Non-Small Cell Lung Cancer
Conditions
Keywords
BGB324, Bemcentinib, Erlotinib, NSCLC
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.
Interventions
DRUGErlotinib
Participants received erlotinib 150 mg for the 21-day cycle.
DRUGBemcentinib
Participants received bemcentinib 600 mg on Days 1 and 2 as loading dose and bemcentinib 200 mg as daily maintenance dose for the 21-day cycle.
Sponsors
BerGenBio ASA
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
General Criteria 1. Provision of written informed consent to participate in this investigational study. 2. Histological or cytological confirmation of Stage IIIb or Stage IV (unresectable) NSCLC. 3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 4. Age 18 years or older at the time of consent. 5. Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to taking their first dose of bemcentinib. Male participants and female participants of reproductive potential must agree to practice highly effective methods of contraception (such as hormonal implants, combined oral contraceptives, injectable contraceptives, intrauterine device with hormone spirals, total sexual abstinence, vasectomy) throughout the study and for ≥ 3 months after the last dose of bemcentinib. Female participants are considered NOT to be of childbearing potential if they have a history of surgical sterility, including tubal ligation, or evidence of post-menopausal status defined as any of the following: * Natural menopause with last menses \>1 year ago. * Radiation induced oophorectomy with last menses \>1 year ago. * Chemotherapy induced menopause with last menses \>1 year ago. Additional Inclusion Criteria for Run-in Cohort 6. Has received previous systemic therapy for unresectable NSCLC. 7. Has exhausted existing licensed therapies, or is unsuitable for treatment with existing licensed therapies for NSCLC. Additional Inclusion Criteria for Arm A 8. Known EGFR mutation status. 9. Either: 1. Has received ≥ 6 weeks historical treatment with erlotinib. Erlotinib treatment must be re started ≥ 1 week before the first dose of bemcentinib (Cycle 1, Day 1). Or: 2. Is currently receiving erlotinib treatment for NSCLC and will have received ≥ 6 weeks treatment at the time of the first dose of bemcentinib (Cycle 1, Day 1). 10. Erlotinib-related toxicities being well-controlled and \<Grade 3 in severity at the time of the first dose of bemcentinib (Cycle 1, Day 1). 11. Toxicity from other prior therapy has resolved to ≤ Grade 1 (previous treatment with bevacizumab and other licensed antibody therapies is permitted). Additional Inclusion Criteria for Arm B 12. Participants must have documented EGFR mutation (including exon 19 deletion or exon 21 L85R substitution or other rearrangement of the EGFR gene). EGFR mutation may be confirmed historically (prior to study entry) and during the 28 day screening period confirmation of negative T790M status (confirmed with blood test or biopsy from a progressing tumor). Participants who have previously been treated with a T790M inhibitor (i.e., osimertinib) and have progressed will not require T790M testing (the 28-day screening period could be extended to allow for confirmation of the T790M status. Other assessments including computed tomography were conducted in the 28-day screening period). 13. Disease that is measurable according to the response evaluation criteria in solid tumors (RECIST) Version 1.1. 14. Has progressed after receiving erlotinib or any other an approved EGFR inhibitor (i.e., afatinib, or gefitinib) at any time during therapy for advanced disease. 15. Erlotinib related toxicities being well-controlled and \<Grade 3 in severity at the time of the first dose of bemcentinib (Cycle 1, Day 1). Toxicities associated with other EGFR inhibitors to be \<Grade 2 in severity at the time of first dose of bemcentinib. 16. Participants must have completed afatinib and/or gefitinib treatment at least 1 week before the first dose of bemcentinib. 17. Toxicity from other prior therapy has resolved to ≤ Grade 1 (previous treatment with bevacizumab and other licensed antibody therapies is permitted). 18. Participants who have an activating EGFR mutation may have up to 4 lines of previous treatment in the advanced setting. Additional chemotherapy may also have been given for treatment of limited stage disease in the adjuvant setting provided this was completed at least 6 months prior to study treatment. Additional Inclusion Criteria for Arm C 19. Known EGFR mutation status: 20. Presence of an activating EGFR mutation (including exon 19 deletion or exon 21 \[L858R\] substitution mutation or other rearrangement of the EGFR gene). 21. Disease that is measurable or evaluable according to RECIST Version 1.1. 22. Is currently receiving erlotinib for NSCLC and will have received ≥12 weeks' treatment at the time of the first dose of bemcentinib (Cycle 1, Day 1). 23. Have erlotinib-related toxicities that are well controlled and \<Grade 3 in severity the time of the first dose of bemcentinib (Cycle 1, Day 1). 24. No prior treatment for advanced NSCLC except erlotinib and/or previous surgery (participants who have received treatment for their NSCLC while awaiting confirmation of EGFR status, may be eligible to participate and the inclusion of such participants should be discussed with the Medical Monitor).
