Trial Title:
Chemotherapy Sequential Tislelizumab After Radical Resection in Patients With dMMR/MSI-H or POLE/POLD1 Mutations
NCT ID:
NCT06118658
Condition:
Gastric
Colorectal Adenocarcinoma
Conditions: Official terms:
Adenocarcinoma
Tislelizumab
Conditions: Keywords:
radical resection
adjuvant therapy
gastric
colorectal adenocarcinoma
esophagogastric junction adenocarcinoma
dMMR/MSI-H or POLE/POLD1 mutations
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
About 30 patients who underwent radical gastrectomy or enterectomy with gastric
adenocarcinoma or esophagogastric junction adenocarcinoma with postoperative pathological
stage III or intestinal adenocarcinoma with postoperative pathological stage T1-3N2M0 or
T4N+M0(American Joint Committee on Cancer,AJCC 8th Edition Cancer Stage) were scheduled
to be enrolled after fully informed and signed informed consent Qualified subjects were
selected to receive the standard XELOX or SOX regimen selected by the investigators
according to the disease and postoperative pathology of the subjects for 4 cycles,
followed by the sequential treatment of monotherapy tislelizumab (200mg,Q3W, IV
infusion,4 cycles) starting from 4-6 weeks after surgery, with a maximum of 12 weeks
Safety assessments such as ECOG physical examination of vital signs and laboratory tests
will be performed regularly during treatment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
tislelizumab
Description:
About 30 patients who underwent radical gastrectomy or enterectomy with gastric
adenocarcinoma or esophagogastric junction adenocarcinoma with postoperative pathological
stage III or intestinal adenocarcinoma with postoperative pathological stage T1-3N2M0 or
T4N+M0(American Joint Committee on Cancer,AJCC 8th Edition Cancer Stage) were scheduled
to be enrolled after fully informed and signed informed consent Qualified subjects were
selected to receive the standard XELOX or SOX regimen selected by the investigators
according to the disease and postoperative pathology of the subjects for 4 cycles,
followed by the sequential treatment of monotherapy tislelizumab (200mg,Q3W, IV
infusion,4 cycles) starting from 4-6 weeks after surgery, with a maximum of 12 weeks
Safety assessments such as ECOG physical examination of vital signs and laboratory tests
will be performed regularly during treatment
Arm group label:
Chemotherapy-sequential tislelizumab adjuvant therapy
Summary:
Objective of this study to evaluate 1-year disease-free survival in patients with
dMMR/MSI-H or POLE/POLD1 gene mutations with gastric or esophagus-gastric junctional
adenocarcinoma or colorectal adenocarcinoma after chemotherapy-sequential tiralizumab
adjuvant radical resection (based on RECIST v1.1 criteria).
Detailed description:
Colorectal cancer and gastric cancer are common malignant tumors of digestive tract. The
latest statistical data show that the number of new cases of colorectal cancer and
gastric cancer in China ranks second and third among all malignant tumors, and the number
of death cases ranks fifth and third. They are one of the main cancers threatening the
life and health of Chinese residents, causing serious social burden In recent years,
immunotherapy represented by immune check point inhibitors (ICI) has made great progress
in the treatment of malignant tumors, among which programmed death receptor 1(pro grammed
death) 1,PD-1) antibody is the most widely used.
