99mTc-rhAnnexin V-128 Imaging and Cardiotoxicity in Patients With Early Breast Cancer

Study Overview
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Brief Summary
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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: Screening/baseline, i.e. 2 weeks prior to initiating AC treatment (Visit 1) After the 2nd and before the 3rd cycle of AC treatment (Visit 2) After the 4th cycle of AC treatment and within 2 weeks (Visit 3) 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
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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.

Official Title
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99mTc-rhAnnexin V-128 Imaging of Apoptosis and Cardiotoxicity in Relationship to Ventricular Function in Patients With Early Stage Breast Cancer Receiving Doxorubicin-Based Chemotherapy

Conditions
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Breast Cancer, Doxorubicin Induced Cardiomyopathy

Intervention / Treatment
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* Radiation: 99mTc-rhAnnexin V-128


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 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) Eastern Cooperative Oncology Group Status (ECOG) ≤ 2 Able and willing to comply with the study procedures Exclusion criteria: Pregnancy or lactation Moderate or severe valvular stenosis or regurgitation History of atrial fibrillation or flutter History of any disease or relevant physical or psychiatric condition which may interfere with the study objectives at the investigator judgment Know hypersensitivity to the investigational product (IP) or any of its components Prosthetic valve or pacemaker Claustrophobia or inability to lie still in a supine position Contraindication(s) to the CMRI procedure 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 Unwillingness to provide consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with breast cancer receiving chemotherapy<br>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. | Radiation: 99mTc-rhAnnexin V-128<br>* Kit for the preparation of 99mTc-rhAnnexin V-128<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 0 (Baseline) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) |