Non-small Cell Lung Cancer
Conditions
Keywords
NSCLC, bevacizumab, pharmacokinetics
Brief summary
BCD-021-02 is a double-blind randomized clinical trial comparing efficacy of BCD-021 (INN: bevacizumab) and paclitaxel + carboplatin to Avastin and paclitaxel + carboplatin in inoperable or advanced non-squamous NSCLC patients with pharmacokinetics substudy. The purpose of the study is to demonstrate the non-inferiority of efficacy and safety of BCD-021 compared to Avastin. Also study includes pharmacokinetics assessment.
Interventions
DRUGBevacizumab
Patients will receive 6 courses of bevacizumab in combination with carboplatin and paclitaxel. Bevacizumab will be administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks (on Day 1 of each cycle).
DRUGPaclitaxel
Paclitaxel will be administered at a dose of 175 mg/m2 as 3 hour intravenous infusion on Day 1 of each 3-week course (6 courses totally)
DRUGCarboplatin
Carboplatin will be administered (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel on Day 1 of each 3-week course (6 courses totally).
Sponsors
Biocad
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent; * Newly diagnosed histologically or cytologically confirmed NSCLC excluding squamous NSCLC (mixed cancer types should be classified according to the prevalent cell type); * IIIb or IV stage of NSCLC (TNM classification version 6); * Age ≥ 18 years and age ≤ 75 years (both inclusive); * Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2, (not declining within 2 weeks prior to the first dose of investigational product); * Life expectancy - 12 weeks or more from the moment of randomization; * Presence of at least 1 measurable tumour with a size not less than 1 cm (revealed with CT slice thickness not more than 5 mm), as defined by modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria (specifically, no ascites, pleural, or pericardial effusions, osteoblastic bone metastases, or carcinomatous lymphangitis of the lung as only lesion; * Patients should be able to follow the Protocol procedures (according to Investigator's assessment); * Patients must implement reliable contraceptive measures during all the study treatment, starting 4 weeks prior to the administration of the first dose of investigational product until 6 months after the last dose of investigational product. This requirement does not apply to participants who have undergone surgical sterilization, or patients who are postmenopausal (documented) for the past 2 years. Reliable contraceptive measures include two methods of contraception, including one barrier method
Exclusion criteria
* Squamous NSCLC; * Proven coagulopathy, clinically significant hemorrhage in the past including nasal hemorrhage; * absolute neutrophil count \<1500/mm3; * Platelets \<100 000/mm3; * Hemoglobin \< 90 g/L; * Creatinine level ≥1.5 mg/dL; * Bilirubin level ≥1.5 × upper limit of normal (ULN); * Aspartate-aminotransferase(AST) and alanine-aminotransferase (ALT) levels ≥2.5 × ULN (≥5 × ULN for patients with liver metastases); * Alkaline phosphatase level ≥5 × ULN; * Current therapeutic anticoagulation treatment, aspirin (more than 325 mg/day), nonsteroidal anti-inflammatory drugs, antiplatelet agents or protracted treatment with these drugs less than 1 month before entering the study; * 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-medical correction methods (low salt diet, physical exercise); * Any previous anticancer therapy (chemotherapy, radiation therapy , surgery etc.) of metastatic NSCLC; * Radiation or hormone therapy within 21 days prior to randomization; * Major surgery 28 days before inclusion into the study; * Previous antiangiogenic therapy; * Hypersensitivity to taxanes, platinum agents, recombinant murine proteins, contrast agents, premedication agents specified by Protocol (dexamethasone, diphenhydramine, ranitidine) or excipients of investigational products; * NSCLC metastases in central nervous system excluding metastases non-progressing without glucocorticosteroids within 4 weeks before inclusion into the trial; * Cardiovascular system pathology (CHF stage III-IV according to New York Heart Association (NYHA) classification); * Pregnancy or lactation; * 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; * Simultaneous 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; * Any other concomitant 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; * Acute or active chronic infections; * Hepatitis C virus, hepatitis B virus, HIV, or syphilis infections; * Obstacles in intravenous administration of study drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall 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. |
| Area Under the Curve After the First Test Drug Administration | up to Day 22, after the first bevacizumab 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stabilization Rate | Day 127 | secondary outcome measure for efficacy evaluation |
| Complete Response Rate | Day 127 | secondary outcome measure for efficacy evaluation |
| Occurrence of Anti-bevacizumab Antibodies | Day 1 (before the drug administration), Day 15, 64 and 127 | Secondary outcome measure for immunogenicity assessment |
| Progression Rate | Day 127 | secondary outcome measure for efficacy evaluation |
| Partial Response Rate | Day 127 | secondary outcome measure for efficacy evaluation |
Countries
Belarus, India, Russia, Ukraine
Participant flow
Pre-assignment details
343 of 353 patients received at least one dose of the study drug/comparator. 10 patients discontinued the study without receiving a single dose of the study drug/comparator. The safety analysis included all data from all randomized subjects who received at least one dose of study therapy, 2 of 343 patients were excluded from the efficacy analysis due to screening failure (1 in each group), n= 341.
