Phase 3 Study of T-DXd and Rilvegostomig Versus SoC in Advanced HER2-expressing Biliary Tract Cancer
NCT Number: NCT06467357
Acronym: DESTINY-BTC01
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE3
Conditions: Biliary Tract Cancer
Interventions: DRUG: Gemcitabine|DRUG: Cisplatin|DRUG: Durvalumab|DRUG: Trastuzumab deruxtecan|DRUG: Rilvegostomig|DIAGNOSTIC_TEST: Agilent HercepTest™ mAb pharmDx|DIAGNOSTIC_TEST: Ventana PD-L1 SP263 assay
Sponsor: AstraZeneca
Collaborators: Daiichi Sankyo Company, Limited 3-5-1 Nihonbashihoncho, Chuo-ku, Tokyo
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 620
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-06-26
Completion Date: 2029-03-30
Locations: Research Site, Linz, 4010, Austria|Research Site, Salzburg, 5020, Austria|Research Site, Wiener Neustadt, 2700, Austria|Research Site, Wien, 1090, Austria|Research Site, Anderlecht, 1070, Belgium|Research Site, Edegem, 2650, Belgium|Research Site, Leuven, 3000, Belgium|Research Site, Liège, 4000, Belgium|Research Site, Roeselare, 8800, Belgium|Research Site, Porto Alegre, 90035-000, Brazil|Research Site, Sao Paulo, 01246-000, Brazil|Research Site, Halifax, Nova Scotia, B3H 1V7, Canada|Research Site, Toronto, Ontario, M5G 2M9, Canada|Research Site, Montreal, Quebec, H3A 1A1, Canada|Research Site, Berlin, 13353, Germany|Research Site, Dresden, 01370, Germany|Research Site, Frankfurt, 60488, Germany|Research Site, Göttingen, 37075, Germany|Research Site, Hamburg, 22763, Germany|Research Site, Köln, 50937, Germany|Research Site, Leipzig, 4103, Germany|Research Site, Lübeck, 23538, Germany|Research Site, Munchen, 81377, DE, Germany|Research Site, Ulm, 89081, Germany|Research Site, Wuerzburg, 97080, Germany|Research Site, Kashiwa, 227-8577, Japan|Research Site, Koto-ku, 135-8550, Japan|Research Site, Osaka-shi, 541-8567, Japan|Research Site, Suita-city, 565-0871, Japan|Research Site, Yokohama-shi, 241-8515, Japan|Research Site, Seoul, 03080, Korea, Republic of|Research Site, Rotterdam, 3015 GD, Netherlands|Research Site, Kaohsiung, 833, Taiwan|Research Site, Taipei, 10002, Taiwan|Research Site, Taipei, 112, Taiwan|Research Site, Taoyuan, 333, Taiwan

Summary:
The purpose of this study is to measure the efficacy and safety of T-DXd with rilvegostomig or T-DXd monotherapy compared with gemcitabine plus cisplatin and durvalumab in patients with advanced treatment naïve HER2-expressing BTC.

