CTRI/2025/07/091729 [Registered on: 25/07/2025] Trial Registered Prospectively
Last Modified On:
07/06/2026
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Randomized, Parallel Group, Multiple Arm Trial
Public Title of Study
Study of Rilvegostomig with Fluoropyrimidine and Trastuzumab Deruxtecan versus Trastuzumab, Chemotherapy, and Pembrolizumab for first-line treatment of metastatic or locally advance Gastric Cancer patient whose tumor express HER2 positive.
Scientific Title of Study
A Randomized, Phase III Study of Rilvegostomig in Combination with Fluoropyrimidine and Trastuzumab Deruxtecan versus Trastuzumab, Chemotherapy, and Pembrolizumab for the First-line Treatment of HER2-positive Gastric Cancer (ARTEMIDE-Gastric01)
Trial Acronym
ARTEMIDE-Gastric-01
Secondary IDs if Any
Secondary ID
Identifier
D702AC00001 Version 2.0 dated 02 Dec 2024
Protocol Number
NCT06764875
ClinicalTrials.gov
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Sandeep AV
Designation
Senior Director, Oncology Country Head, Site Management & Monitoring India
Affiliation
AstraZeneca Pharma India Ltd
Address
Block N1, 12th Floor, Manyata Embassy Business Park
Rachenahalli, Outer Ring Road, Bangalore – 560045, India
Bangalore KARNATAKA 560045 India
Phone
9845079472
Fax
Email
sandeep.av@astrazeneca.com
Details of Contact Person Scientific Query
Name
Sandeep AV
Designation
Senior Director, Oncology Country Head, Site Management & Monitoring India
Affiliation
AstraZeneca Pharma India Ltd
Address
Block N1, 12th Floor, Manyata Embassy Business Park
Rachenahalli, Outer Ring Road, Bangalore – 560045, India
KARNATAKA 560045 India
Phone
9845079472
Fax
Email
sandeep.av@astrazeneca.com
Details of Contact Person Public Query
Name
Sandeep AV
Designation
Senior Director, Oncology Country Head, Site Management & Monitoring India
Affiliation
AstraZeneca Pharma India Ltd
Address
Block N1, 12th Floor, Manyata Embassy Business Park
Rachenahalli, Outer Ring Road, Bangalore – 560045, India
KARNATAKA 560045 India
Phone
9845079472
Fax
Email
sandeep.av@astrazeneca.com
Source of Monetary or Material Support
AstraZeneca AB
151 85 Sodertalje, Sweden
Primary Sponsor
Name
AstraZeneca AB
Address
151 85 Sodertalje, Sweden
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
AstraZeneca Pharma India Ltd
Block N1, 12th Floor, Manyata Embassy Business Park
Rachenahalli, Outer Ring Road, Bangalore – 560045, India
Countries of Recruitment
Argentina Australia Austria Belgium Brazil Canada Chile China France Germany Hong Kong Hungary India Italy Japan Malaysia Netherlands Peru Poland Republic of Korea Spain Taiwan Thailand Turkey United Kingdom United States of America Viet Nam
Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi, India 110029 New Delhi DELHI
9855757667
chethan2190@gmail.com
Dr Rakesh Pinninti
Basavatarkam Indo-American Cancer Hospital & Research Institute
Department of oncology
Road No 10, Banjara Hills, Hyderabad 500034 India Hyderabad TELANGANA
7021538508
Pinninti.rakesh@gmail.com
Dr Satheesh CT
Health CARE Global Enterprises Ltd
Department of oncology
HCG Towers, #8, P.Kalinga Roa Road, Sampangi Ram Nagar, Bangalore, Karnataka, India -560027 Bangalore KARNATAKA
9242698750
drsatheesh.ct@hcge;.com
Dr Bipinesh Sansar
Mahamana Pandit Madan Mohan Malaviya Cancer Centre (MPMMCC)
Department of oncology
Sundar Bagiya, Near Nariya Gate, Banaras Hindu University Campus, Varanasi, Uttar Pradesh – 221005, India Varanasi UTTAR PRADESH
8002583913
bipinesh04@yahoo.co.in
Dr Rajiv Lochan Jena
Netaji Subhas Chandra Bose Cancer Hospital
Department of oncology
