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Clinical Trials List

Protocol NumberDS8201-724
Active

2025-03-01 - 2030-02-01

Phase III

Recruiting5

ICD-10C16.0

Malignant neoplasm of cardia

ICD-10C7A.092

Malignant carcinoid tumor of the stomach

ICD-10Z51.12

Encounter for antineoplastic immunotherapy

ICD-9151.0

Malignant neoplasm of cardia of stomach

A multicenter, randomized, open-label, phase III trial (DESTINY-Gastric05) evaluating trastuzumab Deruxtecan (Enhertu®) with chemotherapy (with or without pembrolizumab) versus chemotherapy with or without trastuzumab as first-line treatment for patients with unresectable, locally advanced, or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) cancer.

  • Trial Applicant

     Daiichi Sankyo Taiwan Ltd. 

  • Sponsor

    daiichi sankyo Taiwan Ltd.

  • Trial scale

    Multi-Regional Multi-Center

  • Update

    2026/08/17

Investigators and Locations

Principal Investigator 陳彥仰 Division of Hematology & Oncology
Kaoshiung Chang Gung Memorial Hospital of the C.G.M.F.

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Kun-Huei Yeh Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Ming-Huang Chen Division of Hematology & Oncology
Taipei Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Jen-Shi Chen
Linkou Chang Gung Medical Foundation

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Condition/Disease

HER2-positive gastric cancer or gastroesophageal junction cancer

Objectives

This multicenter, randomized, open-label, phase 3 clinical trial is designed to evaluate the efficacy and safety of trastuzumab deruxtecan (ENHERTU, T-DXd, DS-8201a) triplet fluoropyrimidine plus pembrolizumab as first-line treatment in the primary cohort of patients with unresectable, locally advanced, or metastatic HER2-positive tumors with a combined programmable cell death-ligand 1 (PD-L1) positive score (CPS) ≥1 in gastric or GEJ cancer. An exploratory cohort will also be evaluated to assess the efficacy and safety of T-DXd plus fluoropyrimidine compared to SoC chemotherapy plus trastuzumab in patients with unresectable, locally advanced, or metastatic HER2-positive tumors with a PD-L1 CPS <1 in gastric or GEJ cancer.

Test Drug

Trastuzumab Deruxtecan (T-DXd)

Active Ingredient

1013000550

Dosage Form

Frozen Crystal Injection

Dosage

100 MG

Endpoints

Based on BICR assessment, compare efficacy between groups within each cohort based on PFS (progression-free survival) measures.

Inclution Criteria

1. Sign and date the tissue pre-screening participant consent form (ICF) before HER2 and planned cell death-ligand 1 (PD-L1) combined positive score (CPS) testing. Sign and date the primary screening ICF before initiating any trial-specific eligibility procedures. Sign and date the selective PGx ICF (included in the primary screening ICF) before performing any pharmacogenetic (PGx) procedures.

2. Adults aged ≥18 years on the date of signing the ICF. If the legal age of consent for trial participation is >18 years, follow local regulatory requirements.

3. Treatment-naïve, unresectable, histologically confirmed locally advanced or metastatic gastric or GEJ adenocarcinoma. Prior treatment in perioperative and/or adjuvant settings is permitted, provided that more than 6 months have passed between the end of perioperative or pre-adjuvant therapy and the diagnosis of disease recurrence.

Note: Prior use of IO (anti-planned cell death-1 [anti-PD-1]/PD-L1) therapy in (pre-)adjuvant therapy is permissible as long as the interval between the completion of cancer immunotherapy (IO) treatment and the confirmed disease recurrence is >6 months.

4. New tumor tissue (core needle section, incision section, excision section) or existing tumor tissue sections collected at the time of diagnosis of locally advanced or metastatic disease, subject to prospective central testing according to the American Society of Clinical Oncology-American Society of Pathology (Gastric Cancer [GC] Division) to determine whether the cancer is classified as HER2-positive (immunohistochemical staining [IHC] 3+ or IHC 2+/in situ hybridization staining [ISH]-positive) gastric cancer or GEJ cancer.

Note: Stock samples taken from previously diagnosed or surgical sections that have not undergone radiation exposure are acceptable. Detailed information on tumor tissue submission can be found in the laboratory manual.

5. Central determination of tumor PD-L1 CPS using the PD-L1 22C3 PharmDx assay:

• For the primary cohort: PD-L1 CPS ≥1

• For the exploratory cohort: PD-L1 CPS <1

6. All subjects must provide tumor specimens for tissue IHC staining to centrally determine HER2 expression, PD-L1 CPS, and other relevant parameters. Necessary formalin-fixed and paraffin-embedded tumor specimens may be from primary or metastatic sections. Specimens with limited tumor content (central determination) and cytological specimens are insufficient to define the HER2 and PD-L1 status of the tumor.

7. At least one measurable target lesion on computed tomography (CT) or magnetic resonance imaging (MRI) is required, as assessed by the trial administrator according to the Responsive Criteria in Solid Tumor Response (RECIST) v1.1. A lesion previously treated with radiotherapy that has shown progression is considered measurable.

8. Left ventricular ejection rate (LVEF) ≥50% within 28 days prior to randomization.

9. East Coast Cancer Clinical Research Group (ECOG) performance status of 0 or 1 within 7 days prior to randomization.

10. Adequate organ and bone marrow function within 14 days prior to randomization. No blood transfusions (red blood cells or platelets) or granulocyte colony-stimulating factor (G-CSF) administration is permitted within 14 days prior to or before day 1 of cycle 1, or at any time thereafter. Adequate organ/bone marrow function is defined as follows:

Adequate organ and bone marrow function parameters:

Adequate bone marrow function:

- Platelet count ≥100,000/mm³

- Heme ≥9.0 g/dL or ≥5.6 mmol/L

- Absolute neutrophil count ≥1500/mm³

Adequate liver function:

- Aspartate transaminase (AST), alanine transaminase (ALT) ≤2.5 times the upper limit of normal (ULN) (≤5 times ULN if the subject has liver metastases)

- Total bilirubin: ≤1.5 times ULN for subjects with total bilirubin >1.5 times ULN or direct bilirubin ≤ ULN

- Serum albumin ≥2.5 g/dL

Adequate kidney function:

Cretinol clearance (CrCl) ≥60 mL/min, measured or calculated using Cockcroft-Gault Formula Calculation

Adequate Coagulation Function:

-Prothrombin Time (PT)/International Normalized Ratio (INR) or Activated Partial Thromboplastin Time (aPTT)/Partial Thromboplastin Time (PTT) ≤1.5 times ULN, unless the subject is receiving anticoagulation therapy, provided that PT/INR or PTT/aPTT is within the therapeutic range for which the anticoagulant is intended.

11. Sufficient treatment clearance period prior to randomization, defined as follows:
Major surgery: ≥4 weeks
Radiation therapy, including palliative stereotactic radiotherapy to the chest: ≥4 weeks
Patient stereotactic radiotherapy to other anatomical regions: ≥2 weeks
Chloroquine/hydroxychloroquine: >14 days
Cell-free concentrated ascites reinfusion (CART), abdominal drainage, or drainage of pleural effusion, ascites, or pericardial effusion: ≥2 weeks prior to screening assessment

12. Both male and female participants of fertility must agree to use highly effective contraception or abstain from sexual intercourse during the trial and until after the last dose of the investigational drug (at least 7 months for women and at least 4 months for men).

Highly effective contraception includes:

• Combined hormonal contraceptives (containing estrogen and progesterone) associated with ovulation suppression:

- Oral

- Intravaginal

- Percutaneous

• Hormonal contraceptives containing only progesterone and associated with ovulation suppression:

- Oral

- Injectable

- Implantable

• Intrauterine devices (IUDs)

• Intrauterine hormonal delivery systems

• Bilateral tubal ligation

• Vasectomy of the partner

• Complete abstinence is defined as avoiding heterosexual sexual intercourse (penile-vaginal intercourse) during and after the trial, and after the last dose of the investigational drug (at least 7 months for women and at least 4 months for men). Periodic abstinence (natural rhythm, basal body temperature, post-ovulation methods) is not considered an acceptable method of contraception.

In addition to highly effective contraception, female subjects (except those with bilateral tubal occlusion or whose partners have undergone vasectomy) should use additional barrier contraception during this trial and for 7 months after the last dose of the investigational drug. Male subjects (except those who have undergone vasectomy or whose partners have bilateral tubal occlusion) should use both highly effective contraception and additional barrier contraception during this trial and for 4 months after the last dose of the investigational drug.

For subjects receiving pembrolizumab, trastuzumab, 5-FU, capecitabine, cisplatin, or oxaliplatin, the trial unit should follow local labeling or institutional guidelines.

Infertility is defined as: premenopausal women with documented evidence of tubal ligation or hysterectomy; or postmenopausal women who have not menstruated naturally for 12 months (confirmed in cases of doubt by the presence of follicle-stimulating hormone >40 mIU/mL and estradiol <40 pg/mL [<147 pmol/L] in a blood sample). Women receiving hormone replacement therapy (HRT) with questionable postmenopausal status who wish to continue HRT during the trial must use one of the contraceptive methods listed for fertile women. Otherwise, they must discontinue HRT before randomization to confirm postmenopausal status. For most forms of HRT, at least 2 to 4 weeks must be allowed between discontinuation and blood draw; this interval depends on the type and dosage of HRT. Once postmenopausal status is confirmed, they can resume HRT during the trial without using contraception.

13. Male participants must not freeze or donate sperm from the start of randomization, throughout the trial, and for at least 4 months after the last dose of T-DXd. For participants receiving pembrolizumab, trastuzumab, 5-FU, capecitabine, cisplatin, or oxaliplatin, the trial unit should follow local labeling or institutional guidelines. Sperm preservation should be considered before randomization in this trial.

14. Female participants must not donate or use eggs for their own purposes from the start of randomization, throughout the trial drug treatment, and for at least 7 months after the last dose of T-DXd. For participants receiving pembrolizumab, trastuzumab, 5-FU, capecitabine, cisplatin, or oxaliplatin, the trial unit should follow local labeling or institutional guidelines. They should avoid breastfeeding throughout this period. Oocyte preservation may be considered before randomization in this trial.

15. Willing and able to adhere to scheduled follow-up visits, the investigational drug treatment plan, laboratory tests, other trial procedures, and trial limitations.

16. Willing and able to participate in the collection of Patient Self-Assessment Outcomes (PRO) data.

Note: If a participant is unable to read the questionnaire (i.e., blind or illiterate), or if the language version does not include the participant's native or preferred language, the participant may be exempt from completing the PRO questionnaire but may still participate in the trial.

Individuals to be included in the primary or exploratory cohort will be ineligible to participate in this trial if they meet any of the following criteria:

1. Previous exposure to other HER2-targeted therapies (including ADCs).

2. Lack of physiological integrity of the upper gastrointestinal tract (i.e., severe Crohn's disease leading to malabsorption) or malabsorption syndrome, which would preclude the feasibility of oral chemotherapy (i.e., capecitabine).

3. Known DPD enzyme deficiency. Note: DPD deficiency screening should be performed according to local requirements.

4. Contraindications to treatment with trastuzumab, 5-FU, capecitabine, cisplatin, or oxaliplatin, according to local labeling.

5. Participants must have a history of myocardial infarction or symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV) within the 6 months prior to randomization. Subjects with troponin concentrations higher than the ULN (as defined by the manufacturer) and no myocardial infarction-related symptoms at screening should be consulted with a cardiologist during screening to rule out the possibility of myocardial infarction.

6. Based on the mean of three consecutive 12-lead electrocardiograms (ECGs) at screening, the corrected QT interval (Fredericia formula corrected QT interval [QTcF]) must be prolonged to >470 ms (female) or >450 ms (male).

7. A history of (non-infectious) interstitial lung disease (ILD)/pneumonia requiring steroid treatment, current ILD/pneumonia, or suspected ILD/pneumonia that could not be ruled out by imaging at screening.

8. Specific clinically significant pulmonary complications, including but not limited to any underlying lung disease (e.g., pulmonary embolism, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc., occurring within 3 months after randomization).

9. Any autoimmune disease, connective tissue disease, or inflammatory disease with documented or suspected lung involvement at screening (e.g., rheumatoid arthritis, Sjogren's disease, sarcomatoid disease, etc.). Complete and detailed information on the diseases of subjects included in the trial should be recorded in the electronic case report form (eCRF).

10. Previous total pneumonectomy (complete).

11. Spinal cord compression, known clinically active central nervous system metastases (defined as untreated and symptomatic), and/or carcinomatous meningitis.

Note: Subjects previously treated for brain metastases may participate if they a) have stable radiographic assessments (i.e., no evidence of deterioration) for at least 4 weeks as confirmed by repeat imaging during trial screening; b) are clinically stable (i.e., asymptomatic and not requiring steroid or antiepileptic therapy for at least 14 days prior to the first dose of the investigational drug); and c) have recovered from acute toxicities of radiation therapy. The completion of whole-brain radiation therapy must be at least 2 weeks after randomization.

12. Known other malignancies that are worsening or have required aggressive treatment within the past 3 years.

Note: Subjects with basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ of the skin (excluding bladder carcinoma in situ) that have received potentially curative therapies are not excluded.

13. History of severe allergic reaction (≥ Grade 3) to any of the drug's components or inactive ingredients.

14. Uncontrolled infection requiring systemic antibiotics, antiviral drugs, or antifungal medications.

15. Substance abuse, other medical conditions (e.g., clinically significant cardiac or psychological conditions), or any other condition that is not in the best interests of the subject and, as determined by the trial commissioner, may interfere with the subject's participation in the clinical trial or the assessment of the clinical trial results.

16. Active primary immunodeficiency, known uncontrolled active human immunodeficiency virus (HIV) infection, including HIV-infected individuals with a history of Kaposi's sarcoma and/or multicentric Castleman disease. Subjects should be tested for HIV prior to randomization if required by local regulations or the Institutional Research Board/Ethics Committee (IRB/EC).

17. Active or uncontrolled hepatitis B virus (HBV) infection. Subjects are eligible if they meet the following criteria:

a. They are hepatitis B surface antigen (HBsAg) positive and have chronic HBV infection (lasting 6 months or longer), and meet the following additional criteria:

• HBV deoxyribonucleic acid (DNA) viral load <2000 IU/mL

• Antiviral therapy initiated or maintained if the trial administrator deems it clinically necessary

b. Transaminase levels are normal, or if liver metastases are present, transaminase levels are abnormal (AST/ALT <3 times ULN) and cannot be attributed to HBV infection.

18. Subjects have active or uncontrolled hepatitis C virus (HCV) infection. Subjects are eligible if they meet the following criteria:

a. They have a history of hepatitis C infection and, in the past 4 weeks, have an HCV viral load below detectable levels when not receiving antiviral therapy.

b. Normal transaminase levels, or abnormal transaminase levels (AST/ALT <3 times) if liver metastasis is present.
ULN), and not attributable to HCV infection.

19. History of vaccination with an active attenuated vaccine (mRNA and replication-defective adenovirus vaccines are not considered live attenuated virus vaccines) within 30 days prior to the first dose of the investigational drug.

20. Unresolved toxicity remaining from previous anticancer therapy, defined as toxicity that has not yet resolved to ≤ Grade 1 or baseline (excluding hair loss).

Note: Participants with chronic, stable Grade ≤2 toxicity (defined as not worsening to Grade >2 within at least 3 months prior to randomization and controlled with standard care) and identified by the trial administrator as related to prior anticancer therapy may be included, including the following:

• Chemotherapy-induced neuropathy

• Fatigue

• Residual toxicity from prior IO therapy: Grade 1 or 2 endocrine disorders, which may include

- Hypothyroidism/Hyperthyroidism

- Type 1 diabetes

- Hyperglycemia

- Adrenal insufficiency

1. Sign and date the pre-screening consent form (ICF) before central HER2 and PD-L1 CPS testing. Sign and date the primary screening ICF before initiating any trial-specific eligibility procedures. Sign and date the selective PGx ICF (included in the primary screening ICF) before performing any PGx procedures.

2. Adults aged ≥18 years on the date of signing the ICF. If the legal age of consent for trial participation is >18 years, follow local regulations.

3. Treatment-naïve, unresectable, histologically confirmed locally advanced or metastatic gastric or GEJ adenocarcinoma. Prior treatment in the perioperative and/or adjuvant setting is permitted, provided that more than 6 months have passed between the end of the perioperative or pre-adjuvant therapy and the diagnosis of disease recurrence.

Note: Prior use of IO (i.e., anti-PD-1/PD-L1) therapy in (pre-)adjuvant therapy is permitted as long as the interval between the completion of cancer immunotherapy (IO) treatment and the confirmed disease recurrence is >6 months.

4. New tumor tissue (core needle section, incision section, excision section) or existing tumor tissue sections collected at the time of diagnosis of locally advanced or metastatic disease should be prospectively centrally assessed according to the American Society of Clinical Oncology-American Society of Pathology to classify it as HER2-positive (IHC 3+ or IHC 2+/ISH-positive) gastric cancer or GEJ cancer.

Note: Stock samples taken from previously diagnosed or surgical sections that have not undergone radiation exposure are acceptable. Detailed information on tumor tissue submission can be found in the Trial Laboratory Manual.

5. All subjects must provide tumor samples for tissue IHC staining to centrally determine HER2 expression, PD-L1 CPS, and other relevant parameters. Necessary formalin fixation and paraffin embedding (FFPE) or new section tumor specimens may be obtained from primary or metastatic sections. Specimens with limited tumor content (central criterion) and cytological specimens are insufficient to define the HER2 and PD-L1 status of the tumor.

6. At least one measurable target lesion on computed tomography (CT) or magnetic resonance imaging (MRI) as assessed by the trial administrator according to RECIST v1.1. A lesion is considered measurable if it has previously undergone radiotherapy and has shown progression.

7. Left ventricular ejection ratio (LVEF) ≥50% within 28 days prior to randomization.

Exclusion Criteria

1. Previous exposure to other HER2-targeted therapies (including ADCs).

2. Lack of physiological integrity of the upper gastrointestinal tract (i.e., severe Crohn's disease leading to malabsorption) or malabsorption syndrome, which would preclude the feasibility of oral chemotherapy in subjects scheduled to receive capecitabine as part of the trial treatment.

3. Known DPD enzyme deficiency. Note: DPD enzyme deficiency screening is only required in regions/countries where DPD testing is classified as SoC and the DPD status is unknown. For regions/countries where DPD testing is not classified as SoC, local practice should be followed. In Spain and Italy, DPD enzyme deficiency screening is mandatory for all subjects with unknown DPD status.

4. Contraindications to treatment with trastuzumab, 5-FU, capecitabine, cisplatin, or oxaliplatin according to local labeling.

5. Participants must have a history of myocardial infarction or symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV) within the 6 months prior to randomization. Subjects with troponin levels higher than the ULN (as defined by the manufacturer) at screening and without any myocardial infarction-related symptoms should consult a cardiologist during screening to rule out the possibility of myocardial infarction.

6. Based on the average of three consecutive 12-lead ECGs at screening, the corrected QT interval (Fredericia formula corrected QT interval [QTcF]) must be prolonged to >470 ms (female) or >450 ms (male).

7. Participants must have a history of (non-infectious) interstitial lung disease (ILD)/pneumonia requiring steroid treatment, currently have ILD/pneumonia, or be suspected of having ILD/pneumonia that cannot be ruled out by angiography at screening.

8. Specific major clinical complications of lung disease, including but not limited to any underlying lung disease (e.g., pulmonary embolism, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc. within 3 months after randomization of the trial).

The Estimated Number of Participants

  • Taiwan

    31 participants

  • Global

    726 participants

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