Primary Outcome Measures: Safety Run In: To evaluate the safety and tolerability of T-DXd with rilvegostomig, Safety and tolerability will be evaluated with multiple endpoints including the proportion of treated patients with occurrence of AEs, SAEs, AESIs, and clinically significant change from baseline for Hematology, clinical chemistry, Urinalysis, vital sign including ECG will be summarized, specifically pts with QTcF prolongation greater than grade 3, number of pts with echocardiogram/MUGA results LVEF greater than 10 percentage points to below 50%., Until all patients have completed at least 1 full Cycle (each cycle is 21 days)|Randomized Portion: To evaluate the efficacy of T-DXd with rilvegostomig vs Standard of Care (SoC) in terms of Overall Survival in the HER2 IHC 3+ population, Overall survival (OS) in HER2 IHC 3+ population OS is defined as time from randomization date until the date of death due to any cause. The comparison will include all randomized patients, regardless of whether the patient withdraws from therapy or receives another anticancer therapy. The measure of interest is the hazard ratio of OS., From date of treatment assignment until the date of death from any cause (estimated to be assessed up to 48 months after first subject randomized)
Secondary Outcome Measures: To evaluate the efficacy of T-DXd with rilvegostomig vs Standard of Care in terms of Overall Survival in the ITT population (HER2 IHC 3+/2+), Overall Survival (OS) in ITT population (HER2 IHC 3+/2+) OS definition as above, From date of randomization until the date of death from any cause (estimated to be assessed up to 48 months after first subject randomized)|To evaluate the efficacy of T-DXd monotherapy vs Standard of Care in terms of Overall Survival in the HER2 IHC 3+ population, Overall Survival (OS) in HER2 IHC 3+ population OS definition as above, From date of randomization until the date of death from any cause (estimated to be assessed up to 48 months after first subject randomized)|To evaluate the efficacy of T-DXd monotherapy vs Standard of Care in terms of Overall Survival in the ITT population, Overall Survival (OS) in ITT population (HER2 IHC 3+/2+) OS definition as above, From date of randomization until the date of death from any cause (estimated to be assessed up to 48 months after first subject randomized)|To further evaluate efficacy of T-DXd with rilvegostomig vs Standard of Care in terms of Progression Free Survival in HER2 IHC 3+ and ITT populations, Progression free survival (PFS) in HER2 IHC 3+ and ITT populations. PFS is defined as time from randomization until progression per RECIST v1.1, or death due to any cause. The analysis will include all randomized patients, regardless of whether the patient withdraws from randomized therapy, receives another anticancer therapy or clinically progresses prior to RECIST v1.1 progression.

The measure of interest is the hazard ratio of PFS., From date of randomization until the date of first documented progression or date of death from any cause, whichever occurs first (estimated to be assessed up to 48 months)|To further evaluate efficacy of T-DXd monotherapy vs Standard of Care in terms of Progression Free Survival in HER2 IHC 3+ and ITT populations, Progression free survival (PFS) in HER2 IHC 3+ and ITT populations. PFS is defined as time from randomization until progression per RECIST v1.1, or death due to any cause. The analysis will include all randomized patients, regardless of whether the patient withdraws from randomized therapy, receives another anticancer therapy or clinically progresses prior to RECIST v1.1 progression.

The measure of interest is the hazard ratio of PFS., From date of randomization until the date of first documented progression or date of death from any cause, whichever occurs first (estimated to be assessed up to 48 months)|To further evaluate the efficacy of T-DXd with rilvegostomig vs Standrad of Care in terms of objective response rate in the HER2 IHC 3+ and ITT populations, Objective response rate (ORR) in HER2 IHC 3+ and ITT populations ORR is defined as the proportion of patients who achieved CR or PR per RECIST 1.1, confirmed by the investigator. The analysis will include objective response data for all randomized patients from randomization until progression, or up to the last evaluable assessment in the absence of progression.

Patients who go off-treatment without a response or progression and then respond while receiving a subsequent therapy will not be included as responders in the ORR calculation.

The measure of interest is the odds ratio of ORR., Estimated up to 6 months since randomization|To further evaluate the efficacy of T-DXd monotherapy vs Standrad of Care in terms of objective response rate in the HER2 IHC 3+ and ITT populations, Objective response rate (ORR) in HER2 IHC 3+ and ITT populations ORR is defined as the proportion of patients who achieved CR or PR per RECIST 1.1, confirmed by the investigator. The analysis will include objective response data for all randomized patients from randomization until progression, or up to the last evaluable assessment in the absence of progression.

Patients who go off-treatment without a response or progression and then respond while receiving a subsequent therapy will not be included as responders in the ORR calculation.

The measure of interest is the odds ratio of ORR., Estimated up to 6 months since randomization|To further evaluate efficacy of T-DXd with rilvegostomig vs Standard if Care in terms of duration of response in patients with HER2-expressing BTC in the IHC 3+ and ITT populations, Duration of response (DoR) in HER2 IHC 3+ and ITT populations DoR will be defined as the time from the date of first documented response until date of documented progression per RECIST v1.1, or death due to any cause. The analysis will include all randomized patients who have a response, regardless of whether the patient withdraws from randomized therapy, receives another anti-cancer therapy or clinically progresses prior to RECIST v1.1 progression.

