NSCLC Stage IV
Conditions
Brief summary
Assess the Efficacy and Safety of MYL-1402O Compared with Avastin®, in the First-line Treatment of Patients with Stage IV Non-Squamous Non-Small Cell Lung Cancer
Detailed description
MYL-1402O is a monoclonal antibody currently being developed by Mylan GmbH, as a proposed biosimilar to European Union and US licensed Avastin (hereafter referred to as Avastin), which is approved as first line treatment in combination with carboplatin and paclitaxel (CP) for patients with Stage IV unresectable, recurrent or metastatic nsNSCLC. This randomized equivalence study is designed to meet the global regulatory requirement for approval of a biosimilar product. For this study, both MYL-1402O and Avastin are considered investigational medicinal products (IMP).
Interventions
BIOLOGICALBevacizumab as MYL-1402O
Bevacizumab as MYL-1402O 15 mg/kg IV + Carboplatin AUC 6 IV+ Paclitaxel 200 or 175 mg/m2 IV
BIOLOGICALBevacizumab as Avastin
Bevacizumab as Avastin 15 mg/kg IV + Carboplatin AUC 6 IV+ Paclitaxel 200 or 175 mg/m2 IV
Sponsors
Mylan Pharmaceuticals Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blind
Intervention model description
Multicenter, Double-Blind, Randomized, Parallel-Group
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Written and signed informed consent 2. Male or female at least 18 years of age with documented imaging diagnosis of Stage IV unresectable, recurrent or metastatic nsNSCLC with at least one measurable lesion as defined by RECIST 1.1 3. Documented histologic or cytologic diagnosis of advanced nsNSCLC with negative or unknown sensitizing epidermal growth factor receptor (EGFR) mutation, and negative or unknown echinoderm microtubule-associated protein like 4 anaplastic lymphoma kinase (EML4 ALK) rearrangement. 4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 5. Has not received any prior systemic therapy for first-line treatment of advanced lung cancer, except adjuvant chemotherapy, and remained disease-free for at least 12 months from time of surgery, and at least 6 months from last dose of chemotherapy. 6. Treated and stable brain metastasis. Key
Exclusion criteria
1. Documented squamous NSCLC or small cell type or large cell neuroendocrine histology 2. History of significant hemoptysis, central tumors with proximity to large vessels and tumor with cavitation 3. Received prior treatment with paclitaxel, bevacizumab or anthracycline or had known hypersensitivity to any of these components. 4. Recent significant cardiac condition or vascular event or inadequately controlled hypertension. 5. On anticoagulant therapy not considered stable 6. Risk of hemorrhage in the central nervous system 7. Recent history of surgery, nonhealing wound, active ulcer, or untreated bone fracture. 8. History of gastrointestinal fistula, perforation, or abscess.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Efficacy Analysis of Overall Response Rate ( ORR) of MYL-1402O as Compared to Avastin | 18 weeks after first dosing per patient | The primary efficacy endpoint Overall Response Rate (ORR) will be based on best tumor responses as assessed by an independent review at any time point during the first 18 weeks, and assessed according to RECIST 1.1. The primary efficacy analysis is based on the ratio of the MYL-1402O ORR to the Avastin ORR at Week 18 based on the Intent to Treat ( ITT) set of patients. |
Countries
Belarus, Bosnia and Herzegovina, Bulgaria, Croatia, Georgia, Hungary, India, Italy, Philippines, Poland, Romania, Russia, Spain, Taiwan, Turkey (Türkiye), Ukraine, Vietnam
Participant flow
Recruitment details
671 subjects enrolled at 89 sites across Eastern Europe, Russia, Asia Pacific, South East Asia. Date of first patient randomized: 21 Jan 2017 Date of last patient randomized: 31 Jan 2019
Pre-assignment details
A total of 1016 patients were screened; 345 patients were screen failures. Most common reasons for screen failures were; 57=met exclusion criteria tumor location in contact with major vessels, 46= withdrew consent; 37= patients who have brain metastasis which was treated and stable at the time of signing ICF and 36= patients did not have at least 1 measurable lesion as defined by RECIST 1.1.
Participants by arm
| Arm | Count |
|---|---|
| MYL-1402O Patients will begin Period 1 receiving bevacizumab combination therapy (MYL-1402O15 mg/kg IV + Carboplatin AUC 6 IV+ Paclitaxel 200 or 175 mg/m2 IV) on Day 0 of Cycle 1 for up to 6 cycles of therapy. Each cycle will consist of 3 weeks (21 days ± 3 days) and a cycle will start with the administration of bevacizumab (as MYL-1402O ).
In Period 2, eligible patients will continue to receive bevacizumab ( MYL- 1402O) every 3 weeks as monotherapy.
Bevacizumab as MYL-1402O: Bevacizumab as MYL-1402O 15 mg/kg IV + Carboplatin AUC 6 IV+ Paclitaxel 200 or 175 mg/m2 IV | 337 |
| Avastin Patients will begin Period 1 receiving bevacizumab combination therapy ( Avastin15 mg/kg IV + Carboplatin AUC 6 IV+ Paclitaxel 200 or 175 mg/m2 IV) on Day 0 of Cycle 1 for up to 6 cycles of therapy. Each cycle will consist of 3 weeks (21 days ± 3 days) and a cycle will start with the administration of bevacizumab (as Avastin).
In Period 2, eligible patients will continue to receive bevacizumab (Avastin) every 3 weeks as monotherapy.
Bevacizumab as Avastin: Bevacizumab as Avastin 15 mg/kg IV + Carboplatin AUC 6 IV+ Paclitaxel 200 or 175 mg/m2 IV | 334 |
| Total | 671 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 28 | 19 |
| Period 1 | Death | 8 | 7 |
| Period 1 | Lost to Follow-up | 3 | 5 |
| Period 1 | Physician Decision | 4 | 12 |
| Period 1 | Progressive disease | 47 | 51 |
| Period 1 | Protocol Violation | 0 | 1 |
| Period 1 | Terminated by Sponsor | 8 | 6 |
| Period 1 | Withdrawal by Subject | 10 | 8 |
| Period 2 | Adverse Event | 3 | 4 |
| Period 2 | Death | 0 | 2 |
| Period 2 | Lost to Follow-up | 0 | 1 |
| Period 2 | Physician Decision | 2 | 4 |
| Period 2 | Progressive Disease | 74 | 82 |
| Period 2 | Terminated by Sponsor | 9 | 3 |
| Period 2 | Withdrawal by Subject | 5 | 1 |
Baseline characteristics
| Characteristic | MYL-1402O | Avastin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 100 Participants | 98 Participants | 198 Participants |
| Age, Categorical Between 18 and 65 years | 237 Participants | 236 Participants | 473 Participants |
| Age, Continuous | 59.3 Years STANDARD_DEVIATION 9.6 | 59.2 Years STANDARD_DEVIATION 9.73 | 59.3 Years STANDARD_DEVIATION 9.66 |
| Race/Ethnicity, Customized Race Asian | 111 Participants | 102 Participants | 213 Participants |
| Race/Ethnicity, Customized Race White | 226 Participants | 232 Participants | 458 Participants |
| Region of Enrollment Belarus | 12 participants | 12 participants | 24 participants |
| Region of Enrollment Bosnia and Herzegovina | 8 participants | 11 participants | 19 participants |
| Region of Enrollment Bulgaria | 3 participants | 4 participants | 7 participants |
| Region of Enrollment Croatia | 0 participants | 4 participants | 4 participants |
| Region of Enrollment Georgia | 28 participants | 30 participants | 58 participants |
| Region of Enrollment Hungary | 15 participants | 14 participants | 29 participants |
| Region of Enrollment India | 99 participants | 92 participants | 191 participants |
| Region of Enrollment Philippines | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Poland | 3 participants | 2 participants | 5 participants |
| Region of Enrollment Romania | 3 participants | 4 participants | 7 participants |
| Region of Enrollment Russia | 65 participants | 75 participants | 140 participants |
| Region of Enrollment Spain | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Taiwan | 1 participants | 2 participants | 3 participants |
| Region of Enrollment Turkey | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Ukraine | 86 participants | 74 participants | 160 participants |
| Region of Enrollment Vietnam | 10 participants | 7 participants | 17 participants |
| Sex: Female, Male Female | 124 Participants | 123 Participants | 247 Participants |
| Sex: Female, Male Male | 213 Participants | 211 Participants | 424 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 101 / 335 | 82 / 329 |
| other Total, other adverse events | 311 / 335 | 304 / 329 |
| serious Total, serious adverse events | 59 / 335 | 55 / 329 |
Outcome results
Primary
Primary Efficacy Analysis of Overall Response Rate ( ORR) of MYL-1402O as Compared to Avastin
The primary efficacy endpoint Overall Response Rate (ORR) will be based on best tumor responses as assessed by an independent review at any time point during the first 18 weeks, and assessed according to RECIST 1.1. The primary efficacy analysis is based on the ratio of the MYL-1402O ORR to the Avastin ORR at Week 18 based on the Intent to Treat ( ITT) set of patients.
Time frame: 18 weeks after first dosing per patient
Population: The primary efficacy analysis was conducted in the Intent To Treat population (ITT)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MYL-1402O | Primary Efficacy Analysis of Overall Response Rate ( ORR) of MYL-1402O as Compared to Avastin | Responders | 140 Participants |
| MYL-1402O | Primary Efficacy Analysis of Overall Response Rate ( ORR) of MYL-1402O as Compared to Avastin | Non-Responders | 197 Participants |
| Avastin | Primary Efficacy Analysis of Overall Response Rate ( ORR) of MYL-1402O as Compared to Avastin | Responders | 144 Participants |
| Avastin | Primary Efficacy Analysis of Overall Response Rate ( ORR) of MYL-1402O as Compared to Avastin | Non-Responders | 190 Participants |
90% CI: [0.83, 1.12]