CTRI/2025/09/094936 [Registered on: 16/09/2025] Trial Registered Prospectively
Last Modified On:
16/01/2026
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Randomized, Parallel Group, Multiple Arm Trial
Public Title of Study
Phase 3 Study Comparing T-DXd & Rilvegostomig vs. Standard Gemcitabine, Cisplatin, and Durvalumab in First-Line HER2+ Biliary Tract Cancer
Scientific Title of Study
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
Trial Acronym
DESTINY BTC
Secondary IDs if Any
Secondary ID
Identifier
D781PC00001 version 3.0 dated 29-Nov-2024
Protocol Number
D781PC00001,Local CSP Add IND, V1.0 dated 24 Dec 2024
Protocol Number
NCT06467357
ClinicalTrials.gov
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Mr Sandeep AV
Designation
Senior Director, Oncology Country Head – Oncology Site Management & Monitoring India
Affiliation
AstraZeneca Pharma India Ltd
Address
Block N1, 12th Floor, Manyata Embassy Business Park
Rachenahalli, Outer Ring Road.
Bangalore
KARNATAKA
560045
India
Bangalore KARNATAKA 560045 India
Phone
9845079472
Fax
08067748857
Email
sandeep.av@astrazeneca.com
Details of Contact Person Scientific Query
Name
Mr Sandeep AV
Designation
Senior Director, Oncology Country Head – Oncology Site Management & Monitoring India
Affiliation
AstraZeneca Pharma India Ltd
Address
Block N1, 12th Floor, Manyata Embassy Business Park
Rachenahalli, Outer Ring Road.
Bangalore
KARNATAKA
560045
India
KARNATAKA 560045 India
Phone
9845079472
Fax
08067748857
Email
sandeep.av@astrazeneca.com
Details of Contact Person Public Query
Name
Mr Sandeep AV
Designation
Senior Director, Oncology Country Head – Oncology Site Management & Monitoring India
Affiliation
AstraZeneca Pharma India Ltd
Address
Block N1, 12th Floor, Manyata Embassy Business Park
Rachenahalli, Outer Ring Road.
Bangalore
KARNATAKA
560045
India
KARNATAKA 560045 India
Phone
9845079472
Fax
08067748857
Email
sandeep.av@astrazeneca.com
Source of Monetary or Material Support
151 85 Sodertalje, Sweden
AstraZeneca AB
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 Austria Belgium Brazil Bulgaria Canada China France Germany Hong Kong Hungary India Italy Japan Malaysia Poland Republic of Korea Singapore Spain Swaziland Taiwan Thailand Turkey United Kingdom United States of America Viet Nam
AA-299, Shaheed Udham Singh Marg, AA Block, Poorbi Shalimar Bagh, Delhi-110088 New Delhi DELHI
9911152107
vineet.gupta1@fortishealthcare.com
Dr Ankit Batra
Himalayan institute of medical sciences
Department of Medical Oncology
Swami Rama Himalayan University
Swami Ram Nagar, Beside Jolly Grant Airport Jolly Grant,
Doiwala, Dehradun Uttarakhand 248016 Dehradun UTTARANCHAL
9411712969
drankitbatra@gmail.com
Dr Santosh Vandanasetti
KAILASH CANCER HOSPITAL AND RESEARCH CENTER
Department of Medical Oncology
Muni Seva Ashram Goraj, Waghodia, Gujarat 391760 Vadodara GUJARAT
9427423693
vandanasetti.santosh@greenashram.org
Dr Poulami Basu
Netaji Shubhash Chandra Bose Cancer Hospital
Department of Medical Oncology
3081 Nayabad, New Garia, Kolkata 700094, West Bengal, India Kolkata WEST BENGAL
8902444454
poulamibasu18386@gmail.com
Dr Vikas Sureshchand Ostwal
TATA Memorial Hospital
Department of Medical Oncology
Dr. Earnesh Borges Road, Parel,
Mumbai- 400012 Maharastra, India Mumbai MAHARASHTRA
9702288801
dr.vikas.ostwal@gmail.com
Dr Kaushal Kalra
Vardhman Mahavir Medical College and Safdarjung Hospital,
Department of Medical Oncology, Vardhman Mahavir Medical College and Safdarjung Hospital,
Ansari Nagar, New Delhi, 110029, India New Delhi DELHI
Apollo Specialty Hospital Kanpur Ethics Commiittee
Approved
Ethics Committee NSCBC Research Institute. Netaji Subhas Chandra Bose Cancer Hospital
Approved
Institutional Ethics committee Swami Rama Himalayan University
Approved
Institutional Ethics Committee VMMC and SJH VMMC And SAFDARJUNG HOSPITAL
Approved
Institutional Ethics Committee, Apollo Multispeciality Hospital
Submittted/Under Review
Institutional Ethics Committee, Fortis hospital
Approved
Institutional Ethics Committee-I & II, TATA Memorial Hospital
Approved
Institutional Ethics committee-KCHRC Kaiash Cancer and Medica centre
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: K839||Disease of biliary tract, unspecified, (2) ICD-10 Condition: C221||Intrahepatic bile duct carcinoma,
Intervention / Comparator Agent
Type
Name
Details
Intervention
Arm A
T-DXd with Rilvegostomig
T-DXd (5.4 mg/kg) and rilvegostomig (750 mg). The agents will be administered starting Day 1 of each cycle, q3w, until disease progression or unacceptable toxicity.
