A Phase 2 interventional study of Radiation Therapy Boost and Pembrolizumab in Triple Negative Breast Cancer, Hormone Receptor Positive (HR+), HER2-negative Breast Cancer and Biopsy-proven, Positive Lymph Node(s), sponsored by Laura M. Spring, MD. Active, not recruiting at 10 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-07-13.
Sponsored by Laura M. Spring, MD · Phase 2, Interventional, and Treatment
This research trial is studying a combination of neoadjuvant radiotherapy (RT), immunotherapy (pembrolizumab) and chemotherapy for lymph node-positive, triple negative (TN) or hormone receptor positive/HER2-negative breast cancer.
The names of the study interventions involved in this study are:
Chemotherapies:
The main purpose of this study is to find out what is the best dose of preoperative RT when combined with pembrolizumab and chemotherapy. The study will assess if combining the RT with the immunotherapy agent, pembrolizumab, will increase the ability of the immune system to destroy cancer cells.
The research study procedures include: screening for eligibility and study treatment, including evaluations and follow-up visits.
The study aims to assess the effectiveness of pembrolizumab (study drug) with or without RT directed to the breast tumor. Participants will then undergo neoadjuvant chemotherapy with pembrolizumab, followed by treatment that can consist of one or more of the following:
Standard of Care Treatment
Participants will be randomized to 1 of 3 groups. Neither the participant not the research doctor will choose the group that the participant is assigned to. However, the participant will be notified of the group prior to the start of study treatment. Participants will receive study treatment for up to 13 months. Participants will be followed for 2 years after the end of the study treatment.
It is expected that a total of 120 people will be participating in total.
This research study is a randomized, phase II study. The U.S. Food and Drug Administration (FDA) has not approved pembrolizumab for your specific disease, but it has been approved for other uses. The U.S. Food and Drug Administration (FDA) has approved the chemotherapies being used in this study (Paclitaxel, Doxorubicin, Cyclophosphamide, Carboplatin, Capecitabine).
1,140 studies on the registry are indexed under Triple Negative Breast Neoplasms; 443 are open to participants now.
This study's planned enrollment of 120 is above the median of 61 across 982 interventional studies indexed under Triple Negative Breast Neoplasms.
Browse Triple Negative Breast Neoplasms studies →This is the only study on the registry with Laura M. Spring, MD as lead sponsor.
Counted across the registry records on this site, refreshed daily.
Participant has non-metastatic, T1*-T2 and N1-3 and one of the following histologically confirmed disease subtypes:
-- Triple negative breast cancer is defined as ER-negative (\<1% cells), PR-negative (\<1% cells) and HER2-negative (\<2+ HER2 IHC or \<2.2 HER2/CEP17 ratio by FISH), as per testing at local institution
Multifocal and multicentric disease is permitted; however only one breast tumor may be preoperatively boosted.
--Note: For patients with multifocal disease and are randomized to receive a preoperative RT boost, all sites of multifocal disease should be contained within the pre-operative boost volume. Subsequently, these patients will not need a post-op boost.
Have adequate organ function as defined in the following table. Bloodwork must be collected within 10 days prior to the start of study treatment.
Hematological --- Absolute neutrophil count (ANC) ≥1500/µL
Renal
--- Creatinine ≤1.5 × ULN OR Measured or calculated b creatinine clearance (GFR can also be used in place of creatinine or CrCl) OR ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN
Hepatic
Coagulation
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
-- a) Not a woman of childbearing potential (WOCBP) OR b) A WOCBP who agrees to follow the contraceptive guidance throughout the study and for at least 4 months after the last dose of pembrolizumab in such a manner that the risk of pregnancy is minimized.
Exclusion Criteria:
Contraindication to radiation therapy including: prior ipsilateral breast or mantle RT, active scleroderma, systemic lupus erythematosis and pregnancy.
--Note: All cardiac implantable electronic devices are permitted, provided that methods to assess radiation doses and minimize damage to the devices during RT is planned, per institutional guidelines.
Prior ipsilateral invasive breast cancer, contralateral breast cancer or a known additional, invasive malignancy that is progressing or required active treatment in the last 5 years.
--Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or cervical carcinoma in situ that has undergone potentially curative therapy and a previous diagnosis of ductal carcinoma in situ are not excluded.
Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization.
--Note: Participants must have recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy may be eligible. If participant received major surgery, she/he must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
Prohibited Treatments and/or Therapies:Use of immunosuppressants and/or systemic corticosteroids is exclusionary, except the following in the absence of active autoimmune disease:
No RT boost plus pembrolizumab, followed by pembrolizumab plus paclitaxel, doxorubicin and cyclophosphamide chemotherapy.There will be up to a total of 8 cycles of pembrolizumab (4 cycle before surgery and 4 cycles after surgery at the discretion of the study doctor).
