Ignite Creation Date:
2024-05-06 @ 12:52 PM
Last Modification Date:
2024-10-26 @ 1:06 PM
Study NCT ID:
NCT03879174
Status:
UNKNOWN
Last Update Posted:
2019-03-18
First Post:
2019-03-14
Brief Title:
Pembrolizumab And Tamoxifen Among Women With Advanced Hormone Receptor Positive Breast Cancer And Esr1 Mutation
Sponsor:
Mediclinic Middle East
Organization:
Mediclinic Middle East
Study Overview
Official Title:
A Phase II Study of Pembrolizumab And Tamoxifen Among Women With Advanced Hormone Receptor Positive Breast Cancer And Esr1 Mutation
Status:
UNKNOWN
Status Verified Date:
2019-03
Last Known Status:
NOT_YET_RECRUITING
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:
Pembro
Brief Summary:
Pembrolizumab is a potent and highly selective humanized monoclonal antibody mAb designed to directly block the interaction between PD-1 and its ligands and enable the T cell to remain active and co-ordinate an attack on tumor cells
We hypothesise that the Clinical Benefit Rate CBR and progression free survival PFS of metastatic breast cancer patients who have ESR1 mutation will improve following administration of a combination of pembrolizumab and tamoxifen
We hypothesise that the Clinical Benefit Rate CBR and progression free survival PFS of metastatic breast cancer patients who have ESR1 mutation will improve following administration of a combination of pembrolizumab and tamoxifen
Detailed Description:
341 Pharmaceutical and Therapeutic Background The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has been known for decades Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes TILs in cancer tissue and favorable prognosis in various malignancies In particular the presence of CD8 T-cells and the ratio of CD8 effector T-cells FoxP3 regulatory T-cells seems to correlate with improved prognosis and long-term survival in many solid tumors
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control The normal function of PD-1 expressed on the cell surface of activated T-cells under healthy conditions is to down-modulate unwanted or excessive immune responses including autoimmune reactions PD-1 encoded by the gene Pdcd1 is an Ig superfamily member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands PD-L1 andor PD L2 The structure of murine PD-1 has been resolved PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-type V-type domain responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling molecules The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs an immunoreceptor tyrosine-based inhibition motif ITIM and an immunoreceptor tyrosine-based switch motif ITSM Following T-cell stimulation PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail leading to the dephosphorylation of effector molecules such as CD3ζ PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade The mechanism by which PD-1 down modulates T-cell responses is similar to but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4 and CD8 T-cells B-cells T regs and Natural Killer cells Expression has also been shown during thymic development on CD4-CD8- double negative T-cells as well as subsets of macrophages and dendritic cells The ligands for PD-1 PD-L1 and PD-L2 are constitutively expressed or can be induced in a variety of cell types including non-hematopoietic tissues as well as in various tumors Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions with no known signaling motifs Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor PD-L1 is expressed at low levels on various non-hematopoietic tissues most notably on vascular endothelium whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments PD-L2 is thought to control immune T-cell activation in lymphoid organs whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues Although healthy organs express little if any PD-L1 a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma MEL This suggests that the PD-1PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as an attractive target for therapeutic intervention
Pembrolizumab is a potent and highly selective humanized monoclonal antibody mAb of the IgG4kappa isotype designed to directly block the interaction between PD-1 and its ligands PD-L1 and PD-L2 KeytrudaTM pembrolizumab has been approved in the United States for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and if BRAF V600 mutation positive a BRAF inhibitor KeytrudaTM pembrolizumab is also a UAE Ministry of Health registered medication
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control The normal function of PD-1 expressed on the cell surface of activated T-cells under healthy conditions is to down-modulate unwanted or excessive immune responses including autoimmune reactions PD-1 encoded by the gene Pdcd1 is an Ig superfamily member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands PD-L1 andor PD L2 The structure of murine PD-1 has been resolved PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-type V-type domain responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling molecules The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs an immunoreceptor tyrosine-based inhibition motif ITIM and an immunoreceptor tyrosine-based switch motif ITSM Following T-cell stimulation PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail leading to the dephosphorylation of effector molecules such as CD3ζ PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade The mechanism by which PD-1 down modulates T-cell responses is similar to but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4 and CD8 T-cells B-cells T regs and Natural Killer cells Expression has also been shown during thymic development on CD4-CD8- double negative T-cells as well as subsets of macrophages and dendritic cells The ligands for PD-1 PD-L1 and PD-L2 are constitutively expressed or can be induced in a variety of cell types including non-hematopoietic tissues as well as in various tumors Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions with no known signaling motifs Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor PD-L1 is expressed at low levels on various non-hematopoietic tissues most notably on vascular endothelium whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments PD-L2 is thought to control immune T-cell activation in lymphoid organs whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues Although healthy organs express little if any PD-L1 a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma MEL This suggests that the PD-1PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as an attractive target for therapeutic intervention
Pembrolizumab is a potent and highly selective humanized monoclonal antibody mAb of the IgG4kappa isotype designed to directly block the interaction between PD-1 and its ligands PD-L1 and PD-L2 KeytrudaTM pembrolizumab has been approved in the United States for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and if BRAF V600 mutation positive a BRAF inhibitor KeytrudaTM pembrolizumab is also a UAE Ministry of Health registered medication
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
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
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| MISP 55574 | OTHER | MSD Inc | None |