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

Sponsor

Cinnagen (Industry)

Overall Status

Completed

CT.gov ID

NCT04957212

Collaborator

(none)

214

Enrollment

Locations

Arms

21.5

Actual Duration (Months)

4.9

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
HER2-positive Breast Cancer	Drug: Trastuzumab Drug: Pertuzumab Drug: Carboplatin Drug: Docetaxel	Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

214 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Patients were randomly assigned to treatment by a central randomization procedure via telephone call for each consecutive eligible patient. Randomization codes were allocated after all eligibility criteria were approved, stratification factors were identified and the informed consent form was signed. After randomization procedure, a code was allocated to each patient that was used as patient identifier throughout the study. The assigned code was denoted by 4 initials (corresponding to the 2 first letter of the first name, the 2 first letter of the first surname) and 3 numbers (center code).

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Aug 11, 2018

Actual Primary Completion Date :

May 27, 2020

Actual Study Completion Date :

May 27, 2020

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

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)
Objective response rate (ORR) [18-20 weeks after first intervention]
ORR defined as the proportion of patients who achieved a complete or partial response
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)
Adverse Events (AEs) [Throughout the study duration (from first visit to week 18-20)]
AEs were monitored continuously and all the reported events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0 . The causality relation was assessed based on World Health Organization (WHO) criteria.
Abnormal laboratory data [Throughout the study duration (from first visit to week 18-20)]
The abnormality in selected laboratory data was considered as adverse event and was reported.
Decline in LVEF of ≥10% points from baseline to <50% [every 6 week (from first visit to week 18-20)]
LVEF decrease was measured by echocardiography.
Incidence of symptomatic left ventricular systolic dysfunction (LVSD) [Throughout the study duration (from first visit to week 18-20)]
symptoms of LVSD were monitored by physician and reported as AEs.
Immunogenicity [Every 3 weeks (from first intervention to week 18)]
antidrug antibody [ADA] assessment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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:

Inadequate bone marrow function: Absolute Neutrophil Count (ANC) < 1500 cells/ µL, Platelet count < 100,000 cells/ µL and Hb < 9 g/dL).
Impaired liver function: serum [total] bilirubin > 1.25 x ULN, AST/ALT > 1. 5 x ULN with ALP > 2.5 x ULN
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)

Contacts and Locations

Locations

	Site	City	State	Country
1	Besat Clinic	Rasht	Guilan	Iran, Islamic Republic of
2	Dr. Behrouz Najafi's office	Rasht	Guilan	Iran, Islamic Republic of
3	Dr. Mehdi Mirblouk's office	Rasht	Guilan	Iran, Islamic Republic of
4	Razi Hospital	Rasht	Guilan	Iran, Islamic Republic of
5	Dr. Aboulqasem Allahyari's office	Mashhad	Khorasan Razavi	Iran, Islamic Republic of
6	Imam Reza Hospital	Mashhad	Khorasan Razavi	Iran, Islamic Republic of
7	Qaem Hospital	Mashhad	Khorasan Razavi	Iran, Islamic Republic of
8	Sanabad Hospital	Mashhad	Khorasan Razavi	Iran, Islamic Republic of
9	Arvand Hospital	Ahvaz	Khozestan	Iran, Islamic Republic of
10	Baqaei Hospital	Ahvaz	Khozestan	Iran, Islamic Republic of
11	Shafa Hospital	Ahvaz	Khozestan	Iran, Islamic Republic of
12	Milad Hospital	Isfahan		Iran, Islamic Republic of
13	Saba Clinic	Isfahan		Iran, Islamic Republic of
14	Seyed-Al-Shohada Hospital	Isfahan		Iran, Islamic Republic of
15	Sheikh Mofid Clinic	Isfahan		Iran, Islamic Republic of
16	Dr. Mehrdad Payende's office	Kermanshah		Iran, Islamic Republic of
17	Dr. Behjat Kalantari's office	Kerman		Iran, Islamic Republic of
18	Javad-Al-Aemeh Clinic	Kerman		Iran, Islamic Republic of
19	Shahid Bahonar Hospital	Kerman		Iran, Islamic Republic of
20	Amir Hospital	Shiraz		Iran, Islamic Republic of
21	Namazi Hospital	Shiraz		Iran, Islamic Republic of
22	Shahid Faghihi Hospital	Shiraz		Iran, Islamic Republic of
23	Shams Hospital	Tabriz		Iran, Islamic Republic of
24	Baqiatallah Hospital	Tehran		Iran, Islamic Republic of
25	BuoAli Hospital	Tehran		Iran, Islamic Republic of
26	Dr. Safa Najjar Najafi's office	Tehran		Iran, Islamic Republic of
27	Ebn-Sina Hospital	Tehran		Iran, Islamic Republic of
28	Firoozgar Hospital	Tehran		Iran, Islamic Republic of
29	Imam Khomeini Hospital	Tehran		Iran, Islamic Republic of
30	Iran-Mehr Hospital	Tehran		Iran, Islamic Republic of
31	Jam Hospital	Tehran		Iran, Islamic Republic of
32	Jihad University Clinic	Tehran		Iran, Islamic Republic of
33	Masih Daneshvari Hospital	Tehran		Iran, Islamic Republic of
34	Massoud Clinic	Tehran		Iran, Islamic Republic of
35	Mehrad Hospital	Tehran		Iran, Islamic Republic of
36	Naft Hospital	Tehran		Iran, Islamic Republic of
37	Rasool Akram Hospital	Tehran		Iran, Islamic Republic of
38	Resalat Hospital	Tehran		Iran, Islamic Republic of
39	Sajjad Hospital	Tehran		Iran, Islamic Republic of
40	Sina Hospital	Tehran		Iran, Islamic Republic of
41	Taleghani Hospital	Tehran		Iran, Islamic Republic of
42	Tehran Hospital	Tehran		Iran, Islamic Republic of
43	Toos Hospital	Tehran		Iran, Islamic Republic of
44	Dr.Mortazavizadeh's office	Yazd		Iran, Islamic Republic of