Drug: Pembrolizumab · Drug: Paclitaxel · Drug: Carboplatin · Drug: Cyclophosphamide · Drug: Doxorubicin · Drug: Capecitabine
Low-dose RT boost plus pembrolizumab, followed by pembrolizumab plus paclitaxel, doxorubicin and cyclophosphamide chemotherapy. There will be up to a total of 8 cycles of pembrolizumab (4 cycle before surgery and 4 cycles after surgery at the discretion of the study doctor).
Radiation: Radiation Therapy Boost · Drug: Pembrolizumab · Drug: Paclitaxel · Drug: Carboplatin · Drug: Cyclophosphamide · Drug: Doxorubicin · Drug: Capecitabine
High-dose RT boost plus pembrolizumab followed by pembrolizumab plus paclitaxel, doxorubicin and cyclophosphamide chemotherapy. There will be up to a total of 8 cycles of pembrolizumab (4 cycle before surgery and 4 cycles after surgery at the discretion of the study doctor).
Radiation: Radiation Therapy Boost · Drug: Pembrolizumab · Drug: Paclitaxel · Drug: Carboplatin · Drug: Cyclophosphamide · Drug: Doxorubicin · Drug: Capecitabine
Participants randomized to the low-dose or high-dose RT boost group will be receiving treatment on Day 1-3 of Cycle 1 of pembrolizumab. Proton therapy may be used in the high dose RT group.
Neoadjuvant Phase: Day 1 (once every 6 weeks) of Cycles 1-4 (by intravenous infusion) over about 30 minutes. Adjuvant Phase: Pembrolizumab may be given post-surgery for up to 4 cycles (once every 6 weeks) by intravenous infusion over about 30 minutes. Pembrolizumab after surgery is optional and should be discussed with the study doctor.
Also known as: Keytruda®.
Starting Week 3 and administered once per week for 12 weeks (up to 12 doses) by intravenous infusion over about 30 minutes.
Also known as: Taxol
Carboplatin is optional for TNBC patients and should be discussed with the study doctor. Starting Week 3 and administered once per week for 12 weeks (up to 12 doses) by intravenous infusion over about 30 minutes.
Also known as: Paraplatin
Starting Week 15 and administered every 2 weeks for 4 cycles (up to 4 doses) into your vein (by intravenous infusion).
Also known as: Cytophosphane
Starting Week 15 and administered every 2 weeks for 4 cycles (up to 4 doses) into your vein (by intravenous infusion). Doxorubicin will be administered after pembrolizumab.
Also known as: Adriamycin
Capecitabine after surgery is optional for TNBC patients and should be discussed with the study doctor. Starting 3-6 weeks after surgery, administered orally twice daily for 6 courses, each 3 weeks long (for a total of 18 weeks).
Tumor Infiltrating Lymphocytes (TILs; CD3+/CD8+ T-cell Breast Immunoscore)
Quantitative immunofluorescence in post-treatment tumor biopsy samples collected on day 14-21 of C1 of Pembrolizumab.
Time frame: 14 through 21 Days
Rate of pathologic response in the lymph node
Defined as the percentage of patients no evidence of residual cancer cells in all sampled regional lymph nodes following completion of neoadjuvant systemic therapy assessed by the study pathologist at the time of definitive surgery.
Time frame: 7 Months
Residual Cancer Burden (RCB) score
RCB is a measure of residual cancer burden in the breast and regional lymph nodes at the time of definitive surgery following completion of neoadjuvant systemic therapy.
Time frame: 24 Weeks
Pathologic response rate
Pathologic response rate is measured by the presence or absence of residual cancer cells in all sampled regional lymph nodes. RCB measures residual disease in the breast and lymph nodes at the time of definitive surgery. CD3+/CD8+ T cell Breast Immunoscore greater than 75% versus patients with Post-treatment CD3+/CD8+ T cell Breast Immunoscore less than or equal to 75%.