3081 Nayabad, New Garia, Kolkata-700094, West Bengal, India Kolkata WEST BENGAL
8617775659
rajivjena1986@gmail.com
Dr Sumit Goyal
Rajiv Gandhi Cancer Institute & Research Centre
Department of oncology
Rohini Institutional Area, Sector 5, Rohini, New Delhi, Delhi 110085 New Delhi DELHI
8447274181
drsumitgoyal@gmail.com
Dr Vikas Ostwal
Tata Memorial Hospital
Department of oncology
Dr. Ernest Borges Marg, Parel, Mumbai (East), Maharashtra, India 400012 Mumbai MAHARASHTRA
9702288801
drvikasostwal@gmail.com
Dr Kaushal Kalra
VMMC & Safdarjung Hospital
Department of oncology
Ansari Nagar East, near to AIIMS Metro Station, New Delhi, Delhi 110029 New Delhi DELHI
Ethics Committee N.S.C.B.C Research Institute, Netaji Subhas Chandra Bose Cancer Hospital,
Approved
HCG Central Ethics Committee HCG- Bangalore
Approved
Institute Ethics Committee, All India Institute of Medical Sciences,
Approved
Institutional Ethics Committee - Basavataram Indo-American Cancer Hospital
Approved
Institutional Ethics Committee - MPMMCC and HBCH Varanasi Mahamana Pandit Madan Mohan Malaviya Cancer Centre
Submittted/Under Review
Institutional Ethics Committee VMMC and SJH VMMC And SAFDARJUNG HOSPITAL
Submittted/Under Review
Institutional Ethics Committee-I Tata Memorial Hospital,
Submittted/Under Review
Institutional Review Board, Rajiv Gandhi Cancer Institute and Research Centre
Submittted/Under Review
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: C162||Malignant neoplasm of body of stomach,
Intervention / Comparator Agent
Type
Name
Details
Comparator Agent
Pembrolizumab + Trastuzumab + FP OR CAPOX (Control arm)
Pembrolizumab: 200 mg IV Q3W
+
Trastuzumab: 8 mg/kg loading dose, followed by 6 mg/kg for subsequent cycles, IV Q3W
+
FP: Cisplatin: 80 mg/m2 IV + 5-FU: 800 mg/m2/day IV as a continuous infusion over 24 hours for the first 5 days of each cycle (120 hours or per local practice), Q3W
OR
CAPOX: Capecitabine: 1000 mg/m2 orally BID for 14 days + oxaliplatin: 130 mg/m2 IV Q3
Intervention
Rilvegostomig + Trastuzumab + FP OR CAPOX (CoC arm)
Rilvegostomig: 750 mg IV Q3W
+
Trastuzumab: 8 mg/kg loading dose, followed by 6 mg/kg for subsequent cycles, IV Q3W
+
FP: Cisplatin: 80 mg/m2 IV + 5-FU: 800 mg/m2/day IV as a continuous infusion over 24 hours for the first 5 days of each cycle (120 hours or per local practice), Q3W
OR
CAPOX: Capecitabine: 1000 mg/m2 orally BID for 14 days + oxaliplatin: 130 mg/m2 IV Q3W
Intervention
T-DXd + Rilvegostomig + Fluoropyrimidine: Capecitabine OR 5-FU (Treatment arm)
T-DXd: 5.4 mg/kg IV Q3W
+
Rilvegostomig: 750 mg IV Q3W
+
Capecitabine: 750 mg/m2 orally BID for 14 days, Q3W
OR
5-FU: 600 mg/m2/day IV as a continuous infusion over 24 hours for the first 5 days of each cycle (120 hours or per local practice), Q3W
Inclusion Criteria
Age From
18.00 Year(s)
Age To
99.00 Year(s)
Gender
Both
Details
Inclusion criteria
Participant and Disease Characteristics
1. HER2-positive (IHC 3Plues or IHC 2Plues ISH-positive) on a tumor biopsy as detected by prospective central test on the primary or metastatic tumor tissue sample.
2. Provision of tumor tissue sample from recent biopsy adequate for HER2 and PD-L1 testing. Additional details on sample requirements will be provided in the Laboratory Manual.
3. Previously untreated, unresectable, locally advanced or metastatic gastric or GEJ adenocarcinoma.
Prior treatment in the neo-adjuvant and/or adjuvant setting is permissible provided there is a Grete then 6-month interval between the last administration of the prior regimen and the diagnosis of locally advanced or metastatic disease.
