Non-small Cell Lung Cancer
Conditions
Brief summary
This is a multicenter, multinational, double-blind, 1:1 randomized, parallel-group, equivalence Phase 3 study to compare the efficacy and safety of MB02 plus chemotherapy (carboplatin and paclitaxel) versus Avastin® plus chemotherapy (carboplatin and paclitaxel) in subjects with Stage IIIB/IV non-squamous NSCLC
Detailed description
Efficacy parameters, safety profiles and immunogenicity will be compared between MB02 (Bevacizumab Biosimilar Drug) and European (EU)-approved Avastin®
Interventions
DRUGMB02 (Bevacizumab Biosimilar Drug)
15 mg/kg IV every 3 weeks on Day 1
DRUGEU-approved Avastin®
15 mg/kg IV every 3 weeks on Day 1
DRUGCarboplatin
Carboplatin Area under the curve (AUC) 6 IV every 3 weeks on Day 1 for 6 cycles
DRUGPaclitaxel
Paclitaxel 200 mg/m2 IV every 3 weeks on Day 1 for 6 cycles
Sponsors
mAbxience Research S.L.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Males and female subjects aged ≤ 18 years to ≤ 80 years. 2. Signed informed consent must be obtained before initiation of any study-specific procedures or treatment as confirmation of the subject's awareness and willingness to comply with the study requirements. 3. Subjects should have newly diagnosed or recurrent Stage IIIB/IV (defined by seventh edition of the Tumor, Node and Metastasis (TNM) classification for Lung Cancer, 2010) non-squamous NSCLC not amenable to curative intent surgery, and not have received any systemic therapy for advanced disease (
Exclusion criteria
3 and 4). For subjects with recurrent disease, at least 6 months must have elapsed before randomization from previous adjuvant treatment. 4. Previous radiation therapy if completed \>4 weeks before randomization. Palliative radiotherapy to bone lesions is allowed if completed \>2 weeks of randomization. 5. Subjects must have at least 1 unidimensional measurable lesion per RECIST version 1.1 (assessed locally). 6. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤1 at Screening. 7. Subjects must have adequate hepatic, renal and hematologic function defined as: * Hepatic function: bilirubin level \<1.5 the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels\<2.5×ULN. * Renal function: serum creatinine level \<1.5×ULN, calculated creatinine clearance (CrCl) \>50 mL/min (Cockcroft-Gault formula), urine protein to creatinine ratio \<1. Subjects with urine protein-to-creatinine ratio \>1 may be enrolled if they have \<1 g of protein in 24-hour urine collection. * Hematological function: Absolute neutrophil count \>1.5×109 /L; platelets \>100×109 /L, hemoglobin (Hb) \>9 g/dL. * Adequate coagulation parameters such as: INR ≤ 2.0 and aPTT ≤ 1.5 x ULN within 7 days prior to randomization for patients not receiving anticoagulation therapy. 8. Eligible subjects must have a systolic blood pressure of ≤ 140 mm Hg and a diastolic blood pressure of ≤90 mm Hg at screening. 9. Women of childbearing potential, and their partners, must agree to adhere to pregnancy prevention methods throughout the duration of the study (including the Follow-up visits, where applicable). Women of childbearing potential are defined as those who are not surgically sterile (did not underwent bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) and not postmenopausal. Subjects and their partners must agree to use a highly effective method of contraception, to avoid women becoming pregnant throughout the course of the study. Medically acceptable forms of birth control can include the following, with approval of the treating physician: * Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, sexual abstinence. 10\. Non fertile women can be included, that is, those who are physiologically incapable of becoming pregnant, because of: * Hysterectomy. * Bilateral oophorectomy (ovariectomy). * Bilateral tubal ligation or, * Postmenopausal women defined as: Subjects not using hormone replacement therapy (HRT) and have experienced total cessation of menses for ≥ 1 year and be greater than 45 years of age, OR, in questionable cases, have a follicle stimulating hormone \>40 mIU/mL and an estradiol value \<40 pg/mL (\<140 pmol/L). Subjects must discontinue HRT before study enrolment because of the potential for inhibition of cytochrome enzymes that metabolize estrogens and progestins. For most forms of HRT, at least 2 to 4 weeks must elapse between the cessation of HRT and determination of menopausal status; the length of this interval depends on the type and dosage of HRT. If a female subject is determined not to be postmenopausal, that subject must use adequate contraception, as defined immediately above (inclusion 8).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) at Week 18 | 18 weeks from randomisation | Objective response rate was assigned for a subject if the subject displayed either complete response (CR) or partial response (PR) per RECIST version 1.1 at Week 18, as assessed by independent radiological review committee (IRC). Overall Response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | At Week 52 from randomisation | Progression-free survival was defined as the time from randomization to subsequent confirmed progression per RECIST version 1.1, or death (whichever occurred first), measured in weeks and months. For PFS assessment clinical progression (i.e., treatment discontinuation due to progression of disease) was also considered as an event. |
