Ignite Creation Date:
2024-10-25 @ 8:02 PM
Last Modification Date:
2024-10-26 @ 3:39 PM
Study NCT ID:
NCT06576921
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-08-26
Brief Title:
Efficacy and Safety of Serplulimab Combined With Chemotherapy as Neoadjuvant Treatment for Locally Advanced Gastric Cancer or Adenocarcinoma of Esophagogastric Junction
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Efficacy and Safety of Serplulimab Combined With Nab-paclitaxel and SOX as Neoadjuvant Treatment for Locally Advanced Gastric Cancer or Adenocarcinoma of Esophagogastric Junction A Multicenter Randomized Controlled Trial
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 AEGGC 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 AEGGC 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 AEGGC
Participants will
Eligible patients were randomly assigned to receive serlulimab 45 mg intravenously on day 1 combined with chemotherapy nap-paclitaxel 260 mgm2 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
The goal of this clinical trial is to learn if serlulimab combined with nab-paclitaxel plus SOX as neoadjuvant treatment for locally advanced AEGGC 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 AEGGC 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 AEGGC
Participants will
Eligible patients were randomly assigned to receive serlulimab 45 mg intravenously on day 1 combined with chemotherapy nap-paclitaxel 260 mgm2 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 worlds 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 679000 new cases of gastric cancer in China and 498000 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 Hpylori 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 30-607-8 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 patients sensitivity to chemotherapy drugs and therefore predict a patients 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 9288 and the proportion of D2 lymph node dissection 9559 showed an increasing trend The R0 removal rates of group A and group B were 8647 and 8783 respectively In patients with locally advanced gastric cancer SOX chemotherapy during perioperative period improved 3-year disease-free survival 6202 vs 5478 P0045 HR079 95CI 062-099 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 P004 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 7014 and the R0 resection rate was significantly improved compared with surgery alone 86 vs 55 P0011 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 755 and R0 removal rate of 878 Chinese researchers have found 16 that SOX neoadjuvant application in advanced gastric cancer has an ORR of 685 and the R0 removal rate is also significantly higher than that of operation alone 813vs 735 P0040 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 ECFECX in terms of R0 removal rate 85 vs 78 P00162
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 B7CD28 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 CD8T cells bind to activate the PD-1PD-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-1PD-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 gastricgastroesophageal junctional adenocarcinoma The randomized ratio was 11 and the median OS follow-up was not reached in the FAS population NR 119 NR and NR 112 NR respectively Median PFS were 97 months 58-NR and 106 months 56-125 respectively The ORR of Nivolumab combined with SOX was 571 and that of Nivolumab combined with XELOX was 765
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 600 including 733 ORR in the PD-LI positive group and 375 ORR in the PD-LI negative group with a median OS of 138 months 86-NR The median PFS was 66 months 59-106 In cohort 3 31 PD-L1 positive CPS1 patients who received Pembrolizumab monotherapy had an ORR of 258 a median OS of 207 months 92-207 and a median PFS of 33 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 PC and placebo combined with chemotherapy in group 3 C had primary endpoints of PFS in people with PD-L1 CPS1 and OS in people with PD-L1 CPS1 and CPS10 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 CPS1 the ORR in group P vs group C vs group PC was 148 vs 372 vs 486 In patients with CPS10 the ORR in group P vs C vs PC was 250 vs 378vs 528 In terms of safety the P vs C group had better safety with the incidence of any grade of AE in the PC 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 58 months vs53 months HR060 P 00001 and the median OS was 153 months vs 118 months HR068 P00020 Among those with PD-L1 CPS10 the median PFS for both groups was 71 months vs 53 months HR048 P 00001 and the median OS was 186 months vs 139 months HR059 P00082 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 AEGGC
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 Hpylori 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 30-607-8 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 patients sensitivity to chemotherapy drugs and therefore predict a patients 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 9288 and the proportion of D2 lymph node dissection 9559 showed an increasing trend The R0 removal rates of group A and group B were 8647 and 8783 respectively In patients with locally advanced gastric cancer SOX chemotherapy during perioperative period improved 3-year disease-free survival 6202 vs 5478 P0045 HR079 95CI 062-099 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 P004 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 7014 and the R0 resection rate was significantly improved compared with surgery alone 86 vs 55 P0011 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 755 and R0 removal rate of 878 Chinese researchers have found 16 that SOX neoadjuvant application in advanced gastric cancer has an ORR of 685 and the R0 removal rate is also significantly higher than that of operation alone 813vs 735 P0040 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 ECFECX in terms of R0 removal rate 85 vs 78 P00162
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 B7CD28 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 CD8T cells bind to activate the PD-1PD-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-1PD-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 gastricgastroesophageal junctional adenocarcinoma The randomized ratio was 11 and the median OS follow-up was not reached in the FAS population NR 119 NR and NR 112 NR respectively Median PFS were 97 months 58-NR and 106 months 56-125 respectively The ORR of Nivolumab combined with SOX was 571 and that of Nivolumab combined with XELOX was 765
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 600 including 733 ORR in the PD-LI positive group and 375 ORR in the PD-LI negative group with a median OS of 138 months 86-NR The median PFS was 66 months 59-106 In cohort 3 31 PD-L1 positive CPS1 patients who received Pembrolizumab monotherapy had an ORR of 258 a median OS of 207 months 92-207 and a median PFS of 33 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 PC and placebo combined with chemotherapy in group 3 C had primary endpoints of PFS in people with PD-L1 CPS1 and OS in people with PD-L1 CPS1 and CPS10 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 CPS1 the ORR in group P vs group C vs group PC was 148 vs 372 vs 486 In patients with CPS10 the ORR in group P vs C vs PC was 250 vs 378vs 528 In terms of safety the P vs C group had better safety with the incidence of any grade of AE in the PC 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 58 months vs53 months HR060 P 00001 and the median OS was 153 months vs 118 months HR068 P00020 Among those with PD-L1 CPS10 the median PFS for both groups was 71 months vs 53 months HR048 P 00001 and the median OS was 186 months vs 139 months HR059 P00082 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 AEGGC
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None