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Submitted by: Ranelle Lou Dorado 2019-01-31 00:00:00 Last Updated by: Ranelle Lou Dorado 2020-05-19 13:28:37


A Phase III, Randomized, Open-Label, Multi-Center, Global Study to Determine the Efficacy and Safety of Durvalumab in Combination with Gemcitabine + Cisplatin for Neoadjuvant Treatment Followed by Durvalumab Alone for Adjuvant Treatment in Patients with Muscle-Invasive Bladder Cancer

PHRR190201-002062

D933RC00001

2018-CT0459

A Phase III, Randomized, Open-Label, Multi-Center, Global Study to Determine the Efficacy and Safety of Durvalumab in Combination with Gemcitabine + Cisplatin for Neoadjuvant Treatment Followed by Durvalumab Alone for Adjuvant Treatment in Patients with Muscle-Invasive Bladder Cancer  (NIAGARA)

This is a Phase III, randomized, open-label, multi-center, global study to determine the efficacy and safety of durvalumab + G+C combination therapy versus G+C for the neoadjuvant and adjuvant treatment of patients with histologically or cytologically documented, resectable MIBC (ie, T2N0M0-T4aN0M) and transitional cell carcinoma (TCC; transitional cell and mixed transitional/nontransitional cell histologies) of the urothelium (excluding renal pelvis and ureters) who are candidates for radical cystectomy and have not received prior systemic chemotherapy or immunotherapy for treatment of MIBC.

Approximately 1050 patients globally will be randomized in 1:1 ratio to receive
durvalumab + G+C combination therapy every 3 weeks (q3w) (Arm 1) or G+C combination therapy q3w (Arm 2) for 4 cycles of neoadjuvant chemotherapy prior to radical cystectomy. Following the radical cystectomy and during adjuvant therapy, patients in Arm 1 will receive durvalumab monotherapy q4w for 8 additional cycles and patients in Arm 2 will receive no adjuvant treatment. Crossover from Arm 1 to Arm 2 will not be permitted.

Patients randomized to the 2 treatment arms, Arm 1 or Arm 2, will be treated according to their 
renal function. Recruitment for borderline renal function patients will be limited to up to 20% of the targeted global population.

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
2018-10-01 84 2025-10-01 0000-00-00

Ongoing

Institution Classification Region LTO #
AstraZeneca Pharmaceuticals (Philippines) Inc. Private Business NCR CDRR-NCR-S-17
Institution Region
AstraZeneca AB Sweden
Name E-Mail Institution and Institution Address
Mary Grace Arbues MaryGrace.Arbues@astrazeneca.com 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, 1634, Philippine
Name E-Mail Institution and Institution Address
Mary Grace Arbues MaryGrace.Arbues@astrazeneca.com 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, 1634, Philippine
Name Expertise Affiliation
Arthur Gregory Lui, MD Oncology Metro Davao Medical and Research Center
Clevelinda Calma, MD Oncology University of Santo Tomas Hospital
Felina Masadao-Adefuin, MD Oncology Baguio General Hospital and Medical Center
Jaime Songco, MD Oncology Makati Medical Center
Jemela Anne Osorio-Sanchez, MD Oncology Perpetual Succour Hospital
John P. Querol, MD Oncology Veterans Memorial Medical Center
Necy Juat, MD Oncology National Kidney and Transplant Institute
Project Location Institutional Ethics Review Board
Metro Davao Medical and Research Center Metro Davao Medical and Research Center – Ethics Review Committee
University of Santo Tomas Hospital University of Santo Tomas Hospital Institutional Review Board
Baguio General Hospital and Medical Center Baguio General Hospital and Medical Center Ethics Review Committee
Makati Medical Center Makati Medical Center Institutional Review Board
Perpetual Succour Hospital Perpetual Succour Hospital Institutional Ethics and Review Board
Veterans Memorial Medical Center Veterans Memorial Medical Center Ethics Review Committee
National Kidney and Transplant Institute National Kidney and Transplant Institute Ethics Review Committee

Muscle-Invasive Bladder Cancer

  • pCR using assessments per central pathology review
  • EFS using assessments per BICR

  • pCR using assessments per central pathology review
  • EFS using assessments per BICR
 

Recruiting

Clinical Trial

D933RC00001

20180829112749

2019-01-11

0000-00-00

60

Unspecified

Unspecified

01 Oct 2018

Inclusion Criteria

Patients are eligible to be included in the study only if all of the following inclusion criteria
apply:

Informed consent

1. Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the ICF and in this protocol.
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. For patients aged
Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.

Type of patient and disease characteristics

4. Patients with histologically or cytologically documented muscle-invasive TCC (also
known as UC) of the bladder. Patients with transitional cell and mixed transitional/non-transitional cell histologies (adenocarcinoma, squamous cell)/variant transitional (eg, micropapillary, plasmacytoid, sarcomatoid, nested variant, lymphoepitheliod, nested variant) with clinical stage of T2N0M0-T4aN0M0 according to the American Joint Committee on Cancer Staging Manual (AJCC Cancer Staging Manual, 8th Edition) TCC of the bladder are eligible. Patients with pure non-transitional cell variant histologies and any small cell histology are not eligible.

Patients should also meet the following additional criteria:

 Must be planning and per the judgment of the Investigator medically fit for 
treatment with neoadjuvant therapy prior to cystectomy (ie, patients should not be randomized if they are not eligible or cannot receive any neoadjuvant treatment)
 Must be planning and per the judgment of the Investigator medically fit to undergo a radical cystectomy at time of enrollment and randomization.
 Have not received prior systemic chemotherapy or immunotherapy for treatment of MIBC. (Prior local intravesical chemotherapy or immunotherapy is allowed if completed at least 6 weeks prior to the initiation of study treatment.)