Time frame: 24 Weeks
Percent change in pre- versus post-treatment intra-tumoral TILs
Intra-tumoral, peri-tumoral and stromal CD3+, CD8+, and CD3+CD8+ T cell densities will be measured using pan-cytokeratin staining and multiplexed QIF
Time frame: 24 Weeks
Percent changes in pre- versus post-treatment peri-tumoral
Intra-tumoral, peri-tumoral and stromal CD3+, CD8+, and CD3+CD8+ T cell densities will be measured using pan-cytokeratin staining and multiplexed QIF
Time frame: 24 Weeks
Percent changes in pre- versus post-treatment stromal CD3+ or CD8+ T cell
Intra-tumoral, peri-tumoral and stromal CD3+, CD8+, and CD3+CD8+ T cell densities will be measured using pan-cytokeratin staining and multiplexed QIF
Time frame: 24 Weeks
Change in TIL counts by H&E in pre-treatment versus post-RT boost tumor biopsy
TIL counts by H\&E in pre-treatment versus post-RT boost tumor biopsy specimens in each RT dose and breast cancer subtype cohort. H\&E will be performed according to Salgado Criteria \[1\].
Time frame: 24 Weeks
Changes in PD-L1 expression
To quantify changes in PD-L1 expression levels after treatment with Pembro + no, low or high RT boost (at the time of the time of interval biopsy). QIF for PD-L1 will be performed in pre- and post-treatment FFPE tumor biopsy samples.
Time frame: 24 Weeks
Changes in intratumoral, per-tumoral, and stromal CD4+Foxp3+ T regulatory cell densities
To quantify changes in intratumoral, per-tumoral, and stromal CD4+Foxp3+ T regulatory cell densities in response to treatment with preoperative Pembro + no, low, or high dose RT boost (at the time of interval biopsy). QIF for CD4 and Foxp3 will be performed in pre- and post-treatment FFPE tumor biopsy samples. Pan-cytokeratin staining will be used to identify tumor regions
Time frame: 24 Weeks
Number of Participants with Treatment Related Adverse Events as Assessed NCI CTCAE version 5.0
NCI CTCAE version 5.0
Time frame: Baseline up 6 months post surgery up to 13 months
Invasive disease-free survival
iDFS is defined as time from completion of surgery to the first occurrence of the following events: invasive ipsilateral, local, regional, or distant recurrence, or death due to breast cancer.
Time frame: time from completion of surgery to the first occurrence of the following events: invasive ipsilateral, local, regional, or distant recurrence, or death due to breast cancer up to 31 months
Event-free survival (EFS)
EFS is defined as the time from the initiation of the study treatment to any of the following events: progression of disease (precluding surgery), recurrence (local or distant), or death due to any cause.
Time frame: time from completion of surgery to the first occurrence of the following events: progression of disease (precluding surgery), recurrence (local or distant), or death due to any cause up to 31 months.
Symptomatic Improvement
PROMIS Global Health Measure Quality of life (e.g., global, physical, mental, and social health) outcomes will be measured by two PROMIS (Patient-Reported Outcomes Measurement Information System) short forms consisting of 4 questions total. This instrument has demonstrated content-validity, cross-sectional validity, and responsiveness to change in numerous publications\[93\].
Time frame: baseline to 21 Weeks
Change in Symptoms and Satisfaction with Treatment
(Breast-Q), four domains will be evaluated both before and after surgery: satisfaction with breasts, psychosocial, sexual, and physical well-being. Scores for each domain range from 0-100, with higher scores indicative of better quality of life
Time frame: baseline to Week 3
Change in Symptoms and Satisfaction with Treatment
(Breast-Q), four domains will be evaluated both before and after surgery: satisfaction with breasts, psychosocial, sexual, and physical well-being. Scores for each domain range from 0-100, with higher scores indicative of better quality of life
Time frame: baseline to week 21
Change Patient Reported Outcomes
PRO-CTCAE will evaluate symptom burden in the previous week using a Likert scale to assess presence/absence, frequency, severity and/or interference for different symptoms. Each symptom will be presented descriptively, using summary statistics and graphical representations across time points.
Time frame: 3 years
Financial Burden
Recently coined term used to describe the potential financial burden patients experience while receiving medical care. Two questions were adapted from the National Health Interview Survey\[95\] and a survey administered to caregivers of participants of the Cancer Car Outcomes Research and Surveillance (CanCORS) study\[96\] to assess financial burden and impact on employment-related metrics (e.g., sick leave, unpaid time off work). Financial burden will be assessed at the post-surgery visit.
Time frame: 3 to 6 wks after last dose in the Neoadjuvant Period up to 8 Months
Trial Satisfaction
The Was It Worth It (WIWI) instrument, also called the "Trial Satisfaction" survey, was developed to investigate the patient experience on clinical trials. Multiple cooperative group studies have utilized this instrument at the completion of treatment to measure patient satisfaction relating to clinical trial enrollment, although formal validity and reliability data is not yet available\[
Time frame: 3 to 6 wks after last dose in the Neoadjuvant Period up to 8 Months
Plan to share: Yes — The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
Supporting information: Study protocol, Sap, Icf
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