Ignite Creation Date:
2024-06-16 @ 11:51 AM
Last Modification Date:
2024-10-26 @ 3:31 PM
Study NCT ID:
NCT06448169
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-06-07
First Post:
2024-05-12
Brief Title:
Observational Study on the Sensitivity of Neoadjuvant Immunotherapy in Early Triple-Negative Breast Cancer
Sponsor:
Shandong University
Organization:
Shandong University
Study Overview
Official Title:
Observational Study on the Sensitivity of Neoadjuvant Immunotherapy in Early Triple-Negative Breast Cancer Based on High-Resolution Dynamic Immune Signature Analysis
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Studies have reported that tumors with the same immunogenic mutations may induce T cell receptor TCR domains with similar antigen recognition functions By assembling the complementarity-determining region 3 CDR3 of TCRs from RNA-seq data and correlating them with 9142 samples from TCGA data an in-depth analysis of the TCR pool in the tumor microenvironment found a strong correlation between the CDR3 sequences of tumor-infiltrating T cells and tumor mutation burden Fairfax et al found that in patients responding to tumor immunotherapy the TCR immune pool of CD8 T cells produces many clones with extremely high abundance exceeding 05 Cader et al also found significant changes in the TCR immune pool of patients with Hodgkins lymphoma responding to PD-1 tumor immunotherapy Based on these theoretical foundations evaluating the dynamic changes of the TCR immune pool is expected to be used to analyze the immune characteristics and changes in diseases such as malignant tumors
Detailed Description:
I Background Approximately 12-17 of breast cancer patients suffer from triple-negative breast cancer TNBC which is prone to visceral and central nervous system metastases poses significant therapeutic challenges and has poor prognosis Clinically starting with early TNBC strengthening precise and individualized treatment and reducing the risk of recurrence and metastasis are effective methods to improve the survival rate of TNBC patients
The optimization of neoadjuvant therapy regimens has always been a research hotspot Traditional neoadjuvant therapy regimens are primarily based on chemotherapy The KEYNOTE-522 study showed that traditional chemotherapy combined with PD-1 inhibitors could significantly increase the pCR pathological complete remission rate improving by 136 648 vs 512 P000055 and reducing the risk of recurrence However this treatment also brings inevitable immune-related adverse events AEs with an overall AE incidence rate of 436 a 3-5 grade AE incidence rate of 149 and a fatal AE rate of 03 Many immune-related AEs are lifelong such as hypothyroidism Therefore how to precisely select immunologically sensitive patients for immunotherapy while administering chemotherapy only to those who are immunologically insensitive to avoid unnecessary immune-related AEs How to predict patients who may experience severe immune-related adverse reactions early These are urgent clinical issues that need to be addressed Meanwhile the mechanism of immunotherapy resistance remains unclear
Studies have reported that tumors with the same immunogenic mutations may induce T cell receptor TCR domains with similar antigen recognition functions By assembling the complementarity-determining region 3 CDR3 of TCRs from RNA-seq data and correlating them with 9142 samples from TCGA data an in-depth analysis of the TCR pool in the tumor microenvironment found a strong correlation between the CDR3 sequences of tumor-infiltrating T cells and tumor mutation burden Fairfax et al found that in patients responding to tumor immunotherapy the TCR immune pool of CD8 T cells produces many clones with extremely high abundance exceeding 05 Cader et al also found significant changes in the TCR immune pool of patients with Hodgkins lymphoma responding to PD-1 tumor immunotherapy Based on these theoretical foundations evaluating the dynamic changes of the TCR immune pool is expected to be used to analyze the immune characteristics and changes in diseases such as malignant tumors
Research Aim and Significance This study aims to utilize deep sequencing technology to capture the molecular characteristics of the TCR immunome pool in the peripheral blood of patients with triple-negative breast cancer at different time points before and after neoadjuvant therapy By combining artificial intelligence analysis algorithms the investigators aim to accurately screen the patient population that will benefit from neoadjuvant immunotherapy for triple-negative breast cancer avoid the occurrence of severe immune-related AEs and explore the mechanisms of resistance to immunotherapy ultimately achieving individualized and precise immunotherapy
Research Content Analyze the changing characteristics of the TCR dynamic molecular group before neoadjuvant therapy in patients with triple-negative breast cancer and compare the benefited and non-benefited patients receiving neoadjuvant therapy to screen for the population that will benefit from neoadjuvant immunotherapy for triple-negative breast cancer
Analyze the changing characteristics of the TCR dynamic molecular population during neoadjuvant therapy in patients with triple-negative breast cancer and compare patients who experience severe immune-related adverse events with those who do not in order to prevent and detect severe immune-related adverse events early
Analyze the changing characteristics of the TCR dynamic molecular population in patients with neoadjuvant therapy resistance for triple-negative breast cancer examine the immune characteristics of resistant patients and explore the mechanisms of resistance to immunotherapy
Research Design
1 Randomized Control Method This is a non-randomized controlled single-arm open-label design
2 Sample Size This study plans to enroll 200 participants
