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

Phase 3

Completed

Conditions: Human Epithelial Receptor (HER)-2 Positive Breast Cancer

Interventions: Drug: Trastuzumab
Drug: Paclitaxel

Registration Number: NCT01764022

Lead Sponsor: Biocad

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 225

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
BCD-022	Trastuzumab	BCD-022 is a product code for trastuzumab biosimilar manufactured by CJSC BIOCAD, Russia. In this arm patients will receive 6 courses of treatment with BCD-022 in combination with paclitaxel. Patients will receive BCD-022 at a loading dose of 8 mg/kg (once), followed by maintenance dose of 6 mg/kg every 3 weeks (5 administrations), + paclitaxel 175 mg/m2 every 3 weeks as 3 hour intravenous infusion (6 administrations).
Herceptin®	Trastuzumab	In this arm patients will receive 6 courses of treatment with Herceptin® (F. Hoffmann-La Roche Ltd., Switzerland) in combination with paclitaxel. Patients will receive Herceptin® at a loading dose of 8 mg/kg (once), followed by maintenance dose of 6 mg/kg every 3 weeks (5 administrations), + paclitaxel 175 mg/m2 every 3 weeks as 3 hour intravenous infusion (6 administrations).
BCD-022	Paclitaxel	BCD-022 is a product code for trastuzumab biosimilar manufactured by CJSC BIOCAD, Russia. In this arm patients will receive 6 courses of treatment with BCD-022 in combination with paclitaxel. Patients will receive BCD-022 at a loading dose of 8 mg/kg (once), followed by maintenance dose of 6 mg/kg every 3 weeks (5 administrations), + paclitaxel 175 mg/m2 every 3 weeks as 3 hour intravenous infusion (6 administrations).
Herceptin®	Paclitaxel	In this arm patients will receive 6 courses of treatment with Herceptin® (F. Hoffmann-La Roche Ltd., Switzerland) in combination with paclitaxel. Patients will receive Herceptin® at a loading dose of 8 mg/kg (once), followed by maintenance dose of 6 mg/kg every 3 weeks (5 administrations), + paclitaxel 175 mg/m2 every 3 weeks as 3 hour intravenous infusion (6 administrations).

Primary Outcome Measures

Name	Time	Method
Overall Response Rate	Day 127	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. The response was assessed at the screening, after 3 therapy cycles and after 6 therapy cycles. If CT after 3 or 6 therapy cycles revealed the complete or partial response, a confirmatory CT scan was performed 4 weeks later. The best response during the study was assessed.
Area Under the Curve After the First Test Drug Administration	up to Day 22, after the first trastuzumab administration (time points for blood samples: 0 h 1.5 h, 3 h, 4.5 h, 6 h, 24 h, 96 h, 168 h, 336 h and 504 h)	Primary outcome measure for pharmacokinetics (PK) substudy. AUC(0-504) of trastuzumab in HER2(+) mBC patients after first administration of BCD-022 with paclitaxel or Herceptin® with paclitaxel.

Secondary Outcome Measures

Name	Time	Method
Occurrence of Neutralizing Anti-trastuzumab Antibodies	Day 1 (before the drug administration), Day 14, 64, 127 and 154	Secondary outcome measure for immunogenicity assessment. Patient was suggested as NAB-positive if neutralizing anti-trastuzumab antibodies were detected at any of the specified timepoints. Total number of NAB-positive patients in each are presented.
Cmax After the First Test Drug Administration	Up to Day 22	Secondary outcome measure for PK substudy. Peak serum concentration of trastuzumab after single administration of BCD-022 + paclitaxel or Herceptin® + paclitaxel
Tmax After the First Test Drug Administration	Up to Day 22	Secondary outcome measure for PK substudy. Time to reach peak serum concentration of trastuzumab after the first administration of BCD-022 + paclitaxel or Herceptin® + paclitaxel
T1/2 After the First Test Drug Administration	Up to Day 22	Secondary outcome measure for PK substudy. Half-life period of trastuzumab after the first administration of BCD-022 + paclitaxel or Herceptin® + paclitaxel.
Complete Response Rate	Day 127	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. The response was assessed at the screening, after 3 therapy cycles and after 6 therapy cycles. If CT after 3 or 6 therapy cycles revealed the complete or partial response, a confirmatory CT scan was performed 4 weeks later. The best response during the study was assessed.
Partial Response Rate	Day 127	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. The response was assessed at the screening, after 3 therapy cycles and after 6 therapy cycles. If CT after 3 or 6 therapy cycles revealed the complete or partial response, a confirmatory CT scan was performed 4 weeks later. The best response during the study was assessed.
Stabilization Rate	Day 127	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. The response was assessed at the screening, after 3 therapy cycles and after 6 therapy cycles. If CT after 3 or 6 therapy cycles revealed the complete or partial response, a confirmatory CT scan was performed 4 weeks later. The best response during the study was assessed.
Progression Rate	Day 127	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. The response was assessed at the screening, after 3 therapy cycles and after 6 therapy cycles. If CT after 3 or 6 therapy cycles revealed the complete or partial response, a confirmatory CT scan was performed 4 weeks later. The best response during the study was assessed.
Treatment Postponed Due to AE/SAE	Day 127	Secondary outcome measure for safety evaluation
Treatment Discontinuation Due to AE/SAE	Day 127	Secondary outcome measure for safety evaluation
Cmax After the Sixth Test Drug Administration	Up to Day 127	Secondary outcome measure for PK substudy. Peak serum concentration of trastuzumab after the sixth administration of BCD-022 + paclitaxel or Herceptin® + paclitaxel.
Tmax After the Sixth Test Drug Administration	Up to Day 127	Secondary outcome measure for PK substudy. Time to reach peak serum concentration of trastuzumab after the sixth administration of BCD-022 + paclitaxel or Herceptin® + paclitaxel