Exclusion criteria
1. Pregnant or lactating. 2. Abnormal left ventricular ejection fraction (less than the lower limit of normal for a participants of that age at the treating institution or \<45%). 3. Treatment with any of the following; histamine receptor 2 inhibitors, proton pump inhibitors or antacids within 3 days or 5 half-lives, whichever is longer. The Investigator may initiate rescue treatment with these medications during the study, providing they are taken in the evening. 4. History of an ischemic cardiac event, including myocardial infarction, within 3 months of consent. 5. Pulmonary hemorrhage or hemoptysis \>2.5 mL blood within 6 weeks of consent unless cause has been addressed and is medically resolved. 6. Congestive cardiac failure of \>Class II severity according to the New York Heart Association (NYHA) defined as symptomatic at less than ordinary levels of activity. 7. Unstable cardiac disease, including unstable angina or unstable hypertension, as defined by the need for change in medication for lack of disease control within 3 months of consent. 8. History or presence of sustained bradycardia (≤ 60 bpm) or history of symptomatic bradycardia, left bundle branch block, cardiac pacemaker or significant atrial tachyarrhythmias, as defined by the need for treatment. tachyarrhythmias, as defined by the need for treatment. 9. Current treatment with agents that may prolong QT interval and may cause Torsade de Points which cannot be discontinued at least 2 weeks prior to treatment. 10. Known family or personal history of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy. 11. Previous history of ≥ Grade 3 drug-induced QTc prolongation. 12. Screening 12-lead triplicate electrocardiogram (ECG) with an average measurable interval utilizing Fridericia's correction (QTcF) \>450 ms. 13. Inadequate liver function as demonstrated by: * Serum bilirubin ≥ 1.5 times the upper limit of normal range (ULN); or * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2.5 times the ULN (up to 5 times the ULN in the presence of liver metastases). 14. Inability to tolerate oral medication. 15. Impaired coagulation as evidenced by: 1. International normalized ratio (INR) \>1.5 times ULN (or equivalent); or 2. Activated partial thromboplastin time (aPTT) \>1.5 times ULN. 16. Existing gastrointestinal disease affecting drug absorption, such as celiac disease or Crohn's disease. 17. Previous bowel resection that may impair study drug absorption. 18. Impaired renal function as demonstrated by creatinine clearance of ≤ 50 mL/min determined by Cockcroft Gault formula. 19. Absolute neutrophil count \<1.5 x 109/L, hemoglobin \<9.0 g/dL, platelet count \<100 x 109/L in the absence of blood product support. 20. Any evidence of severe or uncontrolled systemic conditions (e.g., severe hepatic impairment) or current unstable or uncompensated respiratory or cardiac conditions which makes it undesirable for the participant to participate in the study or which could jeopardize compliance with the protocol. 21. Treatment with any medication which is predominantly metabolized by CYP3A4 and has a narrow therapeutic index. 22. Active, uncontrolled central nervous system (CNS) disease; (previously treated CNS metastases that are asymptomatic and do not require steroid treatment are allowed). Note: Participants with known CNS metastases who have completed radiotherapy at least 2 weeks prior to bemcentinib treatment are eligible. 23. Known active infection with human immunodeficiency virus (HIV), hepatitis B or C viruses (screening not required): * Participants who have a history of hepatitis B infection are eligible provided they are hepatitis B surface antigen negative. * Participants who have a history of hepatitis C infection are eligible provided they have no evidence of hepatitis C ribonucleic acid using a quantitative polymerase chain reaction assay at least 6 months after completing treatment for hepatitis C infection. 