A Study of E7080 Alone, and in Combination With Everolimus in Subjects With Unresectable Advanced or Metastatic Renal Cell Carcinoma Following One Prior Vascular Endothelial Growth Factor (VEGF)-Targeted Treatment
Study Details
Study Description
Brief Summary
This is an open-label, multicenter, Phase 1b/2 study of lenvatinib alone and in combination with everolimus in subjects with unresectable advanced or metastatic renal cell carcinoma following one prior VEGF-targeted treatment.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 1/Phase 2 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Lenvatinib
|
Drug: Lenvatinib
taken orally, once a day
Other Names:
|
Experimental: Lenvatinib plus Everolimus
|
Drug: Lenvatinib
taken orally, once a day
Other Names:
Drug: Everolimus
taken orally, once a day
Other Names:
|
Active Comparator: Everolimus
|
Drug: Everolimus
taken orally, once a day
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT) [First dose of study drug (Cycle 1 Day 1) to end of first 4 weeks of therapy (Cycle 1)]
A DLT was defined as either a treatment-related failure to administer greater than or equal to (>=) 75% of the planned dosage of lenvatinib/everolimus or a specific National Cancer Institute Common Toxicity Criteria (NCI CTC) >= Grade 3 (severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care daily living activities) hematologic or nonhematologic toxicities considered to be possibly related to lenvatinib and/or everolimus therapy assessed during the first treatment cycle of each dose level. Higher grade indicates more severe toxicity.
- Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2) Dose [First dose of study drug (Cycle 1 Day 1) to end of Cycle 2 (1 cycle = 28 days/4 weeks)]
The highest dose level resulting in 0 or 1 DLT in 6 participants was to be considered the MTD of Phase 1b. Once the MTD was established, the participant cohort was expanded to a minimum of 10 participants. The MTD was confirmed by assessing DLTs during Cycle 1 and intolerable toxicities (i.e., not manageable with dose interruption and/or reduction) during Cycle 2 of therapy. Once the dose of lenvatinib/everolimus combination to be used in the succeeding Phase 2 part of the study was established, enrollment into Phase 2 was started. The RP2 dose was the same as the confirmed MTD and was used for the Phase 2 Treatment Arm A of this study.
- Phase 2: Progression-Free Survival (PFS) [Date of randomization into Phase 2 (Cycle 1 Day 1) to the date of first documentation of disease progression or death (whichever occurred first), assessed up to data cutoff date (13 Jun 2014), up to approximately 2 years and 3 months]
PFS was defined as the time (in months) from the date of first dose of study drug to the first documentation of disease progression or death, whichever occurred first. Kaplan-Meier (K-M) estimates were used to estimate median PFS, presented with 2-sided 95% confidence intervals (CIs). Tumor assessments were performed every 8 weeks (or sooner if there was evidence of progressive disease using computed tomography (CT) or magnetic resonance imaging (MRI) and scan acquisition techniques (including use or nonuse of intravenous (IV) contrast). Tumor response was determined at the site by the investigator and radiologist using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 in the evaluation of the tumor assessment scans. The date of objective disease progression was defined as the earliest date of radiological disease progression. Participants removed from therapy due to clinical progression with no radiologic confirmation were censored at their last radiologic assessment date.
Secondary Outcome Measures
- Phase 2: Overall Survival (OS) [Randomization (Cycle 1 Day 1) until date of death from any cause, assessed up to the data cutoff date (10 Dec 2014), up to approximately 2 years and 9 months]
OS was defined as the time (in months) from the date of randomization until date of death from any cause. Median survival time was calculated using K-M estimate for each treatment arm and presented with 2-sided 95% CIs. Participants who were lost to follow-up or alive at the data cutoff date (10 Dec 2014) were censored at the date the participants were last known to be alive.
- Phase 2: Objective Response Rate (ORR) [Randomization (Cycle 1 Day 1) until first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months]
The ORR was defined as the percentage of participants who had the best overall response (BOR) of complete response (CR) or partial response (PR) as determined by the investigator, using RECIST 1.1 in the evaluation of MRI or CT scans of targeted lesions. Tumor assessments were performed every 8 weeks (or sooner if there was evidence of progressive disease). The BOR was defined as the best response recorded from the start of the study treatment until discontinuation from the study. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have 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. ORR = CR + PR was calculated with exact 95% CIs using the method of Clopper and Pearson.