Microsatellite instablehigh (MSI-H) is highly unstable due to DNA mismatch
repairdeficient (dMMR) .The insertion or loss of the base pairs of microsatellite
fragments, the change of the length of microsatellite tandem repeats, and the emergence
of new microsatellite alleles are one of the mechanisms of tumor occurrence. Deficient
mismatch repair (dMMR)/ microsatellite instablehigh (MSI-H) is the first molecular marker
discovered to predict the efficacy of ICI treatment for pancancer .The emergence of ICI
therapy has brought the dawn for prolonging the survival time of patients with advanced
gastrointestinal tumors.Immune checkpoint inhibitors have shown satisfactory results in
patients with MSI-H/dMMR from late-stage to first-line therapy.A 2015 study by Le et
al.was the first to show that molecular phenotypic metastatic colorectal (mCRC) with
mismatch repair defects (dMMR) or high microsatellite instability (MSI-H) can benefit
significantly from the immune checkpoint PD-1 inhibitor pembrolizumab. Immune checkpoint
inhibitors have made significant progress in the treatment of the posterior line of
colorectal cancer.In KEYMAT-016, a pivotal study of MSI-H tumor immunotherapy, multiple
tumors of dMMR benefited from PD-1 monoclonal antibody Pbolizumab. For mCRC patients who
failed standard therapy, 7 out of 13 dMMR/MSI-H patients received pembrolizumab
monotherapy and achieved objective remission (62%) .All patients did not achieve median
progression-free time (PFS) and overall survival time (OS), and the KEYNOTE-164 study
further investigated dMMR/MSI-H The clinical benefit of pabolizumab in mCRC patients was
an objective response rate (ORR) of 32%(median follow-up 12.6 months) and 1-year
progression-free survival and overall survival were 41% 76%, respectively, among 63
previously treated patients in KEYMAT-164 Cohort B This study shows that MSI-H CRC
patients treated with pabolizumab have sustained anti-tumor effects even after first-line
therapy progresses.The KEYNOTE-059 trial, which included patients with metastatic
gastric/gastroesophageal junction tumors after second-line chemotherapy failure, showed
an ORR of 47%(3/7) in the MSI-H group compared to only 9%(15/167) in the non-MSI-H
group.In KEYNOTE 158, the ORR for MSI-H gastric cancer treated with pembrolizumab reached
45.8% (11/24 95% CI: 25.6% ~ 67.2%) .A number of subgroup analyses have shown that MSI-H
gastric cancer has advantages over chemotherapy in immunotherapy, and adverse drug
reactions are within the acceptable range. A number of PD-1/PD-L1 models have been
approved for the treatment of unresectable or metastatic MSI-H/dMMR solid tumors. Immune
checkpoint inhibitors not only show surprising efficacy in the posterior treatment of
patients with advanced tumors, but also have been confirmed as first-line treatment.
CheckMate142、KEYNOTE-177 study explored the efficacy of immunotherapy as first-line
treatment of bowel cancer, and both achieved promising OS and PFS results.KEYNOTE-177
MSI-H first-line patients treated with pembrolizumab for advanced colorectal cancer
significantly extended median PFS(16.5 months vs.8.2 months) and improved
ORR(43.8%vs.33.1%) compared to standard chemotherapy. This study also established the
position of immunotherapy in the first-line treatment of MSI-H advanced colorectal
cancer, further supporting the gradual push of immunotherapy from the back line treatment
to the front line treatment.
However, the role of immunotherapy in the adjuvant treatment of MSI-H/dMMR solid tumors
is still uncertain. No matter NCCN guidelines, ESMO guidelines or China's CSCO
guidelines, for postoperative adjuvant treatment of people with advantages of immune
benefit, observation or chemotherapy is recommended according to the stage and risk
factors. Based on the remarkable results achieved in previous studies, the role of
immunotherapy in MSI-H/dMMR adjuvant therapy for colon and gastric cancer is worthy of
expectation.
tislelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody, which is currently the
only PD-1 antibody modified by Fc segment. It removes the binding ability of FC-γR on the
surface of macrophages, does not mediate the cross-linking of immune cells, avoids the
ADCP effect to the greatest extent, avoids T cell consumption, and theoretically enhances
its anti-tumor activity. RATIONALE 209 study results show that patients with MSI-H
metastatic solid tumor who failed standard therapy receiving tislelizumab monotherapy can
also achieve an impressive objective response rate (ORR(mCRC :39%; G/GEJC :55.6%), the
security is controllable. tislelizumab has been approved by NMPA for the treatment of
urothelial carcinoma, non-small cell lung cancer, hepatocellular carcinoma, esophageal
squamous cell carcinoma, nasopharyngeal carcinoma, and highly microsatellite unstable
solid tumors.
POLE/POLD1 mutations encoding DNA polymerase are involved in the occurrence and
development of various tumors, and the mutation rate of POLE/POLD1 is about 7.4% in
colorectal cancer and 7.1% in esophageal cancer. Mutations in the gene encoding POLE and
POLD1 exonuclide region lead to loss of correction function, which is closely related to
tumor hypermutation, TMB elevation, neogenic antigen increase, and increased intra tumor
immune cell infiltration. Previous studies have shown that these are closely related to
good immune efficacy, which also indicates that POLE/POLD1 mutation is expected to become
a molecular marker for predicting the efficacy of ICI, a new pan-cancer species.
