Trial Title:
Efficacy and Safety of Serplulimab Combined With Chemotherapy as Neoadjuvant Treatment for Locally Advanced Gastric Cancer or Adenocarcinoma of Esophagogastric Junction
NCT ID:
NCT06576921
Condition:
Stomach Neoplasms
Immune Checkpoint Inhibitors
Conditions: Official terms:
Adenocarcinoma
Stomach Neoplasms
Esophageal Neoplasms
Paclitaxel
Albumin-Bound Paclitaxel
Oxaliplatin
Conditions: Keywords:
Gastric cancer
Adenocarcinoma of Esophagogastric junction cancer
PD-1 antibody
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
This study employed block randomization to allocate subjects in a 1:1 ratio to either the
experimental or control group. To ensure balance in sample size between the groups, the
randomization sequence was generated using SAS 9.4 software. The randomization list was
generated by an independent statistician and securely stored in a password-protected
computer system, with corresponding envelopes prepared.
Primary purpose:
Treatment
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Masking description:
During the study, the subjects, the investigator, the sponsor, and the designees are not
aware of the randomized allocation, except in the event of emergency unblinding. During
the course of treatment with the study drug, if the investigator determines that the
study drug is related to a life-threatening situation of the subject, and the
investigator considers that knowing the medication of the subject is conducive to the
handling of adverse events, an emergency unblinding is allowed. Two sets of sealed blind
envelopes were prepared. In the event of an emergency unblinding, the identification
number will be used to open the retained envelope to complete the unblinding process.
Intervention:
Intervention type:
Drug
Intervention name:
Serplulimab Combined With Chemotherapy
Description:
Serplulimab (Dosage form: Lyophilized powder; Unit dose strength: 4.5 mg; Route of
administration: IV infusion; Storage requirements: 2-8℃. Protect from light and
freezing.) Nap-paclitaxel (Dosage form: Lyophilized powder; Unit dose strength: 100 mg;
Route of administration: IV infusion; Storage requirements: <25℃. Protect from light.)
S-1 (Dosage form: Capsule; Unit dose strength: 20 mg; Route of administration: Oral;
Storage requirements: 20-30℃. Protect from light.) Oxaliplatin (Dosage form: Lyophilized
powder; Unit dose strength: 50 mg; Route of administration: IV infusion; Storage
requirements: <25℃. Protect from light.) Surgery: All surgical procedures are performed
according to the guidelines of the Japanese Research Society for the Study of Gastric
Cancer.
Arm group label:
S-P-SOX group
Other name:
Nap-paclitaxel
Other name:
S-1
Other name:
Oxaliplatin
Other name:
surgery
Intervention type:
Drug
Intervention name:
Placebo combined with Chemotherapy
Description:
Placebo (Dosage form: Lyophilized powder; Unit dose strength: 4.5 mg; Route of
administration: IV infusion; Storage requirements: 2-8℃. Protect from light and
freezing.) Nap-paclitaxel (Dosage form: Lyophilized powder; Unit dose strength: 100 mg;
Route of administration: IV infusion; Storage requirements: <25℃. Protect from light.)
S-1 (Dosage form: Capsule; Unit dose strength: 20 mg; Route of administration: Oral;
Storage requirements: 20-30℃. Protect from light.) Oxaliplatin (Dosage form: Lyophilized
powder; Unit dose strength: 50 mg; Route of administration: IV infusion; Storage
requirements: <25℃. Protect from light.) Surgery: All surgical procedures are performed
according to the guidelines of the Japanese Research Society for the Study of Gastric
Cancer.
Arm group label:
P-SOX group
Other name:
Nap-paclitaxel
Other name:
S-1
Other name:
Oxaliplatin
Other name:
surgery
Summary:
This is a multicenter, double-blind, randomized, phase 2 trial to investigate the
efficacy and safety of serlulimab combined with nab-paclitaxel plus SOX versus
nab-paclitaxel plus SOX alone as neoadjuvant treatment for locally advanced GC or AEG.