| Overall Survival (OS) | At Week 52 from randomisation | Overall survival was defined as the time from randomization to subsequent death, measured in weeks and months. |
| Incidence of Treatment-emergent Adverse Events (TEAEs) | Week 1 to week 52 | Comparison of Safety profile. Safety was monitored by incidence of adverse events (AEs). AEs were coded as per MedDRA (version 20.1) and severity was graded according to NCI-CTCAE (version 4.03); |
| Immunogenicity Assessments (Anti-drug Antibodies [ADA] and Neutralizing Antibodies [NAb]) | At Weeks 1, 4, 10, 19, 34 and 52 from randomization and, at the End of Treatment Visit if, an ADA sample has not been collected within the previous 3 weeks | Incidence of anti-drug antibodies (ADA) and neutralizing ADAs (NAb). Analyses of ADA incidence rate, antibody titer, and neutralizing antibodies (NAb) (following the recommended 3-tier approach) were performed. |
Countries
Brazil, Bulgaria, Chile, Georgia, Greece, Hungary, India, Lebanon, Malaysia, Mexico, Oman, Philippines, Russia, Serbia, Spain, Thailand, Turkey (Türkiye), Ukraine
Participant flow
Pre-assignment details
A total of 627 subjects were randomized and assigned to one of the study arms. Two subjects in the MB02 arm failed screening but were randomized in error. These subjects did not receive treatment. Another two subjects did not receive MB02 treatment due to death (one subject) and unacceptable toxicity (one subject). Two subjects in the European (EU)-approved bevacizumab did not receive study treatment due to investigator decision (one subject) and unacceptable toxicity (one subject).
Participants by arm
| Arm | Count |
|---|---|
| MB02 (Bevacizumab Biosimilar Drug) MB02 (Bevacizumab Biosimilar Drug) + Carboplatin/Paclitaxel
MB02 (Bevacizumab Biosimilar Drug): 15 mg/kg IV every 3 weeks on Day 1
Carboplatin: Carboplatin AUC 6 IV every 3 weeks on Day 1 for 6 cycles
Paclitaxel: Paclitaxel 200 mg/m2 IV every 3 weeks on Day 1 for 6 cycles | 315 |
| EU-approved Avastin® EU-approved Avastin® + Carboplatin/Paclitaxel
EU-approved Avastin®: 15 mg/kg IV every 3 weeks on Day 1
Carboplatin: Carboplatin AUC 6 IV every 3 weeks on Day 1 for 6 cycles
Paclitaxel: Paclitaxel 200 mg/m2 IV every 3 weeks on Day 1 for 6 cycles | 312 |
| Total | 627 |
Baseline characteristics
| Characteristic | MB02 (Bevacizumab Biosimilar Drug) | EU-approved Avastin® | Total |
|---|---|---|---|
| Age, Continuous | 61.0 years | 61.0 years | 61.0 years |
| Body surface area (BSA) | 1.780 m^2 | 1.790 m^2 | 1.780 m^2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 71 Participants | 54 Participants | 125 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 243 Participants | 256 Participants | 499 Participants |
| Sex: Female, Male Female | 122 Participants | 122 Participants | 244 Participants |
| Sex: Female, Male Male | 193 Participants | 190 Participants | 383 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 23 / 311 | 24 / 310 |
| other Total, other adverse events | 288 / 311 | 288 / 310 |
| serious Total, serious adverse events | 58 / 311 | 54 / 310 |
Outcome results
Primary
Objective Response Rate (ORR) at Week 18
Objective response rate was assigned for a subject if the subject displayed either complete response (CR) or partial response (PR) per RECIST version 1.1 at Week 18, as assessed by independent radiological review committee (IRC). Overall Response (OR) = CR + PR.
Time frame: 18 weeks from randomisation
Population: Primary efficacy analysis was done in the intention-to-treat (ITT) population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MB02 (Bevacizumab Biosimilar Drug) | Objective Response Rate (ORR) at Week 18 | 40.3 Percentage of participants |
| EU-approved Avastin® | Objective Response Rate (ORR) at Week 18 | 44.6 Percentage of participants |
90% CI: [0.78, 1.06]
90% CI: [-10.51, 2.47]
Secondary
Immunogenicity Assessments (Anti-drug Antibodies [ADA] and Neutralizing Antibodies [NAb])
Incidence of anti-drug antibodies (ADA) and neutralizing ADAs (NAb). Analyses of ADA incidence rate, antibody titer, and neutralizing antibodies (NAb) (following the recommended 3-tier approach) were performed.
Time frame: At Weeks 1, 4, 10, 19, 34 and 52 from randomization and, at the End of Treatment Visit if, an ADA sample has not been collected within the previous 3 weeks
Population: Immunogenicity was assessed in the Safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MB02 (Bevacizumab Biosimilar Drug) | Immunogenicity Assessments (Anti-drug Antibodies [ADA] and Neutralizing Antibodies [NAb]) | ADA positive | 53 participants |
| MB02 (Bevacizumab Biosimilar Drug) | Immunogenicity Assessments (Anti-drug Antibodies [ADA] and Neutralizing Antibodies [NAb]) | NAb positive | 10 participants |
| MB02 (Bevacizumab Biosimilar Drug) | Immunogenicity Assessments (Anti-drug Antibodies [ADA] and Neutralizing Antibodies [NAb]) | NO seroconversion | 239 participants |
| EU-approved Avastin® | Immunogenicity Assessments (Anti-drug Antibodies [ADA] and Neutralizing Antibodies [NAb]) | ADA positive | 50 participants |
| EU-approved Avastin® | Immunogenicity Assessments (Anti-drug Antibodies [ADA] and Neutralizing Antibodies [NAb]) | NAb positive | 13 participants |
| EU-approved Avastin® | Immunogenicity Assessments (Anti-drug Antibodies [ADA] and Neutralizing Antibodies [NAb]) | NO seroconversion | 247 participants |
Secondary
Incidence of Treatment-emergent Adverse Events (TEAEs)
Comparison of Safety profile. Safety was monitored by incidence of adverse events (AEs). AEs were coded as per MedDRA (version 20.1) and severity was graded according to NCI-CTCAE (version 4.03);
Time frame: Week 1 to week 52
Population: Safety analyses were performed in the Safety population, which consisted of all subjects who received at least 1 administration of investigational medicinal product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MB02 (Bevacizumab Biosimilar Drug) | Incidence of Treatment-emergent Adverse Events (TEAEs) | with ≥1 treatment-related TEAE | 264 participants |
| MB02 (Bevacizumab Biosimilar Drug) | Incidence of Treatment-emergent Adverse Events (TEAEs) | with at least one Serious TEAE | 58 participants |
| MB02 (Bevacizumab Biosimilar Drug) | Incidence of Treatment-emergent Adverse Events (TEAEs) | with ≥1 Grade 3 or 4 TEAE | 131 participants |
| MB02 (Bevacizumab Biosimilar Drug) | Incidence of Treatment-emergent Adverse Events (TEAEs) | with ≥1 TEAE leading to discontinuation | 72 participants |
| MB02 (Bevacizumab Biosimilar Drug) | Incidence of Treatment-emergent Adverse Events (TEAEs) | with ≥1 Grade 3 or 4 treatment-related TEAE | 98 participants |
| MB02 (Bevacizumab Biosimilar Drug) | Incidence of Treatment-emergent Adverse Events (TEAEs) | with ≥1 treatment-related TEAE leading to discontinuation | 42 participants |
| MB02 (Bevacizumab Biosimilar Drug) | Incidence of Treatment-emergent Adverse Events (TEAEs) | with ≥1 TEAE | 288 participants |
| EU-approved Avastin® | Incidence of Treatment-emergent Adverse Events (TEAEs) | with ≥1 treatment-related TEAE leading to discontinuation | 33 participants |
| EU-approved Avastin® | Incidence of Treatment-emergent Adverse Events (TEAEs) | with ≥1 TEAE | 288 participants |
| EU-approved Avastin® | Incidence of Treatment-emergent Adverse Events (TEAEs) | with ≥1 Grade 3 or 4 TEAE | 125 participants |
| EU-approved Avastin® | Incidence of Treatment-emergent Adverse Events (TEAEs) | with ≥1 treatment-related TEAE | 270 participants |
| EU-approved Avastin® | Incidence of Treatment-emergent Adverse Events (TEAEs) | with ≥1 Grade 3 or 4 treatment-related TEAE | 91 participants |
| EU-approved Avastin® | Incidence of Treatment-emergent Adverse Events (TEAEs) | with at least one Serious TEAE | 54 participants |
| EU-approved Avastin® | Incidence of Treatment-emergent Adverse Events (TEAEs) | with ≥1 TEAE leading to discontinuation | 63 participants |
Secondary
Overall Survival (OS)
Overall survival was defined as the time from randomization to subsequent death, measured in weeks and months.
Time frame: At Week 52 from randomisation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MB02 (Bevacizumab Biosimilar Drug) | Overall Survival (OS) | NA weeks |
| EU-approved Avastin® | Overall Survival (OS) | NA weeks |
95% CI: [0.827, 1.485]
Secondary
Progression-free Survival (PFS)
Progression-free survival was defined as the time from randomization to subsequent confirmed progression per RECIST version 1.1, or death (whichever occurred first), measured in weeks and months. For PFS assessment clinical progression (i.e., treatment discontinuation due to progression of disease) was also considered as an event.
Time frame: At Week 52 from randomisation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MB02 (Bevacizumab Biosimilar Drug) | Progression-free Survival (PFS) | 36.0 weeks |
| EU-approved Avastin® | Progression-free Survival (PFS) | 37.3 weeks |
95% CI: [0.98, 1.44]