Comparing Efficacy and Safety Between Pertuzumab® and Perjeta® in Neoadjuvant Treatment of HER2+ Breast Cancer

Phase 3

Completed

Conditions: HER2-positive Breast Cancer

Interventions: Drug: Trastuzumab
Drug: Pertuzumab
Drug: Carboplatin
Drug: Docetaxel

Registration Number: NCT04957212

Lead Sponsor: Cinnagen

Brief Summary: This study was a phase III, multicenter, triple-blind, equivalency clinical trial to determine the therapeutic efficacy and safety between Pertuzumab® (CinnaGen Co.) compared to originator pertuzumab in HER2-positive early breast cancer patients.

Patients were stratified dynamically for random assignment to treatment with either Pertuzumab® (CinnaGen Co.) or originator pertuzumab, and received neoadjuvant TCHP regimen every 3- weeks.

Detailed Description: This study was a phase III, multicenter, triple-blind , equivalency clinical trial to determine the therapeutic efficacy and safety between Pertuzumab® (CinnaGen Co.) compared to originator pertuzumab in HER2-positive early breast cancer patients.

Patients stratified dynamically according to two factors: type of breast cancer (inflammatory, locally and operable) and estrogen/ progesterone receptor (ER/PR) (positive or negative) with 1:1 allocation ratio.

Study drugs were administered intravenously on a 3-weekly schedule and were given consecutively on the same day in the following sequence: trastuzumab, followed by pertuzumab, carboplatin, and docetaxel (TCHP regimen).

The primary endpoint was breast pCR (bpCR). Secondary efficacy endpoints included total pCR (tpCR); objective response rate (ORR) and rate of breast-conserving surgery (BCS) for patients for whom mastectomy was planned before treatment (T2-3).

During this study, adverse events (AEs) were monitored continuously. As an adverse event of special interest (AESI), left ventricular ejection fraction (LVEF) decreased was monitored and assessed by echocardiography throughout the study. Immunogenicity was also assessed.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 214

Inclusion Criteria

Female patients aged 18-70 years.
Diagnosed with locally advanced (T2-3, N2-3, M0 or T4a-c, any N, M0), inflammatory (T4d, any N, M0) or operable (T2-3, N0-1, M0), invasive breast cancer.
Primary tumor > 2 cm in diameter.
HER2 positive breast cancer confirmed (Tumors must be IHC 3+ or FISH/CISH + for IHC 2+ tumors).
Baseline LVEF ≥ 55% measured by echocardiography.
Performance status ECOG ≤ 1
Signed informed consent.

Exclusion Criteria

Metastatic disease (Stage IV) or bilateral breast cancer.
Previous anticancer therapy or radiotherapy for any malignancy.
Other malignancy, except for carcinoma in situ of the cervix or basal cell carcinoma.
Received any investigational treatment within 4 weeks of study start.
At least 4 weeks since major surgery.
Uncontrolled hypertension (systolic > 150 and/or diastolic > 100), unstable angina, CHF of any NYHA classification, serious cardiac arrhythmia requiring treatment, history of myocardial infarction within 6 months of enrollment.
Hematological, biochemical and organ dysfunction:
1. Inadequate bone marrow function: Absolute Neutrophil Count (ANC) < 1500 cells/ µL, Platelet count < 100,000 cells/ µL and Hb < 9 g/dL).
2. Impaired liver function: serum [total] bilirubin > 1.25 x ULN, AST/ALT > 1. 5 x ULN with ALP > 2.5 x ULN
3. Inadequate renal function: serum creatinine > 1.5 x ULN.
Dyspnea at rest or other diseases which require continuous oxygen therapy.
Severe uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, metabolic, etc).
Current chronic daily treatment with corticosteroids (dose of ≥10 mg Oral prednisolone, or equivalent [excluding inhaled steroids])
Subjects with known infection with HIV, HBV, and HCV.
Known hypersensitivity to any of the study drugs or excipients.
Pregnant and/or lactating women or subjects with reproductive potential not willing to use effective methods of contraception.
Subjects assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol (e.g.: physical, psychological and mental problems)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
TCHP regimen (trastuzumab, pertuzumab® (CinnaGen Co.), carboplatin, and docetaxel)	Trastuzumab	Study drugs are administered intravenously on a 3-weekly schedule and given consecutively on the same day in the following sequence: trastuzumab, followed by pertuzumab, carboplatin, and docetaxel. Trastuzumab is given at an initial dose of 8 mg/kg, followed by 6 mg/kg; pertuzumab® (CinnaGen Co.) is given at an initial dose of 840 mg, followed by 420 mg. Carboplatin is administered at a dose of AUC6 (area under the plasma concentration-time curve) and docetaxel is given at 75 mg/m2.
TCHP regimen (trastuzumab, pertuzumab® (CinnaGen Co.), carboplatin, and docetaxel)	Pertuzumab	Study drugs are administered intravenously on a 3-weekly schedule and given consecutively on the same day in the following sequence: trastuzumab, followed by pertuzumab, carboplatin, and docetaxel. Trastuzumab is given at an initial dose of 8 mg/kg, followed by 6 mg/kg; pertuzumab® (CinnaGen Co.) is given at an initial dose of 840 mg, followed by 420 mg. Carboplatin is administered at a dose of AUC6 (area under the plasma concentration-time curve) and docetaxel is given at 75 mg/m2.
TCHP regimen (trastuzumab, pertuzumab® (CinnaGen Co.), carboplatin, and docetaxel)	Carboplatin	Study drugs are administered intravenously on a 3-weekly schedule and given consecutively on the same day in the following sequence: trastuzumab, followed by pertuzumab, carboplatin, and docetaxel. Trastuzumab is given at an initial dose of 8 mg/kg, followed by 6 mg/kg; pertuzumab® (CinnaGen Co.) is given at an initial dose of 840 mg, followed by 420 mg. Carboplatin is administered at a dose of AUC6 (area under the plasma concentration-time curve) and docetaxel is given at 75 mg/m2.
TCHP regimen (trastuzumab, pertuzumab® (CinnaGen Co.), carboplatin, and docetaxel)	Docetaxel	Study drugs are administered intravenously on a 3-weekly schedule and given consecutively on the same day in the following sequence: trastuzumab, followed by pertuzumab, carboplatin, and docetaxel. Trastuzumab is given at an initial dose of 8 mg/kg, followed by 6 mg/kg; pertuzumab® (CinnaGen Co.) is given at an initial dose of 840 mg, followed by 420 mg. Carboplatin is administered at a dose of AUC6 (area under the plasma concentration-time curve) and docetaxel is given at 75 mg/m2.
TCHP regimen (trastuzumab, Perjeta®, carboplatin, and docetaxel)	Trastuzumab	Study drugs are administered intravenously on a 3-weekly schedule and given consecutively on the same day in the following sequence: trastuzumab, followed by pertuzumab, carboplatin, and docetaxel. Trastuzumab is given at an initial dose of 8 mg/kg, followed by 6 mg/kg; Perjeta® is given at an initial dose of 840 mg, followed by 420 mg. Carboplatin is administered at a dose of AUC6 (area under the plasma concentration-time curve) and docetaxel is given at 75 mg/m2.
TCHP regimen (trastuzumab, Perjeta®, carboplatin, and docetaxel)	Carboplatin	Study drugs are administered intravenously on a 3-weekly schedule and given consecutively on the same day in the following sequence: trastuzumab, followed by pertuzumab, carboplatin, and docetaxel. Trastuzumab is given at an initial dose of 8 mg/kg, followed by 6 mg/kg; Perjeta® is given at an initial dose of 840 mg, followed by 420 mg. Carboplatin is administered at a dose of AUC6 (area under the plasma concentration-time curve) and docetaxel is given at 75 mg/m2.
TCHP regimen (trastuzumab, Perjeta®, carboplatin, and docetaxel)	Pertuzumab	Study drugs are administered intravenously on a 3-weekly schedule and given consecutively on the same day in the following sequence: trastuzumab, followed by pertuzumab, carboplatin, and docetaxel. Trastuzumab is given at an initial dose of 8 mg/kg, followed by 6 mg/kg; Perjeta® is given at an initial dose of 840 mg, followed by 420 mg. Carboplatin is administered at a dose of AUC6 (area under the plasma concentration-time curve) and docetaxel is given at 75 mg/m2.
TCHP regimen (trastuzumab, Perjeta®, carboplatin, and docetaxel)	Docetaxel	Study drugs are administered intravenously on a 3-weekly schedule and given consecutively on the same day in the following sequence: trastuzumab, followed by pertuzumab, carboplatin, and docetaxel. Trastuzumab is given at an initial dose of 8 mg/kg, followed by 6 mg/kg; Perjeta® is given at an initial dose of 840 mg, followed by 420 mg. Carboplatin is administered at a dose of AUC6 (area under the plasma concentration-time curve) and docetaxel is given at 75 mg/m2.

Primary Outcome Measures

Name	Time	Method
Breast Pathological Complete Response (bpCR)	18-20 weeks after first intervention	bpCR defined as the absence of invasive neoplastic cells in the breast at microscopic examination of the primary tumor at surgery following primary systemic therapy (ypT0/is)

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	18-20 weeks after first intervention	ORR defined as the proportion of patients who achieved a complete or partial response
Decrease in Left Ventricular Ejection Fraction (LVEF)	every 6 week (from first visit to week 18-20)	LVEF decrease was measured by echocardiography. All cases with a decrease more than 10% from baseline which meet \<50%, will be recorded as adverse events.
Total Pathological Complete Response (tpCR)	18-20 weeks after first intervention	tpCR defined as no invasive tumor residues in the breast and lymph nodes (ypT0/is ypN0)
Rate of Breast-conserving Surgery (BCS)	18-20 weeks after first intervention	Rate of BCS for patients for whom mastectomy was planned before treatment (T2-3)
Abnormal Laboratory Data	Throughout the study duration (from first visit to week 18-20)	Laboratory data including CBC diff have been assessed. All abnormal values were recorded as adverse event.
Safety Assessment Including Treatment Related Adverse Events	Throughout the study duration (from first visit to week 18-20)	Safety assessment, including the incidence of all reported AEs and abnormal laboratory results was done. All AEs were classified based on the Medical Dictionary for Regulatory Activities (MedDRA Desktop Browser 4.0 Beta) terms as System Organ Class (SOC) and Preferred Term (PT). All the reported events were graded according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Moreover, seriousness of AEs was assessed according to International Council for Harmonization (ICH-E2B) guidelines. The causality relation was assessed based on the World Health Organization (WHO) criteria.
Incidence of Symptomatic Left Ventricular Systolic Dysfunction (LVSD)	Throughout the study duration (from first visit to week 18-20)	In this study, LVSD was evaluated by measuring the decrease in LVEF (outcome measure 5) and assessing the clinical symptoms of the study participants based on physician opinion.
Immunogenicity	Every 3 weeks (from first intervention to week 18)	The enzyme-linked immunosorbent assay (ELISA) method was used for the assessment of anti-drug antibodies (ADAs).

Trial Locations

Locations (44): Qaem Hospital
🇮🇷
Mashhad, Khorasan Razavi, Iran, Islamic Republic of
Amir Hospital
🇮🇷
Shiraz, Iran, Islamic Republic of
Shahid Faghihi Hospital
🇮🇷
Shiraz, Iran, Islamic Republic of
Baqiatallah Hospital
🇮🇷
Tehran, Iran, Islamic Republic of
Dr. Safa Najjar Najafi's office
🇮🇷
Tehran, Iran, Islamic Republic of
BuoAli Hospital
🇮🇷
Tehran, Iran, Islamic Republic of
Imam Khomeini Hospital
🇮🇷
Tehran, Iran, Islamic Republic of
Jam Hospital
🇮🇷
Tehran, Iran, Islamic Republic of
Masih Daneshvari Hospital
🇮🇷
Tehran, Iran, Islamic Republic of
Resalat Hospital
🇮🇷
Tehran, Iran, Islamic Republic of
Sina Hospital
🇮🇷
Tehran, Iran, Islamic Republic of
Taleghani Hospital
🇮🇷
Tehran, Iran, Islamic Republic of
Tehran Hospital
🇮🇷
Tehran, Iran, Islamic Republic of
Toos Hospital
🇮🇷
Tehran, Iran, Islamic Republic of
Razi Hospital
🇮🇷
Rasht, Guilan, Iran, Islamic Republic of
Dr. Aboulqasem Allahyari's office
🇮🇷
Mashhad, Khorasan Razavi, Iran, Islamic Republic of
Saba Clinic
🇮🇷
Isfahan, Iran, Islamic Republic of
Mehrad Hospital
🇮🇷
Tehran, Iran, Islamic Republic of
Imam Reza Hospital
🇮🇷
Mashhad, Khorasan Razavi, Iran, Islamic Republic of
Iran-Mehr Hospital
🇮🇷
Tehran, Iran, Islamic Republic of
Jihad University Clinic
🇮🇷
Tehran, Iran, Islamic Republic of
Naft Hospital
🇮🇷
Tehran, Iran, Islamic Republic of
Dr. Behrouz Najafi's office
🇮🇷
Rasht, Guilan, Iran, Islamic Republic of
Milad Hospital
🇮🇷
Isfahan, Iran, Islamic Republic of
Dr. Behjat Kalantari's office
🇮🇷
Kerman, Iran, Islamic Republic of
Firoozgar Hospital
🇮🇷
Tehran, Iran, Islamic Republic of
Sajjad Hospital
🇮🇷
Tehran, Iran, Islamic Republic of
Besat Clinic
🇮🇷
Rasht, Guilan, Iran, Islamic Republic of
Arvand Hospital
🇮🇷
Ahvaz, Khozestan, Iran, Islamic Republic of
Baqaei Hospital
🇮🇷
Ahvaz, Khozestan, Iran, Islamic Republic of
Shafa Hospital
🇮🇷
Ahvaz, Khozestan, Iran, Islamic Republic of
Seyed-Al-Shohada Hospital
🇮🇷
Isfahan, Iran, Islamic Republic of
Javad-Al-Aemeh Clinic
🇮🇷
Kerman, Iran, Islamic Republic of
Ebn-Sina Hospital
🇮🇷
Tehran, Iran, Islamic Republic of
Massoud Clinic
🇮🇷
Tehran, Iran, Islamic Republic of
Dr.Mortazavizadeh's office
🇮🇷
Yazd, Iran, Islamic Republic of
Dr. Mehdi Mirblouk's office
🇮🇷
Rasht, Guilan, Iran, Islamic Republic of
Sanabad Hospital
🇮🇷
Mashhad, Khorasan Razavi, Iran, Islamic Republic of
Sheikh Mofid Clinic
🇮🇷
Isfahan, Iran, Islamic Republic of
Dr. Mehrdad Payende's office
🇮🇷
Kermanshah, Iran, Islamic Republic of
Shahid Bahonar Hospital
🇮🇷
Kerman, Iran, Islamic Republic of
Namazi Hospital
🇮🇷
Shiraz, Iran, Islamic Republic of
Shams Hospital
🇮🇷
Tabriz, Iran, Islamic Republic of
Rasool Akram Hospital
🇮🇷
Tehran, Iran, Islamic Republic of