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

Primary Purpose

Triple Negative Breast Cancer

Status
Recruiting
Phase
Phase 2
Locations
Switzerland
Study Type
Interventional
Intervention
stereotactic body radiotherapy
CMP-001
Sponsored by
Centre Hospitalier Universitaire Vaudois
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Triple Negative Breast Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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%
    • 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)
  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.

Sites / Locations

  • CHUV Oncology DepartmentRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm 1: SBRT

Arm 2: CMP-001 + SBRT

Arm Description

Outcomes

Primary Outcome Measures

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) 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.

Secondary Outcome Measures

Toxicity of CMP-001 combined with SBRT and of SBRT alone
Assessement of the incidence and severity of AEs and SAEs
Tumor response: pCR and pPR
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)
Tumor response: minimal residual cancer
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)
Tumor response: Ki-67
Mean change of proliferation index Ki-67 from baseline at surgery.
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 surgery. Data will also be compared to previously reported findings.
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)
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; 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.
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.
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).
Biological activity (difference between the 2 arms)
sTILs increase will be compared between the two arms

Full Information

First Posted
February 12, 2021
Last Updated
July 6, 2021
Sponsor
Centre Hospitalier Universitaire Vaudois
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1. Study Identification

Unique Protocol Identification Number
NCT04807192
Brief Title
CMP-001 and Pre-operative Stereotactic Body Radiation Therapy (SBRT) in Early Stage Triple Negative Breast Cancer (TNBC)
Official Title
CMP-001 in Combination With Pre-Operative Stereotactic Body Radiation Therapy in Patients With Early Stage Triple Negative Breast Cancer: An Open-Label, Window of Opportunity, Randomized Phase 2 Clinical Study
Study Type
Interventional

2. Study Status

Record Verification Date
July 2021
Overall Recruitment Status
Recruiting
Study Start Date
April 8, 2021 (Actual)
Primary Completion Date
September 2023 (Anticipated)
Study Completion Date
December 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Centre Hospitalier Universitaire Vaudois

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief 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).
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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Triple Negative Breast Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm 1: SBRT
Arm Type
Experimental
Arm Title
Arm 2: CMP-001 + SBRT
Arm Type
Experimental
Intervention Type
Radiation
Intervention Name(s)
stereotactic body radiotherapy
Intervention Description
one administration of SBRT 8 Gy at D1
Intervention Type
Drug
Intervention Name(s)
CMP-001
Intervention Description
4 sequential administrations of CMP001 at Day 1 (SC), Day 5 (±1) (IT), Day 9 (±1) (IT) and Day 16 (±1) (IT)
Primary Outcome Measure Information:
Title
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
Description
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 hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) as per current consensus.
Time Frame
Evaluated between baseline and surgery (up to 7 weeks)
Secondary Outcome Measure Information:
Title
Toxicity of CMP-001 combined with SBRT and of SBRT alone
Description
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.
Title
Tumor response: pCR and pPR
Description
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)
Time Frame
evaluation at surgery (between day 21 and day 30 post-SBRT) or change from baseline to surgery (up to 7 weeks)
Title
Tumor response: minimal residual cancer
Description
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)
Time Frame
evaluation at surgery (between day 21 and day 30 post-SBRT) or change from baseline to surgery (up to 7 weeks)
Title
Tumor response: Ki-67
Description
Mean change of proliferation index Ki-67 from baseline at surgery.
Time Frame
evaluation at surgery (between day 21 and day 30 post-SBRT) or change from baseline to surgery (up to 7 weeks)
Title
Tumor response: change in tumor characteristics
Description
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.
Time Frame
evaluation at surgery (between day 21 and day 30 post-SBRT) or change from baseline to surgery (up to 7 weeks)
Title
Time-to-event (TTE)
Description
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)
Title
Event-free survival (EFS) rate
Description
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.
Time Frame
at 24 months
Title
Distant disease-free survival (DDFS) rate
Description
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
Title
Overall survival (OS) rate
Description
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
Title
Biological activity (difference between the 2 arms)
Description
sTILs increase will be compared between the two arms
Time Frame
Evaluated between baseline and surgery for both arms (up to 7 weeks)

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 β-Human chorionic gonadotropin [β-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 History of allergic reactions attributed to compounds of similar chemical or biologic composition to CMP-001 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Lana Kandalaft, Pharm D, PhD
Phone
+41213147823
Email
do.ion.ref@chuv.ch
Facility Information:
Facility Name
CHUV Oncology Department
City
Lausanne
State/Province
Vaud
ZIP/Postal Code
1011
Country
Switzerland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Khalil Zaman, MD
Phone
+41 21 314 79 05
Email
khalil.zaman@chuv.ch

12. IPD Sharing Statement

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

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