Intervention
Arm B
T-DXd
T-DXd (5.4 mg/kg). The agent will be administered starting Day 1 of each cycle, q3w, until disease progression or unacceptable toxicity
Intervention
Arm C (SoC)
Gemcitabine (1000 mg/m2), cisplatin (25 mg/m2) and durvalumab (1500 mg). Gemcitabine and cisplatin will be administered for up to 8 cycles as tolerated and as per local guidelines. Gemcitabine and cisplatin will be administered on
Comparator Agent
Gemcitabine, Cisplatin, and Durvalumab
Day 1 and Day 8 of each cycle, q3w. When administered in combination with gemcitabine plus cisplatin, durvalumab will be administered on Day 1 of each cycle, q3w. Thereafter, durvalumab (1500 mg) will be administered on Day 1 of each cycle, q4w, until disease progression or unacceptable toxicity.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
99.00 Year(s)
Gender
Both
Details
Inclusion criteria
1. Sign and date the written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.
2. Male and female patients must be at least 18 years of age. Other age restrictions may apply as per local regulations.
Male and female patients must be Greater than or equal 30 kg.
4. Unresectable, previously untreated, locally advanced or metastatic BTC. Prior treatment in the perioperative and/or adjuvant setting is permissible provided there is Greater than 6 months (180 days) between the end of adjuvant treatment and the diagnosis of locally advanced or metastatic disease.
5. Has histologically confirmed HER2-expressing (IHC 3Plus or IHC 2Plus) BTC
established by prospective central testing of tumor tissue or a histologically confirmed HER2-expressing (IHC 3Plus) BTC from an existing local result.
6. Patients must provide an FFPE tumor sample that is no older than 3 years for tissue-based IHC staining to centrally determine HER2 expression, PD-L1 status, and other correlatives. The mandatory FFPE tumor sample should be from the most recent biopsy but can be either from the primary tumor or metastatic biopsy. Archival samples taken from a surgical or diagnostic biopsy confirming HER2 status can be accepted. Specimens with limited tumor content and cytology samples are inadequate for defining tumor HER2 or PD-L1 status. Additional details on sample requirements are defined in the Diagnostic Testing Manual and Central Laboratory Manual. Note: This is a requirement for all patients including IHC 3Plus patients enrolled via local results.
7. Has at least one target lesion assessed by the Investigator based on RECIST v1.1
a. Note: This is a requirement for the randomized portion of trial only.
8.Left ventricular ejection fraction Greater than or equal 50% within 28 days before study intervention.
9 WHO/ECOG performance status of 0 or 1.
10. Adequate organ and bone marrow function within 14 days before randomization (Parameters for Adequate Organ and Bone Marrow Function).
a. Note: Transfusion (red blood cell or platelet) or G-CSF administration is not allowed within 14 days prior to the day on which bone marrow function is assessed, or at any time after this day and prior to C1D1.
11. Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta-human chorionic gonadotropin pregnancy test prior to each administration of investigational product. Women of childbearing potential are defined as those who are not surgically sterile (ie, underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause (Section 5.3).
12. Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, as presented in Table 12, from the time of screening and must agree to continue using such precautions for 7 months after the last dose of IMP. Female patients must refrain from breastfeeding while on study and for 7 months after the last dose of IMP (Section 5.3).
13. Female patients must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study treatment administration. Preservation of ova may be considered prior to enrollment in this study.
14. Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening for 6 months after the last dose of IMP. It is strongly recommended for the female partners of a male patient to also use at least one highly effective method of contraception, as described in Table 12 (Section 5.3).
15. Patients with HBV infection (as characterized by positive HBsAg and/or anti-HBc with detectable HBV DNA Greater than or equal10 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 (Lass than10 IU/mL or under the limit of detection per local laboratory) do not require antiviral therapy unless HBV DNA exceeds 10 IU/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.
16. Adequate treatment washout period before randomization,
ExclusionCriteria
Details
Exclusion criteria
Patients are eligible to be included only if none of the exclusion criteria apply:
1. Prior exposure to other HER2 targeting therapies, ADCs, immune checkpoint inhibitors (eg, anti-PD-1/PD-L1 or CTLA-4) and therapeutic anticancer vaccines.
2. Has histologically confirmed ampullary carcinoma.
3. Has a history of substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the Investigator, interfere with the patient’s participation in the clinical study or evaluation of the clinical study results.
4. Has 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. Patients with clinically inactive brain metastases may be included in the study. Patients with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study randomization.
5. Patients with a 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 (Lass than 6 months) cardiovascular event including stroke. Patients with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out myocardial infarction.
6. 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.
7. Has an active autoimmune, connective tissue or inflammatory disorders (eg, rheumatoid arthritis, Sjogrens, sarcoidosis etc) that has required systemic treatment in the past 2 years (eg, with the use of disease modifying agents, corticosteroids, or immunosuppressive drugs), or where there is documented, or a suspicion of pulmonary involvement at the time of screening. Replacement therapy (eg, thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. Full details of the disorder should be recorded in the eCRF for patients who are included in the study.
8. Corrected QT interval (QTcF) prolongation to Greater Than 470 msec (females) or Greater Than 450 msec (males) based on average of the screening triplicate 12-lead ECG.
9. Criteria related to lung disorders: 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 (eg, pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion etc). Prior pneumonectomy (complete).
10. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
11. Active primary immunodeficiency, known uncontrolled active HIV infection or HCV. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Subjects should be tested for HIV prior to randomization/enrollment if required by local regulations or institutional review board/ethics committee.
12. Acute hepatitis A.
13. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30
14. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade lass than or equal1 or baseline. Chemotherapy-induced neuropathy
a. Fatigue
b. Residual toxicities from prior immune-oncology treatment: Grade 1 or Grade 2 endocrinopathies which may include: o Hypothyroidism/hyperthyroidism
c. Type 1 diabetes
d. Hyperglycemia
e. Adrenal insufficiency
f. Adrenalitis
g. Skin hypopigmentation (vitiligo)
Note: Patients may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to Greater Than Grade 2 for at least 3 months prior to [randomization/enrollment/Cycle 1 Day 1 and managed with Standard-of-Care treatment) that the Investigator deems related to previous anticancer therapy, such as:
15. Known allergy or hypersensitivity to study treatment or any of the study drug and/or any of the excipients.
16. History of severe hypersensitivity reactions to other monoclonal antibodies.
17. Pregnant or breastfeeding female patients, or patients who are planning to become pregnant.
18. History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence, adequately resected basal cell carcinoma of the skin or squamous cell carcinoma of the skin, lentigo maligna that has undergone potentially curative therapy or adequately treated in situ disease without evidence of disease.
19. A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or CART (Drainage and CART are not allowed within 2 weeks prior to screening assessment).
20. Current or prior use of immunosuppressive medication within 14 days before the first dose of study drugs. The following are exceptions to this criterion:
• Intranasal, inhaled, topical steroids or local steroid injections (eg, intra-articular injection).
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
• Steroids as premedication for hypersensitivity reactions or as an anti-emetic (eg, CT scan premedication).
21. Any concurrent anticancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is allowed.
22. History of allogenic organ transplant.
23. Previous randomization in the present study or a previous T-DXd or rilvegostomig study regardless of treatment arm assignment.
24. 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.
Method of Generating Random Sequence
Stratified block randomization
Method of Concealment
Centralized
Blinding/Masking
Outcome Assessor Blinded
Primary Outcome
Outcome
TimePoints
To evaluate the efficacy of T-DXd with rilvegostomig vs SoC in terms of OS in the FAS (HER2 IHC 3+) population
study outcome will be evaluated at Baseline, q6w±1w for the first 24 weeks (relative to the date of randomization) and then q8w±1w thereafter (relative to the date of randomization) till the disease progression
Secondary Outcome
Outcome
TimePoints
To evaluate the efficacy of T-DXd with rilvegostomig vs SoC in terms of OS in the FAS (HER2 IHC 3+/2+) population
• To evaluate the efficacy of T-DXd monotherapy vs SoC in terms of OS in the FAS (HER2 IHC 3+) population
• To evaluate the efficacy of T-DXd monotherapy vs SoC in terms of OS in the FAS population
OS in FAS (HER2 IHC 3Plus/2Plus) population
OS in FAS (HER2 IHC 3plus) population
OS definition as above (Primary)
To further evaluate efficacy of T DXd with rilvegostomig vs SoC in terms of PFS in FAS (HER2 IHC 3Plus) and FAS population
• To further evaluate efficacy of T DXd monotherapy vs SoC in terms of PFS in FAS (HER2 IHC 3Plus) and FAS populations
PFS Investigator in FAS (HER2 IHC 3Plus) and FAS populations
with rilvegostomig vs SoC in terms of ORR in the FAS (HER2 IHC 3Plus) and FAS populations
• To further evaluate the efficacy of T-DXd monotherapy vs SoC in terms of ORR in the FAS (HER2 IHC 3Plus) and FAS populations
ORR (Investigator) in FAS (HER2 IHC 3Plus) and FAS populations
rilvegostomig vs SoC in terms of DoR in patients with HER2 expressing BTC in the FAS (HER2 IHC 3Plus) and FAS populations
DoR (Investigator) in FAS (HER2 IHC 3Plus) and FAS populations
DoR will be defined as the time from the date of first documented response until date
To further evaluate efficacy of T DXd monotherapy vs SoC in terms of DoR in patients with HER2 expressing BTC in the FAS (HER2 IHC 3Plus) and FAS populations
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 anticancer therapy or clinically progresses prior to RECIST v1.1 progression.
The measure of interest is the median DoR.
To further evaluate the efficacy of T-DXd with rilvegostomig versus T-DXd monotherapy in terms of OS, PFS, DOR and ORR in FAS (HER2 IHC 3Plus) and FAS populations
OS, PFS, DOR and ORR definitions as detailed above.
To assess the safety and tolerability of T DXd with rilvegostomig vs SoC
• To assess the safety and tolerability of T DXd monotherapy vs SoC
Assessed among all treated patients by the occurrence of AEs, SAEs, AESIs, and changes from baseline in laboratory parameters, vital signs, electrocardiogram and echocardiogram/MUGA results.
The comparison will include all treated patients as treated.
To assess the safety and tolerability of T DXd with rilvegostomig vs T-DXd monotherapy
Assessed among all treated patients by the occurrence of AEs, SAEs, AESIs, and changes from baseline in laboratory parameters, vital signs, electrocardiogram and echocardiogram/MUGA results.
The comparison will include all treated patients as treated.
To describe patient-reported tolerability of T DXd with rilvegostomig in comparison to SoC based on a summary of symptomatic AEs and overall side-effect bother
• To describe patient-reported tolerability of T DXd monotherapy in comparison to SoC based on a summary of symptomatic AEs and overall side-effect bother
Patient-reported tolerability will be described using the following outcomes:
• 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)
• Overall side-effect bother: Descriptive summary of the proportion of patients reporting overall side-effect bother on the PGI-TT while on treatment.
The analysis will include all treated patients as treated.
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
To assess TTD in physical functioning in patients treated with T-DXd with rilvegostomig vs SoC
• To assess TTD in physical functioning in patients treated with T-DXd monotherapy vs SoC
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.
To assess TTD in physical functioning in patients treated with T-DXd with rilvegostomig vs T-DXd monotherapy
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.
To assess the PK 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.
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.
To further evaluate the efficacy of T-DXd with rilvegostomig vs SoC in terms of PFS2 in patients with HER2 expressing BTC in the FAS (HER2 IHC 3Plus) and FAS populations.
• To further evaluate the efficacy of T-DXd monotherapy vs SoC in terms of PFS2 in patients with HER2 expressing BTC in the FAS (HER2 IHC 3Plus) and FAS populations.