In summary,MSI-H/dMMR and POLE/POLD1 mutations are advantageous populations for
immunotherapy. The purpose of this study was to explore the efficacy and safety of
chemotherapy followed by tislelizumab for adjuvant treatment of gastric or
esophago-gastric junctional adenocarcinoma or colorectal adenocarcinoma in patients with
radical resection of dMMR/MSI-H or POLE/POLD1 mutations. To provide clinical guidance for
MSI-H/dMMR or POLE/POLD1 gene mutated colon and gastric cancer adjuvant therapy
modalities
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1.Be able to understand and voluntarily sign a written informed consent, which must be
signed prior to performing the specified study procedure required for the study 2.Age and
gender: ≥18 years old and≤75 years old, both men and women. 3.dMMR/MSI-H or POLE/POLD1
gene mutation was confirmed by immunohistochemical PCR or NGS 4.0-1 physical fitness
score by the Eastern United States Cancer Collaboration (ECOG)。 5. Expected survival is
12 weeks 6.Radical gastrectomy or enterectomy, including open surgery or laparoscopic
surgery, to achieve R0 resection (no residual cancer at the margin) 7.According to the
American Joint Committee on Cancer AJCC 8th Edition cancer stage, it was confirmed by
histopathology as gastric adenocarcinoma or esophagogastric junction adenocarcinoma or
intestinal adenocarcinoma, and the postoperative pathological stage of gastric
adenocarcinoma or esophagogastric junction adenocarcinoma was stage III; Patients with
postoperative pathological stage of intestinal cancer T1-3N2M0 or T4N+M0 8.No metastasis
or recurrence was determined based on images taken after surgery and within the first 28
days of randomization 9. Subjects are required to provide sufficient FFPE tumor tissue
specimens or sections for relevant testing 10.The functions of important organs must meet
the following requirements:
1. Hematological system（No blood component or cell growth factor was used to support
treatment within 7 days prior to the start of study therapy）:
Neutrophil count≥1.5×10^9/L; Platelet count≥100×10^9/L; Hemoglobin≥90g/L;
2. Liver function： Serum albumin≥28g/L; Total bilirubin (TBI)≤1.5×ULN; Alanine
aminotransferase (ALT)≤3×ULN Aspartate aminotransferase (AST)≤2.5×ULN
3. Renal function:
Serum creatinine ≤1.5×ULN Calculated creatinine clearance≥50 mL/min (using the
Cockcroft-Gault formula); Female: CrCl = (140- age in years) × weight in kg × 0.85
72 × serum creatinine in mg/ dL
Male: CrCl = (140- age in years) × weight in kg × 1.00 72 × serum creatinine in mg/
dL
4. Coagulation function:
Subjects not receiving anticoagulation therapy: INR or APTT ≤ 1.5×ULN;
5. Cardiac function: Left ventricular ejection fraction (LVEF)≥ 50 10. Fertile female
subjects must undergo a urine or serum pregnancy test within 3 days prior to the
first dosing (if the urine pregnancy test result is not confirmed negative, a serum
pregnancy test is required, depending on the serum pregnancy result), and the result
is negative If a fertile female subject has sex with an unsterilized male partner,
the subject must use a highly effective contraceptive method since screening and
must consent to continued use of the contraceptive method for 120 days after the
last administration of the study drug; Whether to stop contraception after this time
point should be discussed with the investigator 11.If an unsterilized male subject
has sex with a fertile female partner, the subject must use an effective
contraceptive method from the beginning of screening until the 120th day after the
last dose; Whether to stop contraception after this time point should be discussed
with the investigator.
12.Subjects were willing and able to comply with the schedule for visiting treatment
protocol laboratory tests and other study requirements.
