Article Text

Download PDFPDF

Protocol
Fruquintinib plus oxaliplatin combined with S-1 (SOX) as neoadjuvant therapy for locally advanced gastric cancer (GC) or gastro-oesophageal junction adenocarcinoma (GEJ): a multicentre, phase II, single-arm, open-label clinical trial (FRUTINEOGA) protocol
  1. Liucheng Wu,
  2. Haiqing Yan,
  3. Yuzhou Qin,
  4. Mingwei Huang,
  5. Tingan Wang,
  6. Qinwen Jin,
  7. Weiyuan Wei
  1. Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
  1. Correspondence to Professor Yuzhou Qin; qyz402{at}126.com

Abstract

Introduction Curing locally advanced gastric cancer (GC) or gastro-oesophageal junction adenocarcinoma (GEJ) with surgery alone is challenging. Neoadjuvant chemotherapy (NCT) has become the standard treatment for patients with locally advanced GC/GEJ, and SOX is the most common neoadjuvant regimen in China. The generally good tolerability in patients and fruquintinib’s low potential for drug–drug interaction suggest that it may be highly suitable for combinations with other antineoplastic therapies. A combination of fruquintinib, S-1 and oxaliplatin can be a promising neoadjuvant treatment for locally advanced GC/GEJ. In this phase II study, we aim to investigate the efficacy and toxicity of fruquintinib plus SOX as neoadjuvant treatment for locally advanced GC/GEJ.

Methods and analysis The FRUTINEOGA trial is a prospective, multicentre, phase II, single-arm, open-label clinical trial that will enrol 54 patients. Eligible patients will be registered, enrolled and receive 2–4 cycles of fruquintinib plus SOX, after which surgery will be performed and tumour regression will be evaluated. The primary endpoint is the pathological remission rate, and the secondary endpoints are disease-free survival, overall survival, objective response rate, major pathological response rate and R0 resection rate.

Ethics and dissemination Written informed consent will be required from all patients enrolled, and it will be provided by them. The study protocol received approval from the independent ethical review committee of Guangxi Medical University Cancer Hospital, Wuming Hospital of Guangxi Medical University and Wuzhou Red Cross Hospital, Wuzhou Gongren Hospital (approval number: CS2021(96)). We will submit the finalised paper for publication on completing the analyses. This study will provide valuable insights to clinicians regarding the safety and efficacy of incorporating fruquintinib into SOX as neoadjuvant treatment for locally advanced GC/GEJ. The findings have the potential to inform future research proposals and may guide the use of fruquintinib in the neoadjuvant setting for locally advanced GC/GEJ.

Trial registration number NCT05122091.

  • Gastrointestinal tumours
  • CHEMOTHERAPY
  • SURGERY
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

STRENGTHS AND LIMITATIONS OF THIS STUDY

  • This is the first multicentre, single-arm, open-label, prospective phase II trial to evaluate the usage of fruquintinib in the neoadjuvant setting for locally advanced gastric cancer/gastro-oesophageal junction adenocarcinoma.

  • This study will assess clinically relevant intermediate outcomes, including the rate of pCR and toxicities, along with additional outcomes including disease-free survival, overall survival, objective response rate, major pathological response rate and R0 resection rate.

  • One limitation of our study is that open-label design may introduce bias in the assessment of outcomes.

Introduction

The annual estimate of newly diagnosed gastric cancer (GC) or gastro-oesophageal junction adenocarcinoma (GEJ) is approximately 1 000 000, making it the second most common cause of cancer-related death globally, with an annual death toll of 770 000.1 At the time of diagnosis, two-thirds of patients present with locally advanced disease, and their prognosis is notably poor. To enhance the outlook for these patients, neoadjuvant chemotherapy (NCT) emerges as a preferable option, allowing for maximal systemic therapy delivery, tumour downstaging, micrometastases eradication and avoidance of futile resection.2

