To evaluate the safety, tolerability, and anti-tumor activity of the combination of
durvalumab + tremelimumab or durvalumab alone in different solid tumors.
This is an open-label, multi-center, study to determine the short and long term safety of
fixed doses of durvalumab 1500 mg + tremelimumab 75 mg combination therapy or durvalumab 1500
mg monotherapy in patients with advanced solid malignancies. This study is modular in design,
one or more of the modules will be opened in a given country / region based on local patient
population prevalence, and results of feasibility studies. The total number of patients to be
enrolled overall and in each module will depend on the types and number of tumor modules
added to the main study and country-specific ancillary studies. The number of patients and
sites to be involved in individual countries will be dependent on each module or ancillary
study. This study consisted of a screening period, a treatment period, a 90 day safety
follow-up period and a survival follow-up period. Patients will receive the investigation
product (IP) via intravenous (IV) infusion once every 4 weeks (Q4W) in combination therapy or
monotherapy as mentioned below - Combination therapy: Durvalumab 1,500 mg + tremelimumab 75
mg on Week 0, for up to a maximum of 4 doses (or cycles) followed by durvalumab 1,500 mg
starting 4 weeks after the last infusion of the combination or discontinuation of
Monotherapy: Durvalumab 1,500 mg on week 0.
Patients will attend a safety follow-up visit 90 days after study treatment discontinuation.
Thereafter, patients will be contacted by phone or electronic communication every 3 months
for survival status up to 5 years following date of first patient treatment initiation. All
patients will be followed for a minimum of 6 months following enrolment of last patient. It
is anticipated that the total enrolment period for the overall study will be approximately 2
to 3 years, with an overall duration of approximately 5 years.
1. Must have a life expectancy of at least 12 weeks.
2. Age ≥ 18 years at the time of screening. For patients aged <20 years and enrolled in
Japan, a written informed consent should be obtained from the patient and his or her
legally acceptable representative
3. 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 (e.g.,
Health Insurance Portability and Accountability Act in the US, European Union [EU]
Data Privacy Directive in the EU) obtained from the patient/legal representative prior
to performing any protocol-related procedures, including screening evaluations.
4. Disease not amendable to curative surgery
5. Eastern Cooperative Oncology Group (ECOG) performance status as defined in the
6. Body weight >30 kg.
7. No prior exposure to anti-programmed death (PD) 1 or anti-PD-ligand (L) 1.
8. Adequate organ and marrow function.
9. Female patients of childbearing potential (i.e., not surgically sterile or
post-menopausal) who are sexually active with a non-sterilized male partner must use
at least one highly effective method of contraception from the time of screening and
must agree to continue using such precautions for 180 days after the last dose of
durvalumab + tremelimumab combination therapy or 90 days after the last dose of
10. 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. The following
age-specific requirements apply:
- 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).
- 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
11. Non-sterilized male patients who are sexually active with a female partner of
childbearing potential must use a male condom plus spermicide from screening through
180 days after receipt of the final dose of durvalumab + tremelimumab combination
therapy or 90 days after receipt of the final dose of durvalumab monotherapy.
For inclusion in the Module A of the study patients should fulfill the following criteria:
1. Histologically or cytologicaly confirmed locally advanced or metastatic urothelial or
non-urothelial carcinoma of the urinary tract (including the urinary bladder, ureter,
urethra and renal pelvis)
2. Disease that has progressed during or after at least one previous platinum or
nonplatinum based chemotherapy, either for metastatic disease or progressive disease
less than 12 months after adjuvant or neo-adjuvant chemotherapy
3. ECOG performance status 0-2
1. Involvement in the planning and/or conduct of the study.
2. Previous IP assignment in the present study.
3. Concurrent enrollment in another clinical study or another sub-study of this protocol,
unless it is an observational (non-interventional) clinical study or during the
follow-up period of an interventional study.
4. Participation in another clinical study with an IP and receipt of any investigational
anticancer therapy during the last / within 28 days or 5 half-lives, whichever is
shorter, prior to the first dose of study treatment.
5. Any concurrent chemotherapy, investigational agent, biologic, or hormonal therapy for
6. Local treatment of isolated lesions for palliative intent is acceptable (e.g., local
surgery or radiotherapy).
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.
9. History of allogenic organ transplantation.
10. Uncontrolled intercurrent illness (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.
11. History of another primary malignancy, leptomeningeal carcinomatosis and active
12. Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis
identified either on baseline brain imaging (please refer to RECIST for details on the
imaging modality) obtained during the screening period or identified prior to signing
the ICF. Brain metastases will not be recorded as RECIST Target Lesions at baseline.
13. Active infection including tuberculosis, hepatitis B virus, hepatitis C virus, or
human immunodeficiency virus (positive HIV ½ antibodies).
14. Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab or tremelimumab.
15. 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,
16) Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
17) Known allergy or hypersensitivity to study drug(s) or compounds of similar biologic
composition to the study drug(s), or any of the study drug excipients.
18) Any unresolved NCI CTCAE Grade ≥2 toxicities from prior anti-cancer therapy with the
exception of vitiligo, alopecia, and the laboratory values defined in the inclusion
19) Pregnant or breastfeeding women 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 durvalumab + tremelimumab combination therapy or 90 days after the last dose
of durvalumab monotherapy.
20) Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical
study regardless of treatment arm assignment.