Stage IV Melanoma, Unresectable Stage III
Conditions
Brief summary
The purpose of this study is to assess the objective response rate of lenvatinib in previously treated participants with American Joint Committee on Cancer (AJCC) unresectable Stage III or Stage IV melanoma and disease progression.
Detailed description
This was a Phase 2, multicenter, open-label, 2-cohort, 2-stage study that assessed the ORR of lenvatinib in previously treated participants with AJCC unresectable Stage III or Stage IV melanoma and disease progression. Cohort 1 enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma, and is referred to as Cohort 1 or V600E BRAF negative. Other less common BRAF activating mutations were allowed as long as the participant did not receive a BRAF-targeted therapy. Cohort 2 enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy, and is referred to as Cohort 2 or V600E BRAF positive. Eligible participants had measurable disease according to RECIST 1.1.
Interventions
DRUGLenvatinib
Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles until disease progression, development of unacceptable toxicity or withdrawal of consent.
Sponsors
Eisai Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed diagnosis of melanoma. 2. Unresectable Stage III or Stage IV melanoma. 3. Evidence of disease progression according to RECIST 1.1 on prior regimen. 4. Participants with brain metastases will be eligible if they have undergone complete surgical excision and are more then 1 month post surgery with no radiographic evidence of disease recurrence in the brain or have undergone stereotactic radio surgery (gamma knife procedure) and are more then 1 month post procedure and with no radiographic evidence of disease progression in the brain; and are asymptomatic, and discontinued corticosteroid treatment at least 30 days prior starting treatment. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 6. Adequately controlled blood pressure. 7. Adequate renal function, bone marrow function, blood coagulation function, and liver function, as defined in the study protocol.
Exclusion criteria
1. Melanoma of intraocular origin. 2. Leptomeningeal metastases or brain metastases except as for participants with brain metastases will be eligible if they have undergone complete surgical excision and are more then 1 month post surgery with no radiographic evidence of disease recurrence in the brain or have undergone stereotactic radio surgery (gamma knife procedure) and are more then 1 month post procedure and with no radiographic evidence of disease progression in the brain; and are asymptomatic, and discontinued corticosteroid treatment at least 30 days prior starting treatment. 3. More than 2 prior systemic anticancer regimen treatments including immunotherapies for unresectable Stage III or Stage IV disease (if BRAF V600E mutation negative) or not previously treated with BRAF V600E-targeted therapy or received in the past more than 2 prior systemic anticancer regimen treatments, including immunotherapies, in addition to a BRAF-V600E-targeted therapy (if BRAF V600E mutation positive). 4. Significant cardiovascular impairment. 5. Bleeding disorder or a thrombotic disorder requiring anticoagulant therapy. 6. Females who are pregnant or breastfeeding. 7. Prolongation of QTc interval to greater than 480 msec. 8. 24 hour urine protein greater than or equal to 1 gm. 9. Active hemoptysis within 3 wks prior to the first dose of study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | From date of treatment start until all participants completed a minimum of 6 cycles (28-day cycles) or discontinued treatment prior to end of Cycle 6 (up to 24 weeks) | ORR, (ORR = CR + PR) was defined as the percentage of participants in each cohort who had a best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 for target lesions assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans and independent radiologic review (IRR). A BOR of CR required confirmation by a subsequent CR assessment at least 4 weeks later. A BOR of PR required confirmation by a subsequent assessment of CR or PR at least 4 weeks later. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to have a reduction in short axis to less than (\<)10 mm. PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From date of treatment start until date of death from any cause or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months | OS was defined as the length of time in months from the date of first administration of study drug until the date of death from any cause, and was based on the data cutoff date for each cohort. OS was analyzed using Kaplan-Meier (1958) product-limit estimates. Data were presented with 2-sided 95% CI when an adequate number of at risk participants warranted the estimates in the table below. |
| Disease Control Rate (DCR) | From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months | DCR, (DCR = CR + PR + SD) was defined as the percentage of participants who had a BOR of CR or PR or stable disease (SD) based on RECIST v1.1 for target lesions assessed by MRI/CT and IRR. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (target or non-target) had to have a reduction in short axis to \<10 mm.; PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; Overall Response (OR) = CR + PR. SD defined as reduction in tumor volume of \< 30% or an increase in the volume of 1 or more measurable lesions of \< 25% without the appearance of any new lesions which was neither tumor shrinkage corresponding to PR nor tumor expansion corresponding to disease progression. BOR of SD, time from first administration of study drug until date of documented SD needed to be \>=7 weeks based on IRR and Investigator's assessment. |
| Clinical Benefit Rate (CBR) | From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months | CBR, (CBR = CR + PR + durable SD rate) was defined as the percentage of participants who had a BOR of CR or PR or durable SD (dSD, SD lasting \>=23 weeks) based on RECIST v1.1 for target lesions assessed by MRI/CT, IRR and Investigator's assessment. A BOR of CR required confirmation by a subsequent CR assessment at least 4 weeks later. A BOR of PR required confirmation by a subsequent assessment of CR or PR at least 4 weeks later. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (target or non-target) had to have a reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; OR = CR + PR. A BOR of dSD, the time from the first administration of study drug until the date of documented dSD needed to be ≥23 weeks based on IRR and Investigator's assessment. |
