CMP-001 and Pre-operative Stereotactic Body Radiation Therapy (SBRT) in Early Stage Triple Negative Breast Cancer (TNBC)

  • STATUS
    Recruiting
  • End date
    Dec 19, 2025
  • participants needed
    40
  • sponsor
    Centre Hospitalier Universitaire Vaudois
Updated on 19 July 2021
breast surgery
estrogen
measurable disease
growth factor
endocrine therapy
progesterone
hormone therapy
immunohistochemistry
epidermal growth factor receptor
HER2
EGFR
triple negative breast cancer
progesterone receptor
erbb2
epidermal growth factor
estrogen receptor
mastectomy
breast-conserving surgery
mammogram

Summary

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).

Description

This is a Phase 2, proof of principle study that explores the therapeutic window between diagnosis and surgery in patients with early stage invasive TNBC not being candidates for neo-adjuvant chemotherapy.

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 SBRT with or without CpG (CMP-001), a toll-like receptor (TLR) 9 agonist will induce an increase in sTILs in the tumor in patients with early invasive TNBC, which theoretically should improve those patients' prognosis.

There is growing evidence indicating that radiotherapy (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 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 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.

Details
Condition Triple Negative Breast Cancer, Breast Cancer
Treatment CMP-001, Stereotactic body radiotherapy
Clinical Study IdentifierNCT04807192
SponsorCentre Hospitalier Universitaire Vaudois
Last Modified on19 July 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Signed study Informed Consent Form prior to the initiation of any study procedures
Women age 18 years
Histologically confirmed diagnosis of triple negative breast cancer (TNBC) of early stage (cT1-2, at least 5 mm, cN0-1 cM0) determined according to immunohistochemistry (IHC)/ fluorescence in situ hybridization (FISH) and current American Society of Clinical Oncology (ASCO) guidelines. TNBC subtype is defined as
Estrogen receptor (ER) <10%
Progesterone receptor (PR) <10%
Human epidermal growth factor receptor 2 (HER2) negative (not eligible for anti-HER2 therapy) defined as
IHC 0, 1+ without ISH or
IHC 2+ and ISH non-amplified with ratio less than 2.0 and if reported, average HER2 copy number < 6 signals/cells or
ISH non-amplified with ratio less than 2.0 and if reported, average HER2 copy number < 6 signals/cells (without IHC)
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
Women with bilateral breast TNBC can be acceptable if both sides are TNBC (treatment is allowed to be administered to one breast only)
Capable of understanding and complying with protocol requirements
A planned breast surgery (Breast conserving surgery [BCS] or mastectomy)
No planned neoadjuvant chemotherapy/endocrine therapy or other anticancer therapy
Presence of measurable disease in the breast, defined as a lesion that can be accurately measured in at least one dimension with conventional techniques (Magnetic resonance imaging [MRI] and/or ultrasound)
Primary tumor accessible to injections and biopsy. Multifocal and multicentric disease is allowed and the most accessible lesion will be injected. The lesion to be injected should be confined in a single irradiation volume that does not result in more than 30% of the whole breast
The injected tumor should be located at least 5 mm from the skin or pectoral muscle
Most recent laboratory values (within 28 days prior to randomization) meet the following standards
Bone marrow function
neutrophil count 1.5 G/L
hemoglobin 90 g/L
platelet count 100 G/L
Liver function
total bilirubin within normal ranges of each institution (except patients with Gilbert's syndrome who must have total bilirubin < 3.0 mg/dL)
aspartate aminotransferase (AST) 2.5 times the ULN range
alanine aminotransferase (ALT) 2.5 times the ULN range
Renal function: estimated glomerular filtration rate (eGFR) 40 ml/min/1.73 m2 (according to Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula)
For women of childbearing potential (WOCBP)
Agreement to use an acceptable method of effective contraception from screening until 30 days after last study treatment (RT and CMP-001)
WOCBP must have a negative urine/blood pregnancy test within 7 days before registration and prior to the first study treatment. A positive urine test must be confirmed by a serum pregnancy test

Exclusion Criteria

Subjects presenting with any of the following do not qualify for entry into
the study
Breast-feeding women (absence of pregnancy should be confirmed by a negative pregnancy test within 7 days of randomization, a positive urine pregnancy test should be confirmed by a serum -Human chorionic gonadotropin [-HCG] test)
Medical history and concurrent diseases
\. History of malignancy other than TNBC within 5 years prior to screening
with the exception of malignancies with a negligible risk of metastasis or
death (e.g., 5-year OS rate >90%), such as adequately treated carcinoma of the
cervix in situ, non-melanoma skin carcinoma, ductal carcinoma in situ, or
Stage I uterine cancer
\. Known infection with human immunodeficiency virus (HIV), hepatitis B virus
(HBV) or hepatitis C virus (HCV)
\. Developed autoimmune disorders of Grade 4 while on prior immunotherapy
Subjects who developed autoimmune disorders of Grade 3 may enroll if the
disorder has resolved to Grade 1 and the subject has been off systemic
steroids for at least 2 weeks
\. Any concurrent uncontrolled illness, including mental illness or substance
abuse, which in the opinion of the Investigator, would make the subject unable
to cooperate and participate in the trial
\. Severe uncontrolled cardiac disease within 6 months of Screening
including but not limited to uncontrolled hypertension; unstable angina
myocardial infarction (MI) or cerebrovascular accident (CVA)
\. Active, known, or suspected autoimmune disease
Participants with well controlled asthma and/or mild allergic rhinitis (seasonal allergies) are eligible
Participants with the following disease conditions are also eligible
Vitiligo
Type 1 diabetes mellitus
Residual hypothyroidism due to autoimmune condition only requiring hormone replacement
Psoriasis not requiring systemic treatment conditions not expected to recur in the absence of an external trigger are permitted to enroll 8. History of allergic reactions attributed to compounds of similar chemical or biologic composition to CMP-001 9. Any history of adrenal deficiency
Prohibited treatments and/or therapies
\. Any prior ipsilateral breast irradiation
\. Received investigational therapy with another drug or biologic within 28
days prior to randomization
\. Require systemic pharmacologic doses of corticosteroids at or above the
equivalent of 10 mg/day prednisone; replacement doses, topical, ophthalmologic
and inhalational steroids are permitted. Subjects who are currently receiving
steroids at a dose of < 10 mg/d do not need to discontinue steroids prior to
randomization
\. Requires prohibited treatment (i.e., non-protocol specified anticancer
pharmacotherapy, surgery or conventional radiotherapy for treatment of
malignant tumor)
\. For arm 2: Requires concomitant treatment with warfarin. Other
anticoagulants (ie, low molecular weight heparins, non-steroidal anti-
inflammatory drugs) are allowed as long as the institutional guidelines
requiring their withholding for interventional radiology procedures can be
followed
\. Administration of a live, attenuated vaccine within 2 weeks before
randomization
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