The goal of this clinical trial is to learn if serlulimab combined with nab-paclitaxel
plus SOX as neoadjuvant treatment for locally advanced AEG/GC. It will also learn about
the safety of serlulimab combined with nab-paclitaxel plus SOX. The main questions it
aims to answer are:
Does serlulimab increase the pCR of participants with locally advanced AEG/GC ? What
medical problems do participants have when taking serlulimab? Researchers will compare to
a placebo (a look-alike substance that contains no drug) to see if serlulimab combined
with nab-paclitaxel plus SOX as neoadjuvant treatment for locally advanced AEG/GC.
Participants will:
Eligible patients were randomly assigned to receive serlulimab (4.5 mg intravenously on
day 1) combined with chemotherapy (nap-paclitaxel 260 mg/m2 intravenously on days 1, OXA
130mg/ /m2, intravenously on days 1, and S-1 40 to 60 mg orally twice daily depending on
BSA on days 1 to 14) or chemotherapy alone every 3 weeks for 3 preoperative cycles
followed by 3 postoperative cycles. All patients will be followed for survival.
Detailed description:
Gastric Cancer (GC) is the fifth most common malignancy globally and the third leading
cause of cancer death. Half of the world's cases occur in eastern Asia [1], which has the
highest mortality rate. According to the latest data released by the National Tumor
Registration Center, it is estimated that in 2015, there were 679,000 new cases of
gastric cancer in China, and 498,000 deaths, ranking second in both incidence and
fatality rate among malignant tumors [2]. The overall prognosis is poor, posing a serious
threat to human health.
Environmental and genetic factors play an important role in the development of gastric
cancer, with common risk factors including age, male gender, smoking, radiation and
family history. Specific risk factors for gastric cancer include Helicobacter pylori
infection and dietary factors [3]. Helicobacter pylori (H.pylori) infection often leads
to chronic gastritis, gastric atrophy, and then intestinal metaplasia, abnormal
hyperplasia and gastric cancer [4-6]. Dietary factors include low intake of fruits and
vegetables, high salt, and intake of smoked foods.
Radical surgical resection is still the main treatment for non-metastatic gastric cancer,
but the postoperative recurrence and metastasis rate is as high as 40-80%, and the 5-year
survival rate is 30-60%[7-8]. The treatment mode of neoadjuvant chemotherapy + surgery +
adjuvant chemotherapy (perioperative treatment) is an important part of the comprehensive
treatment of gastric cancer at present. A number of studies have proved that compared
with surgery alone, this treatment mode can reduce the tumor stage, increase the R0
resection rate, and improve the overall survival, without increasing postoperative
complications and mortality. The purpose of neoadjuvant chemotherapy is to reduce tumor
load and increase the possibility of R0 resection [9], so as to improve the pathological
complete response rate. Neoadjuvant chemotherapy can measure a patient's sensitivity to
chemotherapy drugs and therefore predict a patient's response to subsequent chemotherapy.
At present, it has been confirmed that pathological complete response rate is correlated
with overall survival [10]. On September 28, 2019, at the ESMO Conference , Chinese
scholars announced the results of the RESOLVE Phase III study on perioperative treatment
of locally advanced gastric cancer [11], adding new evidence-based medical evidence for
perioperative treatment of such patients. The RESOLVE study is A three-arm, randomized,
multicenter, open-label Phase III trial comparing the efficacy and safety of using XELOX
(Group A) or SOX (Group B) after radical D2 surgery versus perioperative use of SOX
(group C). Finally, 1022 cases of ITT population were included in the analysis. In the
perioperative group (group C), the R0 resection rate (92.88%) and the proportion of D2
lymph node dissection (95.59%) showed an increasing trend. The R0 removal rates of group
A and group B were 86.47% and 87.83%, respectively. In patients with locally advanced
gastric cancer, SOX chemotherapy during perioperative period improved 3-year disease-free
survival (62.02% vs 54.78%, P=0.045, HR=0.79, 95%CI 0.62-0.99) compared with XELOX
adjuvant. Results of a multicenter Phase III clinical study in France [12] showed that
preoperative neoadjuvant chemotherapy with PF regimen significantly increased R0
resection rate compared with surgery alone (84% vs 73%, P=0.04). For initially treated
locally advanced gastroesophageal cancer, XELOX regimen has been proven to be as
effective as cisplatin combined with fluorouracil regimen [13]. Results of a Chinese
study showed that for patients with advanced gastric cancer, the ORR of neoadjuvant
chemotherapy with FOLFOX regimen was 70%[14], and the R0 resection rate was significantly
improved compared with surgery alone (86% vs 55%, P=0.011). A study from Japan showed
[15] that neoadjuvant chemotherapy with SP protocol is safe and effective for stage II
and III gastric cancer with lymph node metastasis, with ORR of 75.5% and R0 removal rate
of 87.8%. Chinese researchers have found [16] that SOX neoadjuvant application in
advanced gastric cancer has an ORR of 68.5%, and the R0 removal rate is also
significantly higher than that of operation alone (81.3%vs 73.5%, P=0.040). The results
of the recent FLOT4 study [17] showed that the perioperative regimen of 5-fluorouracil +
docetaxel + oxaliplatin + calcium folinate (FLOT) was superior to the perioperative
regimen of epirubicin + cisplatin + 5-fluorouracil or capecitabine (ECF/ECX) in terms of
R0 removal rate (85% vs 78%). P=0.0162).
