HER2-positive Breast Cancer
Conditions
Keywords
Pertuzumab, HER2-positive Breast Cancer, Neoadjuvant treatment, Equivalency clinical trial
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.
Interventions
DRUGTrastuzumab
An initial dose of 8 mg/kg, followed by 6 mg/kg every 3-weeks
DRUGPertuzumab
An initial dose of 840 mg, followed by 420 mg every 3-weeks
DRUGCarboplatin
A dose of AUC6 (area under the plasma concentration-time curve) every 3-weeks
DRUGDocetaxel
75 mg/m2 every 3-weeks
Sponsors
Cinnagen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, 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).
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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. |
| 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. |
| 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. |
| 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). |
Countries
Iran
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Trastuzumab: An initial dose of 8 mg/kg, followed by 6 mg/kg every 3-weeks
Pertuzumab: An initial dose of 840 mg, followed by 420 mg every 3-weeks
Carboplatin: A dose of AUC6 (area under the plasma concentration-time curve) every 3-weeks
Docetaxel: 75 mg/m2 every 3-weeks | 107 |
| 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.
Trastuzumab: An initial dose of 8 mg/kg, followed by 6 mg/kg every 3-weeks
Pertuzumab: An initial dose of 840 mg, followed by 420 mg every 3-weeks
Carboplatin: A dose of AUC6 (area under the plasma concentration-time curve) every 3-weeks
Docetaxel: 75 mg/m2 every 3-weeks | 107 |
| Total | 214 |
Baseline characteristics
| Characteristic | TCHP Regimen (Trastuzumab, Pertuzumab® (CinnaGen Co.), Carboplatin, and Docetaxel) | Total | TCHP Regimen (Trastuzumab, Perjeta®, Carboplatin, and Docetaxel) |
|---|---|---|---|
| Age, Continuous | 47.56 years STANDARD_DEVIATION 10.31 | 45.95 years STANDARD_DEVIATION 10.17 | 44.35 years STANDARD_DEVIATION 9.81 |
| BMI | 28.27 kg/m^2 STANDARD_DEVIATION 5.3 | 27.77 kg/m^2 STANDARD_DEVIATION 4.87 | 27.27 kg/m^2 STANDARD_DEVIATION 4.38 |
| BSA | 1.79 m^2 STANDARD_DEVIATION 0.18 | 1.79 m^2 STANDARD_DEVIATION 0.18 | 1.79 m^2 STANDARD_DEVIATION 0.18 |
| ER/PR- | 44 Participants | 87 Participants | 43 Participants |
| ER/PR+ | 63 Participants | 127 Participants | 64 Participants |
| IHC2+ CISH+ | 6 Participants | 9 Participants | 3 Participants |
| IHC2+ FISH+ | 3 Participants | 6 Participants | 3 Participants |
| IHC3+ | 98 Participants | 199 Participants | 101 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 107 Participants | 214 Participants | 107 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 107 Participants | 214 Participants | 107 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Type of breast cancer Inflammatory | 6 Participants | 12 Participants | 6 Participants |
| Type of breast cancer Locally advanced | 49 Participants | 97 Participants | 48 Participants |
| Type of breast cancer Operable | 52 Participants | 105 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 107 | 0 / 107 |
| other Total, other adverse events | 107 / 107 | 104 / 107 |
| serious Total, serious adverse events | 24 / 107 | 15 / 107 |
Outcome results
Primary
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)
Time frame: 18-20 weeks after first intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TCHP Regimen (Trastuzumab, Pertuzumab® (CinnaGen Co.), Carboplatin, and Docetaxel) | Breast Pathological Complete Response (bpCR) | 71 Participants |
| TCHP Regimen (Trastuzumab, Perjeta®, Carboplatin, and Docetaxel) | Breast Pathological Complete Response (bpCR) | 73 Participants |
p-value: 0.5495% CI: [-0.16, 0.09]Chi-squared
Secondary
Abnormal Laboratory Data
Laboratory data including CBC diff have been assessed. All abnormal values were recorded as adverse event.
Time frame: Throughout the study duration (from first visit to week 18-20)
Secondary
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.
Time frame: every 6 week (from first visit to week 18-20)
Secondary
Immunogenicity
The enzyme-linked immunosorbent assay (ELISA) method was used for the assessment of anti-drug antibodies (ADAs).
Time frame: Every 3 weeks (from first intervention to week 18)
Population: A total of 214 patients were analyzed for immunogenicity assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TCHP Regimen (Trastuzumab, Pertuzumab® (CinnaGen Co.), Carboplatin, and Docetaxel) | Immunogenicity | 0 Participants |
| TCHP Regimen (Trastuzumab, Perjeta®, Carboplatin, and Docetaxel) | Immunogenicity | 0 Participants |
Secondary
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.
