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Three Fraction Radiation to Induce Immuno-Oncologic Response (TRIO)

Primary Purpose

High-Risk Cancer, Locally Advanced Breast Cancer

Status

Recruiting

Phase

Not Applicable

Locations

Canada

Study Type

Interventional

Intervention

Neoadjuvant radiotherapy

About this trial

This is an interventional treatment trial for High-Risk Cancer focused on measuring locally advanced breast cancer, immune priming, radiation therapy, neoadjuvant radiation, radiotherapy, immuno-oncology

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

London Regional Cancer ProgramRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Neoadjuvant radiotherapy

Arm Description

3 doses of stereotactic radiotherapy administered prior to neoadjuvant chemotherapy in high-risk breast cancers.

Outcomes

Primary Outcome Measures

Pathologic complete response

Pathologic complete response rates after neoadjuvant radiotherapy and chemotherapy will be evaluated.

Secondary Outcome Measures

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

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

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.

Radiation toxicity

Toxicity to surrounding breast and skin tissue, defined by ≥ grade 2 fibrosis.

Surgical wound healing and the overall complication rate.

Percentage of patients experiencing wound infection that requires wound to be opened and/or packed.

Local recurrence rates

Ipsilateral breast recurrence rate.

Ability of imaging to predict patient response to radiotherapy.

Correlation between complete clinical response on imaging and pathological complete response.

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.

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.

Full Information

NCT ID

NCT03978663

First Posted

June 1, 2019

Last Updated

April 25, 2023

Sponsor

Lawson Health Research Institute

1. Study Identification

Unique Protocol Identification Number

NCT03978663

Brief Title

Three Fraction Radiation to Induce Immuno-Oncologic Response

Acronym

TRIO

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

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Recruiting

Study Start Date

September 2, 2020 (Actual)

Primary Completion Date

November 2023 (Anticipated)

Study Completion Date

May 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Lawson Health Research Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

High-Risk Cancer, Locally Advanced Breast Cancer

Keywords

locally advanced breast cancer, immune priming, radiation therapy, neoadjuvant radiation, radiotherapy, immuno-oncology

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Neoadjuvant radiotherapy

Arm Type

Experimental

Arm Description

3 doses of stereotactic radiotherapy administered prior to neoadjuvant chemotherapy in high-risk breast cancers.

Intervention Type

Radiation

Intervention Name(s)

Neoadjuvant radiotherapy

Intervention Description

Neoadjuvant radiation therapy delivered to a portion of the index tumour for high-risk breast carcinoma for immune priming prior to neoadjuvant radiation

Primary Outcome Measure Information:

Title

Pathologic complete response

Description

Pathologic complete response rates after neoadjuvant radiotherapy and chemotherapy will be evaluated.

Time Frame

Measured at time of surgery, typically 6 months after enrollment in trial.

Secondary Outcome Measure Information:

Title

Response rates in the primary post chemotherapy by imaging

Description

Response rates in the primary post chemotherapy by MRI +/- PET scan compared to pre-neoadjuvant radiation imaging

Time Frame

Measured after neoadjuvant radiation and chemotherapy has been completed, prior to surgery, typically 6 months after enrollment in trial.

Title

Response rates in the axillary nodes post chemotherapy by imaging and pathology

Description

Absence of any invasive breast cancer cells in any tissue at time of surgery

Time Frame

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.

Title

Immune priming

Description

Time Frame

Measured 14-20 days after the last dose of neoadjuvant radiation, prior to the start of neoadjuvant chemotherapy.

Title

Radiation toxicity

Description

Toxicity to surrounding breast and skin tissue, defined by ≥ grade 2 fibrosis.

Time Frame

Measured at study enrollment, at first surgical follow-up post-surgery, 6 months post surgery, and 1 year post surgery.

Title

Surgical wound healing and the overall complication rate.

Description

Percentage of patients experiencing wound infection that requires wound to be opened and/or packed.

Time Frame

Measured at the first surgical follow-up post-surgery, 6 months post surgery, and 1 year post surgery.

Title

Local recurrence rates

Description

Ipsilateral breast recurrence rate.

Time Frame

Disease status will be evaluated at routine patient follow-up appointments, including yearly mammography. Will be reported at year 3.

Title

Ability of imaging to predict patient response to radiotherapy.

Description

Correlation between complete clinical response on imaging and pathological complete response.

Time Frame

Pre-treatment imaging to be done after study enrollment (baseline) and 14-20 days after the last dose of neoadjuvant radiation has been delivered.

Title

Ability of imaging markers to predict response to radiotherapy

Description

Ability of FDG uptake, choline levels, perfusion, and ADC obtained from post-radiotherapy imaging to predict tissue response to high dose radiotherapy.

Time Frame

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.

Title

Ability to predict pathological response to treatment based on tumour genetics

Description

Ability to predict pathological response to treatment based on microarray analysis of tumor gene expression.

Time Frame

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.

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Muriel Brackstone, MD PhD

Phone

519-685-8500

Ext

58712

muriel.brackstone@lhsc.on.ca

First Name & Middle Initial & Last Name or Official Title & Degree

Kalan S Lynn

Phone

519-646-6100

Ext

61384

kalan.lynn@lhsc.on.ca

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Muriel Brackstone, MD PhD

Organizational Affiliation

London Health Sciences Centre/Lawson Health Research Institute

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Michael Lock, MD

Organizational Affiliation

London Health Sciences Centre/London Regional Cancer Program

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Brian Yaremko, MD

Organizational Affiliation

London Health Sciences Centre/London Regional Cancer Program

Official's Role

Study Chair

Facility Information:

Facility Name

London Regional Cancer Program

City

London

State/Province

Ontario

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Muriel Brackstone, MD, PhD

Phone

519-685-8712

Muriel.Brackstone@lhsc.on.ca

12. IPD Sharing Statement

Learn more about this trial

Three Fraction Radiation to Induce Immuno-Oncologic Response

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