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A phase I/II trial evaluating the safety of increased-dose S- 1 with oxaliplatin and nivolumab in HER2-negative advanced gastric cancer

BMC Cancer volume 25, Article number: 675 (2025) Cite this article

Abstract

Background

We developed and refined an S-1 dosage formula based on renal function, sex, and body surface area (BSA) to achieve the target area under the concentration–time curve of 5-fluorouracil in two prospective pharmacokinetic studies. The clinical validity of the refined formula (BBT formula) was evaluated using data from the two phase III trials of fist-line chemotherapy including S-1 for advanced gastric cancer, which demonstrated that overall survival and progression-free survival tended to be shorter in patients whose S-1 standard dose, based on BSA alone, was lower than that determined using the BBT formula.

Methods

Chemo-naïve patients with HER2-negative advanced gastric or gastroesophageal junction cancer, whose standard S-1 dose is lower than that determined using the BBT formula, receive S-1 at an increased dose based on the BBT formula plus oxaliplatin (130 mg/m2) and nivolumab (360 mg/body). The primary endpoint is the incidence of dose-limiting toxicity in six patients in the phase I part and the proportion of patients requiring S-1 dose reduction in a total of 20 patients, expecting 30% and rejecting 50% with an alpha error of 0.1 and beta error of 0.2. The secondary endpoints are adverse events, relative dose intensity, response rate, disease control rate, progression-free survival, and overall survival. A correlation study is conducted to investigate the immune profiles associated with efficacy.

Discussion

This phase I/II trial evaluates the safety and efficacy of S-1 at increased doses, determined by the BBT formula, in combination with oxaliplatin and nivolumab in patients with HER2-negative advanced gastric cancer, whose standard dose of S- 1 is lower than the dose recommended dose by the BBT formula.

Trial registration

This study was approved by the University of Tokyo Clinical Research Review Board (URL: https://www.ut-crescent.jp/patients/chiken_jisshi/, review number: 2022529SP) and was initiated at 19 institutions in June 2023 (registered as jRCTs031230127).

Peer Review reports

Background

The prognosis of advanced gastric cancer is poor. S- 1 is a key drug in standard first-line chemotherapy for advanced gastric cancer, including S- 1 plus cisplatin and S- 1 plus oxaliplatin (SOX), with or without a molecular targeted agent or an immune checkpoint inhibitor [1]. S- 1 contains tegafur, which is a prodrug of 5-fluorouracil (5-FU) and 5-chloro- 2,4-dihydroxypyridine (CDHP), which inhibits the rate-limiting enzyme dihydropyrimidine dehydrogenase (DPD) in 5-FU catabolism to maintain its high concentration. The approved daily dose of S- 1, determined based on body surface area (BSA), is 80 mg/m2/day for tegafur monotherapy in Asia [2].

Since more than 50% of CDHP is excreted in the urine, renal dysfunction increases the exposure to CDHP, leading to excessive inhibition of DPD, and results in sustained high concentrations of 5-FU [3, 4]. A post-marketing survey on S- 1 demonstrated that the incidences of adverse events were high in patients with impaired renal function [5]. Due to absence dosage model for S- 1 like the Calvert’s formula calculating the optimal carboplatin dose, dose of S- 1 for patients with impaired renal function (creatinine clearance [CLcr] < 80 ml/min) has been reduced empirically.

We conducted two prospective pharmacokinetic studies in patients with cancer having various renal functions to develop and refine an S- 1 dosage formula (BBT formula) based on renal function and sex [4, 6]: Recommended daily S- 1 dose = Target area under the concentration–time curve (AUC) × (14.5 + 8.23 × sex [0 for female and 1 for male] + 0.301 × CLcr × BSA. We also proposed nomograms for the recommended daily dose of S- 1 to achieve the target AUC (1447.8 ng·h/mL in Asia [7]) according to individual BSA and CLcr, considering the available dosage strengths in tablets (20 and 25 mg as tegafur).

