Three Fraction Radiation to Induce Immuno-Oncologic Response

Study Overview
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Brief Summary
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Patients with high risk breast cancers (any locally advanced breast cancer patient defined as Stages IIB-III [excluding inflammatory breast cancer] with stage IIA being eligible for triple negative and HER2-positive breast cancers) will receive neoadjuvant radiation to any portion of their tumour in three fractions in order to act as an immune primer. Radiation will be delivered to a portion of the tumour in three fractions. The patient will be positioned prone as per the SIGNAL 2.0 protocol. The patient will then go on to standard of care treatment (neoadjuvant chemotherapy and surgery) followed by whole-breast radiation as needed. Pathologic complete response will be the primary outcome. Immune markers will also be evaluated.

Detailed Description
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Patients eligible for neoadjuvant chemotherapy for locally advanced stage III (non-inflammatory) breast cancer or stage IIb (triple negative or Her2+) breast cancers will be approached to participate in this single arm trial. Patients with staging investigations ruling out distant disease will be approached to participate and will undergo pre-treatment image guided core biopsy and blood samples for molecular correlative studies, followed by hypofractionated radiation (delivered prone) to entire tumor with dose constraints to skin, critical organs and contralateral breast, plus a 0.5 cm PTV. As much of the tumor that can receive planned dose of 8 Gy per fraction x 3 fractions every second day, with fall off dose to 4 Gy per fraction x 3 fractions for PTV margin. Two weeks following completion of radiation, patients will undergo a second image guided core needle biopsy of tumor and blood sample. They will then begin standard neoadjuvant chemotherapy (anthracycline and taxane based), followed by a third tissue biopsy under image guidance of any residual tumor and blood sample and then standard surgery (breast conserving or lumpectomy). This will be followed by standard whole breast radiation (50 Gy in 25 fractions). Herceptin therapy and hormonal therapy will be administered as per clinical standard when indicated. Primary outcome will be measured as pathological complete response to treatment, and secondary outcomes will include toxicity, immune markers (tumor infiltrating lymphocytes, PD-1 and PD-L1 up-regulation and changes to the circulating lymphocyte counts.

Official Title
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Evaluating the Use of Stereotactic Radiation Therapy Prior to Neoadjuvant Chemotherapy for High-risk Breast Carcinoma (a SIGNAL Series Clinical Trial): Three Fraction Radiation to Induce Immuno-Oncologic Response (TRIO Trial)

Conditions
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High-Risk Cancer, Locally Advanced Breast Cancer

Intervention / Treatment
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* Radiation: Neoadjuvant radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any biopsy-proven locally advanced breast cancer patient defined as Stages IIB-III (excluding inflammatory breast cancer). Stage IIA is eligible for triple negative and HER2-positive breast cancers Invasive mammary carcinoma of any subtype excluding lobular, sarcomatous, or metaplastic subtypes, or with lobular features Plan to be treated with neoadjuvant chemotherapy Able to fit in/have MRI 18 years of age or older Able to tolerate core needle biopsies Able to provide informed consent No evidence of metastatic disease Exclusion Criteria: Any serious medical comorbidities or other contraindications to radiotherapy, chemotherapy, or surgery Prior treatment for current breast cancer Previous radiation therapy to the same breast Inflammatory breast carcinoma Invasive lobular carcinoma or invasive mammary carcinoma with lobular, sarcomatous, or metaplastic subtypes, or with lobular features Recurrent breast cancer Bilateral breast cancer Evidence of distant metastatic disease Collagen vascular disease (particularly lupus, scleroderma, dermatomyositis, psoriatic arthritis) Any other malignancy at any site (except non-melanomatous skin cancer) <5 years prior to study enrollment Inability to lay prone with arms above the head for extended periods of time Inability to fit in/have an MRI Inability to tolerate core needle biopsies Pregnant or lactating Under 18 years of age Inability or unwillingness to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant radiotherapy<br>3 doses of stereotactic radiotherapy administered prior to neoadjuvant chemotherapy in high-risk breast cancers. | Radiation: Neoadjuvant radiotherapy<br>* Neoadjuvant radiation therapy delivered to a portion of the index tumour for high-risk breast carcinoma for immune priming prior to neoadjuvant radiation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic complete response | Pathologic complete response rates after neoadjuvant radiotherapy and chemotherapy will be evaluated. | Measured at time of surgery, typically 6 months after enrollment in trial. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rates in the primary post chemotherapy by imaging | Response rates in the primary post chemotherapy by MRI +/- PET scan compared to pre-neoadjuvant radiation imaging | Measured after neoadjuvant radiation and chemotherapy has been completed, prior to surgery, typically 6 months after enrollment in trial. | 
| Response rates in the axillary nodes post chemotherapy by imaging and pathology | Absence of any invasive breast cancer cells in any tissue at time of surgery | Measured after neoadjuvant radiation and chemotherapy has been completed, prior to surgery (imaging) and at time of surgery, typically 6 months after enrollment in trial. | 
| Immune priming | Immune priming as measured by amount of tumour infiltrating lymphocytes (CD8) into tumour specimen, as well as the expression of immune markers (PDL1, Fox3) and immune panel in blood (CD4, CD8, neutrophil, and macrophage counts). Angiogenesis will be examined using the CD31 or VEGF-a cell markers, proliferation will be examined using the Ki67 marker, hypoxia will be examined using the Carbonic Anhydrase 9 (CAH IX), or HIF1/HIF2 markers, apoptosis will be examined using the Caspase-3, or Tunnel markers, invasion will be analyzed using the vimentin, or SDF1-a markers. | Measured 14-20 days after the last dose of neoadjuvant radiation, prior to the start of neoadjuvant chemotherapy. | 
| Radiation toxicity | Toxicity to surrounding breast and skin tissue, defined by ≥ grade 2 fibrosis. | Measured at study enrollment, at first surgical follow-up post-surgery, 6 months post surgery, and 1 year post surgery. | 
| Surgical wound healing and the overall complication rate. | Percentage of patients experiencing wound infection that requires wound to be opened and/or packed. | Measured at the first surgical follow-up post-surgery, 6 months post surgery, and 1 year post surgery. | 
| Local recurrence rates | Ipsilateral breast recurrence rate. | Disease status will be evaluated at routine patient follow-up appointments, including yearly mammography. Will be reported at year 3. | 
| Ability of imaging to predict patient response to radiotherapy. | Correlation between complete clinical response on imaging and pathological complete response. | Pre-treatment imaging to be done after study enrollment (baseline) and 14-20 days after the last dose of neoadjuvant radiation has been delivered. | 
| Ability of imaging markers to predict response to radiotherapy | Ability of FDG uptake, choline levels, perfusion, and ADC obtained from post-radiotherapy imaging to predict tissue response to high dose radiotherapy. | Pre-treatment imaging to be done after study enrollment (baseline measurements) and 14-20 days after the last dose of neoadjuvant radiation has been delivered. | 
| Ability to predict pathological response to treatment based on tumour genetics | Ability to predict pathological response to treatment based on microarray analysis of tumor gene expression. | Tissue samples for analysis will be taken 14-20 days after completion of neoadjuvant radiation, prior to the start of neoadjuvant chemotherapy and will be compared with tissue taken prior to the start of neoadjuvant radiation. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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locally advanced breast cancer, immune priming, radiation therapy, neoadjuvant radiation, radiotherapy, immuno-oncology