The UK MAGIC trial marked a pivotal milestone by demonstrating the survival advantages of perioperative chemotherapy combined with surgery over surgery alone in resectable GC, with a 5-year survival of 36% vs 23%.3 The epirubicin, cisplatin and fluorouracil (ECF) regimen, comprising epirubicin, cisplatin and fluorouracil was initially used. However, due to the suboptimal of the anthracycline epirubicin, it is no longer recommended in modern NCT.4 Lately, the FLOT-AIO trial revealed that perioperative FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) surpasses ECF, achieving superior overall survival (OS) (median OS, 50 vs 35 months). Despite concerns about the three-drug regimen’s toxicity, FLOT has emerged as the new standard in NCT. For less fit patients, a fluoropyrimidine plus platinum doublet regimen is preferred. Thus, clinical guidelines widely recommend NCT for patients with locally advanced GC/GEJ.5 6

Nevertheless, several unresolved issues persist concerning neoadjuvant therapy, including the optimal regimen, the role of human epidermal growth factor 2-targeted agents, immunotherapy and vascular endothelial growth factor (VEGFR) inhibition. Hence, ongoing research explores the integration of these agents in combination with NCT in the perioperative setting.

A single-arm phase II trial evaluated the efficacy and safety of S-1, oxaliplatin and apatinib (SOXA) in locally advanced GC, showing a 79.3% objective response rate (ORR) and a 13.8% pathological complete rate in 29 patients. SOXA followed by surgery demonstrated favourable activity and manageable safety.7 Another non-randomised controlled trial assessed apatinib plus chemotherapy as neoadjuvant treatment for 48 locally advanced GC patients, revealing an R0 resection rate of 75.0% and a pathological response rate of 54.2% with tolerable toxicity.8 Additionally, a randomised controlled trial evaluating chemotherapy and apatinib in the neoadjuvant treatment for locally advanced GC/GEJ is ongoing (NCT04208347).

Fruquintinib is an orally available VEGFR inhibitor that blocks new blood vessel growth associated with tumour proliferation.9 It is a potent, highly selective small-molecule inhibitor of VEGFR-1, VEGFR-2 and VEGFR-3.10 In the FRESCO trial, fruquintinib improved both OS and progression-free survival (PFS) compared with placebo in mCRC. Fruquintinib showed many advantages, such as low off-target toxicity, good drug tolerance and strong effects.11 Following this success, fruquintinib received its first global approval from the China Food and Drug Administration in 2018 for metastatic CRC treatment. The FRESCO-2 study further demonstrated the efficacy of fruquintinib plus best supportive care in refractory mCRC, meeting its primary endpoint of improved OS and PFS.12

Fruquintinib is now under investigation in GC and other solid tumours. The FRUTIGA study, a randomised, double-blind, phase III trial, is evaluating the efficacy and safety of fruquintinib combined with paclitaxel for advanced GC/GEJ patients who did not respond to first-line standard chemotherapy (NCT03223376).

However, limited evidence supports the use of fruquintinib combined with chemotherapy in neoadjuvant treatment. To address this gap, this phase-II FRUTINEOGA trial aims to assess the safety and efficacy of fruquintinib plus SOX for locally advanced GC/GEJ in the neoadjuvant setting, providing crucial evidence for optimal neoadjuvant treatment in these patients.

Methods and analysis

Study design

FRUTINEOGA is a phase II, multicentre, single-arm, open-label clinical trial to evaluate the efficacy and safety of fruquintinib plus SOX as neoadjuvant treatment for locally advanced GC/GEJ. All eligible patients will receive 2–4 cycles of neoadjuvant treatment with SOX plus fruquintinib, followed by surgery and adjuvant chemotherapy with SOX for 4–6 cycles. The study design is outlined in figure 1. Surgical procedures are documented according to the Japanese Gastric Cancer Treatment Guidelines 2018 (fifth edition).13 Tumour response is documented following the Response Evaluation Criteria in Solid Tumours guideline (V.1.1).14 Adverse events are monitored and documented based on the NCI-Common Terminology Criteria for Adverse Events V.5.0.15 Performance status is documented following Eastern Cooperative Oncology Group criteria. Any serious adverse events are defined in line with good clinical practice rules, promptly reported to the lead centre (Guangxi Medical University Cancer Hospital) and subsequently communicated to other participating centres.

Figure 1

Participant flow diagram. ECOG, Eastern Cooperative Oncology Group; GC, gastric cancer.

Patients

Eligibility criteria and exclusion criteria

Patients with initially resectable locally advanced GC/GEJ, presenting a clinical stage of cT3/4aN+M0 and who have not received antineoplastic therapy are eligible for enrolment. GC staging adheres to the tumour, node, metastasis (TNM) staging The American Joint Committee on Cancer eighth Edition. The eligibility and exclusion criteria for this trial are listed in boxes 1 and 2, respectively.

Box 1

Eligibility criteria

  1. Fully understand the study and voluntarily sign the informed consent form.

  2. Ages 18–75 (including 18 and 75).

  3. Pathologically confirmed resectable or potentially resectable locally advanced gastric/gastro-oesophageal junction adenocarcinoma (cT3/4aN+M0).

  4. If bone metastasis is suspected, bone scanning should be performed. If peritoneal metastasis is suspected, laparoscopy should be performed, and distant metastasis should be excluded.

  5. ECOG physical condition 0–1 points and no deterioration within 7 days days.

  6. BMI≥18 kg/m2.

  7. Expected survival ≥12 months.

  8. Have not received any antitumour treatment in the past (such as radiotherapy, chemotherapy, targeted therapy, immunotherapy).

  9. The functions of important organs meet the following requirements (no blood components and cell growth factors are allowed to be used within 14 days before enrolment).

    1. Absolute neutrophil count ≥1.5×109/L, leucocyte ≥4.0×109/L.

    2. Platelet ≥100×109/L.

    3. Haemoglobin ≥90 g/L.

    4. TBIL ≤1.5 times ULN.

    5. ALT and AST ≤2.5 times ULN.

    6. Urea/urea nitrogen (BUN) and creatinine ≤1.5 times ULN (and creatinine clearance rate ≥50 mL/min).

    7. Left ventricular ejection fraction ≥50%.

    8. Fridericia corrected QT interval (QTcF) <470 ms.

    9. INR ≤1.5 times ULN, APTT≤1.5 times ULN.

  10. Women of childbearing age need to take effective contraceptive measures.

  • ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate transaminase; BMI, body mass index; BUN, blood urea nitrogen; ECOG, Eastern Cooperative Oncology Group; TBIL, total bilirubin; ULN, upper limit of normal.

Box 2

Exclusion criteria

  1. Failure to follow the protocol or procedure.

  2. Previous treatment with VEGFR inhibitors.

  3. Known HER-2 positive patients.

  4. Live vaccine inoculation within 4 weeks before enrolment or possibly during the study period.

  5. Other malignant tumours within 5 years before enrolment, except skin basal cell or squamous cell carcinoma after radical surgery or cervical carcinoma in situ.

  6. Active autoimmune disease or history of autoimmune disease within 4 weeks before enrolment.

  7. Have received allogeneic bone marrow transplantation or organ transplantation in the past.

  8. Serious cardiovascular disease, including unstable angina or myocardial infarction, occurred within 6 months before enrolment.

  9. Subjects allergic to the research drug or any adjuvant thereof.

  10. Distant metastasis of any part.

  11. Participated in clinical trials of other drugs that have not been approved or marketed in China within 4 weeks before enrolment and received corresponding experimental drug treatment.

  12. Investigator judges clinically significant electrolyte abnormalities.

  13. There was hypertension that could not be controlled by drugs before enrolment, which was defined as: systolic blood pressure ≥150 mm Hg and/or diastolic blood pressure ≥90 mm Hg.