Participants by arm
| Arm | Count |
|---|---|
| BCD-021 (CISC BIOCAD) In this arm patients received 6 courses of treatment with BCD-021 in combination with carboplatin and paclitaxel. BCD-021 was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks (on Day 1 of each course). Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1. | 206 |
| Avastin (F. Hoffmann-La Roche Ltd) In this arm patients received 6 courses of treatment with Avastin in combination with carboplatin and paclitaxel.
Avastin was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks on Day 1.
Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1. | 137 |
| Total | 343 |
Baseline characteristics
| Characteristic | BCD-021 (CISC BIOCAD) | Avastin (F. Hoffmann-La Roche Ltd) | Total |
|---|---|---|---|
| Age, Continuous | 57.79 years STANDARD_DEVIATION 8.88 | 58.67 years STANDARD_DEVIATION 8.33 | 58.23 years STANDARD_DEVIATION 8.61 |
| Sex: Female, Male Female | 142 Participants | 88 Participants | 230 Participants |
| Sex: Female, Male Male | 63 Participants | 48 Participants | 111 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 14 / 206 | 8 / 137 |
| other Total, other adverse events | 206 / 206 | 137 / 137 |
| serious Total, serious adverse events | 36 / 206 | 20 / 137 |
Outcome results
Primary
Area Under the Curve After the First Test Drug Administration
primary outcome measure for pharmacokinetics (PK) substudy
Time frame: up to Day 22, after the first bevacizumab 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)
Population: Patients who received one dose of study drug and after 504 hours after injection had missed \<= 1 blood sample collection to analyze pharmacokinetics.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-021 (CISC BIOCAD) | Area Under the Curve After the First Test Drug Administration | 26951463 (ng/ml)*hour |
| Avastin (F. Hoffmann-La Roche Ltd) | Area Under the Curve After the First Test Drug Administration | 23970112.875 (ng/ml)*hour |
Primary
Overall Response Rate
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.
Time frame: Day 127
Population: The efficacy analysis included only those patients who received at least one dose of BCD-021 or Avastin®, and in whom it was possible to assess the response to therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCD-021 (CISC BIOCAD) | Overall Response Rate | 34.63 percentage of participans |
| Avastin (F. Hoffmann-La Roche Ltd) | Overall Response Rate | 33.82 percentage of participans |
Secondary
Complete Response Rate
secondary outcome measure for efficacy evaluation
Time frame: Day 127
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCD-021 (CISC BIOCAD) | Complete Response Rate | 1.85 percentage of patients |
| Avastin (F. Hoffmann-La Roche Ltd) | Complete Response Rate | 1.79 percentage of patients |
Secondary
Occurrence of Anti-bevacizumab Antibodies
Secondary outcome measure for immunogenicity assessment
Time frame: Day 1 (before the drug administration), Day 15, 64 and 127
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCD-021 (CISC BIOCAD) | Occurrence of Anti-bevacizumab Antibodies | 1.47 percentage of patients |
| Avastin (F. Hoffmann-La Roche Ltd) | Occurrence of Anti-bevacizumab Antibodies | 1.52 percentage of patients |
Secondary
Partial Response Rate
secondary outcome measure for efficacy evaluation
Time frame: Day 127
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCD-021 (CISC BIOCAD) | Partial Response Rate | 40.74 percentage of patients |
| Avastin (F. Hoffmann-La Roche Ltd) | Partial Response Rate | 37.50 percentage of patients |
Secondary
Progression Rate
secondary outcome measure for efficacy evaluation
Time frame: Day 127
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCD-021 (CISC BIOCAD) | Progression Rate | 5.56 percentage of patients |
| Avastin (F. Hoffmann-La Roche Ltd) | Progression Rate | 8.93 percentage of patients |
Secondary
Stabilization Rate
secondary outcome measure for efficacy evaluation
Time frame: Day 127
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCD-021 (CISC BIOCAD) | Stabilization Rate | 51.85 percentage of patients |
| Avastin (F. Hoffmann-La Roche Ltd) | Stabilization Rate | 51.79 percentage of patients |