PFS2 using local standard clinical practice. PFS2 is defined as the time from randomization date to the earliest of the progression events following first objective progression subsequent to first subsequent anticancer therapy, or death. The date of second progression will be recorded by the Investigator in the eCRF and defined according to local standard clinical practice. The analysis will include all randomized patients regardless of whether the patient
To further evaluate the efficacy of T-DXd with rilvegostomig vs T-DXd monotherapy terms of PFS2 in patients with HER2 expressing BTC in the FAS (HER2 IHC 3Plus) and FAS populations.
PFS2 definition as above
To explore the impact of treatment on symptoms associated with BTC among patients receiving T-DXd with rilvegostomig relative to patients receiving SoC.
The analysis will include all randomized patients as randomized.
To explore the impact of treatment on symptoms associated with BTC among patients receiving T-DXd with rilvegostomig relative to patients receiving T-DXd monotherapy
The analysis will include all randomized patients as randomized.
To explore the impact of treatment and disease on select functioning and health related QoL/GHS outcomes in patients receiving T-DXd with rilvegostomig relative to patients receiving SoC.
• To explore the impact of treatment and disease on select functioning and health related QoL/GHS outcomes in patients receiving T-DXd monotherapy relative to patients receiving SoC.
Change from baseline and time to worsening in select functioning (role, emotional, cognitive, social) and health related QoL/GHS outcomes as measured by the EORTC IL172.
• The measure of interest will be mean change from baseline GHS/QoL scores.
The analysis will include the FAS.
To explore the impact of treatment and disease on select functioning and health related QoL/GHS outcomes in patients receiving T-DXd with rilvegostomig relative to patients receiving T-DXd monotherapy.
Change from baseline and time to worsening in on select functioning (role, emotional, cognitive, social) and health related QoL/GHS outcomes as measured by the EORTC IL172.
• The measure of interest will be mean change from baseline GHS/QoL scores.
To explore the impact of treatment and disease on health state in patients receiving T-DXd with rilvegostomig relative to patients receiving SoC.
• To explore the impact of treatment and disease on health state in patients receiving T-DXd monotherapy relative to patients receiving SoC
VAS mean score and change from baseline, and 5-dimension response, as measured by the EQ-5D-5L.
• The measure of interest will be mean and mean change from baseline of VAS score, and proportion of patients reporting different levels of each of the 5-dimension scores.
The analysis will include all randomized patients, as randomized.
To explore the impact of treatment and disease on health state in patients in patients receiving T-DXd with rilvegostomig relative to patients receiving T-DXd monotherapy.
VAS mean score and change from baseline and 5-dimension response as measured by the EQ-5D-5L.
• The measure of interest will be mean and mean change from baseline of VAS score, and proportion of patients reporting different levels of each of the 5-dimension scores.
The analysis will include all randomized patients, as randomized.
To evaluate pulmonary symptom tolerability of:
• T-DXd with rilvegostomig relative to patients receiving SoC
• T-DXd monotherapy relative to patients receiving SoC
Describe weekly rates and average severity of pulmonary symptoms while on study treatment.
Pulmonary symptoms include cough, shortness of breath (SoB), chest discomfort, wheezing, extreme tiredness and weakness, lack of appetite, and fever. Severity is reported for cough, SoB, and chest discomfort.
The analysis will include all randomized patients as randomized
To evaluate pulmonary symptom tolerability of T-DXd with rilvegostomig relative to patients receiving T-DXd monotherapy
Pulmonary symptoms definition as above
To further evaluate the efficacy of T-DXd with rilvegostomig vs SoC in patients with centrally confirmed HER2-positive status
Efficacy (OS, PFS, DOR and ORR)/safety (occurrence of AEs, SAEs, AESIs) endpoints in patients confirmed as HER2-positive by central testing
• Samples/data may be used to support companion diagnostic development
To collect blood and tissue samples for defining biological responses to T-DXd with rilvegostomig and T-DXd monotherapy and identifying candidate markers that may correlate with clinical benefit and/or intrinsic or acquired resistance, and participant safety and tolerability.
•Biomarkers include but are not limited to:
•Protein expression (IHC, PD-L1, and proteomics)
•ctDNA: quantitation, mutational profile, and dynamic changes
•Tumor mutational profiling
•Tumor and blood gene expression profiling
•TCR analysis
•Circulating biomarkers including but not limited to cytokines and chemokines
Exploratory biomarker analyses may be reported separately.
