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CTRI Number  CTRI/2019/07/020184 [Registered on: 15/07/2019] Trial Registered Prospectively
Last Modified On: 19/10/2020
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Biological 
Study Design  Randomized, Parallel Group, Active Controlled Trial 
Public Title of Study   Study in Patients with surgically non removeable Urothelial Cancer with Durvalumab in Combination with Chemotherapy and Durvalumab in Combination with Tremelimumab and Chemotherapy Versus Chemotherapy Alone 
Scientific Title of Study   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 
Trial Acronym   
Secondary IDs if Any
Modification(s)  
Secondary ID  Identifier 
NCT03682068, D933SC00001, Version 2.0 dated 16 Aug 2019  ClinicalTrials.gov 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name   
Designation   
Affiliation   
Address 




 
Phone    
Fax    
Email    
 
Details of Contact Person
Scientific Query
 
Name  Mr Tapankumar M Shah 
Designation  Director, Site Management and Monitoring, India 
Affiliation  AstraZeneca Pharma India Ltd. 
Address  AstraZeneca Pharma India Ltd. Block N1, 12th Floor, Manyata Embassy Business Park Rachenahalli, Outer Ring Road, Bangalore – 560045, India

Bangalore
KARNATAKA
560045
India 
Phone  918067748006  
Fax  080-67748857  
Email  Tapankumar.Shah@astrazeneca.com  
 
Details of Contact Person
Public Query
 
Name  Mr Tapankumar M Shah 
Designation  Director, Site Management and Monitoring, India 
Affiliation  AstraZeneca Pharma India Ltd. 
Address  AstraZeneca Pharma India Ltd. Block N1, 12th Floor, Manyata Embassy Business Park Rachenahalli, Outer Ring Road, Bangalore – 560045, India


KARNATAKA
560045
India 
Phone  918067748006  
Fax  080-67748857  
Email  Tapankumar.Shah@astrazeneca.com  
 
Source of Monetary or Material Support  
AstraZeneca AB, Forskargatan 18, 151 85 Södertälje, Sweden 
 
Primary Sponsor  
Name  AstraZeneca AB  
Address  151 85 Sodertalje, Sweden 
Type of Sponsor  Pharmaceutical industry-Global 
 
Details of Secondary Sponsor  
Name  Address 
AstraZeneca Pharma India Ltd  Block N1, 12th Floor, Manyata Embassy Business Park, Rachenahalli, Outer Ring Road, Bangalore – 560045, India  
 
Countries of Recruitment     Australia
Brazil
Bulgaria
Canada
China
Czech Republic
Hungary
India
Israel
Italy
Japan
Philippines
Poland
Republic of Korea
Russian Federation
Spain
Taiwan
Thailand
Turkey
United States of America
Viet Nam  
Sites of Study
Modification(s)  
No of Sites = 11  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Samit Purohit  Action Cancer hospital   Department of Medical Oncology, A4 Paschim vihar-110063
New Delhi
DELHI 
011-49222222

samitmedonc@gmail.com 
Dr Hari Goyal  Artemis Hospital  Department of Medical Oncology, Sector-51 – 122001
Gurgaon
HARYANA 
9868086500

drgoyalhari@hotmail.com 
Dr Ashish Kaushal  HCG Cancer Centre  Department of Medical Oncology, Sola-Science City Road Near Sola Bridge, S.G. Highway-380060
Ahmadabad
GUJARAT 
9978297842

drashish4@yahoo.co.in 
Dr Vaibhav Choudhary  Meditrina Institute of Medical Sciences  Department of Medical Oncology, 278.central bazar Road, Ramdaspeth-440010
Nagpur
MAHARASHTRA 
9833621049

dr.vaibhav155@gmail.com 
Dr PS Sreedharan  MVR Cancer Centre & Research Institute  Dept. of Medical Oncology Vellalassery P.O, NIT (Via), Calicut, PIN 678603
Kozhikode
KERALA 
9496286696