3 Study Population Early-stage triple-negative breast cancer patients receiving neoadjuvant therapy with PD-1 inhibitors combined with chemotherapy
4 Treatment Factors Placebo Drugs or Other Interventions Neoadjuvant therapy drugs include PD-1 inhibitors 200mg intravenous infusion administered on day 1 of each cycle with 21 days as a cycle albumin-bound paclitaxel 260 mgm2 intravenous infusion administered on day 1 of each cycle with 21 days as a cycle and carboplatin AUC 4 administered on day 1 of each cycle with 21 days as a cycle
5 PrimarySecondary Observation Indicators Pathological complete response rate clinical response rate immune-related adverse events and drug resistance
6 Safety and Effectiveness Evaluation Indicators Perform imaging examinations every 2 cycles during the treatment period to evaluate efficacy based on the RECIST 11 standard After completing 6 cycles of neoadjuvant therapy surgery will be performed and pathological evaluation of the therapeutic effect will be conducted
InclusionExclusion Criteria and WithdrawalTermination Criteria of the Subjects
1 Recognized Diagnostic Criteria for the Target Disease Pathological examination by core needle biopsy
2 Inclusion Criteria
1 Age 18-60 years old 2 Histologically confirmed triple-negative breast cancer with immunohistochemistry showing ER 1 PR 1 HER2-negative IHC 0 or 1 or IHC 2 ISH-negative 3 Imaging-confirmed non-metastatic disease 4 Clinical efficacy can be evaluated according to RECIST criteria 5 European Functional Handicap Scale MRC of 0-2 6 The investigator determines that the treatment is tolerable based on the patients organ function level 7 Volunteers willing to participate in this study sign the informed consent have good compliance and are willing to cooperate with follow-up
3 Exclusion Criteria
1 Immunohistochemistry showing HER2-positive IHC 3 or IHC 2 ISH-amplified
2 Previously treated
3 Severe dysfunction of important organs such as heart liver and kidneys
4 Patients with diseases unsuitable for immunotherapy
5 Known allergy history to any component of the drugs in this regimen
6 History of immune deficiency including HIV-positive HCV active hepatitis B or other acquired or congenital immune deficiency diseases or a history of organ transplantation
7 Any cardiac disease including ① Medically treated or clinically significant arrhythmias ② Myocardial infarction ③ Heart failure ④ Any other cardiac disease judged by the investigator as unsuitable for participation in this trial
8 Pregnant or lactating women fertile women with positive baseline pregnancy test or those unwilling to take effective contraceptive measures during the entire trial
9 According to the investigators judgment there are accompanying diseases that seriously endanger the safety of the patient or affect the completion of the study including but not limited to severe hypertension uncontrollable by drugs severe diabetes active infections etc
10 Long-term use of drugs that affect the components of peripheral blood immune cells such as recombinant human erythropoietin recombinant human granulocyte colony-stimulating factor recombinant human interleukin or Likejun tablets
11 Received immunosuppressive therapy within 2 weeks
12 Hematological precancerous diseases such as myelodysplastic syndrome and coagulation disorders
4 Have high-risk populations been excluded Yes 5 Have interfering factors been excluded Yes 6 WithdrawalTermination Criteria
1 The subject withdraws the informed consent and requests withdrawal
2 Medical imaging or clinical progression
3 Any clinical adverse event abnormal laboratory test or other medical condition occurs leading to the possibility that continued medication may no longer benefit the subject
4 Serious violation of the trial protocol and the investigator assesses that treatment should be terminated
5 Pregnancy occurs during the study
6 Other reasons why the investigator believes that drug treatment cannot be continued
The optimization of neoadjuvant therapy regimens has always been a research hotspot Traditional neoadjuvant therapy regimens are primarily based on chemotherapy The KEYNOTE-522 study showed that traditional chemotherapy combined with PD-1 inhibitors could significantly increase the pCR pathological complete remission rate improving by 136 648 vs 512 P000055 and reducing the risk of recurrence However this treatment also brings inevitable immune-related adverse events AEs with an overall AE incidence rate of 436 a 3-5 grade AE incidence rate of 149 and a fatal AE rate of 03 Many immune-related AEs are lifelong such as hypothyroidism Therefore how to precisely select immunologically sensitive patients for immunotherapy while administering chemotherapy only to those who are immunologically insensitive to avoid unnecessary immune-related AEs How to predict patients who may experience severe immune-related adverse reactions early These are urgent clinical issues that need to be addressed Meanwhile the mechanism of immunotherapy resistance remains unclear
Studies have reported that tumors with the same immunogenic mutations may induce T cell receptor TCR domains with similar antigen recognition functions By assembling the complementarity-determining region 3 CDR3 of TCRs from RNA-seq data and correlating them with 9142 samples from TCGA data an in-depth analysis of the TCR pool in the tumor microenvironment found a strong correlation between the CDR3 sequences of tumor-infiltrating T cells and tumor mutation burden Fairfax et al found that in patients responding to tumor immunotherapy the TCR immune pool of CD8 T cells produces many clones with extremely high abundance exceeding 05 Cader et al also found significant changes in the TCR immune pool of patients with Hodgkins lymphoma responding to PD-1 tumor immunotherapy Based on these theoretical foundations evaluating the dynamic changes of the TCR immune pool is expected to be used to analyze the immune characteristics and changes in diseases such as malignant tumors
