Ignite Creation Date:
2024-05-06 @ 8:01 PM
Last Modification Date:
2024-10-26 @ 3:19 PM
Study NCT ID:
NCT06225284
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-01-30
First Post:
2023-12-10
Brief Title:
Neoadjuvant Chemotherapy With or Without GnRH Agonist for Premenopausal Triple-negative Early Breast Cancer Patients
Sponsor:
National Taiwan University Hospital
Organization:
National Taiwan University Hospital
Study Overview
Official Title:
A Randomized Phase II Study of Neoadjuvant Chemotherapy With or Without GnRH Agonist for Premenopausal Triple-negative Early Breast Cancer Patients ESCALATE Study
Status:
NOT_YET_RECRUITING
Status Verified Date:
2023-11
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:
ESCALATE
Brief Summary:
Breast cancer BC especially premenopausal is emerging rapidly in East Asia in recent 20 years Half of the breast cancer patients in Asia are younger than 50 years of age In general younger or premenopausal patients are associated with poorer prognosis
Premenopausal patients have higher estrogen levels than those in older postmenopausal patients Estrogen is known to suppress anti-tumor T cell response and leading to tumor progression in different animal models Clin Cancer Res 2016 226204 including lung cancer melanoma ovarian cancer One of the mechanisms that contributes to estrogens suppression of T cell function is via the mobilization of myeloid-derived suppressor cells MDSC Targeting ER signaling with hormonal therapy can abolish MDSC mobilization and sensitize tumor cells to antigen specific T cell or NK cell killing Cancer Discovery 2018 772 2017 These study results further support the hypothesis that E2 is associated with immunosuppressive effect and may contribute to the suppression of immune surveillance in young female breast cancer patients These results suggest that E2 may suppress anti-tumor immunity and E2 reduction improve the anti-tumor immunity In our preliminary works the investigators found higher dose equivalent to premenopausal women serum level of E2 suppressed T cell activities while lower dose E2 postmenopausal serum level activated T cell activity The investigators have investigated the combination of anti-PD1 antibody and GnRH agonist plus exemestane an aromatase inhibitor which will block the production of E2 from adipose tissue in ER positive premenopausal breast cancer patient refractory to prior endocrine therapy in metastatic setting The response rate was 384 and median progression-free survival PFS was 102 months This outstanding result were presented in AACR 2021 oral session Cancer Res 2021 8113_Supplement CT028 On the other hand progesterone is also well known for its anti-inflammation and immune tolerance activity This possibly makes estrogen reduction treatments such as gonadotropin-releasing hormone agonist GnRH agonist an important partner in augmenting neoadjuvant therapy for patients with premenopausal breast cancer
For triple negative breast cancer TNBC endocrine therapy has no anti-tumor effect On the other hand the use of GnRH agonist has been tested for the protection of ovary function of young female while receiving adjuvant chemotherapy Surprisingly the concomitant use of goserelin and adjuvant chemotherapy improved disease-free survival HR 047 P004 and overall survival HR 045 P005 versus chemotherapy alone in ER negative premenopausal early BC patients in POEMS study which was initially aimed to improve the success pregnant rate N Engl J Med 2015 372923 Endocrine therapy is theoretically antagonist to chemotherapy therapy when concomitantly use In another report analyzed the outcome of both pre- and postmenopausal women who entered two randomized trials Gruppo Oncologico Nord-Ovest-Mammella Intergruppo studies on adjuvant chemotherapy and received either concomitant or sequential hormonal therapy The result showed a decreasing trend P 0015 in hazard ratio of death with increasing age was observed indicating that concomitant therapy is more effective than sequential therapy in young patients Annals of Oncology 2008192299-307 These results support the hypothesis that E2 suppressionER inhibition therapy may modulate immune microenvironment thereby enhancing the chemotherapy induced immunogenic death effect
The investigators hypothesized that estrogen level reduction by ovarian function suppression can modulate immune microenvironment thereby augmenting adjuvant chemotherapy efficacy regardless of the estrogen receptor ER status of cancer cell Therefore the investigators plan to test this hypothesis in real clinical model with standard clinical recommended treatment doses
The study is designed to evaluate whether the GnRH agonist can provide the therapeutic benefit for premenopausal TNBC patients via modulating immune microenvironment Premenopausal TNBC patients will receive GnRH agonist and neoadjuvant chemotherapy and the efficacy and immune microenvironment change of co-administration arm will be measured and compared with chemotherapy alone control arm
Premenopausal patients have higher estrogen levels than those in older postmenopausal patients Estrogen is known to suppress anti-tumor T cell response and leading to tumor progression in different animal models Clin Cancer Res 2016 226204 including lung cancer melanoma ovarian cancer One of the mechanisms that contributes to estrogens suppression of T cell function is via the mobilization of myeloid-derived suppressor cells MDSC Targeting ER signaling with hormonal therapy can abolish MDSC mobilization and sensitize tumor cells to antigen specific T cell or NK cell killing Cancer Discovery 2018 772 2017 These study results further support the hypothesis that E2 is associated with immunosuppressive effect and may contribute to the suppression of immune surveillance in young female breast cancer patients These results suggest that E2 may suppress anti-tumor immunity and E2 reduction improve the anti-tumor immunity In our preliminary works the investigators found higher dose equivalent to premenopausal women serum level of E2 suppressed T cell activities while lower dose E2 postmenopausal serum level activated T cell activity The investigators have investigated the combination of anti-PD1 antibody and GnRH agonist plus exemestane an aromatase inhibitor which will block the production of E2 from adipose tissue in ER positive premenopausal breast cancer patient refractory to prior endocrine therapy in metastatic setting The response rate was 384 and median progression-free survival PFS was 102 months This outstanding result were presented in AACR 2021 oral session Cancer Res 2021 8113_Supplement CT028 On the other hand progesterone is also well known for its anti-inflammation and immune tolerance activity This possibly makes estrogen reduction treatments such as gonadotropin-releasing hormone agonist GnRH agonist an important partner in augmenting neoadjuvant therapy for patients with premenopausal breast cancer
For triple negative breast cancer TNBC endocrine therapy has no anti-tumor effect On the other hand the use of GnRH agonist has been tested for the protection of ovary function of young female while receiving adjuvant chemotherapy Surprisingly the concomitant use of goserelin and adjuvant chemotherapy improved disease-free survival HR 047 P004 and overall survival HR 045 P005 versus chemotherapy alone in ER negative premenopausal early BC patients in POEMS study which was initially aimed to improve the success pregnant rate N Engl J Med 2015 372923 Endocrine therapy is theoretically antagonist to chemotherapy therapy when concomitantly use In another report analyzed the outcome of both pre- and postmenopausal women who entered two randomized trials Gruppo Oncologico Nord-Ovest-Mammella Intergruppo studies on adjuvant chemotherapy and received either concomitant or sequential hormonal therapy The result showed a decreasing trend P 0015 in hazard ratio of death with increasing age was observed indicating that concomitant therapy is more effective than sequential therapy in young patients Annals of Oncology 2008192299-307 These results support the hypothesis that E2 suppressionER inhibition therapy may modulate immune microenvironment thereby enhancing the chemotherapy induced immunogenic death effect
The investigators hypothesized that estrogen level reduction by ovarian function suppression can modulate immune microenvironment thereby augmenting adjuvant chemotherapy efficacy regardless of the estrogen receptor ER status of cancer cell Therefore the investigators plan to test this hypothesis in real clinical model with standard clinical recommended treatment doses
The study is designed to evaluate whether the GnRH agonist can provide the therapeutic benefit for premenopausal TNBC patients via modulating immune microenvironment Premenopausal TNBC patients will receive GnRH agonist and neoadjuvant chemotherapy and the efficacy and immune microenvironment change of co-administration arm will be measured and compared with chemotherapy alone control arm
Detailed Description:
None
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?:
None
Is an FDA AA801 Violation?:
None