample.
2. Evidence of any metastatic lesion outside the primary tumour site identified in the
radiological evaluation.
3. 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:
- Intranasal, inhaled, topical steroids or local steroid injections (eg,
intra-articular injection).
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or equivalent.
- Steroids as premedication for hypersensitivity reactions (eg, CT scan
premedication).
4. Previous therapy with PD-1, PD-L1 or CTLA-4 inhibitors, including durvalumab and
tremelimumab.
5. Any concurrent chemotherapy, immunotherapy (IMT), or biologic or hormonal therapy for
cancer treatment. Concurrent use of hormones for non-cancer-related conditions (eg,
insulin for diabetes and hormone replacement therapy) is acceptable.
6. History of severe allergic reactions (ie, Grade 4 allergy, anaphylactic reaction from
which the subject did not recover within 6 hours of institution of supportive care) to
any unknown allergens or any components of the study drug formulations.
7. 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:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only
after consultation with the study physician
- Patients with celiac disease controlled by diet alone
8. Major surgery within 4 weeks of study randomization.
9. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue.
10. Prior radiation therapy to >25% of the bone marrow.
11. Current treatment on another clinical trial.
12. Diagnosis of any second malignancy within the last 3 years, except for adequately
treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.
13. Any of the following within the 12 months prior to starting study treatment:
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
graft, congestive heart failure, cerebrovascular accident including transient ischemic
attack, or pulmonary embolus.
14. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) =470 ms
calculated from 3 electrocardiograms (ECGs).
15. Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria
for Adverse Events (CTCAE) Grade =2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria
- Patients with Grade =2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Study Physician.
- Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab or tremelimumab may be included only after consultation
with the Study Physician.
16. Hypertension that cannot be controlled by medications (>150/100 mmHg despite optimal
medical therapy)
17. Current treatment with therapeutic doses of Coumadin (low dose Coumadin up to 2 mg PO
daily for deep vein thrombosis prophylaxis is allowed).
18. History of active primary immunodeficiency
19. Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and tuberculosis (TB) testing
in line with local practice), hepatitis B (known positive hepatitis B virus (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 Ribonucleic acid (RNA).
20. Known positive for human immunodeficiency virus (HIV), chronic or active hepatitis B
or C or active hepatitis A.
21. Receipt of live, attenuated vaccine within 30 days prior to the first dose of
investigational products.
22. Pregnancy or breastfeeding. All female patients with reproductive potential must have
a negative pregnancy test (serum or urine) prior to randomization.
23. Other severe acute or chronic medical or psychiatric condition, or laboratory
abnormality that would impart, in the judgment of the investigator, excess risk
associated with study participation or study drug administration, or which, in the
judgment of the investigator, would make the patient inappropriate for entry into this
study.
24. 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
informed consent
25. History of leptomeningeal carcinomatosis
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