Durvalumab or Placebo in Combination With Gemcitabine/Cisplatin in Patients With 1st Line Advanced Biliary Tract Cancer (TOPAZ-1) (TOPAZ-1)

• ClinicalTrials.gov Identifier: NCT03875235
• Recruitment Status: Active, not recruiting
• First Posted: March 14, 2019
• Results First Posted: April 13, 2023
• Last Update Posted: May 16, 2024
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: March 13, 2019
• First Posted Date: March 14, 2019
• Results First Submitted Date: August 10, 2022
• Results First Posted Date: April 13, 2023
• Last Update Posted Date: May 16, 2024
• Actual Study Start Date: April 16, 2019
• Actual Primary Completion Date: August 11, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 21, 2023)

• Overall Survival (OS) [ Time Frame: From date of randomization until death due to any cause. Assessed up to maximum of approximately 27 months (from date of randomization to primary analysis data cut-off) ]
  Overall Survival (OS) was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. The second interim analysis was pre-specified after approximately 397 OS events occurred in both arms (59% maturity).
• Overall Survival (OS) Rate at 18 Months [ Time Frame: From date of randomization until death due to any cause. Calculated at 18 months using the Kaplan-Meier technique. ]
  Overall Survival (OS) was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. The second interim analysis was pre-specified after approximately 397 OS events occurred in both arms (59% maturity).
• Overall Survival (OS) Rate at 24 Months [ Time Frame: From date of randomization until death due to any cause. Calculated at 24 months using the Kaplan-Meier technique. ]
  Overall Survival (OS) was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. The second interim analysis was pre-specified after approximately 397 OS events occurred in both arms (59% maturity).

Original Primary Outcome Measures (submitted: March 13, 2019)

Overall survival [ Time Frame: 36 months ]

Assessments for Overall survival will be collected regularly at predefined time points until death

Current Secondary Outcome Measures (submitted: March 21, 2023)

• Progression-free Survival (PFS) [ Time Frame: Tumor assessments every 6 weeks after randomization for the first 24 weeks and then every 8 weeks thereafter until date of RECIST 1.1 defined radiological progressive disease or death. Assessed up to maximum of approximately 27 months. ]
  PFS based on investigator assessments according to RECIST version 1.1 was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Progression (i.e., PD) was defined as at least a 20% increase in the sum of diameters of target lesions (TLs) and an absolute increase of ≥5mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters, or a measurable increase in a non-target lesion, or the appearance of new lesions. Median PFS was calculated using the Kaplan-Meier technique.
• Progression-free Survival (PFS) Rate at 9 Months [ Time Frame: Tumor assessments every 6 weeks after randomization for the first 24 weeks and then every 8 weeks thereafter until date of RECIST 1.1 defined radiological progressive disease or death. Calculated at 9 months using the Kaplan-Meier technique. ]
  PFS based on investigator assessments according to RECIST version 1.1 was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Progression (i.e., PD) was defined as at least a 20% increase in the sum of diameters of target lesions (TLs) and an absolute increase of ≥5mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters, or a measurable increase in a non-target lesion, or the appearance of new lesions. Median PFS was calculated using the Kaplan-Meier technique.
• Progression-free Survival (PFS) Rate at 12 Months [ Time Frame: Tumor assessments every 6 weeks after randomization for the first 24 weeks and then every 8 weeks thereafter until date of RECIST 1.1 defined radiological progressive disease or death. Calculated at 12 months using the Kaplan-Meier technique ]
  PFS based on investigator assessments according to RECIST version 1.1 was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Progression (i.e., PD) was defined as at least a 20% increase in the sum of diameters of target lesions (TLs) and an absolute increase of ≥5mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters, or a measurable increase in a non-target lesion, or the appearance of new lesions. Median PFS was calculated using the Kaplan-Meier technique.
• Objective Response Rate (ORR) [ Time Frame: Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. Assessed up to maximum of approximately 27 months. ]
  Disease assessments based on investigator assessments were determined by using RECIST version 1.1 guidelines. The ORR was defined as the percentage of patients with confirmed complete response (CR) or confirmed partial response (PR). The CR was defined as disappearance of all target and non-target lesions and no new lesions. The PR was defined as >= 30% decrease in the sum of diameters of target lesions (compared to baseline) and no new non-target lesion. A confirmed CR or PR was defined as 2 CRs or 2 PRs with no evidence of progression in-between. Patients who discontinued randomized treatment without progression, received a subsequent anti-cancer therapy and then responded were not included as responders for ORR.
• Duration of Response (DoR) [ Time Frame: Tumor assessments (per RECIST 1.1) every 6 weeks for first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. Assessed up to maximum of approximately 27 months. ]
  The DoR was defined as the time from the date of first documented OR (confirmed CR or confirmed PR) until date of documented progression (PD) based on investigator assessments by using RECIST version 1.1 or death in absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1) . A confirmed CR was defined in above outcome measures. The PD was defined at least 20% increase in sum of diameters of target lesions (compared with nadir at 2 consecutive visits with an absolute increase of 5 mm), unequivocal progression of existing non-target lesions or new lesion. For participants who were alive and no documented PD at the time of data cutoff for analysis, DoR was censored at the last evaluable disease assessment date. Median DoR was calculated using Kaplan-Meier method.
• Duration of Response (DoR): Percentage Remaining in Response at 9 Months [ Time Frame: Tumor assessments (per RECIST 1.1) every 6 weeks for first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. Calculated at 9 months using the Kaplan-Meier technique ]
  The DoR was defined as the time from the date of first documented OR (confirmed CR or confirmed PR) until date of documented progression (PD) based on investigator assessments by using RECIST version 1.1 or death in absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1) . A confirmed CR was defined in above outcome measures. The PD was defined at least 20% increase in sum of diameters of target lesions (compared with nadir at 2 consecutive visits with an absolute increase of 5 mm), unequivocal progression of existing non-target lesions or new lesion. For participants who were alive and no documented PD at the time of data cutoff for analysis, DoR was censored at the last evaluable disease assessment date. Median DoR was calculated using Kaplan-Meier method.
• Duration of Response (DoR): Percentage Remaining in Response at 12 Months [ Time Frame: Tumor assessments (per RECIST 1.1) every 6 weeks for first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. Calculated at 12 months using the Kaplan-Meier technique ]
  The DoR was defined as the time from the date of first documented OR (confirmed CR or confirmed PR) until date of documented progression (PD) based on investigator assessments by using RECIST version 1.1 or death in absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1) . A confirmed CR was defined in above outcome measures. The PD was defined at least 20% increase in sum of diameters of target lesions (compared with nadir at 2 consecutive visits with an absolute increase of 5 mm), unequivocal progression of existing non-target lesions or new lesion. For participants who were alive and no documented PD at the time of data cutoff for analysis, DoR was censored at the last evaluable disease assessment date. Median DoR was calculated using Kaplan-Meier method.
• Disease Control Rate (DCR) - Overall [ Time Frame: Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. Assessed up to maximum of approximately 27 months. ]
  Disease control rate based on investigator assessments according to RECIST version 1.1 was defined as the rate of best objective response of complete response (CR), partial response (PR) or stable disease (SD).
• Disease Control Rate (DCR) - 24 Weeks [ Time Frame: Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization. ]
  Disease control rate based on investigator assessments according to RECIST version 1.1 was defined as the rate of best objective response of complete response (CR) or partial response (PR) by week 24 or who have stable disease (SD) at least 24 weeks following start of treatment.
• Disease Control Rate (DCR) - 32 Weeks [ Time Frame: Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. ]
  Disease control rate based on investigator assessments according to RECIST version 1.1 was defined as the rate of best objective response of complete response (CR) or partial response (PR) by week 32 or who have stable disease (SD) at least 32 weeks following start of treatment.
• Disease Control Rate (DCR) - 48 Weeks [ Time Frame: Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. ]
  Disease control rate based on investigator assessments according to RECIST version 1.1 was defined as the rate of best objective response of complete response (CR) or partial response (PR) by week 48 or who have stable disease (SD) at least 48 weeks following start of treatment.

