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CTRI Number  CTRI/2020/08/027208 [Registered on: 18/08/2020] Trial Registered Prospectively
Last Modified On: 09/10/2020
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group, Placebo Controlled Trial 
Public Title of Study   Study of Durvalumab in Combination with Gemcitabine and Cisplatin in Patients with First Line Advanced Biliary Tract Cancers (TOPAZ-1) 
Scientific Title of Study   A Phase III Randomized, Double-Blind, Placebo-Controlled, Multi- Regional, International Study of Durvalumab in Combination with Gemcitabine plus Cisplatin versus Placebo in Combination with Gemcitabine plus Cisplatin for Patients with First-Line Advanced Biliary Tract Cancers (TOPAZ-1) 
Trial Acronym   
Secondary IDs if Any
Modification(s)  
Secondary ID  Identifier 
D933AC00001 Version 4.0, dated 17 APR 2020  Protocol Number 
NCT03875235  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  Tapankumar M Shah 
Designation  Country Director, Clinical Operations 
Affiliation  AstraZeneca Pharma India Ltd 
Address  Block N1, 12th Floor, Manyata Embassy Business Park, Rachenahalli, Outer Ring Road

Bangalore
KARNATAKA
560045
India 
Phone  91-9535104975   
Fax  91-8067748857   
Email  tapankumar.shah@astrazeneca.com  
 
Details of Contact Person
Public Query
 
Name  Tapankumar M Shah 
Designation  Country Director, Clinical Operations 
Affiliation  AstraZeneca Pharma India Ltd 
Address  Block N1, 12th Floor, Manyata Embassy Business Park, Rachenahalli, Outer Ring Road


KARNATAKA
560045
India 
Phone  91-9535104975   
Fax  91-8067748857   
Email  tapankumar.shah@astrazeneca.com  
 
Source of Monetary or Material Support  
AstraZeneca AB 151 85 Sodertalje, 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     Argentina
Brazil
Chile
China
France
Hong Kong
India
Italy
Japan
Poland
Republic of Korea
Russian Federation
Taiwan
Thailand
Turkey
United Kingdom
United States of America  
Sites of Study  
No of Sites = 8  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Sushant Mittal  Action Cancer Hospital  Dept. of Medical Oncology Room no 824, A-4 block, A6 Block, Paschim Vihar, PIN- 110063
New Delhi
DELHI 
01149222222

sushantmittal80@gmail.com 
Dr Vineet Govinda Gupta  Artemis Hospitals  Dept. of Medical Oncology Sector-51, PIN-122001
Gurgaon
HARYANA 
01246767999

vineet.gupta@artemishospitals.com 
Dr Manish Singhal  Indraprastha Apollo Hospitals Sarita Vihar  Dept. of Medical Oncology Sarita Vihar, Delhi - Mathura Road, PIN - 1100076
New Delhi
DELHI 
01126925858

singhaloncocare@yahoo.co.in 
Dr Vineet Talwar  Rajiv Gandhi Cancer Institute and Research Centre  Dept. of Medical Oncology Sir Chhotu Ram Marg, Sector -5, Rohini, PIN- 110085
New Delhi
DELHI 
0114702222

drvineettalwar@yahoo.com 
Dr Lokesh K N  Shettys Hospital  Dept. of Medical Oncology Plot no. 11 &12, 12th F Main, Kaveri Nagar, Bommanahalli, PIN- 560068
Bangalore
KARNATAKA 
08040943039

knloki@gmail.com 
Dr Satheesh CT  Sri Venkateshwara Hospitals  Dept. of Medical Oncology #27th, 29th, Main Road, Rashtra Kuvempu Nagara, BTM 2nd Stage, BTM Layout, PIN-560076
Bangalore
KARNATAKA 
080-49730808

drsatheeshct@gmail.com 
Dr Joydeep Ghosh  Tata Medical Centre Kolkata   Dept. of Medical Oncology 14 Major arterial road E-W, New Town, Rajarhat, PIN 700160
Kolkata
WEST BENGAL 
03366057000

dr.joydeep.ghosh@gmail.com 
Dr Vikas Sureshchand Ostwal  Tata Memorial Hospital  3rd Floor, Room No. 323, Dr Ernest Borges Marg, Parel, PIN- 400012
Mumbai
MAHARASHTRA 
02224177000

dr.vikas.ostwal@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 8  
Name of Committee  Approval Status 
Artemis Health Sciences Institutional Ethics Committee  Approved 
Institutional Ethics Committee TATA Memorial Hospital  Approved 
Institutional Ethics Committee - Clinical studies, Indraprastha Apollo Hospitals  Submittted/Under Review 
Institutional Ethics Committee, Action Cancer Hospital  Submittted/Under Review 
Institutional ethics committee, Tata Medical Center, Kolkata  Submittted/Under Review 
Institutional Review Board, Rajiv Gandhi Cancer Institute and Research Centre  Approved 
Shettys Hospital Ethics Committee  Approved 
Sri Venkateshwara Hospital Ethics Committee  Approved 
 