Prior use of approved immune CPIs (ie, anti-PD-1/PD-L1) in the neo-adjuvant and/or adjuvant setting is permissible provided there is Grete then 6 months between the last administration of immune CPIs and the diagnosis of locally advanced or metastatic disease. However, patients with progression on neo-adjuvant or recurrence on adjuvant immune CPIs treatment should be excluded.
4. WHO or ECOG PS of 0 or 1 with no deterioration over the 2 weeks prior to the day of the first dosing.
5. Have measurable target disease assessed by the Investigator based on RECIST v1.1. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
6. Have adequate organ and bone marrow function within 14 days before randomization as described in Table 6. All parameters must be the most recent results available.
7. Have a life expectancy of at least 6 months.
8. LVEF Grete then equals to 55% within 28 days before randomization. Participants with ejection fraction of 50% to 54% may still be eligible with discussion with Sponsor AND after consultation with cardiology AND after being medically optimized
9. Adequate treatment washout period before randomization, defined in Table 7.
10. Participants must be Grete then equals to 30 kg
Contraceptive/Barrier Requirements
11. Evidence of post-menopausal status or negative serum pregnancy test for FOCBP who are sexually active with a non-sterilized male partner. For FOCBP, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU or mL) must be available at the Screening Visit and urine HCG pregnancy test prior to each administration of study intervention. FOCBP are defined as those who are not surgically sterile (ie, underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal (Appendix G). Women will be considered post menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
13. FOCBP who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, presented in Table 27, from the time of screening and must agree to continue using such precautions for 7 months after the last dose of study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 14 months), whichever is longer. Not all methods of contraception are highly effective. It is strongly recommended that non-sterilized male partners of FOCBP use a male condom plus spermicide while on study and for 7 months after the last dose of study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 14 months), whichever is
longer. (Note: Male condoms are not reliable as a sole contraception method). Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is in line with the participant’s usual lifestyle (consideration must be made to the duration of the clinical study); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable.
14. Female participants 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 last dose of study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 14 months), whichever is longer. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrollment in this study.
15. Non-sterilized male participants who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 6 months after the last dose of study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 11 months), whichever is longer. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is in line with the participant’s usual lifestyle (consideration must be made to the duration of the clinical study); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. It is strongly recommended for the female partners of a male participant to also use at least one highly effective method of contraception throughout this period, as described in Table 27. In addition, male participants should refrain from fathering a child throughout the study treatment period and for 6 months after the last dose of study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 11 months), whichever is longer. Male participants should refrain from freezing or donating sperm from the time of screening until 6 months after the last dose of the study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 11 months), whichever is longer. Preservation of sperm may be considered prior to enrollment in this study.
Informed Consent
16. Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
17. Provision of signed and dated written ICF prior to any mandatory study specific procedures, sampling, and analyses.
Optional Genetic Research
18. Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics initiative research that supports the Genomic Initiative.
ExclusionCriteria
Details
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Lack of physiological integrity of the upper gastrointestinal tract.
2. Known partial or total DPD enzyme deficiency based on local or central laboratory testing, with testing required only in regions where it is SoC. Central testing will be available for participants where testing is SoC and with unknown DPD status. For regions where DPD testing is not SoC, local practice should be followed.
3. Contraindication to pembrolizumab or trastuzumab, contraindications to fluoropyrimidine (5-FU and capecitabine) or platinum (cisplatin and oxaliplatin) treatment as per local label
4. 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. Exceptions also include adequately resected basal cell carcinoma 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.
5. Persistent toxicities caused by previous anti-cancer therapy excluding alopecia, not yet improved to Grade 1 or baseline. Note: Participants may be enrolled with the following chronic, stable Grade 2 toxicities (defined as no worsening to Grade 2 for at least 3 months prior to the first dose of study intervention and managed with SoC treatment) which the Investigator deems related to previous anti-cancer therapy:
Chemotherapy-induced neuropathy
Fatigue
Vitiligo
Endocrine disorders, that are controlled with replacement hormone therapy. Residual Grade 1 or Grade 2 endocrinopathies from prior immune CPIs may be allowed (eg, hypothyroidism/hyperthyroidism, type I diabetes, hyperglycemia, adrenal insufficiency, adrenalitis).
Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the Investigator may be included (eg, hearing loss).
6. Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring corticosteroid or anticonvulsant 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 or spinal cord compression and study randomization.