The measure of interest is the median DoR., From the date of first documented response until date of documented progression or death due to any cause, whichever occurs first (estimated up to 48 months)|To further evaluate efficacy of T-DXd monotherapy vs Standard if Care in terms of duration of response in patients with HER2-expressing BTC in the IHC 3+ and ITT populations, Duration of response (DoR) in HER2 IHC 3+ and ITT populations DoR will be defined as the time from the date of first documented response until date of documented progression per RECIST v1.1, or death due to any cause. The analysis will include all randomized patients who have a response, regardless of whether the patient withdraws from randomized therapy, receives another anti-cancer therapy or clinically progresses prior to RECIST v1.1 progression.

The measure of interest is the median DoR., From the date of first documented response until date of documented progression or death due to any cause, whichever occurs first (estimated up to 48 months)|To further evaluate the efficacy of T-DXd with rilvegostomig versus T-DXd monotherapy in terms of Overall survival in HER2 IHC 3+ and ITT populations., Overall survival (OS) in HER2 IHC 3+ population OS is defined as time from randomization date until the date of death due to any cause. The comparison will include all randomized patients, regardless of whether the patient withdraws from therapy or receives another anticancer therapy. The measure of interest is the hazard ratio of OS., From the date of randomisation until progression or death due to any cause, whichever occurs first (estimated up to 48 months)|To further evaluate the efficacy of T-DXd with rilvegostomig versus T-DXd monotherapy in terms of PFS in HER2 IHC 3+ and ITT populations., Progression free survival (PFS) in HER2 IHC 3+ and ITT populations. PFS is defined as time from randomization until progression per RECIST v1.1, or death due to any cause. The analysis will include all randomized patients, regardless of whether the patient withdraws from randomized therapy, receives another anticancer therapy or clinically progresses prior to RECIST v1.1 progression.

The measure of interest is the hazard ratio of PFS., From the date of randomisation until progression or death due to any cause, whichever occurs first (estimated up to 48 months)|To further evaluate the efficacy of T-DXd with rilvegostomig versus T-DXd monotherapy in terms of Duration of response in HER2 IHC 3+ and ITT populations., Duration of response (DoR) in HER2 IHC 3+ and ITT populations DoR will be defined as the time from the date of first documented response until date of documented progression per RECIST v1.1, or death due to any cause. The analysis will include all randomized patients who have a response, regardless of whether the patient withdraws from randomized therapy, receives another anti-cancer therapy or clinically progresses prior to RECIST v1.1 progression.

The measure of interest is the median DoR., From the date of first response until progression or death due to any cause, whichever occurs first (estimated up to 48 months)|To further evaluate the efficacy of T-DXd with rilvegostomig versus T-DXd monotherapy in terms of Objective response rate in HER2 IHC 3+ and ITT populations., Objective response rate (ORR) in HER2 IHC 3+ and ITT populations ORR is defined as the proportion of patients who achieved CR or PR per RECIST 1.1, confirmed by the investigator. The analysis will include objective response data for all randomized patients from randomization until progression, or up to the last evaluable assessment in the absence of progression.

Patients who go off-treatment without a response or progression and then respond while receiving a subsequent therapy will not be included as responders in the ORR calculation.

