Phase 3 Study of T-DXd and Rilvegostomig Versus SoC in Advanced HER2-expressing Biliary Tract Cancer

Biliary Tract Cancer Clinical Trial

— DESTINY-BTC01  

Official title:

DESTINY-Biliary Tract Cancer-01: A Phase 3 Study of Trastuzumab Deruxtecan (T-DXd) and Rilvegostomig Versus Standard-of-Care Gemcitabine, Cisplatin, and Durvalumab for First Line Locally Advanced or Metastatic HER2-expressing Biliary Tract Cancer

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06467357
• Other study ID #: D781PC00001
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: June 26, 2024
• Est. completion date: March 30, 2029

Study information

• Verified date: June 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 620
• Est. completion date: March 30, 2029
• Est. primary completion date: April 26, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Key Inclusion Criteria:

• Participants must be = 18 years of age at the time of screening. Other age restrictions may apply as per local regulations;
• Male and female;
• Unresectable, previously untreated, locally advanced or metastatic BTC. Prior treatment in the perioperative and/or adjuvant setting is permissible provided there is > 6 months (180 days) between the end of adjuvant treatment and the diagnosis of locally advanced or metastatic disease.
• histologically confirmed HER2-expressing (IHC 3+ or IHC 2+) BTC;
• Provision of FFPE tumor sample that is no older than 3 years;
• At least one target lesion assessed by the Investigator based on RECIST v1.1 (randomized portion only);
• WHO/ECOG performance status of 0 or 1;
• Adequate organ and bone marrow function within 14 days before randomization;
• Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential;

Key Exclusion Criteria:

• Prior exposure to other HER2 targeting therapies, ADCs, immune checkpoint inhibitors and therapeutic anticancer vaccines;
• histologically confirmed ampullary carcinoma;
• history of substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions;
• spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms;
• medical history of myocardial infarction within 6 months before randomization/enrollment, symptomatic congestive heart failure (New York Heart Association Class II to IV), unstable angina pectoris, clinically important cardiac arrhythmias, or a recent (< 6 months) cardiovascular event including stroke;
• Serious chronic gastrointestinal conditions associated with diarrhea (eg, active inflammatory bowel disease); active non-infectious skin disease (including any grade rash, urticaria, dermatitis, ulceration, or psoriasis) requiring systemic treatment;
• active autoimmune, connective tissue or inflammatory disorders that has required systemic treatment in the past 2 years, or where there is documented, or a suspicion of pulmonary involvement at the time of screening;
• Corrected QT interval (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on average of the screening triplicate 12-lead ECG;
• History of (non-infectious) ILD/pneumonitis, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening;
• Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder;
• Prior pneumonectomy (complete);
• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals;
• Active primary immunodeficiency, known uncontrolled active HIV infection or HCV;
• Pregnant or breastfeeding female patients, or patients who are planning to become pregnant;
• Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 6 months prior to randomization, or 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 (only randomized portion).

Related Conditions & MeSH terms

• Biliary Tract Cancer
• Biliary Tract Neoplasms

Intervention

Drug:
• Gemcitabine
Standard of care chemotherapy by intravenous infusion
• Cisplatin
Standard of care chemotherapy by intravenous infusion
• Durvalumab
Standard of care immunotherapy by intravenous infusion
• Trastuzumab deruxtecan
Experimental therapy by intravenous infusion
• Rilvegostomig
Experimental therapy by intravenous infusion

Diagnostic Test:
• Agilent HercepTest™ mAb pharmDx
A semi-quantitative immunohistochemical assay to determine HER2 overexpression in FFPE breast cancer tissues routinely processed for histological evaluation. Based on a primary monoclonal rabbit antibody which visualises Her2 overexpression utilising a fully automated IHC platform (Dako Omnis).
• Ventana PD-L1 SP263 assay
A qualitative immunohistochemical assay to determine the level of PD-L1 expression in FFPE non-small cell lung cancer (NSCLC) tissues routinely processed for histological evaluation. Based on a rabbit monoclonal anti-PD-L1 clone SP263 which visualises PD-L1 protein using a VENTANA BenchMark ULTRA instrument

Locations

Country	Name	City	State
Austria	Research Site	Linz
Austria	Research Site	Salzburg
Austria	Research Site	Wien
Austria	Research Site	Wiener Neustadt
Belgium	Research Site	Anderlecht
Belgium	Research Site	Edegem
Belgium	Research Site	Leuven
Belgium	Research Site	Liège
Belgium	Research Site	Roeselare
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Sao Paulo
Canada	Research Site	Halifax	Nova Scotia
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Toronto	Ontario
Germany	Research Site	Berlin
Germany	Research Site	Dresden
Germany	Research Site	Frankfurt
Germany	Research Site	Göttingen
Germany	Research Site	Hamburg
Germany	Research Site	Köln
Germany	Research Site	Leipzig
Germany	Research Site	Lübeck
Germany	Research Site	Munchen
Germany	Research Site	Ulm
Germany	Research Site	Wuerzburg
Japan	Research Site	Kashiwa
Japan	Research Site	Koto-ku
Japan	Research Site	Osaka-shi
Japan	Research Site	Suita-city
Japan	Research Site	Yokohama-shi
Korea, Republic of	Research Site	Seoul
Netherlands	Research Site	Rotterdam
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taoyuan

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Daiichi Sankyo Company, Limited 3-5-1 Nihonbashihoncho, Chuo-ku, Tokyo

Countries where clinical trial is conducted

Austria,  Belgium,  Brazil,  Canada,  Germany,  Japan,  Korea, Republic of,  Netherlands,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)