Breast Cancer, Doxorubicin Induced Cardiomyopathy
Conditions
Brief summary
This was a single center, proof-of-concept (PoC), Phase II study. Patients with histologically confirmed early stage (Stage I, II or III) HER-2 negative breast cancer and scheduled to receive doxorubicin-based (neo)adjuvant therapy to be followed by paclitaxel or docetaxel as per clinical practice. The planned doxorubicin-based chemotherapy treatment consisted of doxorubicin 60 mg/m2 in combination with cyclophosphamide 600 mg/m2 (AC) intravenous (IV) every 2 or 3 weeks for 4 cycles. Patients were scheduled for CMRI and 99mTc-rhAnnexin V-128 imaging (planar and SPECT / CT) at the following visits: 1. Screening/baseline, i.e. 2 weeks prior to initiating AC treatment (Visit 1) 2. After the 2nd and before the 3rd cycle of AC treatment (Visit 2) 3. After the 4th cycle of AC treatment and within 2 weeks (Visit 3) 4. At 12 weeks after the 4th cycle of AC treatment (Visit 4). The imaging procedures were conducted and analyzed. Bloodwork for cardiotoxicity biomarkers (troponin, N terminal pro B-type natriuretic peptide \[NT-proBNP\]) was performed at each visit.
Detailed description
Overall, it was planned to recruit 30 adults with early stage breast cancer. The first 10 patients were to be enrolled in the PoC phase of the study to assess the potential of 99mTc-rhAnnexin V-128 in terms of imaging quality, uptake and medical relevance. Based on the results of the first 10 patients, the DMC was to decide whether to terminate the study or continue to the Phase II and enroll the next 20 planned patients. The maximum study duration was 26 (±4) weeks per patient (including the screening and follow-up periods). The sponsor decided to terminate the study earlier than planned due to strategic decisions to focus the AAA development portfolio on oncology theragnostics and not based on safety concerns.
Interventions
RADIATION99mTc-rhAnnexin V-128
Kit for the preparation of 99mTc-rhAnnexin V-128
Sponsors
Advanced Accelerator Applications
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Females \>= 18 years of age with histologically confirmed early stage (Stage I, II or III) HER-2 negative breast cancer and planned for (neo)adjuvant doxorubicin-based chemotherapy (AC every 2 or 3 weeks x 4 cycles) 2. Eastern Cooperative Oncology Group Status (ECOG) ≤ 2 3. Able and willing to comply with the study procedures
Exclusion criteria
1. Pregnancy or lactation 2. Moderate or severe valvular stenosis or regurgitation 3. History of atrial fibrillation or flutter 4. History of any disease or relevant physical or psychiatric condition which may interfere with the study objectives at the investigator judgment 5. Know hypersensitivity to the investigational product (IP) or any of its components 6. Prosthetic valve or pacemaker 7. Claustrophobia or inability to lie still in a supine position 8. Contraindication(s) to the CMRI procedure 9. Participation in another clinical trial within 4 weeks before study inclusion, except for patients who have participated or who are currently participating in a study without any study drug administration 10. Unwillingness to provide consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part I / Proof of Concept (PoC): Number of Participants Evaluated for Imaging Feasibility | Day 0 (Baseline) | The feasibility of imaging apoptotic activity using 99mTc-rhAnnexin V-128 was assessed in the first 10 patients who enrolled and completed the PoC phase of the study by the data monitoring committee (visual image review and consensus). The three reviewers of the DMC did an independent visual assessment of the images using a 1 to 4 point grading system: each observer reviewed the images of each patient and scored either 1 or 2 (uptake was less than or equal to blood pool), these images were considered normal; 3 was equivocal and four equalled abnormal. Only descriptive analysis performed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 99mTc-rhAnnexin V-128 Myocardial Uptake | 60 and 120 minutes post injection at: Day 0 (Baseline), Visit 2 (After the 