| Eligibility |
Inclusion Criteria:
For inclusion in the study, patients should fulfill the following criteria:
1. Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this
protocol. Written informed consent and any locally required authorization (eg,
European Union [EU] Data Privacy Directive) obtained from the patient/legal
representative prior to performing any protocol-related procedures, including
screening evaluations.
2. Patients with histologically or cytologically documented metastatic or irresectable
(i.e. T4b, N1-3 and/or M1a/b) urothelial cell carcinoma (including renal pelvis,
ureters, urinary bladder, and urethra).
3. Patients ineligible for cisplatin-based chemotherapy OR previous treatment with
platinum-based chemotherapy, either in the neo-adjuvant setting or in any other
setting. This is defined as progression on or after at least 2 cycles of
platinum-based chemotherapy (e.g. MVAC, cisplatin/gemcitabine,
carpoblatin/gemcitabine). Patients who had to stop platinum-based therapy because of
toxicity after at least 2 cycles are eligible if progressive disease has been
confirmed.
4. Previous treatment with anti-PD(L)1 immunotherapy. The following conditions apply for
inclusion:
1. Must not have experienced a toxicity that led to permanent discontinuation of
prior anti-PD(L)1 immunotherapy;
2. All treatment-related AEs while receiving prior anti-PD(L)1 immunotherapy must
have completely resolved or resolved to baseline prior to screening for this
study;
3. Must not have experienced a =Grade 3 immune related AE or an immune related
neurologic or ocular AE of any grade while receiving prior anti-PD(L)1
immunotherapy;
4. Patients with endocrine AE of =Grade 2 are permitted to enroll if the AEs are
stably maintained on appropriate replacement therapy and are asymptomatic;
5. Must not have required the use of additional immunosuppression other than
corticosteroids for the management of an AE, not have experienced recurrence of
an AE if re-challenged, and not currently require maintenance doses of >10 mg
prednisone or equivalent per day;
5. At least 1 lesion, not previously irradiated, that can be accurately measured at
baseline as =10 mm in the longest diameter (except lymph nodes which must have a
Revised Clinical Study Protocol short axis =15 mm) with computed tomography (CT) or
magnetic resonance imaging (MRI) and that is suitable for accurate repeated
measurements as per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST
1.1) guidelines.
6. Age >18 years at time of study entry.
7. World Health Organisation (WHO) performance status of 0 or 1.
8. Body weight >30kg.
9. Adequate normal organ and marrow function as defined below:
1. Haemoglobin =9.0 g/dL = 5.6 mmol/L;
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). (Does not apply
to patients with confirmed Gilbert's syndrome, who will be allowed only in
consultation with the treating 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. Measured creatinine clearance (CL) >30 mL/min or Calculated creatinine clearance
CL>30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by
24-hour urine collection for determination of creatinine clearance:
Males:
Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)
Females:
Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine
(mg/dL)
10. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal in case of
amenorrhoeu for 12 months without an alternative medical cause. The following
age-specific requirements apply:
- Women <50 years of age would be considered post-menopausal in case of amenorrhea
for 12 months or more following cessation of exogenous hormonal treatments and
with luteinizing hormone and follicle-stimulating hormone levels in the
post-menopausal range for the institution or underwent surgical sterilization
(bilateral oophorectomy or hysterectomy);
- Women =50 years of age would be considered post-menopausal in case of amenorrhea
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);
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
up.
12. Must have a life expectancy of at least 12 weeks
Exclusion Criteria:
Patients should not enter the study if any of the following exclusion criteria are
fulfilled:
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).
2. Participation in another clinical study with an investigational product during the
last 4 weeks.
3. Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study.
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. 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
- 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;
- Toxicity caused by treatment with anti-PD(L)1 should return to baseline, except
for endocrine toxicity on a stable dose of replacement therapy.
6. Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal
therapy for cancer treatment. Concurrent use of hormonal therapy for
non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
7. 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.
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 [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. Psoriasis, if
not treated by immunesuppressants, is allowed;
- 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.
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 except for:
- Malignancy treated with curative intent and with no known active disease =2 years
before the first dose of IP and of low potential risk for recurrence;
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease;
- Adequately treated carcinoma in situ without evidence of disease;
- Curatively treated localized prostate cancer without PSA recurrence.
13. History of leptomeningeal carcinomatosis.
14. Brain metastases or spinal cord compression, unless radiographically stable, defined
as 2 brain images, both of which are obtained after treatment to the brain metastases.
These imaging scans should both be obtained at least four weeks apart and show no
evidence of intracranial progression. In addition, any neurologic symptoms that
developed either as a result of the brain metastases or treatment thereof must have
resolved or be stable either, without the use of steroids, or are stable on a steroid
dose of =10mg/day of prednisone or its equivalent for at least 14 days prior to the
start of treatment.. Patients with suspected brain metastases at screening should have
an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study
entry.
15. History of active primary immunodeficiency.
16. Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings), 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.
17. 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 (e.g., intra
articular injection);
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent;
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication).
18. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
30 days after the last dose of IP.
19. 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 180 days after the last dose of tremelimumab, durvalumab, or durvalumab +
tremelimumab combination therapy.
20. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.
21. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical
study regardless of treatment arm assignment.
22. Previous treatment with anti-CTLA-4 immunotherapy.
23. Known allergy or hypersensitivity to IP or any excipient. Procedures for withdrawal of
incorrectly enrolled patients are presented in Section 4.3 of the clinical protocol.
If a patient withdraws from participation in the study, then that specific
enrollment/randomization code cannot be reused. Withdrawn patients will not be
replaced.
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