Subsequently, we retrospectively evaluated the clinical validity of the BBT formula and nomograms using data from two phase III trials (SPIRITS trial comparing S- 1 vs. S- 1 plus cisplatin and G-SOX trial comparing S- 1 plus cisplatin vs. S- 1 plus oxaliplatin for advanced gastric cancer [1, 8, 9]). The starting daily dose of S- 1 in these trials was determined only by BSA; 80 mg/m2 (< 1.25 m2, 80 mg; ≤ 1.25 – < 1.5 m2, 100 mg; ≥ 1.5 m2, 120 mg). Although the prescription information of S- 1 indicates that the daily dose can be increased up to 150 mg based on individual patient tolerability, a dose increase higher than 120 mg was not allowed in these trials. Overall, 938 patients in these trials were classified into three groups according to their actual starting doses of S- 1 compared with the doses calculated by the nomograms derived from the BBT formula: under-dosed group (< recommended dose), equal-dosed group (= recommended dose), and overdosed group (> recommended dose). While the incidences of neutropenia of any grade were the highest in the overdosed group and the lowest in the under-dosed group among the three groups, the multivariate analysis demonstrated that overall survival in the under-dosed group was inferior to that of the equal-dosed group. These results suggest that patients classified into the under-dosed group who could tolerate S- 1 at the starting dose might not achieve the target AUC ensuring efficacy. Therefore, it is expected that the recommended dose determined by the BBT formula may improve treatment outcomes for patients classified into the under-dosed group.

Currently, nivolumab is used as the first-line chemotherapy for HER2-negative advanced gastric cancer [10, 11]. This phase I/II trial aims to evaluate the safety and efficacy of S- 1 at increased doses, determined by the BBT formula, in combination with oxaliplatin and nivolumab in patients with HER2-negative advanced gastric cancer, whose standard dose of S- 1 is lower than the dose determined by the BBT formula.

This study is conducted under the Clinical Trials Act and approved by Clinical Research Review Board of the University of Tokyo (2022529SP) and Research Ethics Committee of the Institute of Medical Science at the University of Tokyo (2023–50–1108). It is registered with the Japan Registry of Clinical Trials (jRCTs031230127, June 8, 2023).

Methods

Objective

This study aims to evaluate the safety and efficacy of S- 1 at increased dose, determined by the BBT formula to achieve the target AUC, in combination with oxaliplatin and nivolumab in patients with HER2-negative advanced gastric cancer.

Study design

This study comprises two parts:

  1. 1)

    Phase I part: Assess the incidence of dose-limiting toxicities (DLT) during the first course of chemotherapy.

  2. 2)

    Expansion part: Evaluates the incidence of dose reduction of S- 1 due to adverse events during the entire treatment course, including patients in phase I. Patient enrollment in the expansion part starts after confirming tolerability in the first six evaluable patients in phase I. Patients in phase I, who are not suitable for DLT evaluation for any reason, such as hypersensitivity or patient refusal due to adverse events not corresponding to DLT, are replaced until DLT is evaluated in six patients. If DLTs are observed in two or fewer patients, the study will expand. However, if three or more patients experience DTLs in phase I, the protocol will be amended to use an oxaliplatin dose of 100 mg/m2, and the study will restart after the protocol amendment.

Endpoints

Primary endpoint

This study has two primary endpoints: one in the phase I part and the other for all patients enrolled in phase I and expansion parts. In phase I part, the primary endpoint is the incidence of DLT. The primary endpoint for all patients is the proportion of patients who require dose reduction of S- 1 from the recommended dose owing to toxicity during the entire treatment course.

Secondary endpoints

The secondary endpoints are: 1) incidence of adverse events; 2) relative dose intensity of S- 1, oxaliplatin, and nivolumab during the entire treatment course; 3) response rate in patients with measurable lesions; 4) disease control rate in patients with measurable lesions; 5) progression-free survival; and 6) overall survival. Toxicity is assessed according to the US National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.

Dose limiting toxicities

DLT is defined as the following adverse events observed during the first course: 1) grade ≥ 3 nausea, vomiting, anorexia, diarrhea, stomatitis or fatigue persisting for ≥ 7 days regardless of the supportive treatment; 2) grade ≥ 3 non-hematological adverse events for which the attending physician judges that the protocol treatment cannot be continued; 3) S- 1 administration for ≤ 7 days due to adverse events; and 4) delay of starting the second course beyond 14 days from the planned schedule due to adverse events.

Eligibility criteria

The enrolled patients are required to satisfy all eligibility criteria and not meet any exclusion criteria. Inclusion criteria are:

  1. 1)

    Advanced (unresectable or recurrent) gastric or esophagogastric junction cancer with histologically diagnosed HER2-negative adenocarcinoma;

  2. 2)

    No prior systemic chemotherapy for gastric cancer except for perioperative adjuvant chemotherapy completed ≥ 180 days before diagnosis of recurrence;

  3. 3)

    Planned treatment with SOX plus nivolumab;

  4. 4)

    S- 1 recommended dose determined by the nomogram derived from the BBT formula is higher than the standard dose (< 1.25 m2, 80 mg; ≤ 1.25 – < 1.5 m2, 100 mg; ≥ 1,5 m2, 120 mg);

  5. 5)

    Age ≥ 18 years;

  6. 6)

    ECOG performance status 0 or 1;

  7. 7)

    Sufficient oral intake;

  8. 8)

    At least one evaluable lesion on contrast-enhanced CT (slice thickness ≤ 7 mm) within 28 days before enrollment;

  9. 9)

    Laboratory tests within 14 days before enrollment:

    1. i)

      Neutrophil count ≥ 1,500/mm3,

    2. ii)

      Platelet count ≥ 10 × 104/mm3,

    3. iii)

      Hemoglobin ≥ 8.0 g/dL,

    4. iv)

      Aspartate aminotransferase (AST) ≤ 100 U/L (≤ 200 U/L in case of liver metastasis),

    5. v)

      Alanine aminotransferase (ALT) ≤ 100 U/L (≤ 200 U/L in case of liver metastasis),

    6. vi)

      Total bilirubin ≤ 1.5 mg/dL,

    7. vii)

      Creatinine ≤ 1.5 mg/dL;

  10. 10)

    Agreement to use contraception; and.

  11. 11)

    Written informed consent for participation in this study.

Exclusion criteria are

  1. 1.

    HER2-positive gastric cancer (IHC 3 +, or IHC 2 + with a positive result on ISH).

  2. 2.

    Patients receiving enteral or intravenous nutritional supplementation or those requiring continuous infusion therapy.

  3. 3.

    Presence of pericardial effusion, pleural effusion, or ascites requiring drainage. However, if the fluid can be controlled with oral medications alone, the patient remains eligible.

  4. 4.

    Peripheral neuropathy of Grade 2 or higher.

  5. 5.

    Brain or meningeal metastasis. If the patient is asymptomatic and does not require treatment, brain imaging is not mandatory.

  6. 6.

    Concurrent active double cancers.

  7. 7.

    Previous treatment with an anti–PD- 1 antibody, anti–PD-L1 antibody, anti–PD-L2 antibody, anti-CD137 antibody, anti–CTLA- 4 antibody, or any other antibody or pharmacotherapy that modulates T-cell function.

  8. 8.

    Current or past history of severe hypersensitivity to any antibody drug.

  9. 9.

    Concurrent or past medical history of an autoimmune disease. However, the following are permissible: type 1 diabetes, hypothyroidism managed by hormone replacement therapy, or skin diseases (e.g., vitiligo, psoriasis, alopecia) not requiring systemic therapy.

  10. 10.

    Evidence or history of interstitial lung disease or pulmonary fibrosis on CT.

  11. 11.

    Comorbid diverticulitis or symptomatic gastrointestinal ulcerative disease.

  12. 12.

    Current use of warfarin, phenytoin, or flucytosine at the time of registration.

  13. 13.

    Receipt or requirement of systemic corticosteroids (other than temporary use for diagnostic procedures, prophylaxis for allergic reactions, or to reduce edema due to radiation therapy) or immunosuppressive therapy within 28 days prior to registration.

  14. 14.

    History of transient ischemic attack, cerebrovascular disease, thrombosis, or thromboembolism (e.g., pulmonary embolism, deep vein thrombosis) within 180 days prior to registration.

  15. 15.

    History of any of the following cardiac disorders:

    1. A)

      Myocardial infarction within 180 days prior to registration

    2. B)

      Uncontrolled angina within 180 days prior to registration

    3. C)

      Congestive heart failure of NYHA Class III or IV

  16. 16.

    Uncontrolled diabetes.

  17. 17.

    Ongoing systemic infection requiring treatment.

  18. 18.

    Underwent surgery (any procedure under general anesthesia) within 28 days prior to registration.

  19. 19.

    Received radiation therapy for gastric cancer within 28 days prior to registration or radiation therapy for bone metastases within 14 days prior to registration.

  20. 20.

    Administration of radioactive drugs within 56 days prior to registration (excluding use for testing or diagnostic purposes).

  21. 21.

    Received any unapproved drugs within 28 days (or within 90 days for antibody drugs) prior to registration.

  22. 22.

    Positive test for HIV- 1 antibody, HIV- 2 antibody, HTLV- 1 antibody, HBs antigen, or HCV antibody.

  23. 23.

    Negative for HBs antigen but positive for either HBs antibody or HBc antibody with detectable HBV-DNA.

  24. 24.

    Pregnant or breastfeeding, or potential pregnancy.

  25. 25.

    Unable to provide informed consent (e.g., due to dementia or other factors).

  26. 26.

    Receipt of a live (attenuated) vaccine within 28 days prior to registration.

  27. 27.

    Deemed inappropriate for participation in the study by the principal investigator or sub-investigator.

Treatment

Patients receive 130 mg/m2 intravenous oxaliplatin on day 1, plus oral S- 1 at the recommended dose determined using the nomogram derived from the BBT formula (Fig. 1) on days 1–14 (SOX) in addition to 360 mg intravenous nivolumab every 3 weeks. The daily dose of S- 1 is limited to 150 mg according to the approved maximum dose, even when the recommended daily dose determined by the BBT formula is > 150 mg. Treatment is continued until disease progression, adverse events requiring a dose reduction of S- 1 by more than two levels, other unacceptable adverse events, or patient refusal to continue the study treatment. If body weight or creatinine clearance changes by more than 10% during treatment, the dose of S- 1 is redetermined according to the BBT formula. Protocol treatment without S- 1 is not allowed; however, doublet chemotherapy containing S- 1 or S- 1 monotherapy can be continued even after oxaliplatin or nivolumab are discontinued. Oxaliplatin is discontinued when grade ≥ 3 peripheral neuropathy, grade ≥ 3 pneumonitis, grade ≥ 3 hypersensitivity, or other adverse events requiring discontinuation, as judged by the investigator. Nivolumab is discontinued when any of the following adverse events are observed: grade 4 diarrhea, grade 4 creatinine elevation, grade 4 AST or ALT elevation, grade 4 pancreatitis, grade 4 rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, grade ≥ 3 pneumonitis, grade ≥ 3 total bilirubin elevation, grade ≥ 3 myocarditis, grade ≥ 3 adrenal insufficiency or adrenal crisis, grade ≥ 3 hypersensitivity, grade ≥ 3 uveitis, uncontrollable adrenal insufficiency, uncontrollable hyperglycemia, uncontrollable hypopituitarism, uncontrollable hypothyroidism, any grade Guillain–Barre syndrome, any grade encephalitis, any grade myelitis, or other adverse events judged to require discontinuation of the protocol treatment by the investigator. Discontinued agents cannot be readministered during protocol treatment.

Fig. 1
figure 1

The nomogram derived from the BBT formula

Full size image

Dose reduction

Dose-reduction criteria for each agent are specified. The dose of S- 1 is reduced by one level if any of the following adverse events are observed: grade 4 neutropenia, grade 4 thrombocytopenia, grade ≥ 3 febrile neutropenia, grade ≥ 3 stomatitis, grade ≥ 3 diarrhea, delay of the treatment cycle ≥ 8 days due to adverse events caused by S- 1, or other adverse event requiring dose reduction as judged by the investigator. Dose reduction by more than two levels is not allowed.

