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Submitted by: Ranelle Lou Dorado 2018-11-16 00:00:00 Last Updated by: Ranelle Lou Dorado 2020-05-18 17:33:09


A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global Study of First-Line Durvalumab in Combination with Standard of Care Chemotherapy and Durvalumab in Combination with Tremelimumab and Standard of Care Chemotherapy Versus Standard of Care Chemotherapy Alone in Patients with Unresectable Locally Advanced or Metastatic Urothelial Cancer

PHRR190110-001981

D933SC00001

2018-CT0457

A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global Study of First-Line Durvalumab in Combination with Standard of Care Chemotherapy and Durvalumab in Combination with Tremelimumab and Standard of Care Chemotherapy Versus Standard of Care Chemotherapy Alone in Patients with Unresectable Locally Advanced or Metastatic Urothelial Cancer (NILE)

This is a randomized, open-label, controlled, multi-center, global Phase III study to determine the efficacy and safety of combining durvalumab ± tremelimumab with 6 cycles of standard of care chemotherapy (cisplatin + gemcitabine or carboplatin + gemcitabine doublet) followed by durvalumab monotherapy versus SoC alone as first-line chemotherapy in patients with histologically or cytologically documented transitional cell carcinoma (transitional cell and mixed transitional/non-transitional cell histologies) of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra), unresectable, locally advanced or metastatic (ie, T4b, any N; or any T, N2-N3; or M1).

Approximately 1265 patients will be enrolled into the study to randomize approximately 885 patients equally (1:1:1) to each of the three treatment arms (295 patients per arm). It is currently anticipated that approximately 176 will participate in this study. The countries currently planned to participate in this study, include: Australia, Bulgaria, Brazil, Canada, China, Czech Republic, Hungary, Israel, Italy, Japan, Philippines, Poland, Russian Federation, South Korea, Spain, Thailand, Turkey, Taiwan, United States and Vietnam.

Regime Classification Priority
2017 - 2022 Global competitiveness and innovation in health Drug discovery and development
Start Date Duration in Months Target Completion Date Actual Completion Date
2018-07-01 48 2022-07-01 0000-00-00

Ongoing

Institution Classification Region LTO #
AstraZeneca Pharmaceuticals (Philippines) Inc. Private Business NCR CDRR-NCR-S-17
Institution Region
AstraZeneca Pharmaceuticals (Philippines) Inc. NCR
Name E-Mail Institution and Institution Address
Scarlette De Luna scarlette.deluna@astrazeneca.com 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, 1634, Philippine
Name E-Mail Institution and Institution Address
Scarlette De Luna scarlette.deluna@astrazeneca.com 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, 1634, Philippine
Name Expertise Affiliation
Abdias Aquino, MD Oncology Riverside Medical Center
Arthur Gregory Lui, MD Oncology Metro Davao Medical and Research Center
Felina Masadao-Adefuin, MD Oncology Baguio General Hospital and Medical Center
Jemela Anne Osorio-Sanchez, MD Oncology Perpetual Succour Hospital
John P. Querol, MD Oncology Veterans Memorial Medical Center
Julie Tapispisan, MD Oncology University of Santo Tomas Hospital
Maria Belen E. Tamayo, MD Oncology Makati Medical Center
Necy Juat, MD Oncology National Kidney and Transplant Institute
Project Location Institutional Ethics Review Board
Riverside Medical Center N/A
Metro Davao Medical and Research Center Metro Davao Medical and Research Center – Ethics Review Committee
Baguio General Hospital and Medical Center Baguio General Hospital and Medical Center Ethics Review Committee
Perpetual Succour Hospital Perpetual Succour Hospital Institutional Ethics and Review Board
Veterans Memorial Medical Center Veterans Memorial Medical Center Ethics Review Committee
University of Santo Tomas Hospital University of Santo Tomas Hospital Institutional Review Board
Makati Medical Center Makati Medical Center Institutional Review Board
National Kidney and Transplant Institute National Kidney and Transplant Institute Ethics Review Committee

Locally Advanced or Metastatic Urothelial Cancer

PFS using BICR assessments according to RECIST 1.1-

PFS, APF12, ORR, DoR, and DCR using investigator and BICR assessments according to RECIST 1.1.

Recruiting

  • Australia
  • Brazil
  • Bulgaria
  • Canada
  • China
  • Czech Republic
  • Hungary
  • Israel
  • Italy
  • Japan
  • Philippines
  • Poland
  • Russia
  • South Korea
  • Spain
  • Taiwan
  • Thailand
  • Turkey
  • United States
  • Vietnam

