E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2-Positive and HR-Negative Early-stage or Locally advanced Breast Cancer |
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E.1.1.1 | Medical condition in easily understood language |
HER2-Positive and HR-Negative Early-stage or Locally advanced Breast Cancer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10065430 |
E.1.2 | Term | HER2 positive breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10083232 |
E.1.2 | Term | HER2 negative breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To prove that HLX11 and EU Perjeta® have similar clinical efficacy on HER2 positive and HR negative early stage or locally advanced breast cancer. |
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E.2.2 | Secondary objectives of the trial |
To compare the safety, pharmacokinetics and immunogenicity of HLX11 vs. EU Perjeta®. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed Informed Consent Form; 2. Male or female aged ≥ 18 years old at the time of signing the informed consent form; 3. Primary breast cancer that is: 1) Histologically confirmed invasive breast carcinoma with a primary tumor size of > 2 cm by standard local assessment technique; 2) Breast cancer staging ( in accordance with the AJCC staging system (8th edition)): early-stage (T2–3, N0–1, M0) or locally advanced (T2–3, N2 or N3, M0; T4, any N, M0); 3) HER2 positive confirmed by central laboratory, defined as immunohistochemistry (IHC) 3 +, or IHC2 + and ISH positive; 4) Hormone receptor (HR, including estrogen receptor [ER] and progesterone receptor [PR]) negative by central laboratory. Note: In accordance with the AJCC staging system (8th edition), ER negative is defined as < 1% nuclear staining, and PR negative is defined as < 1% nuclear staining. In the screening period, tumor sample that consists unstained cut slides must be provided to the central laboratory for relevant testing according to the manual. 4. Subjects agree to undergo surgery while meeting the criteria for surgery after neoadjuvant therapy. 5. (Within 28 days prior to the first dose) Left ventricular ejection fraction (LVEF) at baseline ≥ 55% measured by echocardiography (ECHO) or multiple gated acquisition (MUGA) scan. 6. Adequate major organ functions as defined by the following criteria (no blood transfusions or treatment with recombinant human thrombopoietin or colonystimulating factor (CSF) within 14 days prior to the first dose): Hematologic system White blood cell count (WBC) ≥ 3.0 × 109/L Absolute neutrophil count (ANC) ≥ 1.5 × 109/L Hemoglobin (Hb) ≥ 90 g/L Platelet (PLT) ≥ 100 × 109/L Liver and renal functions Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN) For patients with Gilbert's syndrome, ≤ 2 × ULN Aspartate aminotransferase (AST) ≤2.5×ULN Alanine aminotransferase (ALT) ≤2.5×ULN Alkaline phosphatase (ALP) ≤2.5×ULN Serum creatinine (Cr) ≤ 1.5 × ULN, In case of > 1.5 × ULN, creatinine clearance must be ≥ 50 mL/min (Calculated by Cockcroft-Gault formula) Coagulation function Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN Prothrombin time (PT) ≤ 1.5 × ULN International normalized ratio (INR) ≤ 1.5 × ULN 7. An Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of ≤ 1 within 7 days prior to the first dose. 8. Women with child-bearing potential have a negative result of serum pregnancy test at screening period (within 7 days prior to the first dose) or if they are infertile, nonlactating, reproduction-age men and women following highly effective contraceptive measures until 7 months after investigational/reference product administration. |
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E.4 | Principal exclusion criteria |
1. Inflammatory breast cancer. 2. Stage IV (metastatic) breast cancer, bilateral breast cancer, or multicentric (multiple tumors involving more than 1 quadrant with more than 5 cm interval) breast cancer. 3. History of other malignancy within 5 years prior to screening (except for those who have received radical treatment of localized carcinomas such as carcinoma in situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin, etc.). 4. No prior or current systemic anti-tumor therapy for this invasive breast cancer (including systemic chemotherapy, molecular targeted therapy, biological therapy, and other investigational therapies, etc.). 5. Subjects have participated in another clinical trial within 4 weeks (in the case of a clinical trial of a monoclonal antibody drug, 3 months) prior to the enrollment, or intend to participate in another clinical trial during the period of the study. 6. With serious heart disease or medical history, including but not limited to the following conditions: 1) History of documented heart failure or systolic dysfunction with any NYHA classification; 2) High-risk uncontrolled arrhythmia, such as atrial tachycardia with a heart rate> 100 bpm at rest, significant ventricular arrhythmia (e.g., ventricular tachycardia), or higher-grade atrioventricular (AV) block (i.e., Mobitz II second-degree AV block or third degree AV block); 3) Unstable angina pectrois, or angina pectoris requiring anti-angina medication; 4) Evidence of transmural myocardial infarction on ECG; 5) Clinically-significant valvular heart disease; 6) Poorly controlled hypertension (systolic blood pressure> 160 mmHg and/or diastolic blood pressure> 100 mmHg). 7. History of doxorubicin exposure > 360 mg/m2 (or equivalent). Note: Equivalent agents include: epirubicin > 720 mg/m2, mitoxantrone > 120 mg/m2, idarubicin > 90 mg/m2, liposomal doxorubicin or other anthracyclines exceeding 360 mg/m2 doxorubicin equivalents. If more than one anthracycline is used, the cumulative dose should not exceed 360 mg/m2 doxorubicin equivalent. 8. Subjects with viral hepatitis. Subjects with Hepatitis B (positive test for HBsAg or HBcAb and positive test for HBV-DNA) or Hepatitis C (positive tests for HCV antibody and HCV-RNA). Subjects with a co-infection of hepatitis B and hepatitis C (tested positive for HBsAg or HBcAb, and positive for anti-HCV antibody). Note: Hepatitis B subjects whose disease status are stable after antiviral treatment (HBV-DNA ≤ 2500 copies/mL or 500 IU/mL) during the screening period can be enrolled in the study. 9. Human immunodeficiency virus (HIV) infection, and positive anti-HIV antibody. 10. Sensitivity to any study medications or any of its ingredients or excipients. 11. Subjects who underwent any major surgery (defined as surgeries requiring at least 3 weeks to recovery) within 28 days prior to the first dose. Or subjects who have received local radiotherapy, radiofrequency ablation, or interventional therapy (previous diagnostic biopsy is acceptable) within 2 weeks prior to the first dose. 12. Other concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions/illness. 13. Any other conditions which are inappropriate for the study in the opinion of the investigator. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The total pathological complete response (tpCR) rate will be assessed by the Independent Review Committee (IRC). tpCR is defined as the histological absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy(i.e., ypT0/is, ypN0 in accordance with the AJCC staging system). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
tpCR rate, as assessed by the investigator; Breast pathologic complete response (bpCR) rate, as assessed by IRC. bpCR is defined as the histological evidence of no malignancy in the primary lesion of breast cancer, or only carcinoma in situ (i.e., ypT0/Tis in the AJCC staging system, 8th edition); Breast pathologic complete response (bpCR) rate, as assessed by the investigator; Objective response rate (ORR), as assessed by the investigator, defined as the percentage of subjects whose best overall responses are evaluated as complete response (CR) or partial response (PR) according to RECIST v1.1 criteria during the neoadjuvant therapy period; Event-free survival (EFS), defined as the time from randomization to the first documentation of one of the following events: (Before surgery) Progressive disease (PD) as determined by the investigator (according to RECIST v1.1). Any evidence of in situ contralateral disease will not be identified as PD, and any evidence of invasive contralateral disease will be considered as PD. ➢ (After surgery) Disease recurrence or metastasis (local, regional, distant, or contralateral) ➢ Death from any cause Disease-free survival (DFS), defined as the time from no lesion after surgery to the first documentation of one of the following events: ➢ (After surgery) Disease recurrence or metastasis (local, regional, distant, or contralateral) ➢ Death from any cause |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | Yes |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 46 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as 30 ± 7 days after the end/discontinuation of study therapy for the last subject. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 17 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 17 |