Research Aim and Significance This study aims to utilize deep sequencing technology to capture the molecular characteristics of the TCR immunome pool in the peripheral blood of patients with triple-negative breast cancer at different time points before and after neoadjuvant therapy By combining artificial intelligence analysis algorithms the investigators aim to accurately screen the patient population that will benefit from neoadjuvant immunotherapy for triple-negative breast cancer avoid the occurrence of severe immune-related AEs and explore the mechanisms of resistance to immunotherapy ultimately achieving individualized and precise immunotherapy
Research Content Analyze the changing characteristics of the TCR dynamic molecular group before neoadjuvant therapy in patients with triple-negative breast cancer and compare the benefited and non-benefited patients receiving neoadjuvant therapy to screen for the population that will benefit from neoadjuvant immunotherapy for triple-negative breast cancer
Analyze the changing characteristics of the TCR dynamic molecular population during neoadjuvant therapy in patients with triple-negative breast cancer and compare patients who experience severe immune-related adverse events with those who do not in order to prevent and detect severe immune-related adverse events early
Analyze the changing characteristics of the TCR dynamic molecular population in patients with neoadjuvant therapy resistance for triple-negative breast cancer examine the immune characteristics of resistant patients and explore the mechanisms of resistance to immunotherapy
Research Design
1 Randomized Control Method This is a non-randomized controlled single-arm open-label design
2 Sample Size This study plans to enroll 200 participants
3 Study Population Early-stage triple-negative breast cancer patients receiving neoadjuvant therapy with PD-1 inhibitors combined with chemotherapy
4 Treatment Factors Placebo Drugs or Other Interventions Neoadjuvant therapy drugs include PD-1 inhibitors 200mg intravenous infusion administered on day 1 of each cycle with 21 days as a cycle albumin-bound paclitaxel 260 mgm2 intravenous infusion administered on day 1 of each cycle with 21 days as a cycle and carboplatin AUC 4 administered on day 1 of each cycle with 21 days as a cycle
5 PrimarySecondary Observation Indicators Pathological complete response rate clinical response rate immune-related adverse events and drug resistance
6 Safety and Effectiveness Evaluation Indicators Perform imaging examinations every 2 cycles during the treatment period to evaluate efficacy based on the RECIST 11 standard After completing 6 cycles of neoadjuvant therapy surgery will be performed and pathological evaluation of the therapeutic effect will be conducted
InclusionExclusion Criteria and WithdrawalTermination Criteria of the Subjects
1 Recognized Diagnostic Criteria for the Target Disease Pathological examination by core needle biopsy
2 Inclusion Criteria
1 Age 18-60 years old 2 Histologically confirmed triple-negative breast cancer with immunohistochemistry showing ER 1 PR 1 HER2-negative IHC 0 or 1 or IHC 2 ISH-negative 3 Imaging-confirmed non-metastatic disease 4 Clinical efficacy can be evaluated according to RECIST criteria 5 European Functional Handicap Scale MRC of 0-2 6 The investigator determines that the treatment is tolerable based on the patients organ function level 7 Volunteers willing to participate in this study sign the informed consent have good compliance and are willing to cooperate with follow-up
3 Exclusion Criteria
1 Immunohistochemistry showing HER2-positive IHC 3 or IHC 2 ISH-amplified
2 Previously treated
3 Severe dysfunction of important organs such as heart liver and kidneys
4 Patients with diseases unsuitable for immunotherapy
5 Known allergy history to any component of the drugs in this regimen
6 History of immune deficiency including HIV-positive HCV active hepatitis B or other acquired or congenital immune deficiency diseases or a history of organ transplantation
7 Any cardiac disease including ① Medically treated or clinically significant arrhythmias ② Myocardial infarction ③ Heart failure ④ Any other cardiac disease judged by the investigator as unsuitable for participation in this trial
8 Pregnant or lactating women fertile women with positive baseline pregnancy test or those unwilling to take effective contraceptive measures during the entire trial
9 According to the investigators judgment there are accompanying diseases that seriously endanger the safety of the patient or affect the completion of the study including but not limited to severe hypertension uncontrollable by drugs severe diabetes active infections etc
10 Long-term use of drugs that affect the components of peripheral blood immune cells such as recombinant human erythropoietin recombinant human granulocyte colony-stimulating factor recombinant human interleukin or Likejun tablets
11 Received immunosuppressive therapy within 2 weeks
12 Hematological precancerous diseases such as myelodysplastic syndrome and coagulation disorders
4 Have high-risk populations been excluded Yes 5 Have interfering factors been excluded Yes 6 WithdrawalTermination Criteria
1 The subject withdraws the informed consent and requests withdrawal
2 Medical imaging or clinical progression
3 Any clinical adverse event abnormal laboratory test or other medical condition occurs leading to the possibility that continued medication may no longer benefit the subject
4 Serious violation of the trial protocol and the investigator assesses that treatment should be terminated
5 Pregnancy occurs during the study
6 Other reasons why the investigator believes that drug treatment cannot be continued
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None