Clinical Trial

D933SC00001

20180802103705

2018-10-31

0000-00-00

27

Unspecified

Unspecified

01 Jul 2018

Inclusion criteria

Patients are eligible to be included in the study only if all of the following inclusion criteria and
none of the exclusion criteria apply:
Informed consent
1. Capable of giving signed informed consent that includes compliance with the
requirements and restrictions listed in the ICF and in this protocol. For patients
patient and his or her legally acceptable representative.
2. Provision of signed and dated, written ICF prior to any mandatory study-specific
procedures, sampling, and analyses
The ICF process is described in Appendix A 3.
Age
3. Age ≥18 years at the time of screening.
Type of patient and disease characteristics
4. Individuals with histologically or cytologically documented transitional cell carcinoma
(transitional cell and mixed transitional/non-transitional cell histologies) of the
urothelium (including renal pelvis, ureters, urinary bladder, and urethra), unresectable,
locally advanced, or metastatic (ie, T4b, any N; or any T, N2-N3, or M1; based on
clinical TNM [tumor/node/metastasis] staging) (see NCCN Bladder Cancer
Guidelines), who have not been previously treated with first-line chemotherapy.
(Patients who have received prior definitive chemoradiation, adjuvant or neoadjuvant
treatment for locally advanced disease are eligible provided that progression to locally
advanced or metastatic disease has occurred >12 months from the last therapy [for
chemoradiation and adjuvant treatment] or >12 months from the last surgery [for
neoadjuvant treatment].)
5. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG)
performance status (PS) of 0 or 1 at enrollment
6. At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion
(TL) at baseline. Tumor assessment by computed tomography (CT) scan or magnetic
resonance imaging (MRI) must be performed within 28 days prior to randomization
7. Tumor PD-L1 status, with immunohistochemistry (IHC) assay confirmed by a
reference laboratory, must be known prior to randomization. As such, all patients
must be able to provide a newly acquired tumor biopsy ((preferred) or provide an available tumor sample taken ≤3 years prior to screening.
Tumor lesions used for newly acquired biopsies should not be target lesions, unless
there are no other lesions suitable for biopsy, and in this instance, only core needle
(not excisional/incisional) biopsy is allowed. For patients with a single target lesion, if
screening biopsy is collected prior to screening imaging for baseline tumor
assessment, allow at least approximately 2 weeks before imaging scans are acquired.
Samples with limited tumor content and fine-needle aspirate specimens are not
acceptable. Specimens from metastatic bone lesions are typically unacceptable unless
there is a significant soft-tissue component. The tumor specimen submitted to
establish eligibility should be of sufficient quantity to allow for PD-L1 IHC and
exploratory biomarker analyses, as appropriate (see Section 8.8.2) and is preferred in
formalin-fixed paraffin-embedded blocks.
8. Patients eligible or ineligible for cisplatin-based chemotherapy (see Section 6.2.3).
Cisplatin ineligibility is defined as meeting one of the following criteria:
- Creatinine clearance (CrCl) 30 mL/min calculated by
Cockcroft-Gault equation (using actual body weight; see Inclusion Criterion 9) or
by measured 24-hour urine collection. (In cases where both are performed,
measured 24-hour urine collection will be used to determine eligibility, providing
an adequate collection was performed.)*
- Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2
audiometric hearing loss
- CTCAE Grade ≥2 peripheral neuropathy
*Method used to determine CrCl for study eligibility will be the same method used to
determine cisplatin eligibility at study entry. See Section 6.2.1 for detailed
requirements regarding IVRS data entry for purposes of randomization.
9. Adequate organ and marrow function as defined below:
- Hemoglobin ≥9.0 g/dL
- Absolute neutrophil count ≥1.5×109/L
- Platelet count ≥100×109/L
- Serum bilirubin ≤1.5 × the ULN. This will not apply to patients with confirmed
Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia [predominantly
unconjugated bilirubin] in the absence of evidence of hemolysis or hepatic
pathology), who will be allowed in consultation with their physician and
AstraZeneca.
- ALT and AST ≤2.5×ULN; for patients with hepatic metastases, ALT and AST
≤5×ULN
- Measured creatinine clearance (CL) >30 mL/min calculated by Cockcroft-Gault
(using actual body weight) or by measured 24-hour urine collection for
determination. (In cases where both are performed, measured 24-hour urine
collection will be used to determine eligibility, providing an adequate collection
was performed)*
Males
Creatinine CL = Weight (kg) × (140 - Age)
(mL/min) 72 × serum creatinine (mg/dL)
Females:
Creatinine CL = Weight (kg) × (140 - Age) × 0.85
(mL/min) 72 × serum creatinine (mg/dL)
*Method used to determine CrCl for study eligibility will be the same method
used to determine cisplatin eligibility at study entry. See Section 6.2.1 for
detailed requirements regarding IVRS data entry for purposes of randomization.
10. Life expectancy ≥12 weeks in the opinion of the investigator
Weight
11. Body weight >30 kg
Reproduction
12. 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 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 hysterectomy).
Other inclusions
13. Genetic research (optional): All patients will be asked to participate in the genetic
research component of this study. Participation is voluntary, and if a patient declines
to participate, there will be no penalty or loss of benefit, and he/she will not be
excluded from any other component of the study (see Section 8.7 and Appendix D). A
patient is eligible to be included in the voluntary/optional genetics (deoxyribonucleic
acid [DNA]) research component of the study only if all of the above inclusion criteria
and none of the exclusion criteria described below apply, and he/she provides signed
and dated written genetic informed consent prior to collection of the sample for
genetic analysis.