24. Major surgery requiring general anesthesia within 28 days prior to the start of bemcentinib, excluding biopsies and procedures for insertion of central venous access devices. 25. Treatment with cytotoxic chemotherapy, within the 3 weeks prior to the first dose of bemcentinib (Cycle 1, Day 1) with the exception of treatment with other EGFR inhibitors which must be completed 1 week prior to commencing treatment with bemcentinib. There is no requirement to discontinue ongoing treatment with erlotinib. 26. Treatment with other non-cytotoxic agents for NSCLC in the 10 days or 4 half-lives, prior to the first dose of bemcentinib (Cycle 1, Day 1) whichever is shorter. 27. Prior biological therapies in the 4 weeks or 5 half-lives, whichever is shorter before the first dose of bemcentinib (Cycle 1, Day 1). Note prior treatment with an alternative EGFR inhibitor and/or programmed cell death protein 1 (PD-1) blockade is permitted.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1- Run in Arm (Bemcentinib Monotherapy) Participants received bemcentinib at a loading dose of 600 mg on Days 1 and 2 of Cycle 1, followed by 200 mg daily thereafter. | 8 |
| Phase 1- Arm A (Bemcentinib + Erlotinib) Participants received 150 mg of erlotinib daily along with bemcentinib, starting with a loading dose of 600 mg over 2 days (Days 1 and 2), followed by a daily dose of 200 mg in 21-day treatment cycles. However, following the report of DLTs, participants received daily loading dose of bemcentinib 400 mg on Days 1, 2 and 3 of Cycle 1 followed by a maximum daily maintenance dose of 200 mg thereafter. Hence, some participants received 600 mg and some received 400 mg of bemcentinib as loading dose. | 8 |
| Phase 2- Arm B (Bemcentinib + Erlotinib) Participants received 150 mg of erlotinib daily along with bemcentinib 400 mg on Days 1, 2, and 3 as loading dose and bemcentinib 200 mg as daily maintenance dose for the 21-day cycle with an activating EGFR mutation who had progressed after receiving prior EGFR TKI or who had progressed on osimertinib. | 11 |
| Phase 2- Arm C (Bemcentinib + Erlotinib) Participants received 150 mg of erlotinib daily along with bemcentinib 400 mg on Days 1, 2, and 3 as loading dose and bemcentinib 200 mg as daily maintenance dose for the 21-day cycle with activating EGFR mutation ≥ 12 weeks of erlotinib without disease progression at the time of first dose of bemcentinib, with erlotinib related toxicities well-controlled. | 13 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 |
| Overall Study | Investigator Decision | 0 | 0 | 0 | 1 |
| Overall Study | Other | 0 | 0 | 0 | 1 |
| Overall Study | Progressive Disease | 7 | 6 | 11 | 10 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Phase 1- Run in Arm (Bemcentinib Monotherapy) | Phase 1- Arm A (Bemcentinib + Erlotinib) | Phase 2- Arm B (Bemcentinib + Erlotinib) | Phase 2- Arm C (Bemcentinib + Erlotinib) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 63.1 years STANDARD_DEVIATION 6.15 | 57.9 years STANDARD_DEVIATION 9.14 | 64.0 years STANDARD_DEVIATION 8.97 | 64.3 years STANDARD_DEVIATION 13.24 | 62.7 years STANDARD_DEVIATION 10.13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 7 Participants | 11 Participants | 12 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 6 Participants | 6 Participants | 16 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 5 Participants | 5 Participants | 5 Participants | 6 Participants | 21 Participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 7 Participants | 10 Participants | 27 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 4 Participants | 3 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 11 | 0 / 13 |
| other Total, other adverse events | 8 / 8 | 8 / 8 | 11 / 11 | 13 / 13 |
| serious Total, serious adverse events | 2 / 8 | 3 / 8 | 2 / 11 | 5 / 13 |
Outcome results
Primary
Number of Participants With Clinically Significant Abnormalities in Echocardiogram and Multi-gated Acquisition (MUGA) Scan
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.