Regulatory Clearance Status from DCGI
Modification(s)  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  C221||Intrahepatic bile duct carcinoma, C23||Malignant neoplasm of gallbladder,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Durvalumab (MEDI4736)   Durvalumab plus Cisplatin and Gemcitabine Frequency: every 03 weeks for first 8 cycles followed by every 4 weeks till progression Root of Administration: IV (Intravenous) Duration of therapy: until progression  
Comparator Agent  Placebo  Placebo plus Cisplatin and Gemcitabine. Frequency: every 03 weeks for first 8 cycles followed by every 4 weeks till progression Root of Administration: IV (Intravenous) Duration of therapy: until progression  
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  99.00 Year(s)
Gender  Both 
Details  Informed consent
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.
2. Provision of a signed and dated written ICF prior to any mandatory study-specific procedures, sampling, and analyses.
3. Provision of a signed and dated written informed consent prior to the collection of sample for optional genetic analysis
Age
4. Age ≥18 years at the time of screening
Type of patient and disease characteristics

5. Histologically confirmed, unresectable advanced or metastatic adenocarcinoma of biliary tract, including cholangiocarcinoma (intrahepatic or extrahepatic) and gallbladder carcinoma.
6. Patients with previously untreated disease if unresectable or metastatic at initial diagnosis will be eligible.
7. Patients who developed recurrent disease >6 months after surgery with curative intent and, if given, >6 months after the completion of adjuvant therapy (chemotherapy and/or radiation) will be eligible.
8. A World Health Organization (WHO)/ECOG PS of 0 or 1 at enrollment.
9. At least 1 lesion that qualifies as a RECIST 1.1 Target Lesion (TL) at baseline.
10. No prior exposure to immune-mediated therapy, including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.
11. Adequate organ and marrow function, as defined below:
a. Hemoglobin ≥9.0 g/dL.
b. Absolute neutrophil count ≥1.5 × 109 /L.
c. Platelet count ≥100 × 109/L.
d. Serum bilirubin ≤2.0 × the upper limit of normal (ULN); This will not apply to
e. patients with confirmed Gilbert’s syndrome. Any clinically significant biliary
f. obstruction should be resolved before randomization.
g. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 × ULN.
h. Creatinine clearance (CL) >50 mL/min per 24hr urine or as calculated by Cockcroft-Gault
12. Patients must have a life expectancy of at least 12 weeks at the time of screening
Sex

14. Male and/or female.

Other

15. Patients must provide a recent tumor biopsy or an available unstained archived tumor tissue sample in a quantity sufficient to allow for analysis (taken ≤3 years prior to screening). The tumor lesions to be used for biopsy should not be those used as RECIST TLs, unless there are no other lesions suitable for biopsy.
16. Patients with HBV infection (as characterized by positive hepatitis B surface antigen [HBsAg] and/or anti-hepatitis B core antibodies (anti-HBc) with detectable HBV deoxyribonucleic acid (DNA) [≥10 IU/mL or above the limit of detection per local laboratory]) must receive antiviral therapy prior to randomization per institutional practice to ensure adequate viral suppression. Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment. Patients who test positive for anti-HBc with undetectable HBV DNA (<10 IU/mL or under the limit of detection per local laboratory) do not require antiviral therapy unless HBV DNA exceeds 10IU/mL or reaches detectable limits per local laboratory during the course of treatment. Patients with active co-infection of HBV and HCV as evidenced by positive anti-HCV antibody and actively co-infected with HBV and hepatitis D virus are not eligible.
 
 
ExclusionCriteria 
Details  Medical conditions
1. Ampullary carcinoma.
2. History of allogeneic organ transplantation.
3. 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. Any chronic skin condition that does not require systemic therapy.
d. Patients without an active disease in the last 5 years may be included but only after consultation with the Study Physician.
f. Patients with celiac disease controlled by diet alone.
4. 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 (ILD), serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase the risk of incurring AEs, or compromise the ability of the patient to give written informed consent.
5. History of another primary malignancy, except for:
a. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of investigational product (IP) and of low potential risk for recurrence.
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
c. Adequately treated carcinoma in situ without evidence of disease.
6. History of leptomeningeal carcinomatosis.
7. History of active primary immunodeficiency.
8. Active infection, including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), or human immunodeficiency virus (positive HIV 1/2 antibodies).
9. Any unresolved toxicity NCI Common Terminology Criteria for Adverse Event (CTCAE) Grade ≥2 from a 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 may be included only after consultation with the Study Physician.
10. Brain metastases or spinal cord compression (including asymptomatic and adequately treated disease). Patients with suspected brain metastases at screening should have an MRI (preferred) or CT scan, each preferably with IV contrast, of the brain prior to study entry.
11. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

