Breast Cancer
Conditions
Brief 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.
Detailed 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.
Interventions
DRUGBortezomib; pembrolizumab and cisplatin injections--bortezomib followed by pembro/cis
injection into a vein
Sponsors
Baylor Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A patient will be eligible for inclusion in this study if she meets all of the following criteria: 1. Female patients ≥18 years of age 2. Have a diagnosis of metastatic TNBC previously treated with standard anthracycline, cyclophosphamide, and taxane chemotherapy, unless there was a contraindication to doxorubicin, in which case prior treatment with this agent is not required. NOTE: TNBC defined as ER-negative tumors with \< or = 10% tumor nuclei immunoreactivity, or "ER Low Positive" as defined by the updated ASCO/CAP guidelines 2020. 3. Have not received more than 3 prior chemotherapy regimens for metastatic disease. Prior platinum and/or taxane therapy in the adjuvant or metastatic setting is permitted. 4. Have locoregional (eg, breast, chest wall, regional lymphatic) or pulmonary or hepatic metastatic disease that is amenable to core needle biopsy. If a research biopsy from a patient's metastatic disease cannot be safely obtained, a skin biopsy is permitted. If a skin biopsy cannot be safely obtained, patients may still be eligible, per physician discretion. 5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (See Appendix I) 6. Have adequate hematologic function, defined by: 1. Absolute neutrophil count (ANC) \>1500/μL 2. Platelet count ≥100,000/μL 3. Hemoglobin ≥9 g/dL or ≥5.6 mmol/L 7. Have adequate liver function, defined by: 1. AST and ALT ≤2.5 x the upper limit of normal (ULN) or ≤5 x ULN in presence of liver metastases 2. Total bilirubin ≤1.5 x ULN OR direct bilirubin ≤ULN for patients with total bilirubin levels \>1.5 × ULN 8. Have adequate renal function, defined by: a. Serum creatinine ≤1.5 x ULN or calculated creatinine clearance of ≥30 mL/min 9. Have adequate coagulation function, defined by: 1. International Normalized Ratio (INR) OR prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤1.5 × ULN. 2. If patient is receiving anticoagulant therapy, PT or aPTT must be within therapeutic range of intended use of anticoagulants. 10. Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met: 1. Brain metastases which have been treated 2. Off-treatment with steroids for 2 weeks before administration of the first dose of bortezomib 3. No ongoing requirement for dexamethasone or anti-epileptic drugs 4. No clinical or radiological evidence of progression of brain metastases 11. Patient must be accessible for treatment and follow-up. 12. All patients must be able to understand the investigational nature of the study and give written informed consent prior to study entry.
Exclusion criteria
*
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Calculate objective response rate (CR+PR) associated with bortezomib followed at disease progression with pembrolizumab and cisplatin in metastatic TNBC | 18 months | objective response rate will be calculated by defining the proportion of patients who have a complete or partial response to the study therapy, as determined by the treating physician |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Calculate response | 18 months | duration of response will be calculated from the time of tumor response to disease progression in patients responding to study therapy; |
Countries
United States
Contacts
CONTACTPage Blas, MA
PRINCIPAL_INVESTIGATORJoyce O'Shaughnessy, MD
Texas Oncology
Outcome results
None listed