A phase II study of preoperative stereotactic radiation therapy boost combined with short-course immunotherapy (pembrolizumab versus placebo, randomized, double-blind) and standard chemotherapy in patients with newly diagnosed HER2-negative non-metastatic breast cancer with lack of early metabolic response in 18-fluorodeoxyglucoseFDG-PET/CT after 1st chemoterapy cycle

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie-Panstwowy Instytut Badawczy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Jun 2024 → ongoing

Decision date (initial)

2023-06-26

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Agencja Badań Medycznych (project ABM No. 2021/ABM/03/00032-00)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

The assessment of the safety and effectiveness of the combination of anti-PD1 immunotherapy (pembrolizumab) and radiotherapy in the preoperative treatment of HER2-negative breast cancer resistant to classical chemotherapy

Secondary objectives 4

1. Evaluation of complete regression in the postoperative histopathological examination in the population of all 78 patients who will be treated with radiation preoperatively
2. Evaluation of regression under the influence of pembrolizumab in postoperative histopathological examination by quantitative method, taking into account the degree of partial regression
3. Assessment of time to recurrence of invasive cancer - (Invasive Disease Free Survival, IDFS), comparison of the group treated with pembrolizumab plus radiotherapy to the group treated with placebo plus radiotherapy
4. Comparison of quality of life - general health status of the group treated with pembrolizumab plus radiotherapy to the group treated with placebo plus radiotherapy

Conditions and MedDRA coding

HER2 negative breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. Woman or man over 18 years of age at the time of signing the informed consent for the study
2. Diagnosis of invasive breast cancer
3. Patient eligible for standard preoperative breast cancer chemotherapy with anthracyclines and paclitaxel, as assessed by the investigator
4. Breast cancer stage: any T at least cN1-cN3 or cT4 any N (stages IIAB-III, excluding patients cT1-3 N0). Oligometastatic disease (grade IV, up to 3 foci in one organ or 2 foci in 2 different organs in total) is acceptable, if radical treatment using local methods is possible, both in the treatment of the primary tumor and in the treatment of the metastatic focus (radiotherapy, surgery). Patients with distant metastases who are not eligible for radical treatment cannot be included
5. Triple negative estrogen receptor negative tumor (ER<1% and PR<1%) or HER2-negative luminal tumor. In postmenopausal patients with luminal A tumors (ER>30%, Ki67 below 20% and PR>30%), in postmenopausal patients no decrease in Ki67 to below 10% after 2-6 weeks of induction preoperative antihormonal therapy
6. HER2-negative tumor (expression assessed as 0 or + by immunohistochemistry, ++ expression negative by in situ hybridization assessment of HER2 amplification)
7. Clearly multifocal or multicenter tumors are acceptable if the HER2-negative status is confirmed in all identified foci of invasive neoplasm; it is not required in the case of satellite foci adjacent to the tumor mass or small foci less than 1 cm in diameter, identified in an MRI examination
8. No prior chemotherapy due to a current diagnosis of breast cancer and no prior anthracycline chemotherapy for any reason; earlier preoperative hormone therapy is allowed if the patient, in the opinion of the investigator, requires chemotherapy; it is allowed to include patients after 1 module of AC chemotherapy (4 cycles), if the patient has performed a PET/CT scan with the use of 18-FDG before starting treatment
9. Oncological treatment for another cancer is acceptable if it was radical, completed at least 1 year prior to inclusion in the study, and did not include ipsilateral chest radiotherapy to the ipsilateral chest area as the currently treated breast cancer
10. No contraindications to radiation treatment, including those related to the diagnosis of a systemic disease (e.g. scleroderma), previous radiotherapy in the area covered by the planned irradiation, significant limitation of mobility, or the presence of implantable devices in the irradiated area; patients with a pacemaker/cardioverter can be treated if it is possible to safely perform radiotherapy procedures under the supervision of a cardiologist (confirmed by consultation)
11. ECOG PS performance status 0 or 1
12. Bone marrow function confirmed by hemoglobin concentration ≥9 g/dL and neutrophil count (ANC) ≥1500/μL and platelet count ≥100,000/μL
13. Bilirubin concentration ≤ 1.5 x upper limit of normal (ULN), except in patients with a confirmed diagnosis of Gilbert's syndrome by previous measurements or other method (then direct bilirubin ≤ ULN)
14. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 3 x ULN
15. Creatinine level ≤ ULN or creatinine clearance ≥50 mL/min according to the Cockcroft-Gault method in patients with a creatinine level above the upper limit of normal
16. Left ventricular ejection fraction EF ≥ 50%
17. No contraindications for breast magnetic resonance imaging (MR)
18. In patients with procreative ability: consent to the implementation of adequate methods of contraception before inclusion in the study, during therapy and for at least 12 months after the end of systemic treatment (women) or 14 weeks (men)
19. Giving informed written consent to participate in the study

