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Bortezomib Followed by Pembrolizumab and Cisplatin in metTNBC

2020-02-16 17:40:49 | BioPortfolio

Summary

The hypothesis of this pilot trial is that administration of bortezomib will inhibit NHEJ in metastatic TNBC leading at the time of disease progression to metastases that are HR-deficient and sensitive to pembrolizumab and cisplatin therapy. The trial will include in depth analysis of the patients' TNBC genome and phosphoproteome to evaluate HR-proficiency and deficiency, and nuclear proteins that drive NHEJ, before and upon progression with bortezomib therapy.

Description

Seventy to 80% of breast cancers have a basal gene expression profile which is characterized by homologous recombination deficiency (HRD) and high proliferation. HRD leads to upregulation of the activity of the non-homologous end joining (NHEJ) error-prone pathway that repairs DNA double strand breaks, a process required for TNBC survival. The hypothesis of this pilot trial is that administration of bortezomib will inhibit NHEJ in metastatic TNBC leading at the time of disease progression to metastases that are HR-deficient and sensitive to pembrolizumab and cisplatin therapy. A patient with an exceptional complete and durable response of her primary-refractory metastatic TNBC with PI3K pathway inhibition followed at disease progression by nab paclitaxel/cisplatin provides the clinical rationale for the present trial which will utilize bortezomib to inhibit HR proficiency prior to administration of pembrolizumab and cisplatin in pretreated metastatic TNBC patients.

Patients will receive bortezomib until PD, followed by pembrolizumab and cisplatin until PD or a maximum of 6 cycles on study. If patients are responding, they may continue pembrolizumab at the physician's discretion off study. Metastatic TNBC patients will undergo core needle biopsies of a metastatic lesion at study entry and at disease progression from bortezomib for NGS, RPPA, and other molecular analyses.

Patients whose disease does not respond to pembrolizumab and cisplatin may be treated with standard of care breast cancer therapies off study, at the recommendation of the treating physician.

Study Design

Conditions

Breast Cancer

Intervention

Bortezomib; pembrolizumab and cisplatin injections--bortezomib followed by pembro/cis

Location

Baylor University Medical Center, Baylor Charles A Sammons Cancer Center
Dallas
Texas
United States
75246

Status

Not yet recruiting

Source

Baylor Research Institute

Results (where available)

View Results

Links

Published on BioPortfolio: 2020-02-16T17:40:49-0500

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Medical and Biotech [MESH] Definitions

A pyrazine and boronic acid derivative that functions as a reversible PROTEASOME INHIBITOR. It is used as an ANTINEOPLASTIC AGENT in the treatment of MULTIPLE MYELOMA and MANTLE CELL LYMPHOMA.

An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle.

A fluid-filled closed cavity or sac that is lined by an EPITHELIUM and found in the BREAST. It may appear as a single large cyst in one breast, multifocal, or bilateral in FIBROCYSTIC BREAST DISEASE.

Injections into the lymph nodes or the lymphatic system.

Injections introduced directly into localized lesions.

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