Pre-op Pembro + Radiation Therapy in Breast Cancer (P-RAD)

NCT04443348 | Active Not Recruiting Phase 2 DMC FDA Drug FDA Device

• 1 other identifier: 20-157
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 10

Brief Summary

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:

• Radiation Therapy (RT)
• Immunotherapy: Pembrolizumab (MK-3475)
• Chemotherapies:
• Paclitaxel
• Doxorubicin (also called Adriamycin)
• Cyclophosphamide
• Carboplatin (optional, and in TN only)
• Capecitabine (optional, and in TN only)

Conditions

Triple Negative Breast Cancer; Hormone Receptor Positive (HR+), HER2-negative Breast Cancer; Biopsy-proven, Positive Lymph Node(s)

Keywords

Triple Negative Breast Cancer; Hormone Receptor Positive breast cancer; Estrogen Receptor Positive breast cancer

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  7 Months

Secondary Outcomes (17)

• Residual Cancer Burden (RCB) score

  24 Weeks

• Pathologic response rate

  24 Weeks

• Percent change in pre- versus post-treatment intra-tumoral TILs

  24 Weeks

• Percent changes in pre- versus post-treatment peri-tumoral

  24 Weeks

• Percent changes in pre- versus post-treatment stromal CD3+ or CD8+ T cell

  24 Weeks

Study Arms (3)

Group A (No RT Boost)

EXPERIMENTAL

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

Group B (Low Dose RT Boost)

EXPERIMENTAL

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

Group C (High Dose RT Boost)

EXPERIMENTAL

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

Interventions

Radiation Therapy Boost RADIATION

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.

Group B (Low Dose RT Boost); Group C (High Dose RT Boost)

Pembrolizumab DRUG

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®.

Group A (No RT Boost); Group B (Low Dose RT Boost); Group C (High Dose RT Boost)

Paclitaxel DRUG

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

Group A (No RT Boost); Group B (Low Dose RT Boost); Group C (High Dose RT Boost)

Carboplatin DRUG

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

Group A (No RT Boost); Group B (Low Dose RT Boost); Group C (High Dose RT Boost)

Cyclophosphamide DRUG

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

Group A (No RT Boost); Group B (Low Dose RT Boost); Group C (High Dose RT Boost)

Doxorubicin DRUG

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

Group A (No RT Boost); Group B (Low Dose RT Boost); Group C (High Dose RT Boost)

Capecitabine DRUG

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).

Group A (No RT Boost); Group B (Low Dose RT Boost); Group C (High Dose RT Boost)

Eligibility Criteria

• Age: 18 Years+
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years old
• 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
• High-risk HR+/HER2-negative breast cancer is defined as ER≥1%, HER2-negative (\<2+ Her2 IHC or \<2.2 HER2/CEP17 ratio by FISH) and either histologic grade II-III or a high-risk genomic assay score (Oncotype RS\>25, high risk Mammaprint, PAM-50, EndoPredict or ProSigna score).
• Note: Eligibility requires primary tumor size ≥1.0 cm in maximum diameter and axillary node-positive breast cancer
• Primary breast tumor measuring ≥1.5 cm in maximal diameter as measured by any available standard of care imaging (mammogram, breast ultrasound, breast MRI).
• Biopsy-proven, axillary lymph node-positive breast cancer at diagnosis. Note: Clinically node-positive disease is classified as cN1-3. cN1: without matted nodes, even if several/multiple appear matted on ultrasound or MRI; cN2: clinically fixed or matted nodes on examination or clinically or imaging-detected internal mammary node involvement.
• Clips or fiducial placement within the biopsy-proven axillary lymph node and breast primary tumor are required.
• 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.
• Synchronous bilateral invasive breast cancer is permitted; however only one breast tumor may be preoperatively boosted.
• No indication of distant metastases. Staging scans are not required and are per the discretion of the treating physician.
• Neoadjuvant chemotherapy (NAC) with paclitaxel, dose-dense doxorubicin and cyclophosphamide (dd AC) is planned. Note: For TNBC patients, administration of carboplatin is optional, as per MD choice. For HR+ patients, carboplatin will not be administered.
• The boost volume is determined to be able to meet study dose constraints by the treating radiation oncologist.
• Breast-conserving surgery or mastectomy +/- reconstruction is planned following NAC.

You may not qualify if:

• HER2-positive breast cancer by ASCO/CAP guidelines (HER2 IHC 3+ or ≥ 2.2 HER2/CEP17 ratio by FISH)
• Inflammatory (cT4d) breast cancer
• Metastatic breast cancer (M1)
• Contraindication(s) to breast-conserving therapy or mastectomy
• 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 breast, chest wall or thoracic radiotherapy
• 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 a known history of active tuberculosis (Bacillus tuberculosis
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
• 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.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has known severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.

Sponsors & Collaborators

• Laura M. Spring, MD: lead
• Merck Sharp & Dohme LLC: collaborator
• Breast Cancer Research Foundation: collaborator
• Translational Breast Cancer Research Consortium: collaborator

Study Sites (10)

Sibley Memorial Hospital

Washington D.C., District of Columbia, 20016, United States

Location

Johns Hopkins

Baltimore, Maryland, 21231, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02115, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Mayo Clinic - Rochester

Rochester, Minnesota, 55905, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Montefiore Medical Center

The Bronx, New York, 10467, United States

Location

University of North Carolina Medical Center

Chapel Hill, North Carolina, 27514, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Triple Negative Breast Neoplasms

Interventions

pembrolizumab; Paclitaxel; Carboplatin; Cyclophosphamide; Doxorubicin; Capecitabine

Condition Hierarchy (Ancestors)

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Coordination Complexes; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Laura M Spring, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Medical Oncologist

Study Record Dates

• First Submitted: June 19, 2020
• First Posted: June 23, 2020
• Study Start: December 16, 2020
• Primary Completion: August 8, 2025
• Study Completion (Estimated): August 1, 2027
• Last Updated: October 14, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Partners Innovations team at http://www.partners.org/innovation

Locations

US (10)