Follow-up

The planned enrollment period is 18 months, with a follow-up period of 12 months after enrollment of the last patient.

Statistics

As one of the primary endpoints of phase I, the incidence of DLT during phase I is evaluated, and the decision to proceed to the expanded part is made in six eligible patients who are evaluated for DLT. All other endpoints are analyzed in the Final Analysis Set (FAS), which includes all enrolled patients who receive at least one of the study treatments and in the Per Protocol Set (PPS), excluding ineligible cases from the FAS.

Statistical hypothesis

In this study, we expect that the proportion of patients requiring S- 1 dose reduction is 30%, and a threshold is set at 55%, based on the results that the proportions of patients who required S- 1 dose reduction were 8.9/29.3/48.6% in the under-dosed (n = 56)/equal-dosed (n = 75)/overdosed (n = 185) groups in the SOX arm of the G-SOX study in which the dose of oxaliplatin was 100 mg/m2 [9]. The sample size is 20, ensuring a power of 80% and a one-sided alpha error of 10%.

Immune profiling

As a companion study, immune profiles are investigated to assess the association with the efficacy of SOX plus nivolumab therapy. Peripheral blood is collected immediately before the first and second courses of treatment, and peripheral blood mononuclear cells are analyzed using mass cytometry (Helios, Standard BioTools) and flow cytometry (Attune NxT, Thermo Fisher Scientific). Formalin-fixed paraffin-embedded specimens of surgically resected or biopsied tumor tissues of patients before or during the continuation of the protocol treatment are used to analyze infiltrating immune cells using imaging mass cytometry (Hyperion, Standard BioTools).

Discussion

Many anticancer agents, either cytotoxic or molecular targeted, have narrow therapeutic ranges with unique and specific pharmacokinetic and pharmacodynamic profiles [12, 13]. Previous studies have reported an association between adverse events and the efficacy of anti-tumor agents [14,15,16]. In a randomized clinical trial, increasing the dose of paclitaxel until experiencing grade 2 or higher neutropenia improved progression-free survival [17]. Conversely, insufficient doses of anti-tumor agents may result in mild toxicity and reduced efficacy.

In Japan, the package insert for S- 1, specifies the approved daily doses based on BSA: 80 mg for patients with BSA of < 1.25 m2, 100 mg for those with BSA of ≤ 1.25 m2 to < 1.50 m2, and 120 mg for those with BSA of ≥ 1.50 m2. Although an increase in the S- 1 daily dose up to 150 mg/body after confirming the safety of the starting dose is allowed in the Japanese package insert, S- 1 at a dose higher than 120 mg/kg is rarely administered in Japan. In Korea, S- 1 doses up to 160 mg/body are allowed for patients with large BSA. Initially, the 5-week schedule of S- 1 plus cisplatin using the Japanese daily dose of S- 1 (80 mg/m2/day, maximum 120 mg/body, for 21 days) showed superiority in overall survival to S- 1 monotherapy (80 mg/m2/day, maximum 120 mg/body, for 28 days followed by rest for 14 days) in the SPIRITS trial. Subsequently, a 3-week schedule of S- 1 plus cisplatin using the Korean daily dose of S- 1 (80 mg/m2/day, maximum 160 mg/body, for 14 days) was developed in Korea.

In the SOS study conducted in Japan and Korea, 3- and 5-week schedules of S- 1 plus cisplatin were compared, and all patients assigned to the 5-week schedule received a daily Japanese dose of S- 1 (maximum 120 mg/body) in both countries. In the 3-week schedule, Korean and Japanese patients received the Korean daily dose (maximum 160 mg/body) and the Japanese daily dose (maximum 120 mg/body) of S- 1, respectively, depending on the approval in each country [18]. In the subset analysis according to country, the response rate in the 3-week schedule was higher in Korean patients than in Japanese patients (63% [100/160] vs. 45% [14/31]), while that in the 5-week schedule was slightly lower in Korean patients than in Japanese patients (49% [78/158] vs. 58% [18/31]). Considering the younger age of Korean patients, the Japanese dose of S- 1 in both schedules of S- 1 plus cisplatin might be insufficient to achieve the target AUC of 5-FU for some patients in both Japan and Korea, such as young males.