| Progression Free Survival (PFS) | From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months | PFS was measured as the time from the date of first administration of study treatment until the date of first documentation of disease progression or date of death from any cause (whichever occurred first), as determined by IRR and Investigator based on RECIST v1.1. Disease progression per RECIST v1.1 was defined as at least a 20% relative increase and 5 mm absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was analyzed using Kaplan-Meier (1958) product-limit estimates. Data were presented with 2-sided 95% confidence interval (CI) when an adequate number of at risk participants warranted the estimates in the table below. |
| Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Cycle 1 Day 15 (C1 D15), Cycle 2 Day 1 (C2 D1), Cycle 3 Day 1 (C3 D1), Off-Treatment/Phase Visit 98 (V98) | Blood samples were drawn at specific time points. Utilizing a standard protocol, the deoxyribonucleic acid (DNA) from whole blood was extracted and analyzed for specific biomarkers of absorption, distribution, metabolism, and excretion of lenvatinib. Some of the biomarkers analyzed included; Angiopoietin, Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), FMS Like Tyrosine Kinase 3 Ligand (Flt3l) Granulocyte Colony Stimulating Factor (G-CSF), Granulocyte Macro Colony Stimulating Factor (GM-CSF), Interleukin 1 Receptor Antagonist (IL-1RA), Interferon (IFN), Macrophage Inflammatory Protein (MIP) 1 alpha, Platelet Derived Growth Factor (PDGF), Stromal Cell Derived Factor (SDF) 1 alpha, Interleukin (IL), Transforming Growth Factor (TGF), Tumor Necrosis Factor (TNF), Vascular Endothelial Growth Factor (VEGF). |
| Summary of Plasma Concentration of Lenvatinib | Predose and 2 to 12 hours postdose at Cycle 1 Day 1 (C1D1), Cycle 1 Day 15 (C1D15), and Cycle 2 Day 1 (C2D1) | Blood samples for the quantification of lenvatinib in plasma were obtained and processed using a standardized protocol. The lower limit of quantification was 0.25 ng/mL. Pharmacokinetic (PK) analysis was conducted using nonlinear mixed effects modeling. Descriptive statistics were used to summarize lenvatinib plasma concentration data. |
| Number of Participants With Adverse Events (AEs)/ Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | From date of treatment start up to 30 days after the last dose, or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 9 months | Safety was assessed by monitoring and recording all AEs including all Common Terminology Criteria for Adverse Events (CTCAE) grades and SAEs; regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECGs), and multi-gated acquisition (MUGA) scans or echocardiogram. |
Countries
Australia, Germany, United Kingdom, United States
Participant flow
Recruitment details
A total of 298 participants were screened. Of these, 116 were screen failures and 182 received treatment (93 participants in Cohort 1 and 89 participants in Cohort 2).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (V600E BRAF Negative) Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles. | 93 |
| Cohort 2 (V600E BRAF Positive) Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles. | 89 |
| Total | 182 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 12 |
| Overall Study | Clinical Progression | 3 | 5 |
| Overall Study | Diagnosis of Second Primary Cancer | 0 | 1 |
| Overall Study | Increase in Lesion Size | 0 | 2 |
| Overall Study | Investigator's Choice | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Non-compliance | 1 | 0 |
| Overall Study | Participant Choice | 8 | 3 |
| Overall Study | Radiation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Cohort 2 (V600E BRAF Positive) | Total | Cohort 1 (V600E BRAF Negative) |
|---|---|---|---|
| Age, Continuous | 55.0 Years STANDARD_DEVIATION 14.18 | 58.8 Years STANDARD_DEVIATION 13.47 | 62.5 Years STANDARD_DEVIATION 11.71 |
| AJCC Melanoma Tumor, Node, Metastasis (TNM) Stage at Study Entry Unresectable Stage III | 7 Participants | 12 Participants | 5 Participants |
| AJCC Melanoma Tumor, Node, Metastasis (TNM) Stage at Study Entry Unresectable Stage IV | 82 Participants | 170 Participants | 88 Participants |
| Sex/Gender, Customized Female | 39 Participants | 68 Participants | 29 Participants |
| Sex/Gender, Customized Male | 50 Participants | 114 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 93 / 93 | 88 / 89 |
| serious Total, serious adverse events | 39 / 93 | 36 / 89 |
Outcome results
Primary
Objective Response Rate (ORR)
ORR, (ORR = CR + PR) was defined as the percentage of participants in each cohort who had a best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 for target lesions assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans and independent radiologic review (IRR). A BOR of CR required confirmation by a subsequent CR assessment at least 4 weeks later. A BOR of PR required confirmation by a subsequent assessment of CR or PR at least 4 weeks later. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to have a reduction in short axis to less than (\<)10 mm. PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From date of treatment start until all participants completed a minimum of 6 cycles (28-day cycles) or discontinued treatment prior to end of Cycle 6 (up to 24 weeks)
Population: Full Analysis Set (Intent-to-Treat \[ITT\] Analysis Set) included all participants who received at least 1 dose study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (V600E BRAF Negative) | Objective Response Rate (ORR) | 8.6 Percentage of participants |
| Cohort 2 (V600E BRAF Positive) | Objective Response Rate (ORR) | 9.0 Percentage of participants |
Secondary
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood
Blood samples were drawn at specific time points. Utilizing a standard protocol, the deoxyribonucleic acid (DNA) from whole blood was extracted and analyzed for specific biomarkers of absorption, distribution, metabolism, and excretion of lenvatinib. Some of the biomarkers analyzed included; Angiopoietin, Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), FMS Like Tyrosine Kinase 3 Ligand (Flt3l) Granulocyte Colony Stimulating Factor (G-CSF), Granulocyte Macro Colony Stimulating Factor (GM-CSF), Interleukin 1 Receptor Antagonist (IL-1RA), Interferon (IFN), Macrophage Inflammatory Protein (MIP) 1 alpha, Platelet Derived Growth Factor (PDGF), Stromal Cell Derived Factor (SDF) 1 alpha, Interleukin (IL), Transforming Growth Factor (TGF), Tumor Necrosis Factor (TNF), Vascular Endothelial Growth Factor (VEGF).