7. Uncontrolled infection including TB (clinical evaluation that includes clinical history, physical examination, radiographic findings, and TB testing in line with local practice) and active hepatitis A infection.
8. Uncontrolled infection requiring IV antibiotics, anti-virals, or antifungals.
9. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of study intervention. Note: Participants, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of study intervention.
10. Has a known history of active primary immunodeficiency, uncontrolled active HIV infection with serologic evidence of viral infection within 28 days of C1D1. Participants should be tested for HIV prior to randomization if required by local regulations or IRB/IEC.
11. Has chronic or active hepatitis B; however, participants who have chronic hepatitis B are eligible only if they meet all of the following criteria Controlled HBV load: HBV DNA 100 UormL by PCR or undetectable
ALT is normal.
Remain on anti-viral therapy, per institutional practice, during the study intervention and follow-up periods to ensure adequate viral suppression.
Absence of cirrhosis or fibrosis on prior imaging or biopsy.
Absence of HCV co-infection or history of HCV co-infection.
Access to a local hepatitis B expert during and after the study.
12. Has chronic or active hepatitis C; however, participants who have chronic hepatitis C are eligible if ALT is normal (NA for participants with liver metastases) and HCV RNA is undetectable by PCR, either spontaneously or in response to a successful prior course of anti-hepatitis C therapy. Controlled hepatitis C viral load is defined as undetectable hepatitis C RNA by PCR either spontaneously or in response to a successful prior course of anti-hepatitis C therapy.
13. Has 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 participant’s participation in the clinical study or evaluation of the clinical study results
14. Participants with a medical history of MI within 6 months before enrollment, symptomatic CHF (NYHA Class II to IV), or clinically significant arrhythmia. Participants 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 MI
15. QTcF prolongation to 470 ms (females) or 450 ms (males), based on average of the screening triplicate 12 lead ECG.
16. Participants with congenital long QT syndrome and those with a history of QT prolongation associated with other medications that required discontinuation of that medication.
17. Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
18.Lung criteria: History of (non-infectious) ILD or pneumonitis, has current ILD or pneumonitis, or where suspected ILD or 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 3 months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc.)
Prior pneumonectomy (complete).
19. As judged by the Investigator, any evidence of diseases (such as hearing loss, severe or uncontrolled systemic diseases, including ongoing or active infection, uncontrolled hypertension, and active bleeding diseases, serious chronic gastrointestinal conditions associated with diarrhea), which, in the Investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
20. Any active non-infectious skin disease (including any grade rash, urticaria, dermatitis, ulceration, or psoriasis) requiring systemic treatment.
21. A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or CART.
22. Previous severe toxicity, which is clinically significant as judged by the Investigator, observed during the participant’s previous exposure to any of the medications to be used in combination in the study.
23. History of any of the following: drug-induced severe cutaneous adverse reaction (including, but not limited to Stevens-Johnson syndrome/toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms).
24. Participants with a known allergy or hypersensitivity to any of the drugs used as study intervention, or any of the excipients of the product, or a history of severe hypersensitivity reactions to other monoclonal antibodies.
Prior/Concomitant Therapy
25. Prior exposure, without adequate treatment washout period before randomization, defined in Table 7.
26. Prior exposure to other HER2 targeting therapies, ADCs, or therapeutic anti-cancer vaccines.
27. Any concurrent anti-cancer treatment with the exception of receptor activator of nuclear factor kappa-B ligand inhibitors (eg, denosumab for the treatment of complications resulting from bone metastases). Concurrent use of hormonal therapy for non-cancer-related conditions (eg, HRT therapy) is allowed.
28. Herbal and natural remedies which are used with immune-modulating intent.
29. EGFR TKIs must not be given concomitantly and should be used with caution in the 90 days after the last dose of rilvegostomig.
30. Have had major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks prior to the first dose of study intervention or an anticipated need for major surgery during the study.
31. Current or prior use of immunosuppressive medication within 14 days before the first dose of study intervention. 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).
32. History of allogenic tissue/solid organ transplant
Prior/Concurrent Clinical Study Experience
33. Previous randomization in the present study or a prior T-DXd or rilvegostomig study regardless of intervention arm assignment.
34. 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.
Other Exclusions
35. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
36. Judgment by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
For females only: Currently pregnant (confirmed with positive pregnancy test) or breastfeeding female participants, or participants who are planning to become pregnant.