  14. There is any disease or state affecting drug absorption before enrolment, or the patient cannot take the drug orally.

  15. There were active gastric and duodenal ulcers, ulcerative colitis and other gastrointestinal diseases or active bleeding of unresectable tumours before enrolment, or other conditions that may cause gastrointestinal bleeding and perforation as determined by the researcher.

  16. Patients with obvious evidence of bleeding tendency or medical history within 3 months before enrolment (bleeding >30 mL within 3 months, accompanied by haematemesis, melena and haematochezia), haemoptysis (fresh blood >5 mL within 4 weeks), or thromboembolism events (including stroke events and/or transient ischaemic attacks) within 12 months.

  17. Cardiovascular diseases with significant clinical significance, including but not limited to acute myocardial infarction, severe/unstable angina pectoris or coronary artery bypass grafting within 6 months before enrolment; Congestive heart failure New York Heart Association grade >2; ventricular arrhythmias requiring medication; LVEF<50%.

  18. Active or uncontrolled serious infection (≥CTCAE V.5.0 infection grade 2).

  19. Known HIV infection. A known history of liver disease with clinical significance, including viral hepatitis (people who are known to be carriers of hepatitis B virus (HBV) must exclude active HBV infection, ie, HBV DNA positive (>1×104 copies/mL or >2000 IU/mL); known hepatitis C virus infection (HCV) and HCV RNA positive (>1×103 copies/mL).

  20. Unrelieved toxic reaction caused by any previous anticancer treatment higher than CTCAE V.5.0 grade 1 or above, excluding alopecia, lymphopenia and oxaliplatin induced neurotoxicity ≤grade 2.

  21. Pregnancy (positive pregnancy test before medication) or lactating women.

  22. Blood transfusion treatment, blood products and haematopoietic factors, such as albumin and granulocyte colony stimulating factor, were received within fourteen days before enrolment.

  23. Any other disease, clinically significant metabolic abnormality, physical examination abnormality or laboratory examination abnormality, according to the judgement of the investigator, it is reasonable to suspect that the patient has a certain disease or state that is not suitable for the use of the study drug (such as epilepsy and need treatment), or will affect the interpretation of the study results, or put the patient at high risk.

  24. Routine urine test indicates that urinary protein ≥2+ and 24-hour urinary protein volume >1.0 g.

  • CTCAE, Common Terminology Criteria for Adverse Event; HER-2, human epidermal growth factor 2; LVEF, left ventricular ejection fraction; VEGFR, vascular endothelial growth factor.

Recruitment

Patients are recruited and screened from Guangxi Medical University Cancer Hospital, Wuming Hospital of Guangxi Medical University, Wuzhou Red Cross Hospital and Wuzhou GongRen Hospital from November 2021. Oncologists will assess and evaluate patients based on the eligibility and exclusion criteria. Following this, patients will be provided with an information sheet and asked to offer written consent. Patients have the right to withdraw from the study at any time and for any reason.

Neoadjuvant treatment

All eligible patients will be registered and enrolled to undergo two courses of neoadjuvant treatment. The initial neoadjuvant treatment will commence within 14 days after registration. Fruquintinib will be orally administered once daily at a dose of 5 mg during days 1–14 of a 21-day cycle. Oxaliplatin, at a dose of 130 mg/m2, will be intravenously administered on day 1 every 3 weeks. S-1 will be orally administered twice a day, with the dosage determined by the patient’s body surface area (<1.25 m2, 80 mg; ≥1.25 to <1.5 m2, 100 mg; ≥1.5 m2, 120 mg/day) on days 1–14 of a 21-day cycle. After the completion of two courses of treatment, a tumour response evaluation will be conducted. Patients displaying progressive disease will discontinue neoadjuvant treatments, while others will receive another 1–2 courses of treatment.