Time frame: Cycle 1 Day 15 (C1 D15), Cycle 2 Day 1 (C2 D1), Cycle 3 Day 1 (C3 D1), Off-Treatment/Phase Visit 98 (V98)
Population: The Safety Analysis set was used and included all participants who received at least one dose of lenvatinib and had at least 1 postbaseline safety evaluation. Number analyzed (n) signifies participants who were evaluable at specific time points for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF Basic Form V98 | 18.384 pg/mL | Standard Deviation 28.6214 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Tie-2 C3D1 | -2811.765 pg/mL | Standard Deviation 3459.1934 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Tie-2 V98 | -1924.000 pg/mL | Standard Deviation 3215.5684 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | TNF alpha C1D15 | -0.233 pg/mL | Standard Deviation 4.9747 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | EGF 2 C3D1 | -37.600 pg/mL | Standard Deviation 113.8543 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | TNF alpha C2D1 | 0.039 pg/mL | Standard Deviation 3.954 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | EGF 2 V98 | -2.230 pg/mL | Standard Deviation 191.4129 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | TNF alpha C3D1 | 0.614 pg/mL | Standard Deviation 4.6336 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | TNF alpha V98 | 3.027 pg/mL | Standard Deviation 4.7343 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF D C3D1 | 9.894 pg/mL | Standard Deviation 57.114 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF C1D15 | -13.294 pg/mL | Standard Deviation 112.6871 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | EGF 59 C1D15 | -37.07 pg/mL | Standard Deviation 81.051 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF C2D1 | -11.523 pg/mL | Standard Deviation 122.6064 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | EGF 59 C2D1 | -31.58 pg/mL | Standard Deviation 96.2 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF C3D1 | 16.732 pg/mL | Standard Deviation 160.3096 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF V98 | 155.638 pg/mL | Standard Deviation 352.8309 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF A C1D15 | 78.868 pg/mL | Standard Deviation 174.8011 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | EGF 59 V98 | 10.17 pg/mL | Standard Deviation 137.755 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF A C2D1 | 76.041 pg/mL | Standard Deviation 194.1394 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Flt3l C1D15 | -0.037 pg/mL | Standard Deviation 32.5371 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF A C3D1 | 116.800 pg/mL | Standard Deviation 233.1657 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF A V98 | 465.833 pg/mL | Standard Deviation 515.7676 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF D C1D15 | 0.953 pg/mL | Standard Deviation 87.6513 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF 23 C3D1 | 6.691 pg/mL | Standard Deviation 24.5203 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF D C2D1 | -9.776 pg/mL | Standard Deviation 98.0905 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Eotaxin-4 C1D15 | 51.456 pg/mL | Standard Deviation 117.1266 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF D V98 | -21.317 pg/mL | Standard Deviation 88.6689 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 1 C1D15 | 593.613 pg/mL | Standard Deviation 3109.3343 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Flt3l C2D1 | 5.135 pg/mL | Standard Deviation 28.0359 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 1 C2D1 | -3.971 pg/mL | Standard Deviation 739.7875 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Eotaxin-4 C2D1 | 99.974 pg/mL | Standard Deviation 207.0243 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 1 C3D1 | -209.863 pg/mL | Standard Deviation 809.7744 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 1 V98 | -15.567 pg/mL | Standard Deviation 90.6274 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 2 C1D15 | -10110.096 pg/mL | Standard Deviation 5626.0125 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF 23 V98 | 13.430 pg/mL | Standard Deviation 36.713 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 2 C2D1 | -9369.165 pg/mL | Standard Deviation 17982.0625 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Eotaxin-4 C3D1 | 89.878 pg/mL | Standard Deviation 108.6392 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 2 C3D1 | -11389.576 pg/mL | Standard Deviation 10955.1596 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 2 V98 | -9021.217 pg/mL | Standard Deviation 5921.9619 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 3 C1D15 | -1174.650 pg/mL | Standard Deviation 2226.7893 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Eotaxin-4 V98 | 104.613 pg/mL | Standard Deviation 157.7527 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 3 C2D1 | -1320.738 pg/mL | Standard Deviation 3138.381 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF 2 C1D15 | -4.294 pg/mL | Standard Deviation 51.3985 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 3 C3D1 | -1488.140 pg/mL | Standard Deviation 3687.8774 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 3 V98 | -1201.680 pg/mL | Standard Deviation 2441.5741 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 10 C1D15 | -5.170 pg/mL | Standard Deviation 38.0092 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Flt3l C3D1 | 5.439 pg/mL | Standard Deviation 24.1985 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 10 C2D1 | -1.901 pg/mL | Standard Deviation 33.6203 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF 2 C2D1 | -8.085 pg/mL | Standard Deviation 48.8273 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 10 C3D1 | 4.136 pg/mL | Standard Deviation 10.8185 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 10 V98 | -28.065 pg/mL | Standard Deviation 41.7547 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 13 C1D15 | 0.961 pg/mL | Standard Deviation 5.0066 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Flt3l V98 | 13.367 pg/mL | Standard Deviation 17.7279 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 13 C2D1 | 2.451 pg/mL | Standard Deviation 7.6374 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF 2 C3D1 | 7.443 pg/mL | Standard Deviation 45.731 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 13 C3D1 | 5.404 pg/mL | Standard Deviation 16.4719 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 15 C1D15 | 0.128 pg/mL | Standard Deviation 2.2957 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF 2 V98 | -3.917 pg/mL | Standard Deviation 62.3623 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 15 C2D1 | 1.403 pg/mL | Standard Deviation 4.163 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 15 V98 | 3.930 pg/mL | — |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 15 C3D1 | -0.178 pg/mL | Standard Deviation 3.6993 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Hepatocyte Growth Factor C2D1 | -126.667 pg/mL | Standard Deviation 693.2257 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 17 C1D15 | 3.434 pg/mL | Standard Deviation 8.6463 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Hepatocyte Growth Factor C3D1 | 61.257 pg/mL | Standard Deviation 1062.3266 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Hepatocyte Growth Factor V98 | 404.700 pg/mL | Standard Deviation 456.813 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interferon Gamma C1D15 | 4.072 pg/mL | Standard Deviation 19.3994 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Fractalkine C1D15 | -11.700 pg/mL | Standard Deviation 94.5115 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interferon Gamma C2D1 | -0.392 pg/mL | Standard Deviation 14.8083 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 17 C2D1 | 1.264 pg/mL | Standard Deviation 8.0963 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interferon Gamma C3D1 | 2.986 pg/mL | Standard Deviation 5.7591 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interferon Gamma V98 | 2.455 pg/mL | Standard Deviation 5.2255 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 1 alpha C1D15 | 0.159 pg/mL | Standard Deviation 7.9441 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF 4 C1D15 | -24.226 pg/mL | Standard Deviation 100.6823 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 1 alpha C2D1 | 0.226 pg/mL | Standard Deviation 8.2728 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 17 C3D1 | 0.011 pg/mL | Standard Deviation 3.41 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 1 alpha C3D1 | -0.140 pg/mL | Standard Deviation 13.7136 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 1 Beta C1D15 | 0.279 pg/mL | Standard Deviation 1.9668 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 17 V98 | 8.440 pg/mL | Standard Deviation 11.7663 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 1 Beta C2D1 | 1.198 pg/mL | Standard Deviation 5.0044 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 2 C1D15 | -1.004 pg/mL | Standard Deviation 7.1024 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Fractalkine C2D1 | -1.175 pg/mL | Standard Deviation 70.0858 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | GM-CSF C3D1 | 10.036 pg/mL | Standard Deviation 49.8538 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | GM-CSF V98 | -1.495 pg/mL | Standard Deviation 5.1831 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF 23 C1D15 | 6.549 pg/mL | Standard Deviation 22.5297 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 2 C2D1 | 5.853 pg/mL | Standard Deviation 20.3294 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Hepatocyte Growth Factor C1D15 | 102.527 pg/mL | Standard Deviation 1309.4077 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Fractalkine C3D1 | -5.588 pg/mL | Standard Deviation 116.3955 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 12 (p70) C3D1 | -6.099 pg/mL | Standard Deviation 19.5015 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 12 (p70) V98 | 11.275 pg/mL | Standard Deviation 20.0182 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 1 Beta C3D1 | 1.882 pg/mL | Standard Deviation 11.1737 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | IL-1RA C1D15 | 14.490 pg/mL | Standard Deviation 63.5869 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 2 C3D1 | 2.647 pg/mL | Standard Deviation 19.5979 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | IL-1RA C2D1 | 20.295 pg/mL | Standard Deviation 61.9799 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 4 C1D15 | 8.169 pg/mL | Standard Deviation 30.0305 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | IL-1RA C3D1 | 7.048 pg/mL | Standard Deviation 30.9383 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | IL-1RA V98 | 84.614 pg/mL | Standard Deviation 178.159 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 12 (p40) C1D15 | 14.514 pg/mL | Standard Deviation 73.9806 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Fractalkine V98 | 15.838 pg/mL | Standard Deviation 90.6004 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 12 (p40) C2D1 | 16.052 pg/mL | Standard Deviation 40.3849 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 4 C2D1 | 20.167 pg/mL | Standard Deviation 77.0619 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 12 (p40) C3D1 | 11.183 pg/mL | Standard Deviation 36.3506 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 12 (p40) V98 | -8.130 pg/mL | Standard Deviation 5.7276 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 12 (p70) C1D15 | 1.241 pg/mL | Standard Deviation 18.8429 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | G-CSF C1D15 | 4.329 pg/mL | Standard Deviation 20.8343 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 4 C3D1 | 6.583 pg/mL | Standard Deviation 20.3824 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 5 C1D15 | 0.311 pg/mL | Standard Deviation 1.1314 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 2 76 C1D15 | -1015.69 pg/mL | Standard Deviation 946.596 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 5 C2D1 | 0.205 pg/mL | Standard Deviation 1.5931 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | G-CSF C2D1 | 7.366 pg/mL | Standard Deviation 32.5552 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 5 C3D1 | -0.327 pg/mL | Standard Deviation 1.1102 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 6 C1D15 | 0.166 pg/mL | Standard Deviation 6.8774 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 6 C2D1 | 4.778 pg/mL | Standard Deviation 34.0254 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 2 76 C2D1 | -832.29 pg/mL | Standard Deviation 1257.287 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 6 C3D1 | 2.027 pg/mL | Standard Deviation 7.3121 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 6 V98 | 3.160 pg/mL | Standard Deviation 6.6276 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 7 C1D15 | 1.267 pg/mL | Standard Deviation 7.3732 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | G-CSF C3D1 | 11.292 pg/mL | Standard Deviation 24.1828 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 7 C2D1 | 2.413 pg/mL | Standard Deviation 8.8367 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | G-CSF V98 | 34.653 pg/mL | Standard Deviation 101.7055 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 7 C3D1 | 0.616 pg/mL | Standard Deviation 5.059 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 7 V98 | 20.760 pg/mL | Standard Deviation 28.0439 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 8 C1D15 | -5.801 pg/mL | Standard Deviation 46.1572 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | GM-CSF C1D15 | 0.767 pg/mL | Standard Deviation 16.9314 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 8 C2D1 | -5.431 pg/mL | Standard Deviation 43.4197 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF 4 C2D1 | -15.491 pg/mL | Standard Deviation 104.9991 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 8 C3D1 | -7.348 pg/mL | Standard Deviation 43.0509 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 8 V98 | 26.982 pg/mL | Standard Deviation 32.7795 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | IFN gamma Induced Protein 10 C1D15 | 453.684 pg/mL | Standard Deviation 1446.5825 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | GM-CSF C2D1 | 4.371 pg/mL | Standard Deviation 38.3355 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | IFN gamma Induced Protein 10 C2D1 | 246.194 pg/mL | Standard Deviation 246.194 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 2 76 C3D1 | -923.82 pg/mL | Standard Deviation 969.285 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | IFN gamma Induced Protein 10 C3D1 | 201.923 pg/mL | Standard Deviation 483.5088 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | IFN gamma Induced Protein 10 V98 | 359.872 pg/mL | Standard Deviation 501.1082 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Monocyte Chemotactic Protein 