drsreedharan@mvrccri.co 
Dr Pankaj Goyal  Rajiv Gandhi Cancer Institute and Research Centre  Department of Medical Oncology,Room no. 2251, Sector 5 Rohini, Delhi 110085
New Delhi
DELHI 
919711996969
91127051037
pankaj155@yahoo.com 
Dr Tushar Patil  Sahyadri Speciality, Hospital  Department of Oncology, 30C Erandwane Karve Road - 411004
Pune
MAHARASHTRA 
912067213000
912025403270
tussipats@hotmail.com 
Dr Shailesh Bondarde  Shatabdi Hospital  G27/28, Dept. of Clinical Research, Ground Floor, Suyojit City Center, Opp. Mahamarg Bus Stop, Mumbai naka, Nashik
Mumbai
MAHARASHTRA 
919822012427
0253-2501888
shaileshbondarde@yahoo.com 
Dr Bivas Biswas   Tata Medical Center  Department of Medical Oncology, 14 Major Arterial Road (EW),Newtown, Rajarhat, -700160
Kolkata
WEST BENGAL 
913366057000
913366057635
bivas.biswas@tmckolkata.com 
Dr Kiran Ashok Kattimani   The Karnataka Cancer Therapy & Research Institute (KCT & RI),   Department of Medical Oncology, Padmashree Dr. R.B. Patil Cancer Hospital, Navanagar, Hubli-580025
Dharwad
KARNATAKA 
0836-2228217
0836-2323167
dr_kattimani@yahoo.com 
Dr Nikhil S Ghadyalpatil  Yashoda Hospital  Room No. 309, Dept. of Clinical Research, 3rd Floor, B Block, Yashoda Hospital,Rajbhavan Road, Somajiguda
Hyderabad
TELANGANA 
918008037474
040-67232321
nikhilghadyalpatil@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 10  
Name of Committee  Approval Status 
Action Cancer Institutional Ethics Committee  Submittted/Under Review 
Artemis Health Sciences Institutional Ethics Committee  Approved 
Institutional Ethics Committee The Karnataka Cancer Therapy & Research Institute (KCT & RI)  Approved 
Institutional Ethics Committee-HCG Cancer Centre  Approved 
Institutional Review Board -Tata Medical Center  Approved 
Institutional Review Board Rajiv Gandhi Cancer Institute and Research Centre  Approved 
Meditrina Institute Ethics Committee  Approved 
MVR Institute Ethics Committee  Approved 
Sahyadri Hospital Ltd Ethics Committee  Approved 
Shatabdi Hospital Ethics Committee  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  N20-N23||Urolithiasis,  
 
Intervention / Comparator Agent
Modification(s)  
Type  Name  Details 
Intervention  Durvalumab (MEDI4736) and Tremelimumab  Till progression. 
Comparator Agent  SOC  As per standard practice. 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  99.00 Year(s)
Gender  Both 
Details  Inclusion criteria:
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.
2.Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, and analyses
Age
3.Age greater or equal to 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) (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 greater than 12 months from the last therapy [for chemoradiation and adjuvant treatment] or Greater than 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 enrolment
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 (<3 months) during screening (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 and is preferred in formalin-fixed paraffin-embedded blocks.
8. Patients eligible or ineligible for cisplatin-based chemotherapy, Cisplatin ineligibility is defined as meeting one of the following criteria:
a)Creatinine clearance less than 60 mL/min and greater than 30 mL/min calculated by Cockcroft-Gault equation 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.)
b) Common Terminology Criteria for Adverse Events (CTCAE) Grade greater or equal to 2 audiometric hearing loss
c) CTCAE Grade greater or equal to 2 peripheral neuropathy
9. Adequate organ and marrow function as defined below:
a) Hemoglobin greater than or equal to 9.0 g/dL
b) Absolute neutrophil count greater than or equal to 1.5×109/L
c) Platelet count greater than or equal to 100×109/L
d) 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.
e) ALT and AST ≤2.5×ULN; for patients with hepatic metastases, ALT and AST≤5×ULN
F) 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 equals Weight (kg) × (140 - Age)
(mL/min) 72 × serum creatinine (mg/dL)
Females:
Creatinine CL equals Weight (kg) × (140 - Age) × 0.85
(mL/min) 72 × serum creatinine (mg/dL)
10. Life expectancy gretaer than or equal to 12 weeks in the opinion of the investigator

Weight
11. Body weight greater than 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 amenorrhoeic for 12 months without an alternative medical cause.