Original Secondary Outcome Measures (submitted: March 13, 2019)

• PFS accorridng RECSIST1.1 using investigator assessment [ Time Frame: 36 months ]
  Assessments will be made regularly until disease progression or until the end of the study
• ORR according to RECIST 1.1 using investigator assessment [ Time Frame: 36 months ]
  Assessments will be made regularly until disease progression or until the end of the study
• DoR accroding to RECSIST1.1 using investigator assessment [ Time Frame: 36 months ]
  Assessments will be made regularly until disease progression or until the end of the study

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Durvalumab or Placebo in Combination With Gemcitabine/Cisplatin in Patients With 1st Line Advanced Biliary Tract Cancer (TOPAZ-1)
• Official Title: 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
• Brief Summary: Durvalumab or Placebo in Combination With Gemcitabine/Cisplatin in Patients With 1st Line Advanced Biliary Tract Cancer (TOPAZ-1)
• Detailed Description: 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.
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Durvalumab in Combination with Gemcitabine plus Cisplatin Placebo in Combination with Gemcitabine plus Cisplatin

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment

• Condition: Biliary Tract Neoplasms

Intervention

• Drug: Durvalumab
  IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
• Drug: Placebo
  IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.

Study Arms

• Experimental: Treatment Arm
  Durvalumab + Gemcitabine + Cisplatin
  Intervention: Drug: Durvalumab
• Placebo Comparator: Placebo Arm
  Placebo + Gemcitabine + Cisplatin
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 12, 2022): 810
• Original Estimated Enrollment (submitted: March 13, 2019): 474
• Estimated Study Completion Date: March 31, 2025
• Actual Primary Completion Date: August 11, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion

1. Histologically confirmed, unresectable advanced or metastatic biliary tract, including cholangiocarcinoma (intrahepatic or extrahepatic) and gallbladder carcinoma.
2. Patients with previously untreated disease if unresectable or metastatic at initial diagnosis will be eligible.
3. Patient with recurrent disease >6 months after curative surgery or >6 months after the completion of adjuvant therapy (chemotherapy and/or radiation) will be eligible.
4. WHO/ECOG PS of 0 or 1

Exclusion

1. History of another primary malignancy
2. Brain metastases or spinal cord compression
3. Uncontrolled intercurrent illness
4. Major surgical procedure within 28 days prior to the first dose of IP.
5. Prior locoregional therapy such as radioembolization

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Bulgaria, Chile, China, France, Hong Kong, India, Italy, Japan, Korea, Republic of, Poland, Russian Federation, Taiwan, Thailand, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT03875235
• Other Study ID Numbers: D933AC00001; 2018-004688-30 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Gordon Cohen; AstraZeneca

• PRS Account: AstraZeneca
• Verification Date: May 2024