1 C1D15 | 0.733 pg/mL | Standard Deviation 423.2721 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 2 76 V98 | -947.00 pg/mL | Standard Deviation 825.037 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Monocyte Chemotactic Protein 1 C2D1 | -19.036 pg/mL | Standard Deviation 372.5242 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | EGF 59 C3D1 | -24.49 pg/mL | Standard Deviation 93.102 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Monocyte Chemotactic Protein 1 C3D1 | 13.542 pg/mL | Standard Deviation 370.37 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Monocyte Chemotactic Protein 1 V98 | -128.627 pg/mL | Standard Deviation 1234.5888 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | MIP 1 alpha C1D15 | -1.842 pg/mL | Standard Deviation 11.9129 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF 4 C3D1 | 5.283 pg/mL | Standard Deviation 130.3452 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | MIP 1 alpha C2D1 | -2.098 pg/mL | Standard Deviation 12.0121 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 1 C1D15 | -3033.030 pg/mL | Standard Deviation 8808.2059 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | MIP 1 alpha C3D1 | -1.167 pg/mL | Standard Deviation 15.9038 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | MIP 1 alpha V98 | 7.563 pg/mL | Standard Deviation 7.8802 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | MIP 1 beta C1D15 | 0.032 pg/mL | Standard Deviation 20.149 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF 4 V98 | 33.860 pg/mL | Standard Deviation 185.4616 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | MIP 1 beta C2D1 | -1.198 pg/mL | Standard Deviation 31.4522 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 1 C2D1 | -2802.306 pg/mL | Standard Deviation 10202.7814 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | MIP 1 beta C3D1 | 1.850 pg/mL | Standard Deviation 15.208 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | MIP 1 beta V98 | 7.518 pg/mL | Standard Deviation 11.9566 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF Basic Form C1D15 | -0.597 pg/mL | Standard Deviation 18.6851 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 1 C3D1 | -859.021 pg/mL | Standard Deviation 9994.6711 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | PDGF AB C1D15 | -36.637 pg/mL | Standard Deviation 353.6898 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 1 V98 | 8107.400 pg/mL | Standard Deviation 17740.0516 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | PDGF AB C2D1 | -99.852 pg/mL | Standard Deviation 338.5816 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 2 C1D15 | -1462.552 pg/mL | Standard Deviation 1541.8074 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | PDGF AB C3D1 | -7.702 pg/mL | Standard Deviation 311.6834 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | PDGF AB V98 | 130.800 pg/mL | Standard Deviation 382.6282 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | PDGF BB C1D15 | -120.317 pg/mL | Standard Deviation 1758.7655 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 12 (p70) C2D1 | -5.622 pg/mL | Standard Deviation 28.6381 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | PDGF BB C2D1 | -435.311 pg/mL | Standard Deviation 1961.7449 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 2 C2D1 | -1225.462 pg/mL | Standard Deviation 1872.5841 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | PDGF BB C3D1 | 333.637 pg/mL | Standard Deviation 1516.1506 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | PDGF BB V98 | 174.083 pg/mL | Standard Deviation 3221.9009 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Placental Derived Growth Factor C1D15 | 55.444 pg/mL | Standard Deviation 55.0671 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF Basic Form C2D1 | -1.212 pg/mL | Standard Deviation 38.4131 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Placental Derived Growth Factor C2D1 | 50.439 pg/mL | Standard Deviation 58.2571 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 2 C3D1 | -1255.485 pg/mL | Standard Deviation 1738.0891 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Placental Derived Growth Factor C3D1 | 61.080 pg/mL | Standard Deviation 58.2969 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Placental Derived Growth Factor V98 | 112.683 pg/mL | Standard Deviation 110.3416 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 2 V98 | -1374.183 pg/mL | Standard Deviation 1158.2897 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | CD40 Ligand C1D15 | -24020.778 pg/mL | Standard Deviation 62788.2464 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | SDF 1 alpha C1D15 | 441.305 pg/mL | Standard Deviation 385.8988 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF 23 C2D1 | 6.496 pg/mL | Standard Deviation 27.2305 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | SDF 1 alpha C2D1 | 520.051 pg/mL | Standard Deviation 510.8558 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | CD40 Ligand C2D1 | -22957.613 pg/mL | Standard Deviation 73677.4378 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | SDF 1 alpha C3D1 | 509.483 pg/mL | Standard Deviation 550.4383 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | SDF 1 alpha V98 | 836.532 pg/mL | Standard Deviation 686.4434 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Soluble IL2 Receptor alpha C1D15 | -25.869 pg/mL | Standard Deviation 86.0991 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF Basic Form C3D1 | 2.060 pg/mL | Standard Deviation 29.2405 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Soluble IL2 Receptor alpha C2D1 | -13.695 pg/mL | Standard Deviation 65.5643 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | CD40 Ligand C3D1 | -16700.900 pg/mL | Standard Deviation 48016.071 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Soluble IL2 Receptor alpha C3D1 | -12.233 pg/mL | Standard Deviation 31.5415 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Soluble IL2 Receptor alpha V98 | -19.238 pg/mL | Standard Deviation 43.0942 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | TGF alpha C1D15 | -0.874 pg/mL | Standard Deviation 4.6605 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | CD40 Ligand V98 | 2192.177 pg/mL | Standard Deviation 86909.9688 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | TGF alpha C2D1 | -0.350 pg/mL | Standard Deviation 6.5375 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | EGF 2 C1D15 | -46.493 pg/mL | Standard Deviation 101.0772 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | TGF alpha C3D1 | 1.165 pg/mL | Standard Deviation 11.8825 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | TGF alpha V98 | 2.590 pg/mL | Standard Deviation 3.4672 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Tie-2 C1D15 | -2971.948 pg/mL | Standard Deviation 2397.5234 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | EGF 2 C2D1 | -39.636 pg/mL | Standard Deviation 125.0664 |