2nd and before the 3rd cycle of doxorubicin), Visit 3 (After the 4th cycle of doxorubicin and within 2 weeks), Visit 4 (12 weeks after the 4th cycle of doxorubicin) | Single-Photon Emission Computed Tomography (SPECT)/Computed Tomography (CT) scans of the thorax were acquired with a dual head SPECT/CT gamma camera with low-energy high-resolution collimators at 1 and 2 hours post-injection at each collection time point and were to be compared to Baseline. Myocardial uptake was measured from regions of interest (ROIs) placed over the myocardium on the SPECT images coregistered with the corresponding CT images for anatomic delineation. Myocardial uptake was expressed either in absolute units (% injected dose/g) or as a standardized uptake value (SUV). Only descriptive analysis performed. |
| Changes in Left Ventricular (LV) Function | Day 0 (Baseline), Visit 2 (After the 2nd and before the 3rd cycle of doxorubicin), Visit 3 (After the 4th cycle of doxorubicin and within 2 weeks), Visit 4 (12 weeks after the 4th cycle of doxorubicin) | The worsening of LV function was to be assessed by comparing cardiac magnetic resonance imaging (CMRI) left ventricular ejection fraction (LVEF) after the 2nd and the 4th cycle of doxorubicin/cyclophosphamide chemotherapy (AC) treatment and after 12 weeks of the last dose of doxorubicin compared to Baseline. Only descriptive analysis performed. |
| Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | Day 0 (Baseline), Visit 2 (After the 2nd and before the 3rd cycle of doxorubicin), Visit 3 (After the 4th cycle of doxorubicin and within 2 weeks), Visit 4 (12 weeks after the 4th cycle of doxorubicin) | The differences of LV function after the 2nd and the 4th cycle of doxorubicin/cyclophosphamide chemotherapy (AC) treatment and after 12 weeks of the last dose of doxorubicin compared to Baseline were to be correlated with the changes in cardiotoxicity biomarkers: Troponin and N Terminal pro B-type Natriuretic Peptide (NT-proBNP). Only descriptive analysis performed. |
Countries
Canada
Participant flow
Recruitment details
The study was conducted at single center in Canada.
Participants by arm
| Arm | Count |
|---|---|
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) After reconstitution and radiolabeling, 99mTc-rhAnnexin V-128 was administered as a single intravenous bolus of 350 MBq +/- 10% at baseline, after the 2nd cycle, after the 4th cycle and 12 weeks after AC chemotherapy. | 12 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) After reconstitution and radiolabeling, 99mTc-rhAnnexin V-128 was administered as a single intravenous bolus of 350 MBq +/- 10% at baseline, after the 2nd cycle, after the 4th cycle and 12 weeks after AC chemotherapy. | 2 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | 99mTc-rhAnnexin V-128 (Part II / Phase II) | Total |
|---|---|---|---|
| Age, Continuous | 54.3 Years STANDARD_DEVIATION 9.3 | 39.0 Years STANDARD_DEVIATION 0 | 52.1 Years STANDARD_DEVIATION 10.2 |
| Race/Ethnicity, Customized Black | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 11 Participants | 0 Participants | 11 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Female | 12 Participants | 2 Participants | 14 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 2 |
| other Total, other adverse events | 10 / 12 | 2 / 2 |
| serious Total, serious adverse events | 1 / 12 | 1 / 2 |
Outcome results
Primary
Part I / Proof of Concept (PoC): Number of Participants Evaluated for Imaging Feasibility
The feasibility of imaging apoptotic activity using 99mTc-rhAnnexin V-128 was assessed in the first 10 patients who enrolled and completed the PoC phase of the study by the data monitoring committee (visual image review and consensus). The three reviewers of the DMC did an independent visual assessment of the images using a 1 to 4 point grading system: each observer reviewed the images of each patient and scored either 1 or 2 (uptake was less than or equal to blood pool), these images were considered normal; 3 was equivocal and four equalled abnormal. Only descriptive analysis performed.