Prior/concomitant therapy

12. 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.
13. Radiation therapy, including palliative radiation, is not allowed before the study, with an exception of radiation given in an adjuvant setting.
14. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note that patients, if enrolled, should not receive live vaccine while receiving IP and up to 30 days after the last dose of IP.
15. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note that minor surgery of isolated lesions for palliative intent is acceptable if performed more than 14 days prior to the first dose of IP.
16. Patients who have received prior immune-mediated therapy, including, but not limited to, other anti-PD-1, anti PD-L1, or anti CTLA-4.
17. Prior locoregional therapy such as radioembolization.
18. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
a. Intranasal, inhaled, or 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).

Prior/concurrent clinical study experience
19. Participation in another clinical study with an IP administered in the last 3 months.
20. Previous IP assignment in the present study.
21. 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.
22. Prior randomization or treatment in a previous durvalumab clinical study, regardless of treatment arm assignment.

Other exclusions

23. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to use effective birth control from screening to 180 days after the last dose of gemcitabine/cisplatin or 90 days after the last dose of durvalumab/placebo monotherapy.
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 (deoxyribonucleic acid [DNA]) genetic 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.
26. Active infection of hepatitis C as evidenced by detectable HCV RNA per local laboratory. Patients who test positive for hepatitis C (HCV) antibody may be enrolled if HCV RNA is undetectable.
 
 
Method of Generating Random Sequence   Stratified block randomization 
Method of Concealment   Centralized 
Blinding/Masking   Double Blind Double Dummy 
Primary Outcome  
Outcome  TimePoints 
To assess the efficacy of Arm A compared to Arm B in terms of OS (overall survival) in patients with first-line advanced BTC  It will be assessed at the following time points:
1. Interim Analysis-2: Approximately 347 OS events have occurred across Arm A and Arm B (52% maturity) and
2. Final Analysis: Approximately 496 OS events have occurred across Arm A and Arm B (74% maturity).
 
 
Secondary Outcome  
Outcome  TimePoints 
To further assess the efficacy of Arm A compared to Arm B in terms of ORR and DoR in patients with first-line advanced BTC  Interim Analysis -1: When at least 200 patients (100 patients in the each arm) have had the opportunity to be followed for at least 32 weeks or the last patient has been randomized to the global cohort whichever comes later. 
For interim analysis 1: to summarise the efficacy of Arm A compared to Arm B in terms of ORR and DoR in patients with first-line advanced BTC  Interim Analysis -1: When at least 200 patients (100 patients in the each arm) have had the opportunity to be followed for at least 32 weeks or the last patient has been randomized to the global cohort whichever comes later. 
To assess the efficacy of Arm A compared to Arm B by PD-L1 expression  It will be assessed at the following time points:
1. Interim Analysis-2: Approximately 347 OS events have occurred across Arm A and Arm B (52% maturity) and
2. Final Analysis: Approximately 496 OS events have occurred across Arm A and Arm B (74% maturity). 
To assess the PK of durvalumab when used in combination with cisplatin / gemcitabine  It will be assessed at the following time points:
1. Interim Analysis-2: Approximately 347 OS events have occurred across Arm A and Arm B (52% maturity) and
2. Final Analysis: Approximately 496 OS events have occurred across Arm A and Arm B (74% maturity). 
To investigate the immunogenicity of durvalumab  It will be assessed at the following time points:
1. Interim Analysis-2: Approximately 347 OS events have occurred across Arm A and Arm B (52% maturity) and
2. Final Analysis: Approximately 496 OS events have occurred across Arm A and Arm B (74% maturity). 
PROs (secondary):  It will be assessed at the following time points:
1. Interim Analysis-2: Approximately 347 OS events have occurred across Arm A and Arm B (52% maturity) and
2. Final Analysis: Approximately 496 OS events have occurred across Arm A and Arm B (74% maturity). 
Safety objective:
To assess the safety and tolerability profile of Arm A compared to Arm B in patients with first-line advanced BTC
 