| Cohort 1 (V600E BRAF Negative) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Tie-2 C2D1 | -3447.692 pg/mL | Standard Deviation 3577.1791 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 12 (p70) C1D15 | 27.919 pg/mL | Standard Deviation 62.8944 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 12 (p70) C2D1 | 7.820 pg/mL | Standard Deviation 71.1505 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF 4 C1D15 | 50.369 pg/mL | Standard Deviation 253.9626 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF 4 C2D1 | 55.785 pg/mL | Standard Deviation 264.4585 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF Basic Form C1D15 | 43.457 pg/mL | Standard Deviation 224.9856 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF Basic Form C2D1 | 64.237 pg/mL | Standard Deviation 328.6676 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Flt3l C1D15 | -8.877 pg/mL | Standard Deviation 23.0368 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Flt3l C2D1 | -1.362 pg/mL | Standard Deviation 39.2251 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Fractalkine C1D15 | 38.670 pg/mL | Standard Deviation 237.5045 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Fractalkine C2D1 | 4.663 pg/mL | Standard Deviation 58.195 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | G-CSF C1D15 | 6.368 pg/mL | Standard Deviation 61.7181 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | G-CSF C2D1 | 12.601 pg/mL | Standard Deviation 72.5113 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | GM-CSF C1D15 | 44.665 pg/mL | Standard Deviation 220.9124 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 2 90 C1D15 | -1225.322 pg/mL | Standard Deviation 1950.4525 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 2 90 C2D1 | -1100.235 pg/mL | Standard Deviation 1378.4621 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 1 C1D15 | -2717.533 pg/mL | Standard Deviation 16689.4536 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 1 C2D1 | -1743.569 pg/mL | Standard Deviation 15546.4804 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 2 C1D15 | -2154.269 pg/mL | Standard Deviation 3560.0029 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Angiopoietin 2 C2D1 | -1884.439 pg/mL | Standard Deviation 2357.1979 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | CD40 Ligand C1D15 | -4678.661 pg/mL | Standard Deviation 41191.7303 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | CD40 Ligand C2D1 | -7254.754 pg/mL | Standard Deviation 37794.5541 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | EGF 2 C2D1 | -29.803 pg/mL | Standard Deviation 121.1705 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | EGF 80 C1D15 | -31.519 pg/mL | Standard Deviation 126.2579 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | EGF 80 C2D1 | -32.171 pg/mL | Standard Deviation 121.7805 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Eotaxin-4 C1D15 | 46.538 pg/mL | Standard Deviation 128.398 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Eotaxin-4 C2D1 | 60.919 pg/mL | Standard Deviation 114.6134 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF 2 C1D15 | 8.325 pg/mL | Standard Deviation 136.3433 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | FGF 2 C2D1 | -8.003 pg/mL | Standard Deviation 144.9054 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 17 C1D15 | 4.567 pg/mL | Standard Deviation 12.1008 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 17 C2D1 | 3.035 pg/mL | Standard Deviation 15.8736 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 2 C1D15 | 173.878 pg/mL | Standard Deviation 397.2754 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 6 C1D15 | 3.784 pg/mL | Standard Deviation 30.0715 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 2 C2D1 | 191.410 pg/mL | Standard Deviation 461.1991 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 4 C1D15 | 12.815 pg/mL | Standard Deviation 77.431 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 4 C2D1 | 7.815 pg/mL | Standard Deviation 54.5735 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 5 C1D15 | 6.088 pg/mL | Standard Deviation 7.5239 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 5 C2D1 | 11.382 pg/mL | Standard Deviation 9.8663 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 6 C2D1 | 5.524 pg/mL | Standard Deviation 32.1205 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 7 C1D15 | 2.167 pg/mL | Standard Deviation 8.8122 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 7 C2D1 | 5.744 pg/mL | Standard Deviation 18.4339 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 8 C1D15 | -20.769 pg/mL | Standard Deviation 52.1135 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 8 C2D1 | -14.303 pg/mL | Standard Deviation 57.9561 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | IFN gamma Induced Protein 10 C1D15 | 184.891 pg/mL | Standard Deviation 501.5782 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | IFN gamma Induced Protein 10 C2D1 | 306.075 pg/mL | Standard Deviation 792.5621 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Monocyte Chemotactic Protein 1 C1D15 | -101.580 pg/mL | Standard Deviation 371.5381 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Monocyte Chemotactic Protein 1 C2D1 | 128.749 pg/mL | Standard Deviation 541.1034 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | MIP 1 alpha C1D15 | -0.320 pg/mL | Standard Deviation 38.5273 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | MIP 1 alpha C2D1 | -0.473 pg/mL | Standard Deviation 35.4447 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | MIP 1 beta C1D15 | 5.746 pg/mL | Standard Deviation 64.1386 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | MIP 1 beta C2D1 | 31.277 pg/mL | Standard Deviation 261.346 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | PDGF AA 31 P1 C1D15 | -183.36 pg/mL | Standard Deviation 2260.11 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | PDGF AA 31 P1 C2D1 | -268.83 pg/mL | Standard Deviation 2054.666 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | PDGF AB C1D15 | -121.278 pg/mL | Standard Deviation 325.1308 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | PDGF AB C2D1 | -80.778 pg/mL | Standard Deviation 363.1249 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | PDGF BB C1D15 | -567.664 pg/mL | Standard Deviation 1385.674 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | PDGF BB C2D1 | -371.888 pg/mL | Standard Deviation 1186.1 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Placental Derived Growth Factor C1D15 | 55.0671 pg/mL | Standard Deviation 29.8457 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Placental Derived Growth Factor C2D1 | 51.359 pg/mL | Standard Deviation 76.639 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Chemokine Ligand 5 C1D15 | -2373.94 pg/mL | Standard Deviation 46225.695 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Chemokine Ligand 5 C2D1 | 551.64 pg/mL | Standard Deviation 49492.45 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | SDF 1 alpha C1D15 | 506.768 pg/mL | Standard Deviation 487.7603 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | SDF 1 alpha C2D1 | 647.435 pg/mL | Standard Deviation 470.0962 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Soluble IL2 Receptor alpha C1D15 | -414.669 pg/mL | Standard Deviation 765.1544 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Soluble IL2 Receptor alpha C2D1 | -290.918 pg/mL | Standard Deviation 1023.3392 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | TGF alpha C1D15 | 21.148 pg/mL | Standard Deviation 168.7766 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | TGF alpha C2D1 | -6.019 pg/mL | Standard Deviation 24.3258 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Tie-2 C1D15 | -3573.856 pg/mL | Standard Deviation 2996.7139 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Tie-2 C2D1 | -4088.214 pg/mL | Standard Deviation 3191.9812 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | TNF alpha C1D15 | 1.451 pg/mL | Standard