Time frame: First dose of study drug to 28 days post last dose (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days)
Population: The safety analysis population included all participants who received at least 1 dose of bemcentinib or erlotinib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Number of Participants With Clinically Significant Abnormalities in Echocardiogram and Multi-gated Acquisition (MUGA) Scan | Echocardiogram | 0 Participants |
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Number of Participants With Clinically Significant Abnormalities in Echocardiogram and Multi-gated Acquisition (MUGA) Scan | MUGA | 0 Participants |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Abnormalities in Echocardiogram and Multi-gated Acquisition (MUGA) Scan | MUGA | 0 Participants |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Abnormalities in Echocardiogram and Multi-gated Acquisition (MUGA) Scan | Echocardiogram | 0 Participants |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Abnormalities in Echocardiogram and Multi-gated Acquisition (MUGA) Scan | Echocardiogram | 1 Participants |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Abnormalities in Echocardiogram and Multi-gated Acquisition (MUGA) Scan | MUGA | 0 Participants |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Abnormalities in Echocardiogram and Multi-gated Acquisition (MUGA) Scan | Echocardiogram | 0 Participants |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Abnormalities in Echocardiogram and Multi-gated Acquisition (MUGA) Scan | MUGA | 0 Participants |
Primary
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
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.
Time frame: Baseline up to end of the study (28 days post last dose; maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days)
Population: The safety analysis population included all participants who received at least 1 dose of bemcentinib or erlotinib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | 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 | Physical Examination | 0 Participants |
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | 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 | 12- lead Triplicate ECG | 0 Participants |
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | 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 | Vital Signs | 0 Participants |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | 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 | Physical Examination | 0 Participants |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | 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 | 12- lead Triplicate ECG | 0 Participants |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | 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 | Vital Signs | 0 Participants |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | 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 | Physical Examination | 0 Participants |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | 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 | Vital Signs | 0 Participants |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | 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 | 12- lead Triplicate ECG | 0 Participants |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | 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 | Physical Examination | 0 Participants |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | 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 | 12- lead Triplicate ECG | 0 Participants |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | 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 | Vital Signs | 0 Participants |
Primary
Number of Participants With Clinically Significant Laboratory Abnormalities
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.
Time frame: First dose of study drug to 28 days post last dose (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days)
Population: The safety analysis population included all participants who received at least 1 dose of bemcentinib or erlotinib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Number of Participants With Clinically Significant Laboratory Abnormalities | Hematology Abnormality | 1 Participants |
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Number of Participants With Clinically Significant Laboratory Abnormalities | Clinical Chemistry Abnormality | 4 Participants |
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Number of Participants With Clinically Significant Laboratory Abnormalities | Coagulation Abnormality | 0 Participants |
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Number of Participants With Clinically Significant Laboratory Abnormalities | Urinalysis Abnormality | 1 Participants |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Laboratory Abnormalities | Urinalysis Abnormality | 2 Participants |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Laboratory Abnormalities | Coagulation Abnormality | 0 Participants |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Laboratory Abnormalities | Clinical Chemistry Abnormality | 2 Participants |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Laboratory Abnormalities | Hematology Abnormality | 1 Participants |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Laboratory Abnormalities | Coagulation Abnormality | 0 Participants |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Laboratory Abnormalities | Clinical Chemistry Abnormality | 5 Participants |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Laboratory Abnormalities | Urinalysis Abnormality | 1 Participants |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Laboratory Abnormalities | Hematology Abnormality | 1 Participants |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Laboratory Abnormalities | Urinalysis Abnormality | 2 Participants |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Laboratory Abnormalities | Clinical Chemistry Abnormality | 4 Participants |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Laboratory Abnormalities | Hematology Abnormality | 0 Participants |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | Number of Participants With Clinically Significant Laboratory Abnormalities | Coagulation Abnormality | 1 Participants |
Primary
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study
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.