It will be assessed at the following time points:
1. Interim Analysis-2: Approximately 347 OS events have occurred across Arm A and Arm B (52% maturity) and
2. Final Analysis: Approximately 496 OS events have occurred across Arm A and Arm B (74% maturity). 
Exploratory objectives:
1. To investigate the efficacy of Arm A compared to Arm B by candidate biomarkers (for example but not limited to TMB and MSI) that may correlate with drug activity or identify patients likely to respond to treatment
 
It will be assessed at the following time points:
1. Interim Analysis-2: Approximately 347 OS events have occurred across Arm A and Arm B (52% maturity) and
2. Final Analysis: Approximately 496 OS events have occurred across Arm A and Arm B (74% maturity). 
2. To evaluate circulatory-based biomarkers and associations with efficacy parameters, including, but not limited to, ctDNA  It will be assessed at the following time points:
1. Interim Analysis-2: Approximately 347 OS events have occurred across Arm A and Arm B (52% maturity) and
2. Final Analysis: Approximately 496 OS events have occurred across Arm A and Arm B (74% maturity). 
3. To explore the impact of treatment and disease on healthcare resource use  It will be assessed at the following time points:
1. Interim Analysis-2: Approximately 347 OS events have occurred across Arm A and Arm B (52% maturity) and
2. Final Analysis: Approximately 496 OS events have occurred across Arm A and Arm B (74% maturity). 
4. PROs (exploratory):
To assess patient-reported treatment tolerability using PRO-CTCAE and global assessment of treatment tolerability
 
It will be assessed at the following time points:
1. Interim Analysis-2: Approximately 347 OS events have occurred across Arm A and Arm B (52% maturity) and
2. Final Analysis: Approximately 496 OS events have occurred across Arm A and Arm B (74% maturity). 
To assess the patients’ global impression of the severity of cancer symptoms  It will be assessed at the following time points:
1. Interim Analysis-2: Approximately 347 OS events have occurred across Arm A and Arm B (52% maturity) and
2. Final Analysis: Approximately 496 OS events have occurred across Arm A and Arm B (74% maturity). 
To explore the impact of treatment and disease state on health state utility using the EQ-5D-5L  It will be assessed at the following time points:
1. Interim Analysis-2: Approximately 347 OS events have occurred across Arm A and Arm B (52% maturity) and
2. Final Analysis: Approximately 496 OS events have occurred across Arm A and Arm B (74% maturity). 
 
Target Sample Size   Total Sample Size="672"
Sample Size from India="32" 
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)   21/08/2020 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  16/04/2019 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="3"
Months="4"
Days="0" 
Recruitment Status of Trial (Global)   Open to Recruitment 
Recruitment Status of Trial (India)  Not Yet Recruiting 
Publication Details   NIL 
Brief Summary  

This is a Phase III Randomized, Double-Blind, Placebo-Controlled, Multi-Regional, International Study of Durvalumab in Combination with Gemcitabine plus Cisplatin versus Placebo in Combination with Gemcitabine plus Cisplatin for Patients with First-Line Advanced Biliary Tract Cancers (BTC)

 

Approximately 672 patients with previously untreated, unresectable locally advanced or metastatic BTC will be randomized in a 1:1 ratio to receive either Durvalumab plus Gemcitabine and Cisplatin or Placebo plus Gemcitabine and Cisplatin.

 

The primary objective of the study is to confirm the superiority of Arm A compared to Arm B in terms of overall survival (OS) in patients with first-line advanced BTC.

 

Patients will be stratified by disease status (initially unresectable versus recurrent) and primary tumour site (intrahepatic cholangiocarcinoma versus extrahepatic cholangiocarcinoma versus gallbladder cancer).

 

Patients will receive Durvalumab plus cisplatin and gemcitabine (Arm A) or placebo plus cisplatin and gemcitabine (Arm B) via IV infusion q3w, starting on Cycle 1, for up to 8 cycles. After treatment with gemcitabine/cisplatin is complete, the patients will receive durvalumab (Arm A) or placebo (Arm B) via IV infusion q4w until clinical progression or RECIST 1.1-defined radiological PD, unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.

 

During the treatment period, patients who are clinically stable at an initial RECIST 1.1-defined radiological PD may continue to receive study treatment at the discretion of the Investigator and patient. A follow-up scan is to be collected after the initial RECIST 1.1-defined radiological PD, preferably at the next (and no later than the next) scheduled imaging visit and no less than 4 weeks after the prior assessment of PD.

 

Patients with RECIST 1.1-defined radiological PD who continue to receive their assigned treatment at the discretion of the Investigator and patient (following consultation with sponsor) can receive treatment until no longer having clinical benefit, and imaging for tumour assessments should continue on their regular imaging schedule for the duration of treatment.

 

All randomized patients should be followed up for survival.  
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