Method of Generating Random Sequence
Stratified randomization
Method of Concealment
Centralized
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
To evaluate the efficacy of rilvegostomig in combination with fluoropyrimidine and T-DXd compared to trastuzumab, chemotherapy, and pembrolizumab, as measured by PFS.
To evaluate the efficacy of rilvegostomig in combination with fluoropyrimidine and T-DXd compared to trastuzumab, chemotherapy, and pembrolizumab, as measured by OS.
To evaluate the efficacy of rilvegostomig in combination with fluoropyrimidine and T-DXd compared to trastuzumab, chemotherapy, and pembrolizumab, as measured by PFS.
OS is defined as time from randomization until the date of death due to any cause.
The analysis will include all randomized participants, regardless of whether the participant withdraws from study interventions or receives another anti-cancer therapy.
The measure of interest is the HR of OS.
Secondary Outcome
Outcome
TimePoints
To evaluate the efficacy of rilvegostomig in combination with trastuzumab and chemotherapy compared to trastuzumab, chemotherapy, and pembrolizumab, as measured by PFS.
PFS per RECIST v1.1 as assessed by BICR as defined above.
To evaluate the efficacy of rilvegostomig in combination with trastuzumab and chemotherapy compared to trastuzumab, chemotherapy, and pembrolizumab, as measured by OS.
OS as defined above.
To further evaluate the efficacy of rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination with trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab.
Investigator assessments, based on RECIST v1.1, to allow the calculation of:
PFS (Investigator assessment)
As defined in the primary objective but using Investigator assessment instead of BICR.
ORR as assessed by BICR and by Investigator according to RECIST v1.1
ORR is defined as the proportion of participants who have a CR or PR.
The analysis will include all randomized participants. Data obtained from randomization up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of ORR, regardless of whether the participant withdraws from study interventions. Participants who discontinue study interventions without a response or progression, receive a subsequent therapy, and then respond will not be included as responders in the ORR. The measure of interest is the odds ratio of ORR.
DoR as assessed by BICR and by Investigator according to RECIST v1.1
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 participants who have a response, regardless of whether the participant withdraws from study interventions, receives another anti-cancer therapy, or clinically progresses prior to RECIST v1.1 progression.
The measure of interest is the median DoR.
Proportion of all randomized participants alive and progression-free at 6 and 12 months (PFS6 and PFS12) calculated for both BICR- and Investigator-assessed progression.
Proportion of all randomized participants alive at 12 and 24 months (OS12 and OS24).
PFS2 as defined by local standard clinical practice.
PFS2 is defined as the time from randomization to the earliest of the progression event (following the initial Investigator-assessed progression), after the first subsequent therapy, or death, where the first objective progression includes progression occurring after 2 missed visits (ie, date of PFS2 event or censoring date of randomization Plus 1). The date of the 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 participants. All events will be included, regardless of whether the participant withdraws from subsequent therapy and regardless of missed visits.
The measure of interest is the HR of PFS2.
To evaluate the efficacy of rilvegostomig in combination with fluoropyrimidine and T-DXd compared to rilvegostomig in combination with trastuzumab and chemotherapy
PFS per RECIST v1.1 as assessed by BICR and OS endpoints will be repeated for rilvegostomig in combination with fluoropyrimidine and T-DXd versus rilvegostomig in combination with trastuzumab and chemotherapy.
To assess the safety and tolerability of rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination with trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab.
Assessed among all treated participants by the occurrence of AEs, SAEs, AESIs, changes from baseline in laboratory parameters, vital signs, ECG, and ECHO/MUGA results
To assess the PK of rilvegostomig, T-DXd, total anti-HER2 antibody, DXd in serum, 5-FU and capecitabine in plasma.
Descriptive analysis of serum concentration of rilvegostomig, T-DXd, total anti-HER2 antibody, DXd, plasma concentration of 5-FU and capecitabine.
To investigate the immunogenicity of rilvegostomig and T-DXd.
Descriptive summary of presence of ADAs for rilvegostomig and T-DXd.
To evaluate the efficacy of rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination
with trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab, based on an increase in enteral feeding assistance and eating difficulties.
Time to increase in enteral feeding assistance and/or TE while on study intervention among all randomized participants, as randomized, with a composite of:
Enteral feeding assistance based on case report data; and
Participant-reported meaningful increase in eating difficulty as measured by the EORTC IL334 TE items.
