| Eligibility |
Inclusion Criteria:
1. Written informed consent and any locally-required authorization (eg, HIPAA in the USA,
EU Data Privacy Directive in the EU) obtained from the subject prior to performing any
protocol-related procedures, including screening evaluations
2. Age > 18 years at time of study entry
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
4. Body weight >30kg
5. Diagnosis of high grade, non-muscle invasive urothelial carcinoma. High-grade
carcinoma includes the following types
1. TaG3
2. T1G3
3. CIS
6. Tumors with combinations of the above types or containing low grade components in
addition to the high-grade component are acceptable. Disease refractory to Bacillus
Calmette Guerin (BCG) therapy to adequate BCG exposure. BCG refractory disease is
defined as
1. If high-grade tumor appears during BCG therapy
2. If high-grade, non-muscle-invasive papillary tumor is present at three months
3. If CIS (with or without concomitant papillary tumor) is present at three and six
months Adequate exposure is defined as a minimum of 5 out of 6 BCG induction
doses. ?aintenance or re-induction can be used according to local practice but
are not mandatory for the definition of adequate exposure.
7. High grade recurrence after an initial response to BCG therapy.
8. Patients intolerant to adequate BCG exposure, defined as
1. fewer than 5 instillations of BCG induction therapy
2. No more than one cycle of maintenance BCG therapy
9. Subjects may have received other intravesical or systemic therapies XML File
Identifier: goagJWHcccRmyt+fBE00IC1ok+0= Page 12/26 for NMIBC or CIS before or after
receiving BCG, as long as they meet the aforementioned criteria for BCG refractory
disease.
10. Subjects are not candidates for immediate cystectomy or have elected not to undergo
the procedure.
11. Adequate normal organ and marrow function as defined below:
1. Haemoglobin = 9.0 g/dL
2. Absolute neutrophil count (ANC) > 1500 per mm3
3. Platelet count >100,000 per mm3
4. Serum bilirubin = 1.5 x institutional upper limit of normal (ULN). This will not
apply to subjects 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 their
physician.
5. AST (SGOT)/ALT (SGPT) = 2.5 x institutional upper limit of normal unless liver
metastases are present, in which case it must be = 5x ULN
6. Serum creatinine Cl>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault
1976) or by 24-hour urine collection for determination of creatinine clearance
12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal subjects. Women will be considered post-menopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply:
1. Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).
2. 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, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy).
13. Subject 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
up
Exclusion Criteria:
1. Disease of the upper urinary tract or prostatic urethra
2. ECG with QTcF value >470 ms
3. Participation in another clinical study with an investigational product during the
last 4 weeks
4. 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
5. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies, other investigational agent) within 14 days prior to the first dose of
study drug. Immediate postoperative intravesical instillation of epirubicin or
mitomycin C is allowed if occurred more than 14 days prior to the first dose of the
study drug.
6. 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
criteria Subjects with Grade =2 neuropathy will be evaluated on a case-by-case basis
after consultation with the Study Physician. Subjects with irreversible toxicity not
reasonably expected to be exacerbated by treatment with durvalumab may be included
only after consultation with the Study Physician.
7. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
Concurrent use of hormonal therapy for non-cancer related conditions (eg, hormone
replacement therapy) is acceptable.
8. 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
acceptable.
9. History of allogenic organ transplantation.
10. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, 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]) - more details in protocol.
11. 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
12. History of another primary malignancy with exceptions described in protocol
13. History of leptomeningeal carcinomatosis
14. History of active primary immunodeficiency
15. Active infection including tuberculosis, hepatitis B, hepatitis C, or human
immunodeficiency virus. Subjects with a past or resolved HBV infection are eligible.
Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain
reaction is negative for HCV RNA (see details in protocol)
16. Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab with exceptions described in protocol
17. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
Subjects, if enrolled, should not receive live vaccine whilst receiving IP and up to
30 days after the last dose of IP.
18. Female subjects who are pregnant or breastfeeding or male or female subjects of
reproductive potential who are not willing to employ effective birth control from
screening to 90 days after the last dose of durvalumab monotherapy.
19. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.
20. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical
study regardless of treatment arm assignment.
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