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

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ClinicalTrials.gov Identifier: NCT03978663
Recruitment Status : Recruiting
First Posted : June 7, 2019
Last Update Posted : August 14, 2020
Sponsor:
Information provided by (Responsible Party):
Lawson Health Research Institute

Study Description
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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.

Condition or disease Intervention/treatment Phase
High-Risk Cancer Locally Advanced Breast Cancer Radiation: Neoadjuvant radiotherapy Not Applicable

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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Estimated Study Start Date : August 2020
Estimated Primary Completion Date : November 2022
Estimated Study Completion Date : November 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arms and Interventions
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Arm Intervention/treatment
Experimental: Neoadjuvant radiotherapy
3 doses of stereotactic radiotherapy administered prior to neoadjuvant chemotherapy in high-risk breast cancers.
 Radiation: Neoadjuvant radiotherapy
Neoadjuvant radiation therapy delivered to a portion of the index tumour for high-risk breast carcinoma for immune priming prior to neoadjuvant radiation


Outcome Measures
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Primary Outcome Measures :
  1. Pathologic complete response [ Time Frame: Measured at time of surgery, typically 6 months after enrollment in trial. ]
    Pathologic complete response rates after neoadjuvant radiotherapy and chemotherapy will be evaluated.


Secondary Outcome Measures :
  1. Response rates in the primary post chemotherapy by imaging [ Time Frame: Measured after neoadjuvant radiation and chemotherapy has been completed, prior to surgery, typically 6 months after enrollment in trial. ]
    Response rates in the primary post chemotherapy by MRI +/- PET scan compared to pre-neoadjuvant radiation imaging

  2. Response rates in the axillary nodes post chemotherapy by imaging and pathology [ 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. ]
    Absence of any invasive breast cancer cells in any tissue at time of surgery

  3. Immune priming [ Time Frame: Measured 14-20 days after the last dose of neoadjuvant radiation, prior to the start of neoadjuvant chemotherapy. ]
    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.

  4. Radiation toxicity [ Time Frame: Measured at study enrollment, at first surgical follow-up post-surgery, 6 months post surgery, and 1 year post surgery. ]
    Toxicity to surrounding breast and skin tissue, defined by ≥ grade 2 fibrosis.

  5. Surgical wound healing and the overall complication rate. [ Time Frame: Measured at the first surgical follow-up post-surgery, 6 months post surgery, and 1 year post surgery. ]
    Percentage of patients experiencing wound infection that requires wound to be opened and/or packed.

  6. Local recurrence rates [ Time Frame: Disease status will be evaluated at routine patient follow-up appointments, including yearly mammography. Will be reported at year 3. ]
    Ipsilateral breast recurrence rate.

  7. Ability of imaging to predict patient response to radiotherapy. [ 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. ]
    Correlation between complete clinical response on imaging and pathological complete response.

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

  9. Ability to predict pathological response to treatment based on tumour genetics [ 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. ]
    Ability to predict pathological response to treatment based on microarray analysis of tumor gene expression.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03978663


Contacts
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Contact: Muriel Brackstone, MD PhD 519-685-8500 ext 58712 muriel.brackstone@lhsc.on.ca
Contact: Kalan S Lynn 519-646-6100 ext 61384 kalan.lynn@lhsc.on.ca

Locations
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Canada, Ontario
London Regional Cancer Program Recruiting
London, Ontario, Canada
Contact: Muriel Brackstone, MD, PhD    519-685-8712    Muriel.Brackstone@lhsc.on.ca   
Sponsors and Collaborators
Lawson Health Research Institute
Investigators
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Principal Investigator: Muriel Brackstone, MD PhD London Health Sciences Centre/Lawson Health Research Institute
Study Chair: Michael Lock, MD London Health Sciences Centre/London Regional Cancer Program
Study Chair: Brian Yaremko, MD London Health Sciences Centre/London Regional Cancer Program
More Information
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Responsible Party: Lawson Health Research Institute
ClinicalTrials.gov Identifier: NCT03978663    
Other Study ID Numbers: 112626
First Posted: June 7, 2019    Key Record Dates
Last Update Posted: August 14, 2020
Last Verified: August 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Lawson Health Research Institute:
locally advanced breast cancer
immune priming
radiation therapy
 neoadjuvant radiation
radiotherapy
immuno-oncology
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases