Neoadjuvant, SBRT With Intratumoural Pembrolizumab Followed by Neoadjuvant Chemotherapy in Breast Cancer

Official title

A Trial of Neoadjuvant, Hypofractionated Radiation, With Intratumoural Pembrolizumab Followed by Neoadjuvant Chemotherapy, in Stage 3 or High-risk Stage 2 Breast Cancer

Overview

This study will evaluate the immune-priming effects of stereotactic body radiation therapy (SBRT) regimen coupled with two injections of pembrolizumab in high-risk primary breast carcinoma prior to neoadjuvant chemotherapy. Preliminary results from the investigators' local TRIO Trial suggest that SBRT prior to neoadjuvant chemotherapy (NAC) may result in improved response rates due to the combined effect of radiation therapy (RT) and chemotherapy. The investigators aim to augment this effect with the addition of pembrolizumab, a monoclonal antibody that binds to and blocks programmed cell death protein 1 (PD-1).

Detailed description

This study will evaluate the immune-priming effects of stereotactic body radiation therapy (SBRT) combined with intratumoural pembrolizumab in patients with high-risk primary breast carcinoma prior to neoadjuvant chemotherapy. Prior feasibility trials (SIGNAL and TRIO) demonstrated that neoadjuvant SBRT can upregulate immune-related genes, suggesting conversion of tumors toward an "immune hot" phenotype that may enhance responsiveness to immunotherapy.

The current trial builds on this work by adding pembrolizumab, an anti-PD-1 antibody, to determine whether further immune priming can be achieved. Study objectives include assessing feasibility, safety, molecular immune activation, and preliminary clinical outcomes of this regimen before standard chemotherapy.

SBRT is a highly targeted radiotherapy technique that has demonstrated feasibility in early and locally advanced breast cancer trials, with low toxicity. Pembrolizumab is approved for multiple cancers, including triple negative breast cancer, and may act synergistically with radiotherapy to enhance antitumor immune responses. Findings from this study will inform future randomized trials evaluating whether combining SBRT and immunotherapy can improve pathologic complete response rates and long-term outcomes in breast cancer.

Interventions

• Radiation Radiation
  Stereotactic body radiation therapy to the breast
• Drug Pembrolizumab (KEYTRUDA®)
  Two injections

Primary outcome measures

• Pathological Complete Response [Time frame: Measured at time of surgery, typically 6 months after enrollment in trial.]

Secondary outcome measures (4)

• Immune priming [Time frame: Measured 3 to 8 days after last dose of pembrolizumab. Which is Day 20-25, where blood and tissue will be collected.]
• Breast and skin tissue adverse events to evaluate toxicity of treatment [Time frame: Baseline, 3 weeks post-op, 6 months post-op, 1 year post-op]
• Treatment related adverse event [Time frame: Measured at up to surgery, typically 6 months after enrolment in trial.]
• Local Recurrence Rates [Time frame: Disease status will be evaluated at routine patient follow-up appointments, including yearly mammography. Will be recorded at Year 1, Year 2, Year 3, Year 4, Year 5]

Eligibility criteria

Inclusion criteria

• Invasive ductal carcinoma of any subtype (including invasive mammary carcinoma with lobular features), excluding sarcomatous, signet or metaplastic subtypes.
• Invasive mammary carcinoma of stages IIB - III (excluding inflammatory breast cancer). Stage IIA is eligible for triple negative and HER2+ breast cancers.

a. Clinical staging based on AJCC 8th edition.

• Lesion palpable by treating physician.
• Plan to be treated with neoadjuvant chemotherapy.
• Able to tolerate core needle biopsies and pembrolizumab injection.
• 18 years of age or older.
• Able to provide informed consent.

Exclusion criteria

• Any serious medical comorbidities or other contraindications to radiotherapy, chemotherapy, or surgery (e.g., uncontrolled diabetes, serious heart condition, etc).
• Prior treatment for current breast cancer.
• Previous radiation therapy to the same breast.
• Inflammatory breast carcinoma.
• Invasive mammary carcinoma with sarcomatous, signet cell or metaplastic subtypes.
• Recurrent breast cancer.
• Clinical or radiologic evidence or suspicion of distant metastatic disease (metastatic workup that requires additional imaging to follow-up on suspicious findings will exclude patients).
• Any collagen vascular disease precluding radiotherapy at the discretion of the treating radiation oncologist (particularly lupus, scleroderma, dermatomyositis, psoriatic arthritis).
• No prior stem cell transplantation.
• Any poorly controlled autoimmune conditions.
• Current use of corticosteroids or immunosuppressants.
• Any other malignancy at any site (except non-melanomatous skin cancer) <5 years prior to study enrollment. Synchronous bilateral breast cancers are acceptable.
• Inability to tolerate core needle biopsies or pembrolizumab injection.
• Pregnant or lactating.
• Under 18 years of age.
• Inability or unwillingness to provide informed consent.
• Inability or unwillingness to complete study assessments/interventions and follow-up assessments.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Canada · 2 centers

• St. Joseph's Health Care London — London
• St. Joseph's Health Care London — London

Publications

• Barendsen GW. Dose fractionation, dose rate and iso-effect relationships for normal tissue responses. Int J Radiat Oncol Biol Phys. 1982 Nov;8(11):1981-97. doi: 10.1016/0360-3016(82)90459-x. No abstract available. PMID 6759484
• Beal K, McCormick B, Zelefsky MJ, Borgen P, Fey J, Goldberg J, Cohen GN, Sacchini V. Single-fraction intraoperative radiotherapy for breast cancer: early cosmetic results. Int J Radiat Oncol Biol Phys. 2007 Sep 1;69(1):19-24. doi: 10.1016/j.ijrobp.2007.02.010. Epub 2007 Apr 18. PMID 17446003
• Blitzblau RC, Arya R, Yoo S, Baker JA, Chang Z, Palta M, Duffy E, Horton JK. A phase 1 trial of preoperative partial breast radiation therapy: Patient selection, target delineation, and dose delivery. Pract Radiat Oncol. 2015 Sep-Oct;5(5):e513-e520. doi: 10.1016/j.prro.2015.02.002. Epub 2015 Mar 31. PMID 25834942
• Bondiau PY, Courdi A, Bahadoran P, Chamorey E, Queille-Roussel C, Lallement M, Birtwisle-Peyrottes I, Chapellier C, Pacquelet-Cheli S, Ferrero JM. Phase 1 clinical trial of stereotactic body radiation therapy concomitant with neoadjuvant chemotherapy for breast cancer. Int J Radiat Oncol Biol Phys. 2013 Apr 1;85(5):1193-9. doi: 10.1016/j.ijrobp.2012.10.034. Epub 2013 Jan 16. PMID 23332384
• Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Holgado E, Iwata H, Masuda N, Otero MT, Gokmen E, Loi S, Guo Z, Zhao J, Aktan G, Karantza V, Schmid P; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): PMID 33278935
• Cortes J, Rugo HS, Cescon DW, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Perez-Garcia J, Iwata H, Masuda N, Torregroza Otero M, Gokmen E, Loi S, Guo Z, Zhou X, Karantza V, Pan W, Schmid P; KEYNOTE-355 Investigators. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2022 Jul 21;387(3):217-226. doi: 10.1056/NEJMoa2202809. PMID 35857659
• Dai M, Yip YY, Hellstrom I, Hellstrom KE. Curing mice with large tumors by locally delivering combinations of immunomodulatory antibodies. Clin Cancer Res. 2015 Mar 1;21(5):1127-38. doi: 10.1158/1078-0432.CCR-14-1339. Epub 2014 Aug 20. PMID 25142145
• Demaria S, Romano E, Brackstone M, Formenti SC. Immune induction strategies to enhance responses to PD-1 blockade: lessons from the TONIC trial. J Immunother Cancer. 2019 Nov 21;7(1):318. doi: 10.1186/s40425-019-0783-x. PMID 31752991

Identifiers

NCT: NCT07188246 · 122109

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