- Disease Control Rate (DCR) [Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months]
The DCR was defined as the percentage of participants who had a BOR of CR or PR or SD (minimum duration from randomization to SD greater than or equal to 7 weeks). Assessments were performed every 8 weeks and were based on investigator review data using RECIST 1.1. The 95% CI was constructed using the method of Clopper and Pearson. DCR = CR + PR + SD greater than or equal to 7 weeks.
- Durable Stable Disease (SD) Rate [Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months]
The durable SD rate was defined as the percentage of participants whose BOR was SD and the duration of SD was greater than or equal to 23 weeks. The durable SD was based on investigator review data using RECIST 1.1. The 95% CI was constructed using the method of Clopper and Pearson.
- Clinical Benefit Rate (CBR) [Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months]
The CBR was defined as the percentage of participants who had BOR of CR, PR, or durable SD (duration of SD was greater than or equal to 23 weeks) and was based on investigator review data using RECIST 1.1. The BOR was defined as the best response recorded from the start of study treatment until discontinuation from the study. There was no requirement for confirmatory measurement of PR or CR to deem either one the BOR. The 95% CI was constructed using the method of Clopper and Pearson. CBR = CR + PR + SD greater than or equal to 23 weeks.
- Summary of Plasma Concentrations of Lenvatinib for Sparse Pharmacokinetic (PK) Sampling for Phase 1b and Phase 2 [Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1)]
Blood samples were collected during the Randomization Phase. Most participants had 6 samples taken over 3 cycles of treatment (sparse sampling - 2 samples taken per cycle, one at predose and one at 2 to 8 hours postdose). Plasma concentrations of lenvatinib were measured and concentration data were summarized. The summary statistics at time points with one or more below the limit of quantitation (BLQ) values were calculated by assigning zero for each BLQ value.
- Summary of Blood Concentrations of Everolimus for Sparse PK Sampling for Phase 1b and Phase 2 [Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1)]
Blood samples were collected during the Randomization Phase. Most participants had 6 samples taken over 3 cycles of treatment (sparse sampling - 2 samples taken per cycle, one at predose and one at 2 to 8 hours postdose). Whole blood concentrations of everolimus were measured and concentration data were summarized. The summary statistics at time points with one or more BLQ values were calculated by assigning zero for each BLQ value.
- Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours (AUC(0-24)) for Lenvatinib When Administered Alone or in Combination With Everolimus [Phase 2: Cycle 1 Day 15 immediately predose, and 30 minutes, 1, 2, 3, 4, 8, 12 (optional), and 24 hours postdose (predose on Day 16)]
Between 9 and 12 participants in each of the 3 treatment arms participated in an optional substudy where instead of the sparse sampling, 9 samples were to be taken over 1 single 24-hour period (i.e., intensive sampling) for full PK profiling. Blood samples were analyzed for study drug using standardized methods. PK parameters for lenvatinib were derived from lenvatinib concentration data using non-compartmental methods. Data were compared via descriptive statistics between single agent and combination therapy.
- Maximum Concentration (Cmax) of Lenvatinib in Plasma When Administered Alone or in Combination With Everolimus [Phase 2: Cycle 1 Day 15]
Cmax for lenvatinib was defined as the maximum observed concentration of lenvatinib in plasma following administration of study treatment on Cycle 1 Day 15 and was obtained directly from the measured plasma concentration-time curves.
- Time to Cmax (Tmax) for Lenvatinib When Administered Alone or in Combination With Everolimus [Phase 2: Cycle 1 Day 15]
Tmax for lenvatinib was the amount of time taken after administration of study treatment on Cycle 1 Day 15 to reach maximum concentration (Cmax) of lenvatinib in plasma.
- Area Under the Blood Concentration-Time Curve From 0 to 24 Hours for Everolimus When Administered Alone or in Combination With Lenvatinib [Phase 2: Cycle 1 Day 15 immediately predose, and 30 minutes, 1, 2, 3, 4, 8, 12 (optional), and 24 hours postdose (predose on Day 16)]
Between 9 and 12 participants in each of the 3 treatment arms participated in an optional substudy where instead of the sparse sampling, 9 samples were to be taken over 1 single 24-hour period (i.e., intensive sampling) for full PK profiling. Blood samples were analyzed for study drug using standardized methods. PK parameters for everolimus were derived from everolimus concentration data using non-compartmental methods. Data were compared via descriptive statistics between single agent and combination therapy.
- Maximum Concentration of Everolimus (Cmax) in Blood When Administered Alone or in Combination With Lenvatinib [Phase 2: Cycle 1 Day 15]
Cmax for everolimus was defined as the maximum observed concentration of everolimus in blood following administration of study treatment on Cycle 1 Day 15 and was obtained directly from the measured blood concentration-time curves.
- Time to Cmax (Tmax) for Everolimus When Administered Alone or in Combination With Lenvatinib [Phase 2: Cycle 1 Day 15]
Tmax for everolimus was the amount of time taken after administration of study treatment on Cycle 1 Day 15 to reach the maximum concentration (Cmax) of everolimus in blood.
Eligibility Criteria
Criteria
Select Inclusion Criteria:
-
Histologically confirmed diagnosis of renal cell carcinoma.
-
Phase 2: Histological or cytological confirmation of predominant clear cell renal cell carcinoma (RCC) (original tissue diagnosis of RCC is acceptable).
-
Documented evidence of unresectable advanced or metastatic RCC. Phase 2: Radiographic evidence of disease progression according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
-
Phase 2: One prior vascular endothelial growth factor (VEGF)-targeted treatment (for example, but not limited to, sunitinib, sorafenib, pazopanib, bevacizumab, axitinib, vatalanib, AV951/tivozanib) for unresectable advanced or metastatic RCC.
-
Phase 2: Measurable disease meeting the following criteria: a.) at least 1 lesion of greater than or equal to 1.5 cm in the longest diameter for a non-lymph node or greater than or equal to 1.5 cm in the short axis diameter for a lymph node which is serially measurable according to Modified RECIST 1.1 using computerized tomography/magnetic resonance imaging (CT/MRI) or photography. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
-
Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than or equal to 150/90 mmHg at screening and no change in antihypertensive medications within 1 week prior to the Screening Visit.
Select Exclusion Criteria:
Phase 1b or Phase 2 specific per below:
-
Phase 1b only: Subjects with untreated or unstable metastasis to the central nervous system (CNS) are excluded. Subjects who have completed local therapy and have discontinued the use of steroids for this indication at least 4 weeks prior to commencing treatment and in whom stability has been proven by at least 2 CT or MRI scans obtained at least 4 weeks apart are eligible for Phase 1b only. Phase 2 only: Subjects with CNS (e.g., brain or leptomeningeal) metastasis are excluded.
-
Phase 2 only: More than one prior VEGF-targeted treatment for unresectable advanced or metastatic RCC.
Phase 1b or Phase 2 specific per below:
-
Phase 1b only: Prior exposure to lenvatinib. Phase 2 only: Prior exposure to lenvatinib or mammalian target of rapamycin (mTOR) inhibitor.
-
Subjects should not have received any anticancer treatment within 21 days or any investigational agent within 30 days prior to the first dose of study drug and should have recovered from any toxicity related to previous anticancer treatment. Major surgery within 3 weeks prior to the first dose of study drug.
-
Subjects having greater than 1+ proteinuria on urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria.
-
Subjects with urine protein greater than or equal to 1 g/24 hours will be ineligible. Uncontrolled diabetes as defined by fasting serum glucose at 1.5 x ULN.
-
Phase 2 only: Active malignancy (except for renal cell carcinoma, melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 24 months.
-
Known intolerance to any of the study drugs (or any of the excipients) and/or known hypersensitivity to rapamycins (e.g., sirolimus, everolimus, temsirolimus) or any of the excipients.
-
Phase 1b only: Subjects who discontinued prior tyrosine kinase inhibitor due to toxicity will be ineligible.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Tucson | Arizona | United States | ||
2 | Orange | California | United States | ||
3 | San Diego | California | United States | ||
4 | Tampa | Florida | United States | ||
5 | Joliet | Illinois | United States | ||
6 | Louisville | Kentucky | United States | ||
7 | Annapolis | Maryland | United States | ||
8 | Bethesda | Maryland | United States | ||
9 | Boston | Massachusetts | United States | ||
10 | Tupelo | Mississippi | United States | ||
11 | New York | New York | United States | ||
12 | Tulsa | Oklahoma | United States | ||
13 | Charleston | South Carolina | United States | ||
14 | Dallas | Texas | United States | ||
15 | Brno | Czechia | |||
16 | Olomouc | Czechia | |||
17 | Prague | Czechia | |||
18 | Gdansk | Poland | |||
19 | Lodz | Poland | |||
20 | Szczecin | Poland | |||
21 | Warsaw | Poland | |||
22 | Barcelona | Spain | |||
23 | Cordoba | Spain | |||
24 | Madrid | Spain | |||
25 | Pamplona | Spain | |||
26 | Bristol | United Kingdom | |||
27 | Cambridge | United Kingdom | |||
28 | Cardiff | United Kingdom | |||
29 | Glasgow | United Kingdom | |||
30 | Guildford | United Kingdom | |||
31 | Ipswich | United Kingdom | |||
32 | Leicester | United Kingdom | |||
33 | London | United Kingdom | |||
34 | Manchester | United Kingdom | |||
35 | Southampton | United Kingdom | |||
36 | Surrey | United Kingdom | |||
37 | Wirral | United Kingdom |
Sponsors and Collaborators
- Eisai Inc.