Deviation 24.8216 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | TNF alpha C2D1 | 1.741 pg/mL | Standard Deviation 15.0677 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF C1D15 | 10.709 pg/mL | Standard Deviation 285.2533 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF C2D1 | -26.215 pg/mL | Standard Deviation 239.496 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF A C1D15 | 92.748 pg/mL | Standard Deviation 273.619 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF A C2D1 | 140.664 pg/mL | Standard Deviation 336.9135 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF D C1D15 | 3.404 pg/mL | Standard Deviation 42.7585 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF D C2D1 | 11.043 pg/mL | Standard Deviation 116.5445 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 1 C1D15 | -221.867 pg/mL | Standard Deviation 799.9202 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 1 C2D1 | -243.661 pg/mL | Standard Deviation 1031.2376 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 2 C1D15 | -8842.040 pg/mL | Standard Deviation 6078.7151 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 2 C2D1 | -10676.563 pg/mL | Standard Deviation 7064.0825 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 3 C1D15 | -2251.867 pg/mL | Standard Deviation 3231.1485 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | VEGF Rec 3 C2D1 | -2523.257 pg/mL | Standard Deviation 3550.7291 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 10 C1D15 | -7.611 pg/mL | Standard Deviation 22.1926 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 10 C2D1 | 1.687 pg/mL | Standard Deviation 72.7629 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 13 C1D15 | 8.574 pg/mL | Standard Deviation 13.4754 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 13 C2D1 | 8.536 pg/mL | Standard Deviation 18.522 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 15 C1D15 | 85.619 pg/mL | Standard Deviation 234.7106 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 15 C2D1 | 574.776 pg/mL | Standard Deviation 1709.9272 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Hepatocyte Growth Factor C2D1 | -147.796 pg/mL | Standard Deviation 411.1836 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interferon Gamma C1D15 | 33.743 pg/mL | Standard Deviation 100.3678 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interferon Gamma C2D1 | -10.164 pg/mL | Standard Deviation 170.9869 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 1 alpha C1D15 | 67.203 pg/mL | Standard Deviation 200.9806 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 1 alpha C2D1 | -36.352 pg/mL | Standard Deviation 198.1416 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 1 Beta C1D15 | 59.768 pg/mL | Standard Deviation 137.6657 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 1 Beta C2D1 | 27.690 pg/mL | Standard Deviation 61.2456 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | GM-CSF C2D1 | 139.491 pg/mL | Standard Deviation 725.0903 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Growth Regulated Oncogene C1D15 | -141.838 pg/mL | Standard Deviation 410.3579 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Growth Regulated Oncogene C2D1 | -120.148 pg/mL | Standard Deviation 456.3073 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Hepatocyte Growth Factor C1D15 | -91.790 pg/mL | Standard Deviation 781.2225 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | IL-1RA C1D15 | 46.381 pg/mL | Standard Deviation 132.3985 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | IL-1RA C2D1 | 38.131 pg/mL | Standard Deviation 142.7521 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 12 (p40) C1D15 | 5.458 pg/mL | Standard Deviation 28.8514 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | Interleukin 12 (p40) C2D1 | 918.03 pg/mL | Standard Deviation 3917.8689 |
| Cohort 2 (V600E BRAF Positive) | Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood | EGF 2 C1D15 | -0.516 pg/mL | Standard Deviation 219.9787 |
Secondary
Clinical Benefit Rate (CBR)
CBR, (CBR = CR + PR + durable SD rate) was defined as the percentage of participants who had a BOR of CR or PR or durable SD (dSD, SD lasting \>=23 weeks) based on RECIST v1.1 for target lesions assessed by MRI/CT, IRR and Investigator's assessment. A BOR of CR required confirmation by a subsequent CR assessment at least 4 weeks later. A BOR of PR required confirmation by a subsequent assessment of CR or PR at least 4 weeks later. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (target or non-target) had to have a reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; OR = CR + PR. A BOR of dSD, the time from the first administration of study drug until the date of documented dSD needed to be ≥23 weeks based on IRR and Investigator's assessment.
Time frame: From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months
Population: Full Analysis Set (ITT Analysis Set) included all participants who received at least 1 dose study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (V600E BRAF Negative) | Clinical Benefit Rate (CBR) | Determined by IRR | 31.2 Percentage of participants |
| Cohort 1 (V600E BRAF Negative) | Clinical Benefit Rate (CBR) | Determined by Investigator | 33.3 Percentage of participants |
| Cohort 2 (V600E BRAF Positive) | Clinical Benefit Rate (CBR) | Determined by IRR | 14.6 Percentage of participants |
| Cohort 2 (V600E BRAF Positive) | Clinical Benefit Rate (CBR) | Determined by Investigator | 20.2 Percentage of participants |
Secondary
Disease Control Rate (DCR)
DCR, (DCR = CR + PR + SD) was defined as the percentage of participants who had a BOR of CR or PR or stable disease (SD) based on RECIST v1.1 for target lesions assessed by MRI/CT and IRR. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (target or non-target) had to have a reduction in short axis to \<10 mm.; PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; Overall Response (OR) = CR + PR. SD defined as reduction in tumor volume of \< 30% or an increase in the volume of 1 or more measurable lesions of \< 25% without the appearance of any new lesions which was neither tumor shrinkage corresponding to PR nor tumor expansion corresponding to disease progression. BOR of SD, time from first administration of study drug until date of documented SD needed to be \>=7 weeks based on IRR and Investigator's assessment.
Time frame: From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months
Population: Full Analysis Set (ITT Analysis Set) included all participants who received at least 1 dose study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (V600E BRAF Negative) | Disease Control Rate (DCR) | Determined by IRR | 52.7 Percentage of participants |
| Cohort 1 (V600E BRAF Negative) | Disease Control Rate (DCR) | Determined by Investigator | 64.5 Percentage of participants |
| Cohort 2 (V600E BRAF Positive) | Disease Control Rate (DCR) | Determined by IRR | 34.8 Percentage of participants |
| Cohort 2 (V600E BRAF Positive) | Disease Control Rate (DCR) | Determined by Investigator | 48.3 Percentage of participants |
Secondary
Number of Participants With Adverse Events (AEs)/ Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib
Safety was assessed by monitoring and recording all AEs including all Common Terminology Criteria for Adverse Events (CTCAE) grades and SAEs; regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECGs), and multi-gated acquisition (MUGA) scans or echocardiogram.
Time frame: From date of treatment start up to 30 days after the last dose, or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 9 months
Population: Safety Analysis Set included those participants who received at least 1 dose of study drug and had at least 1 post baseline safety evaluation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (V600E BRAF Negative) | Number of Participants With Adverse Events (AEs)/ Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | SAEs | 39 Participants |
| Cohort 1 (V600E BRAF Negative) | Number of Participants With Adverse Events (AEs)/ Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | AEs | 93 Participants |
| Cohort 2 (V600E BRAF Positive) | Number of Participants With Adverse Events (AEs)/ Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | AEs | 89 Participants |
| Cohort 2 (V600E BRAF Positive) | Number of Participants With Adverse Events (AEs)/ Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | SAEs | 36 Participants |
Secondary
Overall Survival (OS)
OS was defined as the length of time in months from the date of first administration of study drug until the date of death from any cause, and was based on the data cutoff date for each cohort. OS was analyzed using Kaplan-Meier (1958) product-limit estimates. Data were presented with 2-sided 95% CI when an adequate number of at risk participants warranted the estimates in the table below.
Time frame: From date of treatment start until date of death from any cause or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months
Population: Full Analysis Set (ITT Analysis Set) included all participants who received at least 1 dose study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (V600E BRAF Negative) | Overall Survival (OS) | 8.9 Months |
| Cohort 2 (V600E BRAF Positive) | Overall Survival (OS) | 6.3 Months |
Secondary
Progression Free Survival (PFS)
PFS was measured as the time from the date of first administration of study treatment until the date of first documentation of disease progression or date of death from any cause (whichever occurred first), as determined by IRR and Investigator based on RECIST v1.1. Disease progression per RECIST v1.1 was defined as at least a 20% relative increase and 5 mm absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was analyzed using Kaplan-Meier (1958) product-limit estimates. Data were presented with 2-sided 95% confidence interval (CI) when an adequate number of at risk participants warranted the estimates in the table below.
Time frame: From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months
Population: Full Analysis Set (ITT Analysis Set) included all participants who received at least 1 dose study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 (V600E BRAF Negative) | Progression Free Survival (PFS) | Determined by IRR | 3.7 Months |
| Cohort 1 (V600E BRAF Negative) | Progression Free Survival (PFS) | Determined by Investigator | 3.7 Months |
| Cohort 2 (V600E BRAF Positive) | Progression Free Survival (PFS) | Determined by IRR | 1.8 Months |
| Cohort 2 (V600E BRAF Positive) | Progression Free Survival (PFS) | Determined by Investigator | 2.3 Months |
Secondary
Summary of Plasma Concentration of Lenvatinib
Blood samples for the quantification of lenvatinib in plasma were obtained and processed using a standardized protocol. The lower limit of quantification was 0.25 ng/mL. Pharmacokinetic (PK) analysis was conducted using nonlinear mixed effects modeling. Descriptive statistics were used to summarize lenvatinib plasma concentration data.
Time frame: Predose and 2 to 12 hours postdose at Cycle 1 Day 1 (C1D1), Cycle 1 Day 15 (C1D15), and Cycle 2 Day 1 (C2D1)
Population: The PK analysis set was used for analysis and included all participants who received at least one dose of lenvatinib and had at least one quantifiable lenvatinib concentration. Number analyzed (n) signifies participants who were evaluable at specific time points for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (V600E BRAF Negative) | Summary of Plasma Concentration of Lenvatinib | C1D1 Pre-dose | 0 ng/mL | Standard Deviation 0 |
| Cohort 1 (V600E BRAF Negative) | Summary of Plasma Concentration of Lenvatinib | C1D1 Post-dose | 229.6 ng/mL | Standard Deviation 148.98 |
| Cohort 1 (V600E BRAF Negative) | Summary of Plasma Concentration of Lenvatinib | C1D15 Pre-dose | 56.8 ng/mL | Standard Deviation 82 |
| Cohort 1 (V600E BRAF Negative) | Summary of Plasma Concentration of Lenvatinib | C1D15 Post-dose | 284.0 ng/mL | Standard Deviation 141.71 |
| Cohort 1 (V600E BRAF Negative) | Summary of Plasma Concentration of Lenvatinib | C2D1 Pre-dose | 38.7 ng/mL | Standard Deviation 32.94 |
| Cohort 1 (V600E BRAF Negative) | Summary of Plasma Concentration of Lenvatinib | C2D1 Post-dose | 244.5 ng/mL | Standard Deviation 182.67 |
| Cohort 2 (V600E BRAF Positive) | Summary of Plasma Concentration of Lenvatinib | C2D1 Pre-dose | 52.0 ng/mL | Standard Deviation 48.73 |
| Cohort 2 (V600E BRAF Positive) | Summary of Plasma Concentration of Lenvatinib | C1D1 Pre-dose | 0 ng/mL | Standard Deviation 0 |
| Cohort 2 (V600E BRAF Positive) | Summary of Plasma Concentration of Lenvatinib | C1D15 Post-dose | 332.1 ng/mL | Standard Deviation 221.98 |
| Cohort 2 (V600E BRAF Positive) | Summary of Plasma Concentration of Lenvatinib | C1D1 Post-dose | 287.6 ng/mL | Standard Deviation 168.97 |
| Cohort 2 (V600E BRAF Positive) | Summary of Plasma Concentration of Lenvatinib | C2D1 Post-dose | 270.4 ng/mL | Standard Deviation 143.64 |
| Cohort 2 (V600E BRAF Positive) | Summary of Plasma Concentration of Lenvatinib | C1D15 Pre-dose | 71.9 ng/mL | Standard Deviation 104.09 |