Trial Locations

Locations (36): Gomel Region Clinical Oncology Dispensary
🇧🇾
Gomel, Belarus
Grodno Regional Hospital
🇧🇾
Grodno, Belarus
HCG Bangalore Institute of Oncology
🇮🇳
Bangalore, India
M.S.Ramaiah Memorial Hospital
🇮🇳
Bangalore, India
Narayana Hrudayalaya Hospitals
🇮🇳
Bangalore, India
Vitebsk State Medical University of Order of Peoples' Friendship
🇧🇾
Vitebsk, Belarus
Institution of Russian Academy of Medical Sciences "Russian Cancer Research Center named after N.N. Blokhin"
🇷🇺
Moscow, Russian Federation
Brest Region Clinical Oncology Dispensary
🇧🇾
Brest, Belarus
Kharkiv Regional Clinical Oncology Center
🇺🇦
Kharkiv, Ukraine
State-financed Health Institution "Republican Clinical Oncology Hospital"
🇷🇺
Izhevsk, Russian Federation
N.N.Petrov Oncology Research Center
🇷🇺
St.Petersburg, Russian Federation
Russian scientific center of radiology and surgery technologies
🇷🇺
St.Petersburg, Russian Federation
Donetsk City Oncology Dispensary
🇺🇦
Donetsk, Ukraine
State-financed Health Institution "Chelyabinsk Region Clinical Oncology Dispansary"
🇷🇺
Chelyabinsk, Russian Federation
Federal Government Budgetary Institution "Rostov Institute of Cancer Research" of Ministry of Health of Russian Federation
🇷🇺
Rostov-on-Don, Russian Federation
Military Medical Academy named after S.M. Kirov
🇷🇺
St.Petersburg, Russian Federation
Kryvyi Rih Oncology Dispensary
🇺🇦
Kryvyi Rih, Ukraine
Donetsk Regional Antitumor Center
🇺🇦
Donetsk, Ukraine
City Hospital №2
🇺🇦
Makiivka, Ukraine
Poltava Regional Clinical Oncology Dispensary
🇺🇦
Poltava, Ukraine
Non-governmental Healthcare Institution "Railway Clinical hospital on the Chelyabinsk Station of JSC Russian Railways"
🇷🇺
Chelyabinsk, Russian Federation
Arkhangelsk District Clinical Oncology Dispensary
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Arkhangelsk, Russian Federation
Federal State Institution "Moscow Institute of Cancer Research named after P.A. Hertsen" Ministry of Health of Russian Federation
🇷🇺
Moscow, Russian Federation
Perm Region Oncology Dispensary
🇷🇺
Perm, Russian Federation
Republican Clinical Oncology Dispensary of Ministry of Health republic Bashkortostan
🇷🇺
Ufa, Russian Federation
State-financed Health Institution "Stavropol Region Clinical Oncology Dispansary"
🇷🇺
Stavropol, Russian Federation
State Health Institution of Moscow "Moscow City Oncology Hospital #62 of Moscow Board of Health"
🇷🇺
Stepanovskoye, Moscow Region, Russian Federation
Regional State Health Institution "Orlov Oncology Dispansary"
🇷🇺
Orel, Russian Federation
State Health Institution "Region Oncology Dispansary"
🇷🇺
Penza, Russian Federation
Lviv Regional State Cancer Diagnostics and Treatment Center
🇺🇦
Lviv, Ukraine
Zakarpatskyi Regional Clinical Oncology Center
🇺🇦
Uzhhorod, Ukraine
Vinnytsia Regional Clinical Oncology Dispensary
🇺🇦
Vinnytsia, Ukraine
Saint Petersburg City Clinical Oncology Center
🇷🇺
Saint Petersburg, Russian Federation
State-financed Health Institution "Samara Region Clinical Oncology Dispansary"
🇷🇺
Samara, Russian Federation
Oncology Dispensary 2
🇷🇺
Sochi, Russian Federation
Volgograd District Oncology Dispensary №1
🇷🇺
Volgograd, Russian Federation