Evaluation of the BBT formula using data from SPIRITS and G-SOX trials, in which a lower dose of S- 1 than the dose determined using the BBT formula was a significant prognostic factor for poor survival, suggests that an increased dose of S- 1 may be necessary for such patients. Because a 3-week schedule of S- 1 plus cisplatin using the Korean S- 1 dose (maximum 160 mg/body) was feasible in Korean patients, it is expected that an increased dose of S- 1 according to the BBT formula will also be associated with acceptable toxicities in Japanese patients.

In Japan, S- 1 plus oxaliplatin using the Japanese approved dose (80 mg/m2/day, maximum 120 mg/body, for 14 days) in a 3-week schedule has been established in the G-SOX trial. Nowadays, because S- 1 plus oxaliplatin in combination with nivolumab using Japanese approved dose (80 mg/m2/day, maximum 120 mg/body, for 14 days), repeated every 3 weeks, is one of standard treatment in Japan based on the results of the Checkmate- 649 and ATRACTION- 4 trials, our study employs a 3-week schedule of this triplet chemotherapy.

The BBT formula includes sex as a factor affecting pharmacokinetics of 5-FU after the administration of S- 1. In the evaluation of its clinical validity using data from the SPIRITS and G-SOX trials, 32 out of 298 patients (10.7%) and 112 out of 640 patients (17.5%) were classified into the under-dosed groups respectively [19]. More than 90% of the patients in the under-dosed group were males with large BSA, anticipating a predominance of young males in this study. Given the poor prognosis of young patients with gastric cancer [20], this study is expected to show promising efficacy as a secondary endpoint.

However, the safety of increasing the dose of S- 1 in combination with oxaliplatin and nivolumab remains unclear. Therefore, the primary endpoint for the phase I part of this study was the incidence of DLT in the first six patients to assess tolerability, and the primary endpoint of all enrolled patients, including both phase I and expansion parts, is the proportion of patients requiring dose reduction from the recommended dose of S- 1. The dose-reduction criteria used in this study generally follow those of the SPIRITS and G-SOX trials. Because it is expected that the dose of S- 1 determined by the BBT formula can achieve the target AUC, the expected proportion of patients requiring a dose reduction from the increased S- 1 dose in this study is set based on a proportion of dose reduction (29.3%) for the equal-dosed group in the SOX arm of the G-SOX study. Similarly, in the post-hoc analysis to explore the clinical utility of the BBT formula in adjuvant chemotherapy with S- 1 alone using the data of the JCOG1001 study, which was a randomized phase III trial investigating the role of bursectomy for cT3/T4 resectable gastric cancer, dose reduction of S- 1 was required in 24.7% of the patients classified into the equal-dosed group, suggesting that more patients may require dose reduction in the combination chemotherapy containing S- 1. Furthermore, in the post-hoc analysis on association of renal function with the safety and efficacy of S- 1 containing chemotherapy in a phase III trial (JCOG1013), which compared doublet chemotherapy with cisplatin plus S- 1 therapy and triplet chemotherapy with docetaxel plus cisplatin plus S- 1 therapy, dose reduction was required in 28.1% of the 169 patients in the S- 1 plus cisplatin group even with good renal function (Ccr > 80 ml/min). From these results, we set the expected dose reduction rate at 30%.