The measure of interest is the odds ratio of ORR., Estimated up to 6 months|To assess the safety and tolerability of T-DXd with rilvegostomig vs Standard of Care, Safety and tolerability will be evaluated with multiple endpoints including the proportion of treated patients with occurrence of AEs, SAEs, AESIs, and clinically significant change from baseline for Hematology, clinical chemistry, Urinalysis, vital sign including ECG will be summarized, specifically pts with QTcF prolongation greater than grade 3, number of pts with echocardiogram/MUGA results LVEF greater than 10 percentage points to below 50%., From first dose of study intervention until 90 days after the last dose except for ILD/pneumonitis, where safety follow-up will be continued until resolution.|To assess the safety and tolerability of T-DXd monotherapy vs Standard of Care, Safety and tolerability will be evaluated with multiple endpoints including the proportion of treated patients with occurrence of AEs, SAEs, AESIs, and clinically significant change from baseline for Hematology, clinical chemistry, Urinalysis, vital sign including ECG will be summarized, specifically pts with QTcF prolongation greater than grade 3, number of pts with echocardiogram/MUGA results LVEF greater than 10 percentage points to below 50%., From first dose of study intervention until 90 days after the last dose except for ILD/pneumonitis, where safety follow-up will be continued until resolution.|To describe patient-reported tolerability of T-DXd with rilvegostomig in comparison to Standard of Care based on a summary of symptomatic AEs, Patient-reported tolerability will be described using the Symptomatic adverse events: Descriptive summary of the proportion of patients reporting symptomatic AEs while on treatment using items from the EORTC Item Library (on EORTC IL form 322)., Until End of Study (estimated up to 48 months)|To describe patient-reported tolerability of T-DXd monotherapy in comparison to SoC based on a summary of symptomatic AEs, Patient-reported tolerability will be described using the Symptomatic adverse events: Descriptive summary of the proportion of patients reporting symptomatic AEs while on treatment using items from the EORTC Item Library (on EORTC IL form 322), Until End of Study (estimated up to 48 months)|To describe patient-reported tolerability of T-DXd with rilvegostomig in comparison to T-DXd monotherapy based on a summary of symptomatic AEs and overall side-effect bother, Symptomatic AEs and overall side-effect bother definitions as above, Until End of Study (estimated up to 48 months)|To assess time to deterioration in physical functioning in patients treated with T-DXd with rilvegostomig vs Standard of Care, Time to deterioration (TTD) in physical function as measured by the PROMIS Short Form v2.0 - Physical Function 8c - TTD is defined as time from the date of randomization to the date of deterioration.

Deterioration is defined as the change from baseline that reaches a clinically meaningful deterioration threshold.

- The measure of interest is the HR of TTD in physical function. The analysis will include all randomized patients as randomized., Until End of Study (estimated up to 48 months)|To assess time to deterioration in physical functioning in patients treated with T-DXd monotherapy vs Standard of care, Time to deterioration (TTD) in physical function as measured by the PROMIS Short Form v2.0 - Physical Function 8c - TTD is defined as time from the date of randomization to the date of deterioration.

Deterioration is defined as the change from baseline that reaches a clinically meaningful deterioration threshold.

- The measure of interest is the HR of TTD in physical function. The analysis will include all randomized patients as randomized., Until End of Study (estimated up to 48 months)|To assess time to deterioration in physical functioning in patients treated with T-DXd with rilvegostomig vs T-DXd monotherapy, Time to deterioration (TTD) in physical function as measured by the PROMIS Short Form v2.0 - Physical Function 8c - TTD is defined as time from the date of randomization to the date of deterioration.

Deterioration is defined as the change from baseline that reaches a clinically meaningful deterioration threshold.

- The measure of interest is the HR of TTD in physical function. The analysis will include all randomized patients as randomized., Until End of Study (estimated up to 48 months)|To assess the pharmacokinetics of T-DXd, total anti- HER2 antibody, DXd and rilvegostomig in serum, Descriptive analysis of serum concentration of T-DXd, total anti-HER2 antibody, DXd and rilvegostomig in all applicable arms., From the time of informed consent until 30 and 90 days after the last dose of T-DXd and rilvegostomig, respectively|To investigate the immunogenicity of T-DXd and of rilvegostomig, Descriptive summary of presence of ADAs for T-DXd and rilvegostomig in all applicable arms., From the time of informed consent until 30 and 90 days after the last dose of T-DXd and rilvegostomig, respectively|To describe patient-reported tolerability of T-DXd with rilvegostomig in comparison to Standard of Care based on overall side-effect bother, Patient-reported tolerability will be described using the Overall side-effect bother that will be mesured using PGI-TT, Until End of Study (estimated up to 48 months)|To describe patient-reported tolerability of T-DXd monotherapy in comparison to SoC based on overall side-effect bother, Patient-reported tolerability will be described using the Overall side-effect bother that will be assessed will be mesured using PGI-TT, Until End of Study (estimated up to 48 months)