Target Sample Size
Total Sample Size="600" Sample Size from India="30" 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)
25/09/2025
Date of Study Completion (India)
Applicable only for Completed/Terminated trials
Date of First Enrollment (Global)
06/06/2025
Date of Study Completion (Global)
Applicable only for Completed/Terminated trials
Estimated Duration of Trial
Years="5" Months="0" Days="0"
Recruitment Status of Trial (Global)
Open to Recruitment
Recruitment Status of Trial (India)
Open to Recruitment
Publication Details
N/A
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
This is a global Phase 3, randomized, open label, multicenter, registrational intent study. It is designed to evaluate the efficacy and safety of T DXd with rilvegostomig or T DXd monotherapy vs gemcitabine, cisplatin and durvalumab as first line treatment in patients with advanced HER2 expressing BTC. Study details include
Patient Population:
Adult patients with previously untreated, unresectable, locally advanced or metastatic, HER2 expressing (IHC 3Plus or IHC 2Plus) BTC will be eligible. Prior treatment in the perioperative and/or adjuvant setting is permissible provided there is Greater Than 6 months between the end of adjuvant treatment and the diagnosis of locally advanced or metastatic disease. Patients in the safety run-in are enrolled based on local HER2 IHC test results.
In the randomized portion of the study, patients will be enrolled based on a prospective HER2 test result. This HER2 result and the PD-L1 status used for stratification should come from a central test whenever possible, however patients who have locally-confirmed HER2 IHC 3Plus status may be enrolled onto the randomized portion of the trial without prospective central results. Patients with local HER2 IHC 3Plus result may also use a local PD-L1 result for stratification. In cases where local HER2 IHC and/or PD-L1 test results are used to enroll a patient, FFPE tissue samples must still be provided for retrospective central assessment of HER2 and/or PD-L1 expression status. The on-treatment visit frequency will be weekly to Q3W.
Study Arms and Duration
Patients will be randomized at a ratio of 1:1:1 between three treatment arms (T-DXd with rilvegostomig, T-DXd monotherapy, or gemcitabine, cisplatin and durvalumab, respectively). All randomized patients will receive the assigned treatment until disease progression per RECIST v1.1, or unacceptable toxicity, or withdrawal of consent, or other criteria for discontinuation are met. Crossover within the study will not be permitted.
This is an open-label study for the personnel at study sites; however, the study will be conducted as “Sponsor-blind” and the specific treatment to be taken by a patient will be assigned using an IRT. To maintain the integrity of the study, AstraZeneca personnel directly involved in the study conduct will not undertake or have access to efficacy data aggregated by the treatment arm prior to final data readout for the primary endpoint.
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.
The visit frequency will be every 3 weeks in the experimental Arms A and B. In the control Arm C, this frequency will be twice every 3 weeks (on Day 1 and Day 8 of each cycle up to 8 cycles), and then once every 4 weeks thereafter.
Number of Patients:
The study plans to randomize a total of approximately 600 patients at a ratio of 1:1:1 to receive T DXd Plus rilvegostomig (N = 200), T-DXd monotherapy (N = 200), or SoC (N = 200) (Table 2). Of the 600 patients, the proportion of patients with HER2 IHC 2Plus will be capped globally at 40% to enrol approximately 360 patients with HER2 IHC 3Plus disease and 240 patients with HER2 IHC 2Plus disease will be randomized into the study. The number of patients with HER2 IHC 2Plus disease may be capped at site and/or country level
Randomization will be stratified based on the following factors:
HER2 status: IHC 3Plus vs IHC 2Plus,
PD L1 status: TAP Greater than or equal 1% vs TAP lass than 1%,
Primary tumor location: GBC vs IHCC vs EHCC.
Follow-up of Patients Post Discontinuation of Study Intervention:
After study intervention discontinuation, all patients will undergo an end-of-treatment visit (within 3 days of discontinuation) and will be followed up for safety assessments at 30 (Plus or minus 7) days, 60 (Plus or minus 7) days, and 90 (Plus or minus 7) days after their last dose of study intervention (ie, the safety follow-up visit).
Patients who have discontinued study intervention in the absence of RECIST 1.1-defined radiological progression will be followed up with tumor assessments according to the SoA until RECIST 1.1-defined PD or death regardless of whether or not the patient started a subsequent anticancer therapy, unless they have withdrawn all consent to undergo study-related assessments.
In addition, all patients will be followed up for survival status after intervention discontinuation every 3 months (Plus or minus14 days) from the date of the 90-day safety follow-up until death, withdrawal of consent, or the end of the study (ie, progression/survival follow-up), as per the SoA.