In the post-hoc analysis evaluating the clinical significance of the BBT formula in the phase III trial comparing S- 1 plus oxaliplatin with S- 1 plus cisplatin, where 48.6% of the overdosed patients required dose reduction. Similarly, in the post-hoc analysis of a phase III trial (JCOG1013), dose reduction of S- 1 was required in 44.4% of patients with Ccr of 60 ≤ and < 80 mL/min and in 48.2% of those with Ccr < 60 mL/min who might be overdosed. In addition, incidences of grade ≥ 3 adverse events were higher by 9% in patients receiving nivolumab combined with S- 1 plus oxaliplatin than those receiving chemotherapy alone in the ATTRACTION- 4 trial. Based on these reports, we set the null hypothesis at 55%. Moreover, the dose of oxaliplatin (130 mg/m2) is higher than that used in the G-SOX study (100 mg/m2). However, because the BBT formula includes sex as a factor, the overdosed group contained more female patients than the other groups, it is concerned that sex may affect the incidence of dose reduction in this study. Including this considerable bias, the increased dose by the BBT formula can be regarded as “truly” overdosed if the 55% or more patients require dose reduction. Therefore, it can be determined that dose increase using the BBT formula is not feasible if the null hypothesis cannot be rejected in this study. Although we do not plan to conduct an interim analysis for safety, we have an investigator meeting every month where severe adverse events are reported. Thus, we can share the safety information on time.

Another concern in this study is the negative impact of the increased dose of S- 1 on nivolumab efficacy because the synergistic or antagonistic effects of S- 1 on immune checkpoint inhibitors remain unclear. In mice administered fluorouracil, bone marrow-derived suppressor cells decreased, accompanied by increased Th17 via IL- 1β production, which may reduce the anti-tumor effect [21]. Additionally, the effect of the increased dose of S- 1 recommended by the BBT formula on the peripheral immune response may differ from that of the standard dose. This translational study aims to analyze the changes in the dynamics of peripheral blood immune cells using the same methods as the translational study of the ongoing KMOG study of SOX plus nivolumab at the standard dose of S- 1. Comparison results with the KMOG study is expected to provide insights into the synergistic or antagonistic effects of S- 1 on immune checkpoint inhibitors. Additionally, we will focus on reinvigorating exhausted CD8+ T-cells in the blood [22] and investigate whether they are truly associated with the efficacy or safety of the protocol treatment. These results deepen our understanding of tumor immunology with checkpoint inhibitors and potentially contribute to developing new treatment strategies using immune checkpoint inhibitors. If our translational research shows that activity by immune checkpoint inhibitors is reduced along with the increased dose of S- 1, these findings should be considered for the future treatment strategies.

The BBT formula has been already referred to in the Clinical Practice Guidelines for the Management of Kidney Injury During Anticancer Drug Therapy 2022 for determining the dose of S- 1 in patients with impaired renal function. However, the BBT formula has not been used so widely in clinical practice because there is no data of efficacy and safety in the combination chemotherapy containing S- 1 at the dose recommended by this formula. If individualized S 1 dosing strategy proves both safe and promising efficacy in this study, the BBT formula can be used not only for patients with impaired renal function to prevent severe toxicities but also those with good renal function to achieve target AUC which may improve efficacy. Thus, it is expected that the BBT formula can be used for all patients planned to receive S- 1 like the Calvert formula which indicates the dose of carboplatin according to renal function to achieve the target AUC. Furthermore, a large phase III trial investigating a survival benefit of the dose adjustment strategy using the BBT formula can be considered in the future.

This study has some limitations. First, most of the participants in this study will be young males; the statistical hypothesis based on equal-dosed patients who were older than the under-dosed patients in our previous study may lead to an underestimation of toxicity. Treatment strategy with an increased dose based on the BBT formula mainly targets male patients with good renal function and large BSA, leading to recommendation of the dose > 120 mg/day. However, the BBT formula recommends dose increase within 120 mg/day for female patients who may be underdosed due to some reasons regardless their small BSA. Thus, the dose increase strategy by the BBT formula targets the patients, mainly males, who may be underdosed, but does not cover all the patients. Second, the impact of increasing the S- 1 dose on efficacy could not be sufficiently evaluated owing to the small sample size. The true benefit of the BBT formula should be evaluated in a randomized clinical trial after the safety of S- 1 at the dose determined by the BBT formula in combination with oxaliplatin and nivolumab is confirmed in this study.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

BSA:

Body surface area

CDHP:

5-Chloro- 2,4-dihydroxypyridine

DLT:

Dose-limiting toxicities

FAS:

Final analysis set

SOX:

S-1 plus oxaliplatin

CLcr:

Creatinine Clearance

AST:

