Clinical Trial to Assess Pharmacokinetic Parameters and Safety of NNG-TMAB (Trastuzumab) on Recurrent or Metastatic Breast Cancer Patients.

Study Overview
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Brief Summary
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Targeted therapy in the treatment of breast cancer targets HER2 receptor (Human Epidermal growth factor Receptor). HER2 receptor plays an important role in cell growth and differentiation (5). However, when HER2 overexpresses, it may lead to cancer. HER2 positive malignance exacerbates pathology and worsens clinical outcome, such as shortened overall survival (OS) compared with non-HER2 overexpression patients (6), (7). About 20-30% overexpression HER2/neogene breast cancer patients and patients having HER2 overexpression tumor have disease progression and poor prognosis in metastatic process (8), (9). Currently, targeted therapeutic, which attaches to the HER2 receptor, inhibiting the growth of cancer cells has been approved. One of these products is Trastuzumab. The study processed on 50 females aged between 18 and 65, recurrent or metastatic breast cancer patients with positive HER2. The subjects were randomly distributed in 2 groups as NNG-TMAB + docetaxel or Herceptin® + docetaxel, in blocks of 4 in a 1:1 ratio (NNG-TMAB: Herceptin®). In each block of 4 will be 2 patients in the experimental group and 2 patients in the control group. Primary endpoint is serum peak concentrations (Cmax), area under the curve from 0 to t (AUC0-t). This trial is intended to assess the biosimilarity of pharmacokinetic parameters, safety between Faceptor (experimental drug) and Herceptin (reference).

Official Title
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Randomized, Single-blind, Multicenter, Parallel Group Clinical Trial to Assess Pharmacokinetic Parameters, Safety of NNG-TMAB (Trastuzumab) in Combination With Docetaxel on Recurrent or Metastatic Breast Cancer Patients With Positive HER2.

Conditions
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Breast Cancer Metastatic, Breast Cancer Female, Breast Cancer Recurrent