Time frame: Day 0 (Baseline)
Population: Full Analysis Set population (FAS). Only the first 10 participants who enrolled and completed the PoC phase of the study were included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | Part I / Proof of Concept (PoC): Number of Participants Evaluated for Imaging Feasibility | 10 Participants |
Secondary
99mTc-rhAnnexin V-128 Myocardial Uptake
Single-Photon Emission Computed Tomography (SPECT)/Computed Tomography (CT) scans of the thorax were acquired with a dual head SPECT/CT gamma camera with low-energy high-resolution collimators at 1 and 2 hours post-injection at each collection time point and were to be compared to Baseline. Myocardial uptake was measured from regions of interest (ROIs) placed over the myocardium on the SPECT images coregistered with the corresponding CT images for anatomic delineation. Myocardial uptake was expressed either in absolute units (% injected dose/g) or as a standardized uptake value (SUV). Only descriptive analysis performed.
Time frame: 60 and 120 minutes post injection at: Day 0 (Baseline), Visit 2 (After the 2nd and before the 3rd cycle of doxorubicin), Visit 3 (After the 4th cycle of doxorubicin and within 2 weeks), Visit 4 (12 weeks after the 4th cycle of doxorubicin)
Population: Full Analysis Set population (FAS). Only the participants who completed the 4 chemotherapy treatment cycles and underwent all study visits were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | 99mTc-rhAnnexin V-128 Myocardial Uptake | Day 0 - 60 mins after injection | 0.0035617 percentage of injected dose/g | Standard Deviation 0.0051846 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | 99mTc-rhAnnexin V-128 Myocardial Uptake | Day 0 - 120 mins after injection | 0.0024177 percentage of injected dose/g | Standard Deviation 0.0036831 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | 99mTc-rhAnnexin V-128 Myocardial Uptake | Visit 2 - 60 mins after injection | 0.0043825 percentage of injected dose/g | Standard Deviation 0.006713 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | 99mTc-rhAnnexin V-128 Myocardial Uptake | Visit 2 - 120 mins after injection | 0.0029255 percentage of injected dose/g | Standard Deviation 0.0045063 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | 99mTc-rhAnnexin V-128 Myocardial Uptake | Visit 3 - 60 mins after injection | 0.0018097 percentage of injected dose/g | Standard Deviation 0.0011105 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | 99mTc-rhAnnexin V-128 Myocardial Uptake | Visit 3 - 120 mins after injection | 0.0016232 percentage of injected dose/g | Standard Deviation 0.0008994 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | 99mTc-rhAnnexin V-128 Myocardial Uptake | Visit 4 - 60 mins after injection | 0.0020756 percentage of injected dose/g | Standard Deviation 0.0008986 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | 99mTc-rhAnnexin V-128 Myocardial Uptake | Visit 4 - 120 mins after injection | 0.0018475 percentage of injected dose/g | Standard Deviation 0.0005084 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | 99mTc-rhAnnexin V-128 Myocardial Uptake | Visit 4 - 120 mins after injection | 0.0006692 percentage of injected dose/g | Standard Deviation 0.0009463 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | 99mTc-rhAnnexin V-128 Myocardial Uptake | Day 0 - 60 mins after injection | 0.0003306 percentage of injected dose/g | Standard Deviation 0.0004675 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | 99mTc-rhAnnexin V-128 Myocardial Uptake | Visit 3 - 60 mins after injection | 0.0000512 percentage of injected dose/g | Standard Deviation 0.0000723 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | 99mTc-rhAnnexin V-128 Myocardial Uptake | Day 0 - 120 mins after injection | 0.0002125 percentage of injected dose/g | Standard Deviation 0.0003004 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | 99mTc-rhAnnexin V-128 Myocardial Uptake | Visit 4 - 60 mins after injection | 0.0010116 percentage of injected dose/g | Standard Deviation 0.0014306 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | 99mTc-rhAnnexin V-128 Myocardial Uptake | Visit 2 - 60 mins after injection | 0.0008123 percentage of injected dose/g | Standard Deviation 0.0011487 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | 99mTc-rhAnnexin V-128 Myocardial Uptake | Visit 3 - 120 mins after injection | 0.0002995 percentage of injected dose/g | Standard Deviation 0.0004236 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | 99mTc-rhAnnexin V-128 Myocardial Uptake | Visit 2 - 120 mins after injection | 0.0004827 percentage of injected dose/g | Standard Deviation 0.0006826 |
Secondary
Changes in Left Ventricular (LV) Function
The worsening of LV function was to be assessed by comparing cardiac magnetic resonance imaging (CMRI) left ventricular ejection fraction (LVEF) after the 2nd and the 4th cycle of doxorubicin/cyclophosphamide chemotherapy (AC) treatment and after 12 weeks of the last dose of doxorubicin compared to Baseline. Only descriptive analysis performed.
