A Safety and Efficacy Study of BCD-022 With Paclitaxel Compared to Herceptin With Paclitaxel in HER2+ Metastatic Breast Cancer Patients

Multicenter Randomized Double-blind Phase III Clinical Trial Comparing Safety and Efficacy of BCD-022 (CJSC BIOCAD, Russia) Used With Paclitaxel to Herceptin® Used With Paclitaxel in the First-line Treatment of HER2+ Metastatic Breast Cancer Patients

BCD-022-02 is a double-blind randomized clinical trial comparing efficacy of BCD-022 (INN: trastuzumab) and paclitaxel to Herceptin and paclitaxel in HER2-positive metastatic breast cancer with pharmacokinetics substudy. The purpose of the study is to demonstrate the non-inferiority of efficacy and safety of BCD-022 compared to Herceptin. Also study includes pharmacokinetics assessment.

The study is based on the hypothesis of equivalence of BCD-022 (trastuzumab by JSC BIOCAD, Russia) in combination with paclitaxel used as the therapy of inoperable or metastatic HER2(+) breast cancer in comparison with Herceptin® (F. Hoffmann-La Roche Ltd., Switzerland) in combination with paclitaxel. The objectives of the study is to evaluate efficacy, safety and pharmacokinetics of BCD-022 compared with reference trastuzumab by 1. overall response rate and other efficacy parameters; 2. incidence and severity of adverse events; 3. serum concentration after the first and multiple trastuzumab administration; 4. incidence and concentration of anti-trastuzumab antibodies.

Inclusion Criteria:

• Written informed consent and ability to follow the Protocol procedures;
• Age from 18 years to 75 years inclusive;
• Female gender;
• Histologically confirmed breast cancer (BC);
• Metastatic BC (stage IV according to TNM classification version 6);
• 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) ;
• Documented results of oestrogen and progesterone receptors expression analysis;
• Eastern Cooperative Oncology Group (ECOG) status 0, 1 or 2, not increasing within 2 weeks prior to randomization;
• Life expectancy - 20 weeks or more from the moment of randomization;
• 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;
• Patients of childbearing potential 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 cytotoxic chemotherapy, or 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 hormonal therapy is allowed;
• Disease progression within 6 months after adjuvant and/or neoadjuvant anti BC therapy;
• Surgery, radiation therapy, use of any experimental medications within 4 weeks (28 days) prior to randomization;
• Hypersensitivity to paclitaxel and all medications containing polyoxyethylated castor oil, hypersensitivity to dexamethasone, diphenhydramine, ranitidine/cimetidine, recombinant murine proteins, contrast agents or excipients of study medications;
• BC metastases in central nervous system, progressing or clinically manifested (e.g. cerebral oedema, spinal cord injury), with exception of non-progressing metastases not requiring treatment with glucocorticosteroids and/or anticonvulsants within 4 weeks prior to randomization;
• 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;
• 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);
• Left ventricular ejection fraction <50% according to electrocardiography;
• Neutrophils ≤1500/mm3;
• Platelets ≤100 000/mm3;
• Hemoglobin ≤90 g/L;
• Creatinine level ≥ 1.5 × upper limit of normal (ULN);
• Bilirubin level ≥ 1.5 × ULN;
• Asparagine transferase (AST) and alanine transferase (ALT) levels ≥ 2.5 × ULN (5 × ULN for patients with liver metastases);
• Alkaline phosphatase level ≥ 5 × ULN;
• Pregnancy or lactation;
• Any other concomitant cancer including contralateral breast cancer revealed within 5 years prior to screening, except curatively treated intraductal carcinoma in situ, curatively treated cervical carcinoma in situ or curatively treated basal cell or squamous cell carcinoma;
• Conditions limiting patient's adherence to protocol requirements (dementia, neurologic or psychiatric disorders, drug addiction, alcoholism and others);
• Stage II-IV neuropathy according to Common Terminology Criteria for Adverse Events (CTCAE) v.4.0;
• Concomitant participation in other clinical trials, previous participation in other clinical trials within 30 days before entering into the trial, previous participation in the same trial;
• Acute or active chronic infections;
• Hepatitis C virus, hepatitis B virus, HIV or syphilis infections;
• Obstacles in intravenous administration of study drugs