Time frame: Throughout the study duration (from first visit to week 18-20)
Secondary
Objective Response Rate (ORR)
ORR defined as the proportion of patients who achieved a complete or partial response
Time frame: 18-20 weeks after first intervention
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TCHP Regimen (Trastuzumab, Pertuzumab® (CinnaGen Co.), Carboplatin, and Docetaxel) | Objective Response Rate (ORR) | Partial Response | 30 Participants |
| TCHP Regimen (Trastuzumab, Pertuzumab® (CinnaGen Co.), Carboplatin, and Docetaxel) | Objective Response Rate (ORR) | Stable Disease | 3 Participants |
| TCHP Regimen (Trastuzumab, Pertuzumab® (CinnaGen Co.), Carboplatin, and Docetaxel) | Objective Response Rate (ORR) | Progressive Disease | 2 Participants |
| TCHP Regimen (Trastuzumab, Pertuzumab® (CinnaGen Co.), Carboplatin, and Docetaxel) | Objective Response Rate (ORR) | Unknown | 8 Participants |
| TCHP Regimen (Trastuzumab, Pertuzumab® (CinnaGen Co.), Carboplatin, and Docetaxel) | Objective Response Rate (ORR) | Complete Response | 64 Participants |
| TCHP Regimen (Trastuzumab, Perjeta®, Carboplatin, and Docetaxel) | Objective Response Rate (ORR) | Unknown | 12 Participants |
| TCHP Regimen (Trastuzumab, Perjeta®, Carboplatin, and Docetaxel) | Objective Response Rate (ORR) | Complete Response | 61 Participants |
| TCHP Regimen (Trastuzumab, Perjeta®, Carboplatin, and Docetaxel) | Objective Response Rate (ORR) | Partial Response | 29 Participants |
| TCHP Regimen (Trastuzumab, Perjeta®, Carboplatin, and Docetaxel) | Objective Response Rate (ORR) | Progressive Disease | 3 Participants |
| TCHP Regimen (Trastuzumab, Perjeta®, Carboplatin, and Docetaxel) | Objective Response Rate (ORR) | Stable Disease | 2 Participants |
p-value: 0.99Fisher Exact
Secondary
Rate of Breast-conserving Surgery (BCS)
Rate of BCS for patients for whom mastectomy was planned before treatment (T2-3)
Time frame: 18-20 weeks after first intervention
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TCHP Regimen (Trastuzumab, Pertuzumab® (CinnaGen Co.), Carboplatin, and Docetaxel) | Rate of Breast-conserving Surgery (BCS) | Lumpectomy | 20 Participants |
| TCHP Regimen (Trastuzumab, Pertuzumab® (CinnaGen Co.), Carboplatin, and Docetaxel) | Rate of Breast-conserving Surgery (BCS) | Mastectomy | 44 Participants |
| TCHP Regimen (Trastuzumab, Pertuzumab® (CinnaGen Co.), Carboplatin, and Docetaxel) | Rate of Breast-conserving Surgery (BCS) | Unknown | 0 Participants |
| TCHP Regimen (Trastuzumab, Perjeta®, Carboplatin, and Docetaxel) | Rate of Breast-conserving Surgery (BCS) | Lumpectomy | 21 Participants |
| TCHP Regimen (Trastuzumab, Perjeta®, Carboplatin, and Docetaxel) | Rate of Breast-conserving Surgery (BCS) | Mastectomy | 37 Participants |
| TCHP Regimen (Trastuzumab, Perjeta®, Carboplatin, and Docetaxel) | Rate of Breast-conserving Surgery (BCS) | Unknown | 1 Participants |
p-value: 0.56Chi-squared
Secondary
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.
Time frame: Throughout the study duration (from first visit to week 18-20)
Population: A total of 214 patients were analyzed for AEs.Reports were based on the Safety set. The safety set included all randomized patients who received at least one dose of the study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TCHP Regimen (Trastuzumab, Pertuzumab® (CinnaGen Co.), Carboplatin, and Docetaxel) | Safety Assessment Including Treatment Related Adverse Events | 107 Participants |
| TCHP Regimen (Trastuzumab, Perjeta®, Carboplatin, and Docetaxel) | Safety Assessment Including Treatment Related Adverse Events | 107 Participants |
Secondary
Total Pathological Complete Response (tpCR)
tpCR defined as no invasive tumor residues in the breast and lymph nodes (ypT0/is ypN0)
Time frame: 18-20 weeks after first intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TCHP Regimen (Trastuzumab, Pertuzumab® (CinnaGen Co.), Carboplatin, and Docetaxel) | Total Pathological Complete Response (tpCR) | 60 Participants |
| TCHP Regimen (Trastuzumab, Perjeta®, Carboplatin, and Docetaxel) | Total Pathological Complete Response (tpCR) | 68 Participants |
p-value: 0.2695% CI: [-0.21, 0.06]Chi-squared