Exclusion Criteria:
1. Subjects with other malignancies in the 5 years prior to enrolment do not exclude
subjects with other malignancies that have been cured by local treatment, such as
basal or skin squamous cell carcinoma superficial bladder cancer cervix or breast
carcinoma in situ
2. Have received non-surgical treatment for gastric/esophagogastric junction/bowel
cancer (e.g., radiotherapy, chemotherapy and hormone therapy)
3. Liver peritoneum or distant metastasis
4. Inability to take medications orally
5. Unrelieved postoperative complications during screening (such as postoperative
infection, suture rupture, gastrointestinal bleeding, pancreatic leakage, etc.)
6. There are chemotherapy drugs contraindicated in this study and any group of adjuvant
therapy regiments specified in the regimen cannot be accepted
7. People with active autoimmune diseases that have required systemic treatment within
the past two years (such as treatment with disease-modifying drugs, corticosteroids,
immunosuppressants) and replacement therapy (such as insulin thyroxine or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency) are not considered a systemic treatment
8. There is a pleural, pericardial or abdominal effusion that is clinically
symptomatic, requires diuretic treatment and/or requires repeated drainage.
9. There are active or recurrent inflammatory gastrointestinal diseases (such as
Crohn's disease ulcerative colitis hemorrhagic enteritis chronic diarrhea, etc.)
10. A history of myocarditis and cardiomyopathy with malignant arrhythmias.Unstable
angina pectoris, myocardial infarction, congestive heart failure (grade 2 or higher
according to the New York Heart Association Functional Scale), or vascular disease
(such as an aortic aneurysm at risk of rupture) requiring hospitalization in the 12
months prior to initial administration,Or other heart damage that may affect the
safety evaluation of the investigational drug (e.g., poorly controlled arrhythmias,
myocardial ischemia)
11. Medically difficult to control hypertension (systolic blood pressure ≥150mmHg and/or
diastolic blood pressure ≥100mmHg) (based on an average of ≥2 measurements).
12. Uncontrolled diabetes.
13. Peripheral neuropathy ≥ grade 2.
14. Severe infection within 4 weeks prior to initial dosing, including but not limited
to comorbidized sepsis or severe pneumonia requiring hospitalization; Active
infections that have received systemic anti-infective therapy within 2 weeks prior
to initial dosing (excluding antiviral therapy for hepatitis B or C)
15. Known active tuberculosis (TB), suspected active TB subjects need to undergo
clinical examination to rule out; Known active syphilis infection
16. Subjects with current active hepatitis B (HBsAg positive with more than 2000 copies
/ml(500 IU/ml) of HBV-DNA or higher than the lower limit of detection, whichever is
higher), for subjects with hepatitis B, are required to receive anti-HBV therapy
during the study treatment; Active hepatitis C subjects (HCV antibody positive with
HCV-RNA levels above the lower limit of detection)
17. History of immune deficiency; HIV antibody test positive; Systemic corticosteroid
hormones or other immunosuppressants are currently being used on a long-term basis
18. Known history of allogeneic organ transplantation and allogeneic hematopoietic stem
cell transplantation
19. Prior treatment with PD-1 receptor or its ligand PD-L1 or cytotoxic T
lymphocyte-associated protein 4(CTLA-4) receptor
20. Known allergy to any component of any investigational drug; There is a known history
of severe hypersensitivity to other monoclonal antibodies
21. Inactivated vaccines are allowed if a live or attenuated vaccine has been
administered in the 30 days prior to the first dose, or if a live or attenuated
vaccine is planned to be administered during the study
22. Known history of mental illness substance abuse alcohol or drugs
23. Pregnant or lactating women
24. The presence of any past or current abnormality in laboratory tests for treatment of
disease that may confuse the study results, affect the subject's full participation
in the study, or participation in the study may not be in the subject's best
interest
25. Local or systemic disease caused by non-malignant tumors; Or disease or symptoms
secondary to the tumor and can lead to higher medical risk and/or uncertainty in the
evaluation of survival
26. Any condition that the investigator believes may cause subjects to receive the study
drug treatment to be at risk of interfering with the evaluation of the study drug,
or affecting the interpretation of the study results
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
Accepts Healthy Volunteers
Locations:
Facility:
Name:
Liaoning Cancer Hospital & Institute
Address:
City:
Shenyang
Zip:
110042
Country:
China
Start date:
November 1, 2023
Completion date:
December 31, 2026
Lead sponsor:
Agency:
China Medical University, China
Agency class:
Other
Source:
China Medical University, China
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06118658