At present, the recommended preoperative chemotherapy for gastric cancer mainly includes:
Epirubicin combined with Cisplatin and fluorouracil (ECF) and its modification, cisplatin
combined with fluorouracil (PF), oxaliplatin combined with capecitabine (XELOX),
oxaliplatin combined with fluorouracil (FOLFOX), Cisplatin combined with S-1 (SP),
oxaliplatin combined with S-1 (SOX), FLOT (5-fluorouracil + docetaxel + oxaliplatin +
calcium folinate).
As a highly heterogeneous malignant tumor, gastric cancer is an extremely complex process
in which the immune microenvironment plays an important role, and the inhibitory immune
microenvironment and immune escape have received more and more attention. programmed
death receptor-1 (PD-1) and programmed death ligand-1 (PD-L1) belong to the B7/CD28
superfamily and are very important negative co-stimulatory molecules discovered in recent
years. It can negatively regulate the activity of immune cells [18]. PD-1 is the main
immunosuppressive molecule on the surface of T cells and B cells. PD-1 has two ligands,
PD-L1 and PD-L2. PD-L1 is widely expressed in activated T cells, B cells, macrophages,
dendritic cells, and tumor cells. PD-L1 expressed by tumor cells and PD-1 expressed by
tumor Infiltrating Lymphocytes (TILs) (mainly CD8+T cells) bind to activate the
PD-1/PD-L1 signaling pathway and inhibit the activation of tumor infiltrating
lymphocytes. Reduced T cell reactivity leads to T cell incapacitated, induces T cell
apoptosis, provides a suitable microenvironment for the development of tumor cells,
mediates tumor immune escape, and promotes tumor growth [19]. Blocking the PD-1/PD-L1
signaling pathway can reverse the tumor immune microenvironment and enhance the
endogenous anti-tumor immune effect. PD-L1 is highly expressed in various solid malignant
tumors [20-21], including non-small cell lung cancer, melanoma, renal cell carcinoma,
prostate cancer, breast cancer, stomach cancer, etc., and its expression level varies
according to different tumor types. At present, the relationship between PD-L1 expression
and prognosis in gastric cancer is still controversial.
In December 2018, the Phase II trial results of the Asian Attract-04 study [22] were
published. The study was designed to explore the safety and efficacy of Nivolumab in
combination with SOX (Ticeo and oxaliplatin) or XELOX (capecitabine and oxaliplatin) in
first-line treatment of advanced, unresectable, or recurrent gastric/gastroesophageal
junctional adenocarcinoma. The randomized ratio was 1:1, and the median OS follow-up was
not reached in the FAS population (NR (11.9, NR) and NR (11.2, NR), respectively). Median
PFS were 9.7 months (5.8-NR) and 10.6 months (5.6-12.5), respectively. The ORR of
Nivolumab combined with SOX was 57.1%, and that of Nivolumab combined with XELOX was
76.5%.
