Clinical trial NCT01764022: A Safety and Efficacy Study of BCD-022 With Paclitaxel Compared to Herceptin With Paclitaxel in HER2+ Metastatic Breast Cancer Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Human Epithelial Receptor (HER)-2 Positive Breast Cancer
Keywords: breast cancer
trastuzumab
Lead sponsor: Biocad
Sponsor class: INDUSTRY
First posted: 2013-01-09
Enrollment: 225
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall Response Rate
timeFrame: Day 127
measure: Area Under the Curve After the First Test Drug Administration
timeFrame: 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)
Secondary outcomes:
measure: Complete Response Rate
timeFrame: Day 127
measure: Partial Response Rate
timeFrame: Day 127
measure: Stabilization Rate
timeFrame: Day 127
measure: Progression Rate
timeFrame: Day 127
measure: Treatment Postponed Due to AE/SAE
timeFrame: Day 127
measure: Treatment Discontinuation Due to AE/SAE
timeFrame: Day 127
measure: Occurrence of Neutralizing Anti-trastuzumab Antibodies
timeFrame: Day 1 (before the drug administration), Day 14, 64, 127 and 154
measure: Cmax After the First Test Drug Administration
timeFrame: Up to Day 22
measure: Tmax After the First Test Drug Administration
timeFrame: Up to Day 22
measure: T1/2 After the First Test Drug Administration
timeFrame: Up to Day 22
measure: Cmax After the Sixth Test Drug Administration
timeFrame: Up to Day 127
measure: Tmax After the Sixth Test Drug Administration
timeFrame: Up to Day 127
Other outcomes:
Locations:
city: Brest
country: Belarus
facility: Brest Region Clinical Oncology Dispensary
city: Gomel
country: Belarus
facility: Gomel Region Clinical Oncology Dispensary
city: Grodno
country: Belarus
facility: Grodno Regional Hospital
city: Vitebsk
country: Belarus
facility: Vitebsk State Medical University of Order of Peoples' Friendship
city: Bangalore
country: India
facility: HCG Bangalore Institute of Oncology
city: Bangalore
country: India
facility: M.S.Ramaiah Memorial Hospital
city: Bangalore
country: India
facility: Narayana Hrudayalaya Hospitals
city: Stepanovskoye
country: Russian Federation
facility: State Health Institution of Moscow "Moscow City Oncology Hospital #62 of Moscow Board of Health"
state: Moscow Region
city: Arkhangelsk
country: Russian Federation
facility: Arkhangelsk District Clinical Oncology Dispensary
city: Chelyabinsk
country: Russian Federation
facility: Non-governmental Healthcare Institution "Railway Clinical hospital on the Chelyabinsk Station of JSC Russian Railways"
city: Chelyabinsk
country: Russian Federation
facility: State-financed Health Institution "Chelyabinsk Region Clinical Oncology Dispansary"
city: Izhevsk
country: Russian Federation
facility: State-financed Health Institution "Republican Clinical Oncology Hospital"
city: Moscow
country: Russian Federation
facility: Institution of Russian Academy of Medical Sciences "Russian Cancer Research Center named after N.N. Blokhin"
city: Moscow
country: Russian Federation
facility: Federal State Institution "Moscow Institute of Cancer Research named after P.A. Hertsen" Ministry of Health of Russian Federation
city: Orel
country: Russian Federation
facility: Regional State Health Institution "Orlov Oncology Dispansary"
city: Penza
country: Russian Federation
facility: State Health Institution "Region Oncology Dispansary"
city: Perm
country: Russian Federation
facility: Perm Region Oncology Dispensary
city: Rostov-on-Don
country: Russian Federation
facility: Federal Government Budgetary Institution "Rostov Institute of Cancer Research" of Ministry of Health of Russian Federation
city: Saint Petersburg
country: Russian Federation
facility: Saint Petersburg City Clinical Oncology Center
city: Samara
country: Russian Federation
facility: State-financed Health Institution "Samara Region Clinical Oncology Dispansary"
city: Sochi
country: Russian Federation
facility: Oncology Dispensary 2
city: St.Petersburg
country: Russian Federation
facility: Military Medical Academy named after S.M. Kirov
city: St.Petersburg
country: Russian Federation
facility: N.N.Petrov Oncology Research Center
city: St.Petersburg
country: Russian Federation
facility: Russian scientific center of radiology and surgery technologies
city: Stavropol
country: Russian Federation
facility: State-financed Health Institution "Stavropol Region Clinical Oncology Dispansary"
city: Ufa
country: Russian Federation
facility: Republican Clinical Oncology Dispensary of Ministry of Health republic Bashkortostan
city: Volgograd
country: Russian Federation
facility: Volgograd District Oncology Dispensary №1
city: Donetsk
country: Ukraine
facility: Donetsk City Oncology Dispensary
city: Donetsk
country: Ukraine
facility: Donetsk Regional Antitumor Center
city: Kharkiv
country: Ukraine
facility: Kharkiv Regional Clinical Oncology Center
city: Kryvyi Rih
country: Ukraine
facility: Kryvyi Rih Oncology Dispensary
city: Lviv
country: Ukraine
facility: Lviv Regional State Cancer Diagnostics and Treatment Center
city: Makiivka
country: Ukraine
facility: City Hospital №2
city: Poltava
country: Ukraine
facility: Poltava Regional Clinical Oncology Dispensary
city: Uzhhorod
country: Ukraine
facility: Zakarpatskyi Regional Clinical Oncology Center
city: Vinnytsia
country: Ukraine
facility: Vinnytsia Regional Clinical Oncology Dispensary
Study officials:
affiliation: Vice-president, R&D
name: Roman Ivanov, MD, PhD
role: STUDY_CHAIR
References:
citation: Alexeev SM, Khorinko AV, Mukhametshina GZ, Shelepen KG, Burdaeva ON, Kulik SA, Satheesh CT, Srivastava K, Vikranth M, Kryukov F, Paltusova AN, Shustova MS, Ivanov RA. Randomized double-blind clinical trial comparing safety and efficacy of the biosimilar BCD-022 with reference trastuzumab. BMC Cancer. 2020 Aug 20;20(1):783. doi: 10.1186/s12885-020-07247-9.