Perioperative Therapies in Locally Advanced Unresectable Gastric Cancer

NCT06630130 | Recruiting Phase 2

• 1 other identifier: 2024-07-077
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Gastric cancer (GC) is the fifth most commonly diagnosed cancer, with over one million cases diagnosed annually worldwide. Human epidermal growth factor receptor 2 (HER2) overexpression in GC (seen in 4.4% to 53.4% of patients in different reports) is predictive biomarker of response to HER2-targeting therapies. Trastuzumab in combination with cisplatin or oxaliplatin, and a fluoropyrimidine (capecitabine or 5-fluorouracil \[5-FU\]), is approved anti-HER2 therapy for first-line treatment of HER2-positive gastric or gastroesophageal junction (GEJ) cancer. Rilvegostomig 750 mg Q3W was selected as recommended Phase 2 dose based on all available ARTEMIDE-01 clinical safety, efficacy, PK, RO data as well as modeling analysis. The dose of 750 mg Q3W is predicted to achieve intra-tumoral RO of ≥ 90% in the majority of participants across a broad spectrum of conditions. This is a phase II study to initially assess the efficacy of perioperative Trastuzumab Deruxtecan (T-DXd) and Capecitabine combination with or without Rilvegostomig in patients with HER2 positive locally advanced unresectable GC and potentially by subsequent protocol amendment in HER2 low locally advanced GC. Other agents may also subsequently be assessed in this protocol, by protocol amendments . \---------------------------------------------------------------------------------------------------- Therefore, these studies provide robust evidence that immune checkpoint inhibitors plus chemotherapy, specifically the perioperative durvalumab plus FLOT regimen, can increase pCR rate and significantly improve long-term survival outcomes for patients with resectable gastric, GEJ, or esophageal cancer.

Conditions

Stomach Neoplasms

Outcome Measures

Primary Outcomes (1)

• Incidence of AEs/SAEs

  To evaluate the safety and tolerability (by NCI-CTCAE v5.0)

  Through study completion, an average of 4 years

Secondary Outcomes (3)

• Pathologic CR(Pathological Complete Response)

  Through study completion, an average of 1 year

• EFS (Event-free survival)

  Through study completion, an average of 4 years

• OS (Overall survival)

  Through study completion, an average of 4 years

Study Arms (4)

Cohort A : T-DXd and Capecitabine combination

EXPERIMENTAL

Neoadjuvant; Trastuzumab Deruxtecan(T-DXd) 5.4mg/kg IV on D1 and Capecitabine 1000mg/m2 PO BID on D1-D14, Q3W for 3 cycles -Adjuvant; Trastuzumab Deruxtecan(T-DXd) 5.4mg/kg IV on D1, Q3W 16 cycles (up to 12 months) and Capecitabine 1000mg/m2 PO BID on D1-D14, Q3W for 4 cycles (up to 3 months)

Drug: Trastuzumab deruxtecan; Drug: Capecitabine

Cohort B : T-DXd and Capecitabine and Rilvegostomig combination

EXPERIMENTAL

* Neoadjuvant; Trastuzumab Deruxtecan(T-DXd) 5.4mg/kg IV on D1 and Capecitabine 1000mg/m2 PO BID on D1-D14 with Rilvegostomig 750mg IV on D1, Q3W for 3 cycles * Adjuvant; Trastuzumab Deruxtecan(T-DXd) 5.4mg/kg IV with Rilvegostomig 750mg IV on D1, Q3W for 16 cycles (up to 12 months) and Capecitabine 1000mg/m2 PO BID on D1-D14, Q3W for 4 cycles (up to 3 months)

Drug: Trastuzumab deruxtecan; Drug: Capecitabine; Drug: Rilvegostomig

<Cohort C> Sonesitatug Vedotin(Sone-Ve) + Capecitabine + Durvalumab combination

EXPERIMENTAL

* Neoadjuvant; Sonesitatug Vedotin(Sone-Ve) 2.2mg /kg IV with Durvalumab 1500mg IV on D1, and Capecitabine 750mg/m2 PO BID on D1-D14 Q3W for 3 cycles (the order of infusion: Durvalumab -\> Sone-Ve) * Adjuvant; Sonesitatug Vedotin(Sone-Ve) 2.2mg/kgIV with Durvalumab 1500mg IV on D1 and Capecitabine 750mg/m2 PO BID on D1-D14, Q3W for 3 cycles (approximately 2 months) then Sonesitatug Vedotin(Sone-Ve) 2.2mg/kgIV with Durvalumab 1500mg IV on D1 Q3W for 13 cycles (up to 10 months) (the order of infusion: Durvalumab -\> Sone-Ve)

Drug: Capecitabine; Drug: Durvalumab; Drug: Sonesitatug Vedotin

<Cohort D> Sonesitatug Vedotin(Sone-Ve) + Capecitabine + Oxaliplatin + Durvalumab combination

EXPERIMENTAL

* Neoadjuvant; Sonesitatug Vedotin(Sone-Ve) 2.2mg /kg IV with Durvalumab 1500mg IV on D1, and Oxaliplatin 100mg/m2 IV on D1, Capecitabine 750mg/m2 PO BID on D1-D14 Q3W for 3 cycles (the order of infusion: Durvalumab -\> Sone-Ve -\> Oxaliplatin) * Adjuvant; Sonesitatug Vedotin(Sone-Ve) 2.2mg/kgIV with Durvalumab 1500mg IV on D1 and , and Oxaliplatin 100mg/m2 IV on D1, Capecitabine 750mg/m2 PO BID on D1-D14, Q3W for 3 cycles (approximately 2 months) then Sonesitatug Vedotin(Sone-Ve) 2.2mg/kg IV with Durvalumab 1500mg IV on D1 Q3W for 13 cycles (up to 10 months) (the order of infusion: Durvalumab -\> Sone-Ve -\> Oxaliplatin)

Drug: Capecitabine; Drug: Durvalumab; Drug: Sonesitatug Vedotin; Drug: Oxaliplatin

Interventions

Capecitabine DRUG

* Neoadjuvant; Capecitabine 1000mg/m2 PO BID on D1-D14, Q3W for 3 cycles * Adjuvant; Capecitabine 1000mg/m2 PO BID on D1-D14, Q3W for 4 cycles (up to 3 months)

Also known as: Xeloda

<Cohort C> Sonesitatug Vedotin(Sone-Ve) + Capecitabine + Durvalumab combination; <Cohort D> Sonesitatug Vedotin(Sone-Ve) + Capecitabine + Oxaliplatin + Durvalumab combination; Cohort A : T-DXd and Capecitabine combination; Cohort B : T-DXd and Capecitabine and Rilvegostomig combination

Rilvegostomig DRUG

(Only Cohort B) * Neoadjuvant; Rilvegostomig 750mg IV on D1, Q3W for 3 cycles * Adjuvant; Rilvegostomig 750mg IV on D1, Q3W for 16 cycles (up to 12 months)

Also known as: AZD2936

Cohort B : T-DXd and Capecitabine and Rilvegostomig combination

Trastuzumab deruxtecan DRUG

* Neoadjuvant; Trastuzumab Deruxtecan(T-DXd) 5.4mg/kg IV on D1, Q3W for 3 cycles * Adjuvant; Trastuzumab Deruxtecan(T-DXd) 5.4mg/kg IV on D1, Q3W 16 cycles (up to 12 months)

Also known as: Enhertu

Cohort A : T-DXd and Capecitabine combination; Cohort B : T-DXd and Capecitabine and Rilvegostomig combination

Durvalumab DRUG

* Neoadjuvant; Durvalumab 1500mg IV on D1, Q3W for 3 cycles * Adjuvant; Durvalumab 1500mg IV on D1 Q3W for 16 cycles (up to 12 months)

<Cohort C> Sonesitatug Vedotin(Sone-Ve) + Capecitabine + Durvalumab combination; <Cohort D> Sonesitatug Vedotin(Sone-Ve) + Capecitabine + Oxaliplatin + Durvalumab combination

Sonesitatug Vedotin DRUG

* Neoadjuvant; Sonesitatug Vedotin(Sone-Ve) 2.2mg /kg IV on D1, Q3W for 3 cycles * Adjuvant; Sonesitatug Vedotin(Sone-Ve) 2.2mg/kg IV on D1 Q3W for 16 cycles (up to 12 months)

Also known as: Sone-Ve

<Cohort C> Sonesitatug Vedotin(Sone-Ve) + Capecitabine + Durvalumab combination; <Cohort D> Sonesitatug Vedotin(Sone-Ve) + Capecitabine + Oxaliplatin + Durvalumab combination

Oxaliplatin DRUG

Neoadjuvant; Oxaliplatin 100mg/m2 IV on D1, Q3W for 3 cycles -Adjuvant; Oxaliplatin 100mg/m2 IV on D1, Q3W for 3 cycles (approximately 2 months)

<Cohort D> Sonesitatug Vedotin(Sone-Ve) + Capecitabine + Oxaliplatin + Durvalumab combination

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of fully informed consent prior to any study specific procedures.
• Patients must be ≥ 19 years of age
• Have a life expectancy of at least 12 weeks
• Body weight \> 30kg( \> 35kg for Rilvegostomig)
• Has a Pathologically documented adenocarcinoma of gastric or gastroesophageal junction with HER2 IHC results.
• In Cohort A＆B, HER2 positive (HER2 IHC 3+ or HER2 IHC 2+/ISH positive) In Cohort C＆D, CLDN18.2 positive
• Locally advanced unresectable disease by physician's discretion (ex. cT4 or bulky Nx node or localized peritoneal seeding) No evident distant organ metastasis.
• ECOG performance status PS 0-1 with no deterioration between screening and the first dose of study treatment.
• Has LVEF ≥ 50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before treatment
• Has measurable target disease assessed by the Investigator based on RECIST version 1.1 before surgery.
• Has adequate organ and bone marrow, liver and renal function within 14 days before treatment 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.
• Hemoglobin ≥ 9.0 g/dL
• Platelet count ≥100 x 109/L
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Total bilirubin ≤ 1.5 ULN if no liver metastases \< 3×ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) at baseline

You may not qualify if:

• \. Patients with evident peritoneal metastasis (including tumor cells in peritoneal fluid) or distant metastasis 2. Known dihydropyrimidine dehydrogenase (DPD) enzyme deficiency based on either local or central laboratory testing. Central laboratory testing will be available for patients where testing is SOC and with unknown DPD status.
• \. CNS metastases or CNS pathology including epilepsy, seizures, aphasia, or stroke within 3 months prior to consent, severe brain injury, dementia, Parkinson's disease, neurodegenerative diseases, cerebellar disease, severe uncontrolled mental illness, psychosis, and CNS involvement of autoimmune diseases.
• \. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, uncontrolled hypertension, serious chronic gastrointestinal conditions associated with nausea, vomiting, diarrhea unstable or active peptic ulcer disease or digestive tract bleeding, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs, or compromise the ability of the participant to give written informed consent.
• \. Unresolved toxicities of including but not limited to peripheral neuropathy, sensory or motor ≥ Grade 2 (Common Terminology Criteria for Adverse Events \[CTCAE\] v5.0) from prior therapy (excluding vitiligo, alopecia, endocrine disorders that are controlled with replacement hormone therapy, asymptomatic laboratory abnormalities).
• \. History of organ transplant. 7. Active primary immunodeficiency(or history of active primary immunodeficiency)/active infectious diseases. Active or prior documented autoimmune or inflammatory disorders (including IBD \[e.g. Crohn's disease, ulcerative colitis or diverticulitis\], SLE, sarcoidosis syndrome, tuberculosis, Wegener syndrome, myasthenia gravis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, at screening, , that requires use of immunosuppressives, glomerulonephritis, nephritic syndrome, Fanconi Syndrome or renal tubular acidosis within the past 2 years prior to the start of treatment. The following are exceptions to this criterion:
• Subjects with vitiligo or alopecia, hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment; patients with coeliac disease controlled by diet alone and patients without active disease in the last 5 years may be included after consultation with Chief Investigator.
• \. History of drug induced (non-infectious) ILD/pneumonitis requiring oral or intravenous steroids, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• \. Active hepatitis B (HBV surface antigen \[HBsAg\] positive) or active hepatitis C. Virus testing is not essential for clinical trial feasiblity assessment. Patients who have had or have resolved HBV infection or HCV infection in the past may participate in clinical trials. Note: For HBsAg-, patient needs to be \>6 months off antiviral treatment 10. Participants with past or resolved HBV infection are eligible only if they meet all of the following criteria\*:
• Anti-HBc (+) (IgG or total Ig),
• HBV DNA undetectable,
• Absence of cirrhosis or fibrosis on prior imaging or biopsy,
• Absence of HCV co-infection or history of HCV co-infection.
• \. Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice). Active or prior documented history of primary immunodeficiency at screening. And HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: A. undetectable viral RNA for 6 months, B. CD4+ count \>350 cells/μL, C. no history of AIDS-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks in Rilvegostomig, or 6 months in Sone-Ve on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen).
• If an HIV infection meets the above criteria, monitoring of viral RNA load and CD4+ count is recommended. Participants must be tested for HIV if acceptable by local regulations or an institutional IRB/IEC.
• \. Patient with any of the following cardiac criteria:

Sponsors & Collaborators

• Jeeyun Lee: lead

Study Sites (1)

Samsung Medical Center

Seoul, 06351, South Korea

RECRUITING

MeSH Terms

Conditions

Stomach Neoplasms

Interventions

trastuzumab deruxtecan; Capecitabine; durvalumab; Oxaliplatin

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Coordination Complexes; Organic Chemicals

Study Officials

• Jeeyun Lee, Ph, MD

  Samsung Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jeeyun Lee, Ph, MD

CONTACT

+82-10-9933-1779; jyun.lee@samsung.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: August 1, 2024
• First Posted: October 8, 2024
• Study Start: January 22, 2025
• Primary Completion (Estimated): October 30, 2028
• Study Completion (Estimated): June 30, 2029
• Last Updated: July 1, 2026

Record last verified: 2026-06

Locations

KR (1)