Pembrolizumab And Tamoxifen Among Women With Advanced Hormone Receptor Positive Breast Cancer And Esr1 Mutation (Pembro)
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|ClinicalTrials.gov Identifier: NCT03879174|
Recruitment Status : Not yet recruiting
First Posted : March 18, 2019
Last Update Posted : March 18, 2019
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.
|Condition or disease||Intervention/treatment||Phase|
|Breast Cancer Female||Drug: Pembrolizumab + Tamoxifen||Phase 2|
3.4.1 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 and/or 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-1/PD-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 IgG4/kappa 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 U.A.E. Ministry of Health registered medication.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||25 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||Recently there has been a growing interest in using immune check point inhibitors in breast cancer especially among patients with triple negative and HER2 positive subtypes that are thought to be more immunogenic compared to the luminal subtypes. However there has been a growing interest in looking at immune check point inhibitors among patients with hormone receptor positive breast cancer as a potential method of overcoming endocrine resistance. In the current study we propose a phase II trial to evaluate the anti-tumor activity of pembrolizumab and tamoxifen among patients with hormone receptor positive, HER2 negative metastatic breast cancer who have progressed on a prior aromatase inhibitor and have acquired an ESR1 mutation.|
|Masking:||None (Open Label)|
|Official Title:||A Phase II Study of Pembrolizumab And Tamoxifen Among Women With Advanced Hormone Receptor Positive Breast Cancer And Esr1 Mutation|
|Estimated Study Start Date :||August 1, 2019|
|Estimated Primary Completion Date :||August 1, 2022|
|Estimated Study Completion Date :||August 1, 2022|
Experimental: Pembrolizumab + Tamoxifen
Pembrolizumab (200mg IV every three weeks) + Tamoxifen (20 mg OD)
Drug: Pembrolizumab + Tamoxifen
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on simulations performed using the population PK model of pembrolizumab showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the exposure range established in melanoma as associated with maximal efficacy response and 3) will maintain individual patients exposure in the exposure range established in melanoma that are well tolerated and safe.
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity in the logistical chain at treatment facilities and reduce wastage.
- Progression Free Survival [ Time Frame: defined as time from enrollment to disease progression or death, whichever occurred first, assessed for a period of up to 36 months. ]time from enrollment to disease progression or death, whichever occurred first
- Overall Response Rate (ORR) [ Time Frame: Time for patient to achieve a complete response, partial response and stable disease in response to pembrolizumab therapy, assessed for a period of up to 36 months. ]percentage of patients with a best overall response of complete response (CR) or partial response (PR)
- Overall Survival [ Time Frame: The length of time from the start of pembrolizumab treatment following which the patients are still alive, assessed for a period of up to 36 months. ]Overall Survival
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03879174
|Contact: Reem Younisfirstname.lastname@example.org|
|Contact: Bushra Bitar||+97144359737||Bushra.Bitar@mediclinic.ae|
|United Arab Emirates|
|Mediclinic City Hospital||Not yet recruiting|
|Dubai, United Arab Emirates|
|Contact: Reem Younis 00971508753443 email@example.com|
|Contact: Bushra Bitar 0097144359737 firstname.lastname@example.org|
|Principal Investigator: Shaheenah Dawood|
|Study Director:||Matthew Dronsfield||Hospital Director- Mediclinic City Hospital|
|Principal Investigator:||Shaheenah Dawood||Consultant Oncologist|