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JOURNAL ONKOLOGIE – STUDIE

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

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NCT-Nummer:
NCT04807192

Studienbeginn:
April 2021

Letztes Update:
19.03.2021

Wirkstoff:
CMP-001

Indikation (Clinical Trials):
Breast Neoplasms, Triple Negative Breast Neoplasms

Geschlecht:
Frauen

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
Centre Hospitalier Universitaire Vaudois

Collaborator:
-

Kontakt

Studienlocations
(1 von 1)

Studien-Informationen

Detailed 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 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'

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.

Ein-/Ausschlusskriterien

Inclusion Criteria:

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

following standards:

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]

formula)

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.

Exclusion Criteria:

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:

- 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:

10. Any prior ipsilateral breast irradiation.

11. Received investigational therapy with another drug or biologic within 28 days prior to

randomization.

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

tumor).

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.

Studien-Rationale

Primary outcome:

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.



Secondary outcome:

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

Studien-Arme

  • Experimental: Arm 1: SBRT
  • Experimental: Arm 2: CMP-001 + SBRT

Geprüfte Regime

  • stereotactic body radiotherapy:
    one administration of SBRT 8 Gy at D1
  • CMP-001:
    4 sequential administrations of CMP001 at Day 1 (SC), Day 5 (±1) (IT), Day 9 (±1) (IT) and Day 16 (±1) (IT)

Quelle: ClinicalTrials.gov


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