Resectable Gasrtic Cancer
Conditions
Brief summary
To address regional disparity, the investigators propose a tailored perioperative strategy for East Asian patients, combining neoadjuvant FLOT plus durvalumab, followed by adjuvant TS-1 plus durvalumab. This approach seeks to balance efficacy, immunologic synergy, and treatment tolerability, offering a more practical regimen for Eastern populations.
Detailed description
This is a single arm, open label, single center, Phase II study to assess the efficacy and safety of neoadjuvant durvalumab in combination with FLOT chemotherapy followed by adjuvant durvalumab in combination with TS-1 in patients with resectable GC/GEJC (ie, radical-surgery eligible; cT2/3N+ or T4Nany with M0, per AJCC 8th edition). A total of 28 evaluable subjects will be required for the study. Eligible participants will receive durvalumab 1500 mg on Day 1 + FLOT on Days 1 and 15 Q4W for 2 cycles (2 cycles neoadjuvant, 1 cycle = Q4W in neoadjuvant setting) followed by durvalumab 1500 mg + TS-1 on Day 1 Q3W for 16 additional cycles (1 cycle = Q3W in adjuvant setting). Neoadjuvant therapy will begin following completion of the screening period, and patients will undergo resection surgery 4 to 8 weeks after the last dose of neoadjuvant therapy. (Surgery \>8 weeks after the last dose of neoadjuvant therapy may be permitted in consultation with the PI). Adjuvant therapy will begin 4 to 12 weeks post-surgery (based on the patient's recovery period).
Interventions
DRUGDurvalumab, TS-1
This is a single-arm, open-label, single center, Phase phase II study to assess the efficacy and safety of neoadjuvant FLOT chemotherapy plus Durvalumab followed by adjuvant durvalumab in combination with TS1 in patients with resectable locally advnaced GC/GEJC.
Sponsors
Taipei Veterans General Hospital, Taiwan
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 2. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up visits. 3. Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses. 4. Age ≥18 years at the time of screening. 5. Histologically documented gastric or gastroesophageal junction adenocarcinoma with resectable disease (cT2/3N+ or T4Nany tumors with M0 per AJCC 8th edition). GEJC includes Siewert\* type 2 and 3 tumor. Siewert\* type 1 tumor is also eligible as long as the patient is intended to be treated in the same way as for Siewert type 2 and 3 tumors. a. Per the judgment of the Investigator, patient must be medically fit for treatment with neoadjuvant FLOT therapy prior to radical surgery. 6. World Health Organization (WHO)/ECOG performance status (PS) of 0 or 1 at enrollment 7. No prior anti-cancer therapy (eg, chemotherapy, radiation therapy, or chemoradiation therapy) for the current malignancy. 8. Adequate organ and marrow function as defined below: 1. Hemoglobin ≥9.0 g/dL 2. Absolute neutrophil count ≥1.0 × 109 /L 3. Platelet count ≥100 × 109/L 4. Serum bilirubin ≤1.5 × the institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome, who will be allowed in consultation with their physician. 5. ALT and AST ≤2.5 × ULN 6. Measured creatinine clearance (CL) \>40 mL/min, as measured by a 24-hour urine collection or calculated creatinine CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976). 9. Must have a life expectancy of at least 24 weeks 10. Body weight \>30 kg at enrollment
Exclusion criteria
1. Patients with peritoneal dissemination (including tumor cells in peritoneal fluid) or distant metastasis 2. Patients with adenosquamous cell carcinoma, squamous cell carcinoma, or GI stromal tumor 3. History of allogeneic organ transplantation. 4. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion: 1. Patients with vitiligo or alopecia 2. Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement 3. Any chronic skin condition that does not require systemic therapy 5. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent 6. History of another primary malignancy except for 1. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of investigational product (IP) and of low potential risk for recurrence 2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease 3. Adequately treated carcinoma in situ without evidence of disease 7. History of active primary immunodeficiency 8. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice). Patients with HBV infection under anti-HBV drugs are eligible. Patients positive for hepatitis C (HCV) antibody are eligible if polymerase chain reaction is negative for HCV RNA. 9. Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies). 10. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms 11. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients 12. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable. 13. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live attenuated vaccines whilst receiving IP and up to 30 days after the last dose of IP. 14. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. 15. Prior immune-mediated therapy including, but not limited to, other anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 (anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines. 16. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: 1. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection) 2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent 3. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) 17. Participation in another clinical study with an investigational product within 30 days or 4 weeks, or within 5 half-lives of the investigational product (whichever is longer), prior to the first dose of study treatment. 18. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study. 19. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of the investigational drugs durvalumab/placebo monotherapy. 20. Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological complete response (pCR) rate | From enrollment to the end of surgical treatment. | Pathological complete response (pCR) was selected as the primary endpoint to enable a feasible sample size and to specifically capture the antitumor activity of the neoadjuvant immunochemotherapy backbone. While the study hypothesis extends beyond neoadjuvant efficacy to include postoperative tolerability and feasibility, these aspects are addressed through predefined secondary endpoints focusing on safety, treatment completion, and postoperative outcomes. |
| Completion rate of Adjuvant Therapy | From the start of adjuvant treatment to the end of adjuvant treatment up to 90 days. | Duration of adjuvant therapy, defined as the time from initiation to permanent discontinuation of adjuvant treatment for any reason. Adjuvant treatment completion rate, defined as the proportion of patients who complete all planned cycles of adjuvant durvalumab plus TS-1 per protocol. |
| Safety of Adjuvant Therapy | From the start of adjuvant treatment to the end of adjuvant treatment up to 90 days. | Incidence and severity of the treatment emergent adverse events of the adjuvant therapy (per NCI-CTCAE 5.0). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival | From enrollment to the end of treatment up to 3 years. | Overall survival is length of time from treatment until the date of death due to any cause. |
| Event free survival | From the start of adjuvant treatment to the end of adjuvant treatment up to 3 years. | Event-free survival (EFS) is defined as the time from first dose of study treatment to the first occurrence of any of the following events, whichever occurs first: (1) Disease progression that precludes curative surgery or requires non-protocol therapy during neoadjuvant treatment (per RECIST 1.1); (2) Pathologically or radiologically confirmed local or distant recurrence after surgery; (3) Death from any cause. |
Countries
Taiwan
Contacts
CONTACTStudy Coordinator
PRINCIPAL_INVESTIGATORMing-Huang Chen
Taipei Veterans General Hospital, Taiwan
Outcome results
None listed