Time frame: Day 0 (Baseline), Visit 2 (After the 2nd and before the 3rd cycle of doxorubicin), Visit 3 (After the 4th cycle of doxorubicin and within 2 weeks), Visit 4 (12 weeks after the 4th cycle of doxorubicin)
Population: Full Analysis Set population (FAS). Only the participants who completed the 4 chemotherapy treatment cycles and underwent all study visits were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | Changes in Left Ventricular (LV) Function | Day 0 | 66.8 Percent | Standard Deviation 5.37 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | Changes in Left Ventricular (LV) Function | Visit 2 | 66.3 Percent | Standard Deviation 6.07 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | Changes in Left Ventricular (LV) Function | Visit 3 | 64.0 Percent | Standard Deviation 4.57 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | Changes in Left Ventricular (LV) Function | Visit 4 | 63.6 Percent | Standard Deviation 4.22 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | Changes in Left Ventricular (LV) Function | Visit 4 | 62.5 Percent | Standard Deviation 2.12 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | Changes in Left Ventricular (LV) Function | Day 0 | 64.0 Percent | Standard Deviation 2.83 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | Changes in Left Ventricular (LV) Function | Visit 3 | 65.0 Percent | Standard Deviation 1.41 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | Changes in Left Ventricular (LV) Function | Visit 2 | 60.5 Percent | Standard Deviation 0.71 |
Secondary
Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP)
The differences of LV function after the 2nd and the 4th cycle of doxorubicin/cyclophosphamide chemotherapy (AC) treatment and after 12 weeks of the last dose of doxorubicin compared to Baseline were to be correlated with the changes in cardiotoxicity biomarkers: Troponin and N Terminal pro B-type Natriuretic Peptide (NT-proBNP). Only descriptive analysis performed.
Time frame: Day 0 (Baseline), Visit 2 (After the 2nd and before the 3rd cycle of doxorubicin), Visit 3 (After the 4th cycle of doxorubicin and within 2 weeks), Visit 4 (12 weeks after the 4th cycle of doxorubicin)
Population: Full Analysis Set population (FAS). For each parameter, only participants with a value at both baseline and post baseline were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | Troponin - Day 0 | 0.015 ng/L | Standard Deviation 0.001 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | Troponin - Visit 2 | 0.019 ng/L | Standard Deviation 0.01 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | Troponin - Visit 3 | 0.025 ng/L | Standard Deviation 0.019 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | Troponin - Visit 4 | 0.060 ng/L | Standard Deviation 0.088 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | NT-proBNP - Day 0 | 49.6 ng/L | Standard Deviation 27.5 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | NT-proBNP - Visit 2 | 271.8 ng/L | Standard Deviation 399.76 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | NT-proBNP - Visit 3 | 123.7 ng/L | Standard Deviation 66.3 |
| 99mTc-rhAnnexin V-128 (Part I / Proof of Concept) | Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | NT-proBNP - Visit 4 | 123.6 ng/L | Standard Deviation 89.27 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | NT-proBNP - Visit 4 | 74.0 ng/L | Standard Deviation 29.7 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | Troponin - Day 0 | 0.015 ng/L | Standard Deviation 0 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | NT-proBNP - Day 0 | 60.0 ng/L | Standard Deviation 63.64 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | Troponin - Visit 2 | 0.015 ng/L | Standard Deviation 0 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | NT-proBNP - Visit 3 | 85.0 ng/L | Standard Deviation 49.5 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | Troponin - Visit 3 | 0.015 ng/L | Standard Deviation 0 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | NT-proBNP - Visit 2 | 104.0 ng/L | Standard Deviation 86.27 |
| 99mTc-rhAnnexin V-128 (Part II / Phase II) | Changes in the Cardiotoxicity Biomarkers (Troponin and NT-proBNP) | Troponin - Visit 4 | 0.028 ng/L | Standard Deviation 0.018 |