Clinical trial NCT03978663: Three Fraction Radiation to Induce Immuno-Oncologic Response
Official title: 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: High-Risk Cancer
Locally Advanced Breast Cancer
Keywords: locally advanced breast cancer
immune priming
radiation therapy
neoadjuvant radiation
radiotherapy
immuno-oncology
Lead sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Sponsor class: OTHER
First posted: 2019-06-07
Enrollment: 40
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. 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
2. Invasive mammary carcinoma of any subtype excluding lobular, sarcomatous, or metaplastic subtypes, or with lobular features
3. Plan to be treated with neoadjuvant chemotherapy
4. Able to fit in/have MRI
5. 18 years of age or older
6. Able to tolerate core needle biopsies
7. Able to provide informed consent
8. No evidence of metastatic disease

Exclusion Criteria:

1. Any serious medical comorbidities or other contraindications to radiotherapy, chemotherapy, or surgery
2. Prior treatment for current breast cancer
3. Previous radiation therapy to the same breast
4. Inflammatory breast carcinoma
5. Invasive lobular carcinoma or invasive mammary carcinoma with lobular, sarcomatous, or metaplastic subtypes, or with lobular features
6. Recurrent breast cancer
7. Bilateral breast cancer
8. Evidence of distant metastatic disease
9. Collagen vascular disease (particularly lupus, scleroderma, dermatomyositis, psoriatic arthritis)
10. Any other malignancy at any site (except non-melanomatous skin cancer) \<5 years prior to study enrollment
11. Inability to lay prone with arms above the head for extended periods of time
12. Inability to fit in/have an MRI
13. Inability to tolerate core needle biopsies
14. Pregnant or lactating
15. Under 18 years of age
16. Inability or unwillingness to provide informed consent

Primary outcomes:
measure: Pathologic complete response
timeFrame: Measured at time of surgery, typically 6 months after enrollment in trial.
Secondary outcomes:
measure: Response rates in the primary post chemotherapy by imaging
timeFrame: Measured after neoadjuvant radiation and chemotherapy has been completed, prior to surgery, typically 6 months after enrollment in trial.
measure: Response rates in the axillary nodes post chemotherapy by imaging and pathology
timeFrame: 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.
measure: Immune priming
timeFrame: Measured 14-20 days after the last dose of neoadjuvant radiation, prior to the start of neoadjuvant chemotherapy.
measure: Radiation toxicity
timeFrame: Measured at study enrollment, at first surgical follow-up post-surgery, 6 months post surgery, and 1 year post surgery.
measure: Surgical wound healing and the overall complication rate.
timeFrame: Measured at the first surgical follow-up post-surgery, 6 months post surgery, and 1 year post surgery.
measure: Local recurrence rates
timeFrame: Disease status will be evaluated at routine patient follow-up appointments, including yearly mammography. Will be reported at year 3.
measure: Ability of imaging to predict patient response to radiotherapy.
timeFrame: Pre-treatment imaging to be done after study enrollment (baseline) and 14-20 days after the last dose of neoadjuvant radiation has been delivered.
measure: Ability of imaging markers to predict response to radiotherapy
timeFrame: 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.
measure: Ability to predict pathological response to treatment based on tumour genetics
timeFrame: 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.
Other outcomes:
Locations:
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
Study officials:
affiliation: London Health Sciences Centre/Lawson Health Research Institute
name: Muriel Brackstone, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: London Health Sciences Centre/London Regional Cancer Program
name: Michael Lock, MD
role: STUDY_CHAIR
affiliation: London Health Sciences Centre/London Regional Cancer Program
name: Brian Yaremko, MD
role: STUDY_CHAIR
References: