A Study of BGB324 (Bemcentinib) in Combination With Erlotinib in Patients With Non-Small Cell Lung Cancer
- Registration Number
- NCT02424617
- Lead Sponsor
- BerGenBio ASA
- Brief Summary
A Phase 1/2 multi-center open-label study of BGB324 (bemcentinib) as a single agent (Run-in Cohort) and in combination with erlotinib (Arms A, B, and C) in participants with Stage IIIb or Stage IV non-small cell lung cancer (NSCLC). Bemcentinib is a potent selective small molecule inhibitor of AXL, a surface membrane protein kinase receptor which is connected with poor prognosis and acquired resistance to therapy.
- Detailed Description
This is a multi-center, multi-arm open-label Phase 1/2 study that was conducted at 10 clinical sites in the United States and in Europe.
Total 40 participants with histologically- or cytologically-confirmed Stage IIIb or Stage IV NSCLC received bemcentinib (BGB324) as a single agent (Run-in Cohort) or in combination with erlotinib (Arms A, B, and C).
Run-in Arm to establish the safety and tolerability of bemcentinib (BGB324) administered as a single agent; bemcentinib was administered at a loading dose of 600 mg on Day 1 and Day 2 of Cycle 1, followed by 200 mg daily thereafter. After 6 participants have been dosed and safety established; Arm A (dose escalation arm) was opened to confirm the bemcentinib dose to be used in combination with erlotinib.
In Arm A the dose of bemcentinib (BGB324) was escalated in a standard 3+3 fashion until a maximum tolerated dose (MTD) of the combination (bemcentinib + erlotinib) was established. The dose of bemcentinib to be investigated in Arm B and C was confirmed upon recommendation of a Safety Review Committee.
Arm B and C was open in parallel to investigate bemcentinib in combination with erlotinib.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 40
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase 1- Run in Arm (Bemcentinib Monotherapy) Bemcentinib Participants in this arm received bemcentinib as monotherapy. This was to determine the safety and tolerability of bemcentinib when administered alone. Phase 1- Arm A (Bemcentinib + Erlotinib) Erlotinib Participants in this arm received erlotinib with bemcentinib. A standard 3+3 design to determine the dose of bemcentinib that could be safely administered in combination with erlotinib in participants who had received prior treatment with erlotinib. This was to determine the maximum tolerated dose of bemcentinib that could be safely administered with erlotinib. Phase 1- Arm A (Bemcentinib + Erlotinib) Bemcentinib Participants in this arm received erlotinib with bemcentinib. A standard 3+3 design to determine the dose of bemcentinib that could be safely administered in combination with erlotinib in participants who had received prior treatment with erlotinib. This was to determine the maximum tolerated dose of bemcentinib that could be safely administered with erlotinib. Phase 2- Arm B (Bemcentinib + Erlotinib) Erlotinib Participants in this arm received erlotinib with bemcentinib in participants with an activating epidermal growth factor receptor (EGFR) mutation who are T790M negative and who had progressed after receiving treatment with an approved EGFR tyrosine kinase inhibitor (TKI) \[osimertinib, afatinib, or gefitinib\]. Phase 2- Arm B (Bemcentinib + Erlotinib) Bemcentinib Participants in this arm received erlotinib with bemcentinib in participants with an activating epidermal growth factor receptor (EGFR) mutation who are T790M negative and who had progressed after receiving treatment with an approved EGFR tyrosine kinase inhibitor (TKI) \[osimertinib, afatinib, or gefitinib\]. Phase 2- Arm C (Bemcentinib + Erlotinib) Erlotinib Participants in this arm received erlotinib daily along with bemcentinib in participants with an activating EGFR mutation (including exon 19 deletion or exon 21 \[L858R\] substitution or other rearrangement of the EGFR gene mutation) who had received greater than or equal to (≥) 12 weeks of erlotinib without disease progression. Phase 2- Arm C (Bemcentinib + Erlotinib) Bemcentinib Participants in this arm received erlotinib daily along with bemcentinib in participants with an activating EGFR mutation (including exon 19 deletion or exon 21 \[L858R\] substitution or other rearrangement of the EGFR gene mutation) who had received greater than or equal to (≥) 12 weeks of erlotinib without disease progression.
- Primary Outcome Measures
Name Time Method Number of Participants With Treatment-emergent Adverse Events (TEAE) First dose of study drug to 28 days post last dose (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days) An adverse event (AE) is any untoward medical occurrence in participants, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAEs were defined as AEs that occurred from the first dose of study drug administration up to 28-days post last dose of study drug.
Number of Participants With Clinically Significant Laboratory Abnormalities First dose of study drug to 28 days post last dose (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days) Laboratory evaluation: assessment of hematology, clinical chemistry, coagulation, and urinalysis. Hematology assessment: full blood count including differential white cell count, hemoglobin, hematocrit and platelets. Clinical chemistry assessment: potassium, calcium, uric acid, electrolytes, blood urea nitrogen, total protein, total bilirubin, alanine aminotransferase, aspartate aminotransferase, creatinine, creatine phosphokinase, alkaline phosphatase, albumin, phosphorus, glucose, magnesium plus amylase and lipase. Coagulation assessment: prothrombin time and/or international normalized ratio, activated partial thromboplastin time. Urinalysis: dipstick measurement of blood, nitrite, glucose, ketones, leukocytes, protein, and pH. Clinical significance was determined based on investigator's decision. In this outcome measure number of participants with clinically significant abnormalities in assessment of hematology, clinical chemistry, coagulation, and urinalysis are reported.
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study End of study visit was 28 days post last dose (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days) The ECOG performance status was scored on a scale of Grade 0 to 5, where: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g. light house work, office work; 2 = Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 3 = Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4 = Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair; 5 = Dead. Higher scores indicated worse condition. Number of participants with each ECOG Grade were reported.
Number of Participants With Clinically Significant Change From Baseline in Physical Examination, Vital Signs, and 12- Lead Triplicate Electrocardiogram (ECG) Parameters up to End of Study Baseline up to end of the study (28 days post last dose; maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days) Number of participants with clinically significant change from baseline in physical examination, vital signs (including blood pressure, pulse, respiratory rate and oral temperature) and 12-lead triplicate ECG parameters was reported. Clinically significant abnormalities were based on the investigator's decision.
Number of Participants With Clinically Significant Abnormalities in Echocardiogram and Multi-gated Acquisition (MUGA) Scan First dose of study drug to 28 days post last dose (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days) Number of participants with clinically significant abnormalities in echocardiogram and MUGA scan was reported. MUGA scan is used to measure the ejection fraction, which reports how well heart is functioning. Clinically significant abnormalities were based on the investigator's decision.
- Secondary Outcome Measures
Name Time Method Area Under the Curve (AUC) Over 24 Hours at Steady State of Bemcentinib Arm A only: Cycle(C)1 Day(D)1: Predose, 2, 4, 6, 8 & 24h post-dose; Arm B only: C1D1 & D2: Predose; Arms A&B: C1D8: Predose, 2, 4, 6, 8 & 24h post-dose: C1D15, C2D1,8 & 15, C3D1: Predose and End of Study The AUC is defined as the area under the curve over 24 hours at steady state. The AUC 0- 24 hours using the linear trapezoidal method was summarized using the predicted plasma concentrations at steady state.
Maximum Observed Plasma Concentration (Cmax) of Bemcentinib Arm A only: Cycle(C)1 Day(D)1: Predose, 2, 4, 6, 8 & 24h post-dose; Arm B only: C1D1 & D2: Predose; Arms A&B: C1D8: Predose, 2, 4, 6, 8 & 24h post-dose: C1D15, C2D1,8 & 15, C3D1: Predose and End of Study Cmax was defined as the observed maximum plasma concentration after single dose administration. Cmax was summarized using the predicted plasma concentrations at steady state.
Time to Reach Maximum Plasma Concentration (Tmax) of Bemcentinib Arm A only: Cycle(C)1 Day(D)1: Predose, 2, 4, 6, 8 & 24h post-dose; Arm B only: C1D1 & D2: Predose; Arms A&B: C1D8: Predose, 2, 4, 6, 8 & 24h post-dose: C1D15, C2D1,8 & 15, C3D1: Predose and End of Study The Tmax defined as the time taken to reach Cmax. The Tmax was summarized using the predicted plasma concentrations at steady state.
AUC Over 24 Hours at Steady State of Erlotinib At Day 8 (in Cycle 1): pre-dose, 2, 4, 6, 8 and 24 hours post-dose (cycle length=21 days) The AUC 0-24 is defined as the area under the curve over 24 hours at steady state. The AUC 0- 24 hours using the linear trapezoidal method was summarized using the predicted plasma concentrations at steady state.
Cmax of Erlotinib At Day 1 and 8 (in Cycle 1): pre-dose, 2, 4, 6, 8 and 24 hours post-dose (cycle length=21 days) Cmax was defined as the observed maximum plasma concentration after single dose administration. Cmax was summarized using the predicted plasma concentrations at steady state.
Tmax of Erlotinib At Day 1 and 8 (in Cycle 1): pre-dose, 2, 4, 6, 8 and 24 hours post-dose (cycle length=21 days) The Tmax defined as the time taken to reach Cmax. The Tmax was summarized using the predicted plasma concentrations at steady state.
Dose Limiting Toxicity (DLT) Assessment First dose of study drug to 28 days post last dose (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days) DLTs included any non-hematological toxicity ≥ Grade 3 except Grade 3 nausea, vomiting or diarrhea that resolved within 72 hours with optimal therapy: Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding. Grade 4 neutropenia persisting for ≥ 5 days or Grade 3 or 4 febrile neutropenia. Treatment discontinuation or dose reduction for greater than (\>) 72 hours during the first cycle as a result of treatment-related toxicity. DLTs were evaluated using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03. Number of participants that reported DLTs were reported in this outcome measure.
Time To Progression (TTP) First dose of bemcentinib to first radiological progression (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days) TTP was calculated as the duration from the date of first administration of bemcentinib to the date of radiological progression of disease first observed, according to the overall response evaluation (progressive disease, measurement proven or progressive disease, symptomatic deterioration). If a participant died without any radiological assessment, the progressive disease date was date of death. Progression was assessed using the Response evaluation criteria in solid tumors (RECIST) version 1.1 criteria.
Trial Locations
- Locations (10)
UC San Diego Moores Cancer Center
🇺🇸La Jolla, California, United States
USC/Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Horizon Oncology Research,
🇺🇸Lafayette, Indiana, United States
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
The Sarah Cannon Research Institute Tennessee Oncology PLLC
🇺🇸Nashville, Tennessee, United States
Mary Crowley Cancer Research Centers
🇺🇸Dallas, Texas, United States
Southwestern Medical Center
🇺🇸Dallas, Texas, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Oncology Consultants PA
🇺🇸Houston, Texas, United States