This is an open-label, randomized, window-of-opportunity phase 2 clinical study evaluating the biological activity of preoperative Stereotactic Body RadioTherapy (SBRT) alone (Arm 1), and combined with subcutaneous (SC) followed by intra-tumoral (IT) administrations of CMP-001 (Arm 2), in subjects with early stage TNBC. Safety and efficacy of the treatments are also examined. The main hypothesis that the study treatment induces an increase in stromal tumor infiltrating lymphocytes (sTILs) will be explored in each arm separately. The study is designed as a randomized selection study, with randomization used to address patient selection bias while each arm is run as an independent study. No formal statistical comparison between the two arms is planned. 40 patients will be equally (1:1) randomized in this study (20 per arm), stratified into two groups according to primary treatment strategy (upfront surgery versus neoadjuvant chemotherapy).
This is a Phase 2, proof of principle study that explores the therapeutic window between diagnosis and upfront surgery or start of the neoadjuvant chemotherapy in patients with early stage invasive TNBC. The presence of tumor infiltrating lymphocytes (TILs) within the tumors of patients with early invasive TNBC has been associated with improved prognosis. The hypothesis of this study is that pre-operative stereotactic radiotherapy (SBRT) and SBRT combined with CpG (CMP-001), a Toll-like receptor (TLR) 9 agonist will induce an increase in stromal TILs (sTILs) in the tumor in patients with early invasive TNBC, which theoretically should improve those patients' prognosis. There is growing evidence indicating that RT induces massive release of tumor-associated antigens (TAAs) during cancer cell death. RT enhances tumor immunogenicity and increases the presence of effector immune cells to the tumor site. It increases availability of tumor antigens and promotes antigen capture, cell migration to the lymph nodes, polarization towards a tolerogenic or immunogenic phenotype or migration of lymphocytes into the tumor. Doses of around 8 Gray (Gy) induce more important immune infiltration. SBRT is a precise technique of irradiation within the tumor permitting high dose delivery in a safe manner with tight margins. In our study, the irradiated tissue will then be removed by surgery, allowing for standard of care irradiation to be administered postoperatively. However, the preoperative SBRT on the tumor might increase intratumoral or stromal TILs' presence. CMP-001 (vidutolimod, CYT003, QbG10) has already been shown to increase CD8+ T cell intratumoral infiltration in early clinical data, and ongoing data of a phase Ib clinical trial combining intratumoral (IT) injections of CMP-001 (3-10 mg) in melanoma lesions with Pembrolizumab show rapid abscopal responses in other skin lesions after 3 injections. The combination of IT CMP-001 and SBRT, through increased TAA release and immunologic enhancement due to the TLR9 agonist, might ultimately result in a clinically meaningful " in-situ vaccination " effect through enhancement of the host's antitumor immunity, promoting immune eradication of micrometastatic disease. The TNBC population is prone to micrometastatic disease, even at early stages; therefore any of these experimental treatments might result in increased TILs' infiltration, which theoretically would bring potential benefits in distant control of the disease and overall survival improvements.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
40
one administration of SBRT 8 Gy at D1
4 sequential administrations of CMP001 at Day 1 (SC), Day 5 (±1) (IT), Day 9 (±1) (IT) and Day 16 (±1) (IT)
CHUV Oncology Department
Lausanne, Canton of Vaud, Switzerland
To assess and describe independently in each arm the biological activity (increase in sTILs) of CMP-001 combined with SBRT and of SBRT alone in patients with early stage TNBC in a preoperative setting
A 10% increase in the presence of TILs (between baseline and surgery/biopsy before start of the neoadjuvant chemotherapy) is the defined threshold for efficacy. Percentage of sTILs will be quantified using hematoxylin and eosin (H\&E) staining and immunohistochemistry (IHC) as per current consensus.
Time frame: Evaluated between baseline and surgery (up to 7 weeks)
Toxicity of CMP-001 combined with SBRT and of SBRT alone
Assessement of the incidence and severity of AEs and SAEs
Time frame: (S)AEs collected continuously from the time of informed consent signature until end of treatment visit, which correspond to Day 51 to 60.
Tumor response: pCR and pPR
Percentage of patients with a pathological complete response (pCR) and pathological Partial Response (pPR) for the patients with upfront surgery in the breast tumoral lesion(s) (lymph node tumoral lesion(s) not included)
Time frame: evaluation at surgery (between day 21 and day 30 post-SBRT) or change from baseline to surgery (up to 7 weeks)
Tumor response: residual tumor cells
Estimated percentage of residual tumor cells in the breast and lymph node biopsies before the start of the neoadjuvant chemotherapy (for patients in the neoadjuvant group)
Time frame: evaluation at breast biopsy (between day 16 and day 30 post-SBRT)
Tumor response: minimal residual cancer
Percentage of patients with minimal residual cancer as assessed by the residual cancer burden index (RCB) at upfront surgery in the breast tumoral lesion(s) (lymph node tumoral lesion(s) not included). The index will also be estimated in the biopsy done before the neoadjuvant chemotherapy of patients without upfront surgery.
Time frame: evaluation at surgery (between day 21 and day 30 post-SBRT) or change from baseline to surgery (up to 7 weeks)
Tumor response: Ki-67
Mean change of proliferation index Ki-67 from baseline at upfront surgery / biopsy before the start of the neoadjuvant chemotherapy.
Time frame: evaluation at surgery (between day 21 and day 30 post-SBRT) or change from baseline to surgery (up to 7 weeks)
Tumor response: change in tumor characteristics
Mean change in tumor characteristics and peritumoral tissues as assessed by breast MRI and/or ultrasound (US) from baseline at upfront surgery / imaging before the start of the neoadjuvant chemotherapy. Data will also be compared to previously reported findings.
Time frame: evaluation at surgery (between day 21 and day 30 post-SBRT) or change from baseline to surgery (up to 7 weeks)
Time-to-event (TTE)
defined as time from the date of randomization to the date of earliest objective tumor recurrence, including progression that precludes surgery, or local or distant disease recurrence (deaths are censored)
Time frame: time from the date of randomization to the date of earliest objective tumor recurrence (up to 2 years from randomization)
Event-free survival (EFS) rate
EFS rate is defined as the percentage of patients who are alive and without event (protocol-defined progression prior to surgery / start of the neoadjuvant chemotherapy; local, regional, or distant recurrence of breast cancer following curative surgery; a new breast cancer; another new onset malignancy; or death as a result of any cause) at month 24, per the Kaplan-Meier estimate of recurrence-free survival at 24 months.
Time frame: at 24 months
Distant disease-free survival (DDFS) rate
DDFS rate is defined as the percentage of patients without objective distant tumor recurrence (outside of the ipsilateral locoregional region) at month 24, per the Kaplan-Meier estimate of distant tumor recurrence-free survival at 24 months.
Time frame: at 24 months
Overall survival (OS) rate
OS rate is defined as the percentage of patients who are alive at month 24, per the Kaplan-Meier estimate of overall survival at 24 months (as event is considered the death from any cause).
Time frame: at 24 months
Biological activity (difference between the 2 arms)
sTILs increase will be compared between the two arms
Time frame: Evaluated between baseline and surgery for both arms (up to 7 weeks)
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