In the event of specific adverse events, such as grade 2 bleeding, grade 2 hand-foot skin reaction, recurrent oral mucositis, grade 2 thrombocytopaenia (50–75×109/L), 24-hour urine protein quantification ≥2.0 g and any grade 3 or grade 4 adverse reactions (excluding those necessitating permanent drug withdrawal), the use of fruquintinib will be temporarily suspended. If the adverse reaction recovers to ≤1 level within 2 weeks of drug suspension, the dosage of fruquintinib will be reduced. However, certain severe adverse events, such as grade 3 or higher bleeding, gastrointestinal perforation, wound dehiscence requiring clinical treatment, fistula, nephrotic syndrome, hypertension crisis, grade 4 liver function abnormality or damage (transaminase >20 times the upper limit of normal value), intolerable dose of 3 mg per day, drug suspension for more than 2 weeks, adverse reactions still not recovered to ≤grade 1, etc, will result in the permanent discontinuation of fruquintinib usage.

Surgery

On confirming the feasibility of R0 resection through image evaluation following the final neoadjuvant treatment, gastrectomy with ≥D2 lymph node dissection is scheduled to be performed within 42 days (preferably within 28 days) from the last administration of fruquintinib in the final course. If R0 resection proves unattainable or if distant metastases, including peritoneal metastases (P1), hepatic metastases (H1) and positive peritoneal cytology (CY1), are identified during surgery, the protocol treatment will be halted.

Postoperative treatment

Postoperative SOX chemotherapy is set to commence within 42 days after surgery, spanning eight cycles of perioperative treatment. Patients with distant metastases detected during surgery will be referred to a multidisciplinary team for further treatment recommendations.

Follow-up

All patients will undergo follow-up assessments every 3 months (±7 days) for survival/follow-up antitumour treatment within the first year after the end of treatment. Subsequently, follow-up appointments will occur every 6 months (±7 days) after the first year, continuing until recorded as death, loss of interview, withdrawal of informed consent, and refusal to continue providing information, or the conclusion of the entire trial. Tumour evaluation will primarily use imaging, with options for additional methods such as ultrasonic gastroscope, PET-CT, etc, if deemed necessary. For patients who discontinue the study and treatment for reasons other than disease progression or death, tumour evaluation will follow the original plan until the disease progresses. The overall duration of this trial is anticipated to be 3 years.

Outcome measures

The primary endpoint is the pathological remission rate (pRR), determined by the Japanese Classification of Gastric Cancer (JCGC) V.3 standard.16 pRR is defined as the proportion of patients with <2/3 residual tumour lesions (grades 1b, 2, 3) in surgical specimens compared with baseline. The histological evaluation criteria for tumour response after preoperative therapy are shown in table 1.

Table 1

Histological evaluation criteria of tumour response after preoperative therapy

Secondary endpoints include disease-free survival, OS, ORR, major pathological response rate (MPR) and R0 resection rate. MPR is specifically defined as the proportion of patients with less than 10% residual carcinoma cells in the specimen.

Sample size calculation

Given the absence of large phase III research data on the pRR after neoadjuvant treatment for locally advanced GC, a study using the neoadjuvant SOX scheme revealed a pRR of 50.0%.17 The null hypothesis posits that the pRR from the fruquintinib plus SOX regimen could reach 70%. With one-sided α=0.05, 1–β= 0.8, registration period of 3 years and follow-up period of 3 years, at least 47 patients are required for sampling. Accounting for a 10% drop-out rate, the total sample size is 53 patients.

Statistical analysis

The primary endpoint involves the proportion of TRG 1b–3 in patients receiving SOX+fruquintinib, which will be analysed based on the intention-to-treat (ITT) population. Descriptive statistics will be used for clinicopathological characteristics and safety evaluation. Mean values and SD will be provided for continuous endpoints, while frequency and percentage distributions will be presented for discrete data. Kaplan-Meier methodology will estimate PFS and OS in the ITT population. Univariate and multivariate survival analyses will use the Cox proportional hazard model, with HRs and 95% CI calculated. Statistical analyses will employ SPSS V.25.0 software (IBM) and R software V.3.6.2 (http://www.R-project.org). The significance level is set at p<0.1, and all statistical tests will be two sided.