Aspartate Aminotransferase

ALT:

Alanine Aminotransferase

5-FU:

5-Fluorouracil

DPD:

Dihydropyrimidine Dehydrogenase

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Acknowledgements

University of Tokyo Hospital, IMSUT Hospital, NTT Medical Center Tokyo, National Hospital Organization Nagoya Medical Center, Kawasaki Municipal Hospital, Ishikawa Prefectural Central Hospital, National Cancer Center Hospital, NTT Medical Center Tokyo, Osaka International Cancer Institute, Osaka University Hospital, Cancer Institute Hospital of JFCR, Hamamatsu University School of Medicine, Keio University Hospital, Showa University Hospital, Kyushu University Hospital, Shizuoka Cancer Center, Okayama University Hospital, Nihon University Itabashi Hospital, Tokyo Metropolitan Police Hospital, Japanese Red Cross Medical Center, Osaka Medical and Pharmaceutical University Hospital and Mie University Hospital We would like to thank Editage for English language editing.

Funding

This work was supported by JSPS KAKENHI (grant number 23 K07393).

Author information

Authors and Affiliations

  1. Department of Oncology and General Medicine, IMSUT Hospital, the Institute of Medical Science Hospital, the University of Tokyo, Tokyo, Japan

    Keisuke Baba & Narikazu Boku

  2. Department of Gastroenterology Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Nobumi Suzuki

  3. Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan

    Chiyo K. Imamura

  4. Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan

    Eisuke Booka & Hiroya Takeuchi

  5. Department of Surgery, Keio University School of Medicine, Tokyo, Japan

    Masashi Takeuchi & Hirofumi Kawakubo

  6. Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan

    Daisuke Takahari

  7. Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan

    Takeshi Kawakami

  8. Medical Oncology and Respiratory Medicine, NHO Nagoya Medical Center, Aichi, Japan

    Chiyoe Kitagawa

  9. Department of Gastroenterology and Hepatology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan

    Yoshiyasu Kono

  10. Department of Gastroenterology, Tokyo Metropolitan Police Hospital, Tokyo, Japan

    Keiji Ogura

  11. Department of Medical Oncology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan

    Yosuke Kito

  12. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan

    Kei Saito

  13. Department of Gastroenterology, Japanese Red Cross Medical Center, Tokyo, Japan

    Shinzo Yamamoto

  14. Department of Medical Oncology, Osaka International Cancer Institute, Osaka, Japan

    Toshihiro Kudo

  15. Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan

    Takuya Tsunoda

  16. Department of Medical Oncology, NTT Medical Center Tokyo, Tokyo, Japan

    Takuro Mizukami

  17. Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Osaka, Japan

    Toshifumi Yamaguchi

  18. Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan

    Hirokazu Shoji

  19. Department of Medical Oncology, Mie University Hospital, Mie, Japan

    Kanako Saito

  20. Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Kenro Tanoue

  21. Department of Comprehensive Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Eishi Baba

  22. Biostatistics Unit, Clinical and Translational Research Center, Keio University Hospital, Tokyo, Japan

    Kengo Nagashima

Authors
  1. Keisuke Baba
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  2. Nobumi Suzuki
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Contributions

N.B. and K.B. drafted the manuscript. N.S., C.K.I., E.B., M.T., D.T., T.K., H.K., C.K., Y.K., K.O., Y.K., K.S., S.Y., H.T., T.K., T.T., T.M., T.Y., H.S., K.S., K.T., E.B. and K.N. corrected the manuscript, agreed to its publication and were involved as investigators in the study.

Corresponding author

Correspondence to Narikazu Boku.

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The University of Tokyo Clinical Research Review Board approved the study protocol and was certified by the Central IRB (2022529SP). All study participants provided written informed consent.

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The authors declare no competing interests.

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Baba, K., Suzuki, N., Imamura, C.K. et al. A phase I/II trial evaluating the safety of increased-dose S- 1 with oxaliplatin and nivolumab in HER2-negative advanced gastric cancer. BMC Cancer 25, 675 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-14084-1

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Keywords

BMC Cancer

ISSN: 1471-2407

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