A Phase II Study of Preoperative Stereotactic Radiation Therapy Boost Combined With Short-course Immunotherapy (Pembrolizumab Versus Placebo, Randomized, Double-blind) and Standard Chemiotherapy in Patients With Newly Diagnosed HER2-negative Nonmetastatic Breast Cancer With Lack of Early Metabolic Response in 18- fluorodeoxyglucoseFDG-PET/CT After 1st Chemoterapy Cycle
Overview
- Phase
- Phase 2
- Intervention
- Keytruda
- Conditions
- Breast Cancer
- Sponsor
- Maria Sklodowska-Curie National Research Institute of Oncology
- Enrollment
- 78
- Locations
- 1
- Primary Endpoint
- The histopathological confirmation of complete tumor regression in postoperative material performed in a population of 52 patients receiving immunotherapy in combination with radiotherapy
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
The goal of the study is to assess the safety and effectiveness of the combination of anti-PD1 immunotherapy (pembrolizumab) and radiotherapy in the preoperative treatment of HER2-negative breast cancer resistant to classical chemotherapy.
The subject of the intervention will be:
- Randomly assigned in a 2:1 ratio and double-blinded addition of pre-operative immunotherapy with pembrolizumab or placebo to standard chemotherapy
- Addition of preoperative radiotherapy boost delivered with a CyberKnife radiosurgery system concomitantly with the use of paclitaxel (+/- carboplatin) and pembrolizumab / placebo.
Detailed Description
The study aims to assess the safety and effectiveness of the combination of anti-PD1 (PD-1, programmed cell death-1) immunotherapy (pembrolizumab) with radiotherapy in the preoperative treatment of triple-negative or luminal HER2-negative (HER2, Human epidermal growth factor receptor 2) (breast cancer, stage IIA/IIB/III/IV (with an acceptable oligometastatic form), resistant to classical chemotherapy After screening and administration of standard induction chemotherapy, the study will be conducted in a group of patients selected on the basis of lack of metabolic response after the 1st cycle of chemotherapy, and the subject of the intervention will be: * addition of preoperative immunotherapy with pembrolizumab or placebo to standard chemotherapy, using a double-blind randomized trial in a ratio of 2:1, respectively * addition of a boost of preoperative robotic stereotactic radiotherapy in all patients, simultaneously with the use of paclitaxel +/- carboplatin and pembrolizumab/placebo.
Investigators
Eligibility Criteria
Inclusion Criteria
- •A woman or a man over 18 years of age.
- •Diagnosis of invasive breast cancer
- •Patient eligible for standard preoperative chemotherapy for breast cancer with anthracyclines and paclitaxel, according to the investigator's assessment
- •Breast cancer stage:
- •any T cN1-cN3
- •cT4 any N (stages IIA/IIB/III/IV, excluding cT1-3 N0 patients).
- •Oligometastatic disease is allowed (stage IV, up to 3 foci in one organ or 2 foci in total in 2 different organs), if radical treatment using local methods is possible, both in the treatment of the primary tumor and in the treatment of the metastatic focus (radiotherapy, surgery). Patients with distant metastases who do not qualify for radical treatment cannot be included.
- •Cancer without estrogen receptor expression (ER\<1% and PR\<1%) or luminal cancer
- •HER2-negative cancer
- •Definitely multifocal or multicentric tumors are acceptable if HER2 negative status is confirmed in all identified invasive tumor foci; this is not required in the case of satellite lesions adjacent to the tumor mass or small lesions less than 1 cm in diameter identified in MRI
Exclusion Criteria
- •Inflammatory breast cancer (cT4d)
- •Hypersensitivity to drugs or excipients used in the study, which, in the opinion of the researcher, does not allow therapy to be initiated
- •Major surgical or medical procedure within 14 days prior to study entry; does not apply to ovariectomy performed laparoscopically, including as a risk-reducing surgical procedure and ovarian biopsy as a fertility preservation procedure and diagnostic procedures
- •Parallel coexisting invasive cancer
- •Co-existing known HIV (human immunodeficiency virus) infection, known active HBV (hepatitis B virus) or HCV (hepatitis C virus) infection
- •Diagnosed autoimmune disease requiring immunosuppressive therapy; does not apply to thyroid diseases if, in the opinion of the endocrinologist, they are not a contraindication to pembrolizumab therapy
- •Any disease requiring systemic steroid therapy within 3 weeks before enrollment in the study
- •Serious, uncontrolled mental illness
- •Condition after organ allotransplantation
- •Condition after implantation of devices that do not allow breast MRI examination (does not apply to examinations with the assistance of a cardiologist, if the patient qualifies for such a procedure);
Arms & Interventions
Experimental (Immunotherapy with pembrolizumab)
Pembrolizumab (Keytruda) + Preoperative Stereotactic Radiotherapy. IP will administered at a dose of 200 mg by intravenous infusion every 21 days - 4 administrations planned.
Intervention: Keytruda
Experimental (Immunotherapy with pembrolizumab)
Pembrolizumab (Keytruda) + Preoperative Stereotactic Radiotherapy. IP will administered at a dose of 200 mg by intravenous infusion every 21 days - 4 administrations planned.
Intervention: Preoperative radiation therapy
Control (placebo)
Placebo+ Preoperative Stereotactic Radiotherapy The solvent is 0.9% NaCl in a volume of 100 ml, with an adequate cover of the drug bag will be used as a placebo.
Intervention: Preoperative radiation therapy
Control (placebo)
Placebo+ Preoperative Stereotactic Radiotherapy The solvent is 0.9% NaCl in a volume of 100 ml, with an adequate cover of the drug bag will be used as a placebo.
Intervention: Placebo
Outcomes
Primary Outcomes
The histopathological confirmation of complete tumor regression in postoperative material performed in a population of 52 patients receiving immunotherapy in combination with radiotherapy
Time Frame: Rating histopathology of the collected material during surgery
The statistical analysis will be performed by comparison to the initial assumptions, according to Simon's scheme. The finding of complete tumor regression (confirmed histopathologically) in more than 11 patients out of the group of 52 enrolled will be treated as fulfillment of the primary endpoint.
Secondary Outcomes
- The comparison of the Invasive Disease Free Survival time the group treated with pembrolizumab with radiotherapy to the group treated with placebo with radiotherapy(The entire observation period,an average of 4 years)
- The assessment of the response to preoperative treatment by assessing postoperative material in histopathological examination(Rating histopathology of the collected material during surgery)
- Quality of life evaluated by QLQ-C30 questionnaire (Quality of Live questionnaire) comparision beteewen groups(Assessment approximately 4 months after surgical treatment)
- Safety and tolerance (number of participants with treatment-related adverse events).(During the study, an average of 5 years)
- Assessment of complete regression in postoperative histopathological examination in the population of all 78 patients receiving preoperative chemotherapy and radiotherapy(Rating histopathology of the collected material during surgery)