Time frame: End of study visit was 28 days post last dose (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days)
Population: The safety analysis population included all participants who received at least 1 dose of bemcentinib or erlotinib. Here, Overall Number of Participants Analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 2 | 1 Participants |
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 3 | 1 Participants |
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 5 | 0 Participants |
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 1 | 2 Participants |
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 0 | 1 Participants |
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 4 | 0 Participants |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 0 | 2 Participants |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 3 | 0 Participants |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 5 | 0 Participants |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 4 | 0 Participants |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 2 | 1 Participants |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 1 | 4 Participants |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 5 | 0 Participants |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 2 | 1 Participants |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 0 | 2 Participants |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 1 | 4 Participants |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 3 | 2 Participants |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 4 | 0 Participants |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 1 | 10 Participants |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 5 | 0 Participants |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 4 | 0 Participants |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 0 | 1 Participants |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 2 | 1 Participants |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study | Grade 3 | 0 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAE)
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.
Time frame: First dose of study drug to 28 days post last dose (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days)
Population: The safety analysis population included all participants who received at least 1 dose of bemcentinib or erlotinib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Number of Participants With Treatment-emergent Adverse Events (TEAE) | 8 Participants |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | Number of Participants With Treatment-emergent Adverse Events (TEAE) | 8 Participants |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | Number of Participants With Treatment-emergent Adverse Events (TEAE) | 11 Participants |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | Number of Participants With Treatment-emergent Adverse Events (TEAE) | 13 Participants |
Secondary
Area Under the Curve (AUC) Over 24 Hours at Steady State of Bemcentinib
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.
Time frame: 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
Population: The pharmacokinetic(PK)analysis population included those participants in Run-in Cohort and Arm B who received at least 1 dose of bemcentinib,had PK data available and those participants in ArmA, ArmB who received at least 1 dose of bemcentinib and erlotinib, had bemcentinib and erlotinib PK data available. For PK outcome measure, Arm A is divided in two arms based on bemcentinib loading dose. PK analysis was not part of primary or secondary objective for Arm C and hence not analyzed for Arm C.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Area Under the Curve (AUC) Over 24 Hours at Steady State of Bemcentinib | 6590 nanogram*hours per milliliter | Standard Deviation 3800 |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | Area Under the Curve (AUC) Over 24 Hours at Steady State of Bemcentinib | 8200 nanogram*hours per milliliter | Standard Deviation 5460 |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | Area Under the Curve (AUC) Over 24 Hours at Steady State of Bemcentinib | 5710 nanogram*hours per milliliter | Standard Deviation 1950 |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | Area Under the Curve (AUC) Over 24 Hours at Steady State of Bemcentinib | 5810 nanogram*hours per milliliter | Standard Deviation 1900 |
Secondary
AUC Over 24 Hours at Steady State of Erlotinib
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.
Time frame: At Day 8 (in Cycle 1): pre-dose, 2, 4, 6, 8 and 24 hours post-dose (cycle length=21 days)
Population: Analysis population included those participants who received erlotinib in Arm A and Arm B and had PK data available are pooled under one reporting group (pooled erlotinib). PK analysis was not part of primary or secondary objective for Arm C, hence not analyzed. Here, 'Number of Participants Analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | AUC Over 24 Hours at Steady State of Erlotinib | 40432.333 nanogram*hours per milliliter | Standard Deviation 9877.386 |
Secondary
Cmax of Erlotinib
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 frame: At Day 1 and 8 (in Cycle 1): pre-dose, 2, 4, 6, 8 and 24 hours post-dose (cycle length=21 days)
Population: Analysis population included those participants who received erlotinib in Arm A and Arm B and had PK data available are pooled under one reporting group (pooled erlotinib). PK analysis was not part of primary or secondary objective for Arm C, hence not analyzed. Here, 'Number analyzed' = participants evaluable at specific timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Cmax of Erlotinib | Cycle 1 Day 1 | 1840.286 nanogram per milliliter | Standard Deviation 715.704 |
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Cmax of Erlotinib | Cycle 1 Day 8 | 2263.750 nanogram per milliliter | Standard Deviation 711.31 |
Secondary
Dose Limiting Toxicity (DLT) Assessment
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 frame: First dose of study drug to 28 days post last dose (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days)
Population: The safety analysis population included all participants who received at least 1 dose of bemcentinib or erlotinib. This outcome measure was planned to be analyzed for only Arm A.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Dose Limiting Toxicity (DLT) Assessment | 2 Participants |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Bemcentinib
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 frame: 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
Population: The PK analysis population included those participants in the Run-in Cohort and Arm B who received at least 1 dose of bemcentinib and had PK data available and those participants in Arm A who received at least 1 dose of bemcentinib and erlotinib and had bemcentinib and erlotinib PK data available. For PK outcome measure, Arm A is divided in two arms based on bemcentinib loading dose. PK analysis was not part of primary or secondary objective for Arm C and hence not analyzed for Arm C.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Maximum Observed Plasma Concentration (Cmax) of Bemcentinib | 282 nanogram per milliliter | Standard Deviation 161 |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | Maximum Observed Plasma Concentration (Cmax) of Bemcentinib | 349 nanogram per milliliter | Standard Deviation 229 |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | Maximum Observed Plasma Concentration (Cmax) of Bemcentinib | 245 nanogram per milliliter | Standard Deviation 77.9 |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | Maximum Observed Plasma Concentration (Cmax) of Bemcentinib | 249 nanogram per milliliter | Standard Deviation 81.9 |
Secondary
Time To Progression (TTP)
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.
Time frame: First dose of bemcentinib to first radiological progression (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days)
Population: The efficacy analysis population included all participants who received ≥ 1 cycle of bemcentinib and underwent a post-treatment assessment of response. Here, 'Overall Number of Participants Analyzed' signifies participants evaluable for this outcome measure. This outcome measure was planned to be analyzed for only Arm C.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Time To Progression (TTP) | 8.2 Months |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of Bemcentinib
The Tmax defined as the time taken to reach Cmax. The Tmax was summarized using the predicted plasma concentrations at steady state.
Time frame: 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
Population: The PK analysis population included those participants in the Run-in Cohort and Arm B who received at least 1 dose of bemcentinib and had PK data available and those participants in Arm A who received at least 1 dose of bemcentinib and erlotinib and had bemcentinib and erlotinib PK data available. For PK outcome measure, Arm A is divided in two arms based on bemcentinib loading dose. PK analysis was not part of primary or secondary objective for Arm C and hence not analyzed for Arm C.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1- Run in Arm (Bemcentinib Monotherapy) | Time to Reach Maximum Plasma Concentration (Tmax) of Bemcentinib | 6.5 hours |
| Phase 1- Arm A (Bemcentinib + Erlotinib) | Time to Reach Maximum Plasma Concentration (Tmax) of Bemcentinib | 8 hours |
| Phase 2- Arm B (Bemcentinib + Erlotinib) | Time to Reach Maximum Plasma Concentration (Tmax) of Bemcentinib | 7 hours |
| Phase 2- Arm C (Bemcentinib + Erlotinib) | Time to Reach Maximum Plasma Concentration (Tmax) of Bemcentinib | 7 hours |
Secondary
Tmax of Erlotinib
The Tmax defined as the time taken to reach Cmax. The Tmax was summarized using the predicted plasma concentrations at steady state.
Time frame: At Day 1 and 8 (in Cycle 1): pre-dose, 2, 4, 6, 8 and 24 hours post-dose (cycle length=21 days)
Population: Data was not available to report time taken to reach Cmax as none of the participants were considered evaluable for this derived PK parameter, due to insufficient dosing records for erlotinib.