Management and quality control

The lead centre will organise periodical training in gastroscopy, enhanced Computed Tomogram (CT), Endoscopic Ultrasound (EUS), pathological examination, staging and response evaluation. Central reviews for observation and evaluation will be independently conducted. The clinical research assistant will independently assess protocol compliance, study safety and data collection accuracy. This monitoring will occur annually.

Ethics and dissemination

All personnel involved in conducting the current study are committed to adhering to the latest Declaration of Helsinki and Ethical Guidelines for Clinical Studies. The study protocol has received approval from the independent ethical review committee of Guangxi Medical University Cancer Hospital, Wuming Hospital of Guangxi Medical University, Wuzhou Red Cross Hospital and Wuzhou GongRen Hospital (approval number: CS2021(96)). Before enrolment, written informed consent will be obtained from all patients. We will submit the finalised paper for publication on completing the analyses.

Discussion

This study is the first phase II, single-arm, open-label study to evaluate the efficacy and safety of fruquintinib plus SOX as neoadjuvant treatment for patients with locally advanced GC. Fruquintinib’s overall well tolerance in patients and low potential for drug interactions, as per preclinical assessment, suggests its potential suitability for combining with other antineoplastic therapies.18

Two trials assessed fruquintinib in GC. The first, a single-arm phase I/II trial (NCT02415023), aimed to determine fruquintinib’s pharmacokinetics and efficacy in combination with paclitaxel.19 20 The other trial, FRUTIGA (NCT03223376), a multicentre, randomised, double-blind phase III trial, further evaluated the efficacy and safety of fruquintinib with paclitaxel versus paclitaxel alone in second-line treatment of advanced GC. The FRUTIGA study indicates that fruquintinib plus paclitaxel demonstrated promising PFS outcomes in second-line GC, though no significant improvement in OS was observed.

The primary endpoint for this study is the pRR for several reasons: tumour regression is deemed as a proper endpoint for neoadjuvant trials in GC21; employing pRR helps mitigate the impact of surgery and postoperative chemotherapy on the endpoint; and it allows for quicker attainment of primary results.

To avoid bias, uniform inclusion and exclusion criteria will be applied. For optimal follow-up, investigators will keep timely and effective contact with patients. Radiologists, endoscopists and pathologists will not participate in the intervention to ensure impartiality.

To the best of our knowledge, this study represents the first phase II, single-arm, multicentre trial aimed at assessing the efficacy and safety of fruquintinib plus SOX as neoadjuvant treatment for locally advanced GC. It directly addresses a significant clinical need for effective neoadjuvant treatments in locally advanced GC, offering valuable insights into a novel therapeutic approach. If the defined endpoints are met, we plan to conduct a further randomised controlled study to confirm fruquintinib plus SOX as an alternative and highly effective neoadjuvant treatment for locally advanced GC. However, the study has some weaknesses. Being a phase II, single-arm trial, the sample size and scope may limit the generalisability of the findings, necessitating larger and more diverse populations to establish broader applicability. Additionally, the lack of a comparative group could pose challenges in attributing observed effects specifically to the fruquintinib plus SOX combination. The current study’s focus on short-term outcomes may not fully capture the long-term efficacy and safety profile of the neoadjuvant regimen.

Ethics statements

Patient consent for publication

Acknowledgments

The authors are grateful to the patients participating in this study and their families.

References

Footnotes

  • Contributors The concept of the trial was proposed and designed by YQ and LW. TW, HY, MH and QJ prepared the manuscript. LW, HY and WW contributed to the statistical analysis. YQ is the corresponding author and checked the manuscript. All authors read and finally approved the manuscript.

  • Funding The present study is funded by Hutchison China MediTech and is supported by National Natural Science Foundation of China (No.82360593) and National Natural Science Foundation of Guangxi (No.2023GXNSFAA026133).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.