Time to first-confirmed worsening of eating symptoms or initiation of feeding assistance among all participants, as randomized. Intercurrent events of disease
progression and death will be handled using a composite strategy.
To assess the tolerability of rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination with trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab by assessment of the proportion of time on study intervention with high side-effect bother.
Proportion of time on study intervention with high side-effect bother relative to low side-effect burden as measured by the PGI-TT. The analysis will include all dosed participants, as treated, during the acute intervention phase defined as the first 24 weeks.
The measure of interest is a descriptive summary of the proportion of time on study intervention with high side-effect bother during the first 24 weeks.
To assess participant-reported PF in participants treated with rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination with trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab.
Participant-reported PF will be evaluated by describing the proportion of participants who maintain their baseline level of PF while on treatment, based on the PF subscale of the EORTC QLQ-C30 (in EORTC IL334 PF items).
The analysis will include all dosed participants, as treated.
The measure of interest is the proportion of participants with stable or improved PF while on treatment at 3 months, 6 months, and one year.
To collect and assess blood and tumor
samples for biomarker analysis in participants treated with rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination with trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab.
Assessment of tumor, immune and/or other cell/biological component associated biomarkers (markers, signatures, and/or profiles) in peripheral blood (whole blood, serum, and plasma) and tumor samples (or images) at baseline, on treatment and at progression as evaluated by, but not limited to, the presence of, profile of, or changes in DNA, RNA, protein, analytes and/or imaging measurements and in relation with participant baseline characteristics, clinical outcomes/endpoints and/or clinical or molecular
assessments. Assessments may include but are not limited to:
Presence of, or changes in phenotype or expression of immune and tumor marker/profile (activated T cells, immune cell receptor repertoires, IFN Y, CD-8, etc.).
Presence or profile of or changes in ctDNA mutations or genomic alteration(s), and tumor mutation burden, from plasma and tumor samples.
Biomarker expression and/or spatial distribution of tumor associated markers (eg, HER2) or in the tumor microenvironment (eg, CD8) as measured by IHC, and mass spectrometry and other assays including analytical methods (eg, Digital Pathology, AI).
To assess participant-reported treatment tolerability in participants treated with rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination with
trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab.
Participant-reported symptomatic AEs will be described as the proportion of participants experiencing each symptomatic AE as measured by the PRO-CTCAE and EORTC IL333 AE items.
The analysis will include all dosed participants, as treated.
The measure of interest is the proportion of participants reporting different levels of each symptomatic AE.
To assess participant-reported cancer symptoms and functioning in participants treated with rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination with trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab.
Participant-reported symptoms and functioning will be described as the proportion of participants experiencing each symptom and functional impact as measured by symptom subscales and items from EORTC QLQ-C30, and the EORTC QLQ-OG25 (C30 and OG25 subscales found in EORTC IL333, 334, and 335). Proportion of participants in each PGIS cancer symptom severity category.
The analysis will include all participants, as randomized.
The measure of interest is the proportion of participants reporting different levels of each symptom
To explore the impact of the study intervention and disease on participant-reported health status in participants treated with rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination with trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab.
VAS mean score and change from baseline and 5-dimension scores as measured by the EQ-5D-5L.
The analysis will include all randomized participants, as randomized.
The measure of interest will be mean and mean change from baseline of VAS score and proportion of participants reporting different levels of each 5-dimension score.
To explore how multi-omics variations, including genetics, may affect clinical parameters, risk and prognosis of diseases and the response to medications as detailed in Appendix D Optional Genomics Initiative Sample. Note: The samples are taken from consented participants for DNA isolation, RNA, blood derivatives and storage. Results will not be reported in the CSR.
Exploratory endpoints are related to the data generated from multi-omics analysis, including genetics which may be part or all of the participant’s genetic information
Target Sample Size
Total Sample Size="880" Sample Size from India="34" 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)
15/08/2025
Date of Study Completion (India)
Applicable only for Completed/Terminated trials
Date of First Enrollment (Global)
25/03/2025
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 Phase III, 3 arm, randomized, open-label, multi-center, global studyassessing the efficacy and safety of rilvegostomig in combination with fluoropyrimidine and T-DXd (Arm A) compared to trastuzumab, chemotherapy, and pembrolizumab (Arm B) in HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma participants whose tumors express PD-L1 CPS grater then equals to 1. Rilvegostomig in combination with trastuzumab and chemotherapy will be evaluated in a separate arm (Arm C) to assess the contribution of each component in the experimental arm.