Exclusion criteria 17

1. Inflammatory breast cancer (cT4d)
2. Hypersensitivity to drugs or auxiliary substances used in the study, in the opinion of the researcher, not allowing for therapy
3. Major surgical or medical procedure within 14 days prior to study entry; does not apply to risk-reducing surgery and diagnostic procedures
4. Parallel coexisting invasive cancer
5. Concomitant known HIV infection, known active HBV or HCV infection
6. Diagnosed autoimmune disease requiring immunosuppressive therapy; does not apply to thyroid diseases, if in the opinion of the endocrinologist they are not a contraindication to starting pembrolizumab therapy
7. Any disease requiring systemic steroid therapy within 3 weeks prior to study entry
8. Serious, uncontrolled mental illness
9. Condition after organ allotransplantation
10. Condition after implantation of devices that do not allow MRI of the breast (does not apply to examinations with the assistance of a cardiologist, if the patient qualifies for such a procedure)
11. Pregnancy or breastfeeding
12. Previous treatment with anti-PD-1, anti-PD-L1, anti-PD-L2 or drugs targeting other T cell receptor inhibitors (e.g. CTLA-4, OX-40, CD-137)
13. History of non-infectious pneumonia requiring steroid therapy or current pneumonia
14. Active infection requiring systemic treatment
15. Significant cardiovascular disease, such as: acute coronary syndrome within the last 6 months, New York Heart Association (NYHA) class II-IV heart failure, or history of heart failure class III or IV
16. History of active tuberculosis
17. Other criteria, coexisting medical conditions, conditions, therapies, deviations in laboratory tests, or circumstances that, in the opinion of the investigator, do not allow the safe conduct of study procedures, may interfere with study results, or may substantially limit patient compliance with study rules

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Histopathological confirmation in the postoperative material of complete tumor regression after preoperative systemic treatment (pCR), defined as the absence of invasive tumor tissue in the breast and regional lymph nodes (AJCC/UICC definition, allows residual DCIS tissue as pCR ypT0/is N0)

Secondary endpoints 4

1. Assessment of complete regression in the postoperative histopathological examination in the population of all 78 patients receiving preoperative chemotherapy and radiotherapy. The presence of pCR in more than 13 patients out of a group of 78 enrolled and receiving chemotherapy and radiotherapy will be treated as fulfillment of the secondary endpoint criterion
2. Evaluation of response to preoperative treatment by evaluating postoperative material in histopathological examination according to the RCB (Residual Cancer Burden) protocol, comparing the group treated with pembrolizumab with radiotherapy to the group treated with placebo and radiotherapy, by comparing the numerical RCB ratio between both groups
3. Assessment of time to recurrence of invasive cancer - (Invasive Disease Free Survival, IDFS), comparison of the group treated with pembrolizumab with radiotherapy to the group treated with placebo + radiotherapy (according to Proposal for Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials: The STEEP System, Hudis et al. Journal of Clinical Oncology 2007)
4. Comparison of quality of life - general health status based on the QL2 scale of the EORTC QLQ-C30 questionnaire of the group treated with pembrolizumab with radiotherapy to the group treated with placebo and radiotherapy

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie-Panstwowy Instytut Badawczy

Sponsor organisation

Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie-Panstwowy Instytut Badawczy

Address

Ul. Wybrzeze Armii Krajowej 15

City

Gliwice

Postcode

44-102

Country

Poland

Scientific contact point

Organisation

Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie-Panstwowy Instytut Badawczy

Contact name

Agnieszka Ciomber

Public contact point

Organisation

Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie-Panstwowy Instytut Badawczy

Contact name

Agnieszka Ciomber

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

2 submissions — initial application plus substantial / non-substantial modifications