Intervention / Treatment
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* Drug: Faceptor
* Drug: Herceptin
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients from 18 to 65 years old. Willing to give written and signed informed consent. Have pathologically or cytologically confirmed breast cancer. Inoperable, recurrent or metastatic breast cancer according to TNM classification and investigator' s assessment. Presence of at least 1 tumour with a size not less than 1 cm (revealed with computed tomography (CT) slice thickness not more than 5 mm). Patients having bone metastasis as the only measurable tumour are not eligible for the trial. Grade 3+ HER2 overexpression confirmed by immunohistochemical (IHC) staining or grade 2+ HER2 overexpression accompanied by HER2 gene amplification confirmed by fluorescent hybridization in situ (FISH). Eastern Cooperative oncology group performance status ≤ 2 Willing to comply the requirements of the study protocol. Have a survival expectancy of at least 6 months. At screening period: Hb ≥ 9 g/dL; Neutrophils ≥ 1,5x10^9/L; platelets ≥ 100x10^9/L; creatinine level ≤ 1,5 x upper limit of normal (ULN); bilirubin level < 1,5 x ULN; ALT/AST < 2,5 x ULN (< 5 x ULN for patients with liver metastases), ALP < 5 x ULN. Patients of childbearing potential and her partner must implement reliable contraceptive measures during the study treatment, starting 4 weeks prior to inclusion into the trial and until 6 months after the last administration of the study drug Exclusion Criteria: Previous anticancer therapy for metastatic BC, including previous anticancer therapy with signal transduction inhibitors (e.g. lapatinib), biological drugs (e.g. trastuzumab, bevacizumab), experimental (not approved for BC therapy) anticancer drugs. Any previous chemotherapy or hormonal therapy is allowed. Previously treated with doxorubicin > 400 mg/m2; epirubicin > 800 mg/m2 in accumulative dosages. Surgery, radiation therapy, use of any experimental medications within 4 weeks prior to randomization. Clinical evidence or X-ray show that breast cancer metastases in central nervous system Patients with metastatic tumor to the bone is the only tumor to be measured Systolic blood pressure >150mmHg and/or diastolic blood pressure >100mmHg. Uncontrolled hypertension comprising all cases of arterial hypertension when no decrease in blood pressure could be achieved despite treatment with a combination of 3 antihypertensive drugs including one diuretic and non-medicamental correction methods (low salt diet, physical exercise) Cardiovascular system pathology (congestive heart failure (CHF) stage III-IV according to New York Heart Association (NYHA) classification, unstable angina pectoris, myocardial infarction) within 12 months prior to randomization. LVEF < 50% according to echocardiogram when screening. Acute or chronic infection (except for acute or chronic infection that is stable and does not affect the study evaluation). Infecting HIV, HBV or HCV, Syphilis Patients with a history of severe allergic reaction to trastuzumab, paclitaxel, docetaxel or other ingredients in the formulation The patient has evidence of a serious illness (such as resting dyspnea or severe lung disease, etc.) or an abnormal laboratory test that, in the judgment of the researcher, will affect participation. research and completion of patient research, or may affect the patient's response evaluation. Pregnancy, intend to get pregnant, lactation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two group: study drug and reference
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Faceptor + Docetacel<br>Patients received a loading dose of Faceptor 8 mg/kg IV + docetaxel 75 mg/m^2 IV on Cycle 1 followed by Faceptor 6 mg/kg IV + docetaxel 75 mg/m^2 IV on the next 5 cycles (each cycle is 21 days) | Drug: Faceptor<br>* NNG-TMAB (trastuzumab) 150 mg, 440 mg, lyophilized power for injection, manufacturered by Nanogen Pharmaceutical Biotechnology JSC.<br>* Other names: Trastazumab;Drug: Docetaxel<br>* The drug Docetaxel in this study has the brand name Taxotere manufactured by Sanofi company.<br>* Other names: Taxotere;|
| Active Comparator: Herceptin + Docetacel<br>Patients received a loading dose of Herceptin 8 mg/kg IV + docetaxel 75 mg/m^2 IV on Cycle 1 followed by Herceptin 6 mg/kg IV + docetaxel 75 mg/m^2 IV on the next 5 cycles (each cycle is 21 days) | Drug: Herceptin<br>* Herceptin (trastuzumab) 150mg, 440mg, powder for concentrate for solution, manufactured by Roche.<br>* Other names: Trastuzumab;Drug: Docetaxel<br>* The drug Docetaxel in this study has the brand name Taxotere manufactured by Sanofi company.<br>* Other names: Taxotere;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic parameters: Cmax | Serum peak concentrations (Cmax) | Blood samples will be collected at following time points: prior to IP administration; 1.5; 3; 4.5; 6; 24; 96; 168; 336 and 504 hours after inject drug cycle 1 | 
| Pharmacokinetic parameters: AUC0-t | Area under the curve from 0 to t (AUC0-t) | Blood samples will be collected at following time points: prior to IP administration; 1.5; 3; 4.5; 6; 24; 96; 168; 336 and 504 hours after inject drug cycle 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic parameters: Ctrough | Serum trough concentration (Ctrough) | Blood samples will be collected at following time points: day 23rd, 65th, 107th and 128th (at the beginning of visits 4, 8, 12, 14) | 
| Pharmacokinetic parameters: AUC0-∞ | Area under the curve from 0 to ∞ (AUC0-∞) | Blood samples will be collected at following time points: prior to IP administration; 1.5; 3; 4.5; 6; 24; 96; 168; 336 and 504 hours after inject drug cycle 1 | 
| Pharmacokinetic parameters: Tmax | Time for the drug to reach peak concentration (Tmax) | Blood samples will be collected at following time points: prior to IP administration; 1.5; 3; 4.5; 6; 24; 96; 168; 336 and 504 hours after inject drug cycle 1 | 
| Pharmacokinetic parameters: T1/2 | Half-life (T1/2) | Blood samples will be collected at following time points: prior to IP administration; 1.5; 3; 4.5; 6; 24; 96; 168; 336 and 504 hours after inject drug cycle 1 | 
| Rate of AE and SAE occurence | Frequency of adverse events, including clinical examination, vital signs and laboratory tests. | up to 128 days (6 cycles - each cycle is 21 days) |