5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at
enrollment.
6. Tumor PD-L1 status, with immunohistochemistry (IHC) assay confirmed by a reference laboratory, must be known prior to randomization. As such, all patients must give valid written consent to provide a newly acquired MIBC tumor biopsy during screening (preferred) or provide an available archival MIBC tumor sample taken ≤3 years prior to screening. Tumor lesions submitted must be when the patient was determined to have MIBC (ie, NMIBC samples will not be acceptable). Samples with limited tumor content are not acceptable. The tumor specimen submitted to evaluate PD-L1 status should be of sufficient quantity to allow for PD-L1 IHC, retrospective evaluation of muscle invasive disease, and other exploratory biomarker analyses and is preferred in formalin-fixed paraffin-embedded (FFPE) blocks. (Refer to Section 6.2.1 for information regarding obtaining tumoral PD-L1 status prior to the 28-day
screening window.)

7. 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 upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome, who will be allowed in consultation with their physician.
 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN
 CrCl calculated by Cockcroft-Gault equation (using actual body weight) or measured by 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.)*
o CrCl for Borderline Renal Function arm: ≥40 mL/min to
o CrCl for Adequate Renal Function arm: ≥60 mL/min
Cockcroft-Gault equation
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)

8. Must have a life expectancy of at least 12 weeks at randomization.

Weight

9. Body weight >30 kg at enrollment and randomization

Reproduction

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
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).


Exclusion Criteria

Patients are not eligible to be included in the study if any of the exclusion criteria apply:
Medical conditions

Medical Conditions

1. Evidence of lymph node or metastatic TCC/UC, extravesical TCC/UC that invades the
pelvic and/or abdominal wall for bladder cancer (T4b), or primary non-bladder
(ie, ureter, urethral, or renal pelvis) TCC/UC of the urothelium. Patients with
radiologically suspected lymph node metastasis should be excluded if the short axis is
≥10 mm as per IV contrast-enhanced CT or MRI scan.

2. Inoperable tumor(s) with fixation to the pelvic wall on clinical exam.
3. History of allogeneic organ transplantation that requires use of immunosuppressive agents. Patients with a history of allogenic stem cell transplantation are also excluded.
4. Active or prior documented autoimmune or inflammatory disorders (including but not limited to 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
 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 AstraZeneca
 Patients with celiac disease controlled by diet alone may be included but only
after consultation with AstraZeneca

5. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, uncontrolled diabetes, symptomatic congestive heart failure, uncontrolled hypertension, 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.
6. History of another primary malignancy, except for:
 Prostate cancer of pathologic stage ≤T2cN0M0 determined from a prior prostatectomy without biochemical recurrence and who in the opinion of the Investigator are not deemed to require active intervention, or patients with incidental histologic findings of prostate cancer that has not been treated prior to the study and who do not require specific therapy for prostate cancer beyond the surgery described in the protocol and also are considered to be at low risk for recurrence per the Investigator
 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
7. History of active primary immunodeficiency
8. History of leptomeningeal carcinomatosis
9. 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 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 virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).
10. 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 irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with AstraZeneca.
11. New York Heart Association Class III or IV heart failure (Criteria Committee NYHA 1964).
12. QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥470 ms calculated. Any clinically significant abnormalities detected require triplicate ECG results and a mean QTcF ≥470 ms calculated from 3 ECGs obtained over a brief period (eg, 30 minutes).
13. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
14. Any medical contraindication to platinum (cisplatin)-based doublet chemotherapy,
including:
 CTCAE Grade ≥2 audiometric hearing loss
 CTCAE Grade ≥2 peripheral neuropathy

Prior/concomitant therapy

15. 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.
16. Prior exposure to immune-mediated therapy (with exclusion of Bacillus-Calmette Guerin [BCG]), including but not limited to other anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies.
17. 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.
18. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
19. Prior pelvic radiotherapy treatment
20. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. 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)

Prior/concurrent clinical study experience

21. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of the treatment arm (until the primary endpoint of that study has read out)
22. Previous IP assignment in the present study
23. 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
24. Participation in another clinical study with an IP administered during the last 28 days

Other exclusions

25. 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.
26. Judgment by the Investigator that the patient should not participate in the study if the

Interventional

Durvalumab

Durvalumab is a human mAb of the immunoglobulin G 1 kappa subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand 2 [PD-L2]) with PD-1 on T cells and CD80 (B7.1) on ICs. It is being developed by AstraZeneca/MedImmune for use in the treatment of cancer. (MedImmune is a wholly owned subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document.) The proposed mechanism of action (MOA) for durvalumab is interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including those that may result in tumor elimination. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells resulting in the restored proliferation of interferon-gamma (IFN-γ) (Stewart et al 2015). In vivo studies have shown that durvalumab inhibits tumor growth in xenograft models via a T-cell-dependent mechanism (Stewart et al 2015). Based on these data, durvalumab is expected to stimulate the patient’s antitumor immune response by binding to PD-L1 and shifting the balance toward an antitumor response. Durvalumab has been engineered to reduce antibodydependent cellular cytotoxicity and complement-dependent cytotoxicity.

None

Randomized

Open Label

Unspecified

Not Applicable

To assess the efficacy of durvalumab + G+C combination therapy (neoadjuvant)/durvalumab
alone (adjuvant) (Arm 1) compared to G+C combination therapy (neoadjuvant)/no adjuvant (Arm 2) in terms of pCR and EFS in MIBC patients with adequate renal function

Phase III

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