CMP-001 and Pre-operative Stereotactic Body Radiation Therapy (SBRT) in Early Stage Triple Negative Breast Cancer (TNBC)
Indikation (Clinical Trials):
Breast Neoplasms, Triple Negative Breast Neoplasms
Centre Hospitalier Universitaire Vaudois
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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
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 permiting 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'
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.
1. Signed study Informed Consent Form prior to the initiation of any study procedures
2. Women age ≥18 years
3. 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%
- Progesteron 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)
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
5. Women with bilateral breast TNBC can be acceptable if both sides are TNBC (treatment
is allowed to be administered to one breast only).
6. Capable of understanding and complying with protocol requirements
7. A planned breast surgery (Breast conserving surgery [BCS] or mastectomy).
8. No planned neoadjuvant chemotherapy/endocrine therapy or other anticancer therapy
9. 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)
10. 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.
11. The injected tumor should be located at least 5 mm from the skin or pectoral muscle
12. Most recent laboratory values (within 28 days prior to randomization) meet the
1. Bone marrow function:
- neutrophil count ≥1.5 G/L
- hemoglobin ≥ 90 g/L
- platelet count ≥ 100 G/L
2. 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
3. Renal function: estimated glomerular filtration rate (eGFR) ≥ 40 ml/min/1.73 m2
(according to Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]
13. For women of childbearing potential (WOCBP):
1. Agreement to use an acceptable method of effective contraception from screening
until 30 days after last study treatment (RT and CMP-001).
2. 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.
Subjects presenting with any of the following do not qualify for entry into the study:
1. 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 β-Human chorionic gonadotropin [β-HCG] test)
Medical history and concurrent diseases:
2. 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
3. Known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or
hepatitis C virus (HCV)
4. 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.
5. 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
6. 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)
7. 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:
- Type 1 diabetes mellitus
- Residual hypothyroidism due to autoimmune condition only requiring hormone
- 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:
10. Any prior ipsilateral breast irradiation.
11. Received investigational therapy with another drug or biologic within 28 days prior to
12. 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.
13. Requires prohibited treatment (i.e., non-protocol specified anticancer
pharmacotherapy, surgery or conventional radiotherapy for treatment of malignant
14. 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.
15. Administration of a live, attenuated vaccine within 2 weeks before randomization.
1. 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 (Time Frame - Evaluated between baseline and surgery (up to 7 weeks)):
A 10% increase in the presence of TILs (between baseline and surgery) is the defined threshold for efficacy. Percentage of sTILs will be quantified using heamatoxylin and eosin (H&E) staining and immunohistochemistry (IHC) as per current consensus.
1. Toxicity of CMP-001 combined with SBRT and of SBRT alone (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.):
Assessement of the incidence and severity of AEs and SAEs
2. Tumor response: pCR and pPR (Time Frame - evaluation at surgery (between day 21 and day 30 post-SBRT) or change from baseline to surgery (up to 7 weeks)):
Percentage of patients with a pathological complete response (pCR) and pathological Partial Response (pPR) at surgery in the breast tumoral lesion(s) (lymph node tumoral lesion(s) not included)
3. Tumor response: minimal residual cancer (Time Frame - evaluation at surgery (between day 21 and day 30 post-SBRT) or change from baseline to surgery (up to 7 weeks)):
Percentage of patients with minimal residual cancer as assessed by the residual cancer burden index (RCB) at surgery in the breast tumoral lesion(s) (lymph node tumoral lesion(s) not included)
4. Tumor response: Ki-67 (Time Frame - evaluation at surgery (between day 21 and day 30 post-SBRT) or change from baseline to surgery (up to 7 weeks)):
Mean change of proliferation index Ki-67 from baseline at surgery.
5. Tumor response: change in tumor characteristics (Time Frame - evaluation at surgery (between day 21 and day 30 post-SBRT) or change from baseline to surgery (up to 7 weeks)):
Mean change in tumor characteristics and peritumoral tissues as assessed by breast MRI and/or ultrasound (US) from baseline at surgery. Data will also be compared to previously reported findings.
6. Time-to-event (TTE) (Time Frame - time from the date of randomization to the date of earliest objective tumor recurrence (up to 2 years from randomization)):
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)
7. Event-free survival (EFS) rate (Time Frame - at 24 months):
EFS rate is defined as the percentage of patients who are alive and without event (protocol-defined progression prior to surgery; 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.
8. Distant disease-free survival (DDFS) rate (Time Frame - at 24 months):
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.
9. Overall survival (OS) rate (Time Frame - at 24 months):
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).
10. Biological activity (difference between the 2 arms) (Time Frame - Evaluated between baseline and surgery for both arms (up to 7 weeks)):
sTILs increase will be compared between the two arms
- Experimental: Arm 1: SBRT
- Experimental: Arm 2: CMP-001 + SBRT
- stereotactic body radiotherapy:
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)
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