Exclusion criteria

Patients should not enter the study if any of the following exclusion criteria are fulfilled:
Medical conditions
1. History of allogeneic organ transplantation.
2. 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]). The following are exceptions to this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on
hormone replacement
- Patients with 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
3. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, uncontrolled cardiac arrhythmia, active 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
4. History of another primary malignancy except for
- 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
- Adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease
- Adequately treated carcinoma in situ without evidence of disease
5. History of leptomeningeal carcinomatosis
6. History of active primary immunodeficiency
7. Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and tuberculosis testing in
line with local practice), 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, DNA negative) are
eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if
polymerase chain reaction is negative for HCV RNA.
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 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 or SoC chemotherapy may be
included only after consultation with the study physician.
9. Untreated central nervous system (CNS) metastases and/or carcinomatous meningitis
identified either on the baseline brain imaging (please see Appendix F [RECIST]) for
details on the imaging modality) obtained during the screening period or identified
prior to signing the ICF. Patients with a history of brain metastases or with suspected
brain metastases at screening must have an MRI (preferred) or CT each preferably
with IV contrast of the brain prior to study entry. Patients whose brain metastases
have been treated may participate provided they show radiographic stability (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 4 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 their treatment must have
resolved or be stable either, without the use of steroids, or are stable on a steroid dose
of ≤10 mg/day of prednisone or its equivalent and anti-convulsants for at least 14 days
prior to the start of treatment. Brain metastases will not be recorded as RECIST target
lesions at baseline.
10. Any medical contraindication to platinum (cisplatin or carboplatin)-based doublet
chemotherapy
11. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients
Prior/concomitant therapy
12. Prior exposure to immune-mediated therapy (with exclusion of Bacillus Calmette
Guerin), including but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, or
anti-PD-L2 antibodies, except therapeutic anticancer vaccines, which are permitted.
Prior local intervesical chemotherapy or immunotherapy is allowed if completed at
least 28 days prior to the initiation of study treatment.
13. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
radiation within 28 days of the first dose of study drug.
14. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
Patients, if enrolled, should not receive live vaccine while receiving IP and up to
30 days after the last dose of IP.
15. Patients who may be eligible for or are being considered for radical resection during
the course of the study.
16. 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.
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 (eg, 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 (eg, CT scan
premedication). Premedication with steroids for chemotherapy is also acceptable.
Prior/concurrent clinical study experience
18. Previous IP assignment in the present study
19. 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
20. Participation in another clinical study with an IP administered in the last 4 weeks
21. Prior randomization or treatment in a previous durvalumab and/or tremelimumab
clinical study regardless of treatment arm assignment (until the primary endpoint of
the previous study has read out)
Other exclusions
22. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site)
23. 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.
24. Judgment by the investigator that the patient should not participate in the study if the
patient is unlikely to comply with study procedures, restrictions, and requirements
25. Genetic research study (optional):
Exclusion criteria for participation in the optional (DNA) genetics research component
of the study include the following:
- Previous allogeneic bone marrow transplant
- Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample
collection
For procedures for withdrawal of incorrectly enrolled or randomized patients, see Section 6.2.2.

Interventional

Durvalumab (MEDI4736) and tremelimumab

Durvalumab in combination with tremelimumab

Because the mechanisms of action of CTLA-4 and PD-1 are non-redundant, targeting both PD-1
and CTLA-4 pathways may have additive or synergistic activity (Pardoll 2012); therefore,
AstraZeneca is also investigating the use of durvalumab + tremelimumab combination therapy
for the treatment of cancer.
To date, more than 3000 patients have received the combination using a number of doses and
dosing schedules. Details on the safety profile of durvalumab + tremelimumab combination
therapy are summarized in Sections 4.3.1.3 and 2.3.2.3. Refer to the current editions of the
durvalumab and tremelimumab IBs for a complete summary of pre-clinical and clinical
information including safety, efficacy, and PK.

Durvalumab ± tremelimumab with chemotherapy

Non-clinical and clinical studies have indicated that blockade of immune checkpoints
(PD-1/PD-L1 and CTLA-4) can have a positive effect on antitumor immunity. Inhibition of the
PD-L1/PD-1 pathway leads to a restored activity of pre-activated exhausted T cells, while
inhibition of CTLA-4 receptors results in an effector T-cell amplification in early stages of
antigen presentation. As these are different pathways of a common cascade resulting in T-cell
activation, a dual immune-checkpoint blockade could be a key option that would allow reaching better clinical outcome than PD-L1/PD-1 or CTLA-4 monotherapy. This combination strategy has been already tested in melanoma with significant improvement of long-term responses compared to single-agent monotherapy (Larkin et al 2015).

Platinum-based chemotherapy is the standard therapy for metastatic or locally advanced
unresectable UC in first-line setting and could play an important role also in association with
immune-checkpoint inhibitors. The goal of combination chemotherapy is to utilize agents that
affect cancer cells by different mechanisms, thus reducing the risk of developing resistance.

None

Randomized

Open Label

Unspecified

Not Applicable

To assess the efficacy of Treatment Arm 1 versus Treatment Arm 3 in terms of PFS/OS in patients
with unresectable locally advanced or metastatic UC

Phase III

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