Investigators
- Study Director: Eisai Medical Services, Eisai Limited
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- E7080-G000-205
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail | A total of 173 participants were enrolled into the study and treated. |
Arm/Group Title | Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 2 (Arm B): 24 mg Lenvatinib | Phase 2 (Arm C): 10 mg Everolimus |
---|---|---|---|---|---|---|---|
Arm/Group Description | Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | The DLT was achieved and no participants were enrolled into this cohort. | Oral lenvatinib (18mg) and everolimus (5 mg) was once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days. | Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. | Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles. |
Period Title: Phase 1b | |||||||
STARTED | 7 | 11 | 2 | 0 | 0 | 0 | 0 |
COMPLETED | 6 | 6 | 0 | 0 | 0 | 0 | 0 |
NOT COMPLETED | 1 | 5 | 2 | 0 | 0 | 0 | 0 |
Period Title: Phase 1b | |||||||
STARTED | 0 | 0 | 0 | 0 | 51 | 52 | 50 |
COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
NOT COMPLETED | 0 | 0 | 0 | 0 | 51 | 52 | 50 |
Baseline Characteristics
Arm/Group Title | Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 2 (Arm B): 24 mg Lenvatinib | Phase 2 (Arm C): 10 mg Everolimus | Total |
---|---|---|---|---|---|---|---|---|
Arm/Group Description | Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | The DLT was achieved and no participants were enrolled into this cohort. | Oral lenvatinib (18 mg) and everolimus (5 mg) was once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days. | Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. | Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles. | Total of all reporting groups |
Overall Participants | 7 | 11 | 2 | 0 | 51 | 52 | 50 | 173 |
Age, Customized (Years) [Geometric Mean (Standard Deviation) ] | ||||||||
Phase 1b |
58.0
(3.92)
|
58.1
(7.97)
|
61.0
(2.83)
|
0
(0)
|
0
(0)
|
0
(0)
|
58.4
(6.29)
|
|
Phase 2 |
0
(0)
|
0
(0)
|
0
(0)
|
61.7
(8.2)
|
63.3
(8.6)
|
58.9
(9.2)
|
61.3
(8.8)
|
|
Sex: Female, Male (Count of Participants) | ||||||||
Female |
3
42.9%
|
2
18.2%
|
1
50%
|
16
Infinity
|
13
25.5%
|
12
23.1%
|
47
94%
|
|
Male |
4
57.1%
|
9
81.8%
|
1
50%
|
35
Infinity
|
39
76.5%
|
38
73.1%
|
126
252%
|
Outcome Measures
Title | Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT) |
---|---|
Description | A DLT was defined as either a treatment-related failure to administer greater than or equal to (>=) 75% of the planned dosage of lenvatinib/everolimus or a specific National Cancer Institute Common Toxicity Criteria (NCI CTC) >= Grade 3 (severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care daily living activities) hematologic or nonhematologic toxicities considered to be possibly related to lenvatinib and/or everolimus therapy assessed during the first treatment cycle of each dose level. Higher grade indicates more severe toxicity. |
Time Frame | First dose of study drug (Cycle 1 Day 1) to end of first 4 weeks of therapy (Cycle 1) |
Outcome Measure Data
Analysis Population Description |
---|
Safety analysis set included all participants who received at least one dose of study treatment. |
Arm/Group Title | Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 2 (Arm B): 24 mg Lenvatinib | Phase 2 (Arm C): 10 mg Everolimus |
---|---|---|---|---|---|---|---|
Arm/Group Description | Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | The DLT was achieved and no participants were enrolled into this cohort. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days. | Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. | Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles. |
Measure Participants | 7 | 11 | 2 | 0 | 0 | 0 | 0 |
Grade 3 abdