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

A Phase III, Randomized, Two-armed, Parallel, Triple-blind, Active-controlled, Equivalency Clinical Trial of Efficacy and Safety Pertuzumab® (CinnaGen Co.) Compared With Perjeta® (Originator Pertuzumab) in Neoadjuvant Treatment of HER2+ Breast Cancer

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.

Study Overview

• Status: Completed
• Conditions: HER2-positive Breast Cancer
• Intervention / Treatment: Drug: Trastuzumab; Drug: Pertuzumab; Drug: Carboplatin; Drug: Docetaxel

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.

• Study Type: Interventional
• Enrollment (Actual): 214
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TCHP regimen (trastuzumab, pertuzumab® (CinnaGen Co.), carboplatin, and 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.	Drug: Trastuzumab; An initial dose of 8 mg/kg, followed by 6 mg/kg every 3-weeks; Drug: Pertuzumab; An initial dose of 840 mg, followed by 420 mg every 3-weeks; Drug: Carboplatin; A dose of AUC6 (area under the plasma concentration-time curve) every 3-weeks; Drug: Docetaxel; 75 mg/m2 every 3-weeks
Active Comparator: TCHP regimen (trastuzumab, Perjeta®, carboplatin, and 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.	Drug: Trastuzumab; An initial dose of 8 mg/kg, followed by 6 mg/kg every 3-weeks; Drug: Pertuzumab; An initial dose of 840 mg, followed by 420 mg every 3-weeks; Drug: Carboplatin; A dose of AUC6 (area under the plasma concentration-time curve) every 3-weeks; Drug: Docetaxel; 75 mg/m2 every 3-weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Breast Pathological Complete Response (bpCR)	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)	18-20 weeks after first intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Pathological Complete Response (tpCR)	tpCR defined as no invasive tumor residues in the breast and lymph nodes (ypT0/is ypN0)	18-20 weeks after first intervention
Objective Response Rate (ORR)	ORR defined as the proportion of patients who achieved a complete or partial response	18-20 weeks after first intervention
Rate of Breast-conserving Surgery (BCS)	Rate of BCS for patients for whom mastectomy was planned before treatment (T2-3)	18-20 weeks after first intervention
Safety Assessment Including Treatment Related Adverse Events	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.	Throughout the study duration (from first visit to week 18-20)
Abnormal Laboratory Data	Laboratory data including CBC diff have been assessed. All abnormal values were recorded as adverse event.	Throughout the study duration (from first visit to week 18-20)
Decrease in Left Ventricular Ejection Fraction (LVEF)	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.	every 6 week (from first visit to week 18-20)
Incidence of Symptomatic Left Ventricular Systolic Dysfunction (LVSD)	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.	Throughout the study duration (from first visit to week 18-20)
Immunogenicity	The enzyme-linked immunosorbent assay (ELISA) method was used for the assessment of anti-drug antibodies (ADAs).	Every 3 weeks (from first intervention to week 18)

Collaborators and Investigators

• Sponsor: Cinnagen
• Investigators: Principal Investigator: Behrouz Najafi, MD, Assistant Professor of Hematology and Oncology Research Center

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2018
• Primary Completion (Actual): May 27, 2020
• Study Completion (Actual): May 27, 2020

Study Registration Dates

• First Submitted: June 22, 2021
• First Submitted That Met QC Criteria: June 30, 2021
• First Posted (Actual): July 12, 2021

Study Record Updates

• Last Update Posted (Actual): July 26, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Pertuzumab; Neoadjuvant treatment; HER2-positive Breast Cancer; Equivalency clinical trial
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Immunological; Docetaxel; Carboplatin; Trastuzumab; Pertuzumab
• Other Study ID Numbers: PER.CIN.BN.95.III

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No