The following age-specific requirements apply:
a) Women <50 years of age would be considered post-menopausal if they have been amenorrhoeic 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).
b) Women ≥50 years of age would be considered post-menopausal if they have been amenorrhoeic 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. 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.
 
 
ExclusionCriteria 
Details  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:
a)Patients with vitiligo or alopecia
b)Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
c)Patients with any chronic skin condition that does not require systemic therapy
d)Patients without active disease in the last 5 years may be included but only after consultation with the study physician
e)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 diarrhoea, 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
a) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
b) 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 ½ 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
a) Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician.
b) 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 metastases and/or carcinomatous meningitis identified either on the baseline brain imaging 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-convulsant 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:
a) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection)
b) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
c) 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 enrolment 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:
a) Previous allogeneic bone marrow transplant
b) Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample collection



 
 
Method of Generating Random Sequence   Permuted block randomization, fixed 
Method of Concealment   Not Applicable 
Blinding/Masking   Not Applicable 
Primary Outcome  
Outcome  TimePoints 
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 Urothelial Cancer  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 Urothelial Cancer 
 
Secondary Outcome  
Outcome  TimePoints 
To assess the efficacy of Treatment Arm 2 compared to Treatment Arm 3 in terms of PFS/OS in patients with UC   a) PFS using BICR assessments according to RECIST 1.1b
b) OS
 
 
Target Sample Size   Total Sample Size="1265"
Sample Size from India="60" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 3 
Date of First Enrollment (India)
Modification(s)  
28/08/2019 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  27/09/2018 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="4"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  
Open to Recruitment 
Recruitment Status of Trial (India)  Open to Recruitment 
Publication Details   NIL 
Brief Summary   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 (SoC) 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).The study will plan to enrol approximately 1265 patients globally in order to randomize (1:1:1) approximately 885 patients to durvalumab + SoC, durvalumab + tremelimumab + SoC combination therapy, or SoC (cisplatin + gemcitabine or carboplatin + gemcitabine). Therefore, approximately 295 patients will be randomized to each of the treatment arms.The primary aim of this study is to assess the efficacy of durvalumab + SoC combination therapy compared with SoC in terms of OS and PFS in patients with unresectable locally advanced or metastatic UC.Antitumor activity will be assessed according to RECIST 1.1 guidelines. The co-primary analysis of PFS will be based on programmatically derived PFS calculated from the tumor assessments according to RECIST 1.1 by BICR. In addition, PFS by RECIST 1.1 modified for confirmation of progression and Immune-related Response Evaluation Criteria in Solid Tumors, version 1.1, using BICR assessments will also be performed for exploratory purposes.Other secondary efficacy endpoints of proportion of patients alive and progression-free at 12 months from randomization (APF12), overall survival at 24 months after randomization (OS24), duration of response (DoR), disease control rate (DCR), and time from randomization to second progression (PFS2) will be examined to further evaluate the antitumor effect and survival benefit of durvalumab + SoC compared with SoC, and durvalumab + tremelimumab + SoC compared with SoC. ORR, APF12, DoR, and DCR will be assessed using investigator and BICR assessments according to RECIST 1.1. Additionally, the secondary endpoints of OS and PFS will be examined to further evaluate the efficacy of durvalumab + tremelimumab + SoC compared with durvalumab + SoC. The patient-reported outcome measures, namely the European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire (EORTC QLQ-C30); patient reported outcomes version of the Common Terminology Criteria for Adverse Events (PROCTCAE); Patient Global Impression of Change (PGIC), Patient Global Impression of Severity (PGIS); and EuroQol 5-dimension, 5-level health state utility index (EQ-5D-5L) will be used. Biological samples will be used to explore potential biomarkers in tumor tissue, whole blood, plasma, serum, and urine that may influence pathogenesis, response, and clinical characteristics. 
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