In March 2019, the results of KEYNOTE-059 study [23] Cohort 2 and cohort 3 Phase II
clinical trials were published. The study cohort 2 and cohort 3 were designed to explore
the safety and efficacy of Pembrolizumab± chemotherapy in first-line treatment of
advanced gastric or gastroesophageal junction adenocarcinoma. In cohort 2, 25 patients
received Pembrolizumab combined with chemotherapy. All patients had an ORR of 60.0%,
including 73.3% ORR in the PD-LI positive group and 37.5% ORR in the PD-LI negative
group, with a median OS of 13.8 months (8.6-NR). The median PFS was 6.6 months
(5.9-10.6). In cohort 3, 31 PD-L1 positive (CPS≥1) patients who received Pembrolizumab
monotherapy had an ORR of 25.8%, a median OS of 20.7 months (9.2-20.7), and a median PFS
of 3.3 months.
At the American Society of Clinical Oncology Symposium (ASCO) in June 2019, Merck
presented the results of the KEYMAT-062 Phase III study [24], which randomized untreated
PD-L1-positive advanced gastric or gastroesophageal junction adenocarcinoma into three
groups, group 1 being Pembrolizumab monotherapy (Group P). Pembrolizumab combined with
chemotherapy in group 2 (P+C) and placebo combined with chemotherapy in group 3 (C) had
primary endpoints of PFS in people with PD-L1 CPS≥1 and OS in people with PD-L1 CPS≥1 and
CPS≥10. The results suggest that Pembrolizumab combined with chemotherapy is not superior
to chemotherapy for OS and PFS in any population. From the perspective of ORR alone, in
patients with CPS≥1, the ORR in group P vs group C vs group P+C was 14.8% vs 37.2% vs
48.6%; In patients with CPS≥10, the ORR in group P vs C vs P+C was 25.0% vs 37.8%vs
52.8%. In terms of safety, the P vs C group had better safety, with the incidence of any
grade of AE in the P+C vs C group being 94% vs 92%, and the incidence of grade 3-4 TRAE
being 71% vs 68%, with no unexpected adverse events.
On November 5, 2022, at the CSCO Annual Meeting, Professor Huang Jing reported on the
research related to the treatment of advanced esophageal cancer with Srulizumab -
ASTRO-007: In the whole population, the median PFS in the srulizumab and placebo groups
was 5.8 months vs5.3 months (HR=0.60, P < 0.0001), and the median OS was 15.3 months vs
11.8 months (HR=0.68, P=0.0020). Among those with PD-L1 CPS≥10, the median PFS for both
groups was 7.1 months vs 5.3 months (HR=0.48, P < 0.0001), and the median OS was 18.6
months vs 13.9 months (HR=0.59, P=0.0082). The study also confirmed the significance of
srulizumab combined with chemotherapy in the first-line treatment of advanced esophageal
cancer, especially in those with CPS > 10.
In other cancers, such as triple negative breast cancer and head and neck squamous cell
carcinoma, Pembrolizumab combined with neoadjuvant chemotherapy has shown promising
antitumor activity and clinical efficacy. At present, immunotherapy is also being
explored in the perioperative period of gastric cancer, such as the phase III clinical
study of KEYKEYNOTE 585 perioperative chemotherapy for gastric cancer combined with or
without PD-1 inhibitor, and the clinical study of mFOLFOX combined with PD-1 inhibitor
for the treatment of gastroesophageal conjoint adenocarcinoma or gastric adenocarcinoma
in perioperative period (NCT03488667), etc. In order to provide a new clinical thinking
for the treatment of locally advanced gastric cancer.
This is a multicenter, double-blind, randomized, phase 2 trial to investigate the
efficacy and safety of serlulimab combined with nab-paclitaxel plus SOX versus
nab-paclitaxel plus SOX alone as neoadjuvant treatment for locally advanced GC or AEG.
The goal of this clinical trial is to learn if serlulimab combined with nab-paclitaxel
plus SOX as neoadjuvant treatment for locally advanced AEG/GC.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Age older than 18 and younger than 75 years
- Primary GC or AEG (Siewert II/III)confirmed pathologically by endoscopic biopsy
- Clinical stage T3/T4N+M0 disease as assessed by CT/MRI, PET-CT, and laparoscopy, if
feasible
- At least one measurable lesion according to the RECIST, version 1.1
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Surgical treatment after neoadjuvant chemotherapy is planned according to clinical
staging criteria.
- Life expectancy of at least 3 months
- Acceptable bone marrow, hepatic, and renal function, including: a)Blood routine
examination(No blood transfusion within 14 days; No granulocyte colony-stimulating
factor (G-CSF) or other hematopoietic stimulating factors were used): white blood
cell count ≥3.5 ×109/L, neutrophils ≥1.5 × 109/L, platelet count >100 × 109/L, and
hemoglobin ≥90 g/L; b)Hepatic function: alanine aminotransferase (ALT) and aspartate
aminotransferase (AST), ALT and AST≤2.5×ULN; total bilirubin (TBIL) ≤1.5×ULN
(Gilbert syndrome patients, ≤3×ULN); c)Renal function: serum creatinine (Cr)
≤1.5×ULN or creatinine clearance (Ccr) ≥60mL/ min; d)Coagulation function: activated
partial thromboplastin time (APTT), international standardized ratio (INR),
prothrombin time (PT) ≤1.5×ULN;
- Written informed consent
Exclusion Criteria:
- Squamous cell carcinoma, adenosquamous cell carcinoma, small cell carcinoma, and
undifferentiated gastric cancer were confirmed by pathology
- Positive Her-2 detection (IHC3+ or IHC2+ amplified by FISH detection)
- Prior chemotherapy, radiotherapy, hormone therapy, targeted therapy, or
immunotherapy
- Contraindications for surgical treatment or chemotherapy
- Presence of distant metastasis
- History of other malignant disease within the past 5 years, except: basal cell
carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical
cancer that have been treated radically and have shown no signs of disease for at
least 5 years
- Any active or history of autoimmune disease, or history of syndrome that required
systemic steroids or immunosuppressive medications, except for subjects with
vitiligo or resolved childhood asthma/atopy
- History of immunodeficiency diseases, including human immunodeficiency virus (HIV),
or other acquired or congenital immune-deficient disease, or transplantation
- Severe mental disorder
- Presence of digestive tract obstruction, jaundice, acute infectious diseases,
inflammatory bowel disease, Crohn's disease, ulcerative colitis, chronic diarrhea,
active tuberculosis
- Immunosuppressive drugs are required for 2 weeks or within 2 weeks or during the
study period, excluding the following: a) intranasal, inhaled, topical or topical
steroid injections (e.g. intra-articular injections); b) Physiological dose of
systemic corticosteroids (≤10mg/ day prednisone or equivalent dose); c) Short-term
(≤7 days) use of steroids for the prevention or treatment of non-autoimmune allergic
diseases;
- Patients who have undergone major surgery or received live virus vaccine within 4
weeks
- Pregnant or breast-feeding women, subjects who are unwilling to receive effective
contraception during treatment and within 6 months after the end of treatment
(including male subjects who have the ability to impregnate women and female
subjects and their male partners)
- Evidence of bleeding tendency or receiving thrombolytics or anticoagulants
- According to the criteria of the term Common Adverse Events (NCI-CTCAE V5.0), the
corresponding symptoms have been diagnosed;
- Hepatitis B or hepatitis C virology tests at the time of screening meet any of the
following: a) HBsAg positive and HBV-DNA titer ≥104 copy number /mL or ≥2000IU/mL
(hepatitis B carriers should ask researchers for appropriate antiviral treatment);
b) Active hepatitis C: HCV antibody positive and HCV-RNA higher than the lower
detection limit of the assay;
- Allergic to study drugs
- The investigator believes that the subjects have other conditions that may affect
their adherence to the protocol and evaluation of the study indicators, and the
subjects are not suitable to participate in the study.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Start date:
September 1, 2024
Completion date:
September 30, 2025
Lead sponsor:
Agency:
Xijing Hospital
Agency class:
Other
Source:
Xijing Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06576921