Approximately1680participantswithLA-HNSCCareplannedtobescreened inorderto randomize approximately 880 participants in a 1:1:1 ratio to one ofthe following arms:
Arm
Study Intervention
Dose and Route of Administration
Arm A
T-DXd + Rilvegostomig + Fluoropyrimidine: Capecitabine a OR 5-FU a
T-DXd: 5.4 mg/kg IV Q3W Rilvegostomig: 750 mg IV Q3W Capecitabine: 750 mg/m2 orally BID for 14 days, Q3W OR 5-FU: 600 mg/m2/day IV as a continuous infusion over 24 hours for the first 5 days of each cycle (120 hours or per local practice), Q3W
Arm B
Pembrolizumab + Trastuzumab + FP a OR CAPOX a
Pembrolizumab: 200 mg IV Q3W Trastuzumab: 8 mg/kg loading dose, followed by 6 mg/kg for subsequent cycles, IV Q3W FP: Cisplatin: 80 mg/m2 IV + 5-FU: 800 mg/m2/day IV as a continuous infusion over 24 hours for the first 5 days of each cycle (120 hours or per local practice), Q3W OR CAPOX: Capecitabine: 1000 mg/m2 orally BID for 14 days + oxaliplatin: 130 mg/m2 IV Q3W
Arm C
Rilvegostomig + Trastuzumab + FP a OR CAPOX a
Rilvegostomig: 750 mg IV Q3W Trastuzumab: 8 mg/kg loading dose, followed by 6 mg/kg for subsequent cycles, IV Q3W FP: Cisplatin: 80 mg/m2 IV + 5-FU: 800 mg/m2/day IV as a continuous infusion over 24 hours for the first 5 days of each cycle (120 hours or per local practice), Q3W OR CAPOX: Capecitabine: 1000 mg/m2 orally BID for 14 days + oxaliplatin: 130 mg/m2 IV Q3W
Randomization will be stratified by HER2 status (IHC 3plus versus IHC 2plus plus ISH-positive), geographic region (Japan/South Korea versus Rest of Asia [including China] versus North America/EU/ROW), and PD-L1 expression (CPS grater then equals 10 versus CPS less than 10).
Randomization of participants with CPS of 1 to less than10 (inclusive of 1 but less than 10) will be capped at approximately 60% of the planned total number of randomized participants to reflect the natural prevalence of PD-L1 expression.
All randomized participants will receive the assigned study interventions until RECIST v1.1defined PD or unacceptable toxicity, withdrawal of consent, or other criteria for discontinuation are met. Cisplatin and oxaliplatin will be administered for up to 6 cycles as tolerated and as per local guidelines. Oxaliplatin may be continued up to 8 cycles at the discretion of the Investigator.
Participants found to derive benefit from and tolerate treatment may continue study intervention after disease progression and separate informed consent needs to be provided.
Participants will receive study intervention for a maximum of 12 months or 18 cycles, or undergoobservationfor12months,oruntilRECIST1.1definedradiologicalPD confirmed byinvestigatorassessment,unlessthereisevidenceofunacceptabletoxicity,orifaparticipant requests to stop the study intervention, as applicable to the arm participants are assigned to
Follow-up of Participants Post-discontinuation of Study Intervention:
After study intervention discontinuation, all participants will undergo an EoT Visit or early study intervention/discontinuation Visit (within 7 days of discontinuation) and will be followed up for safety assessments 30 (Plus 7), 60 (Plus 7), and 90 (Plus 7) days after their last dose of study intervention (ie, the safety follow up visit).
Participants who have discontinued study
intervention in the absence of RECIST v1.1 defined radiological progression
confirmed by BICR assessment will be followed up with tumor assessments
according to the SoA until RECIST v1.1 defined PD by BICR assessment or death
regardless of whether or not the participant started a subsequent anti-cancer
therapy, unless they have withdrawn all consent to study-related assessments.
In addition, all participants will be followed up for
survival status after intervention discontinuation Q3M ( 2 weeks) from the
date of randomization until death, withdrawal of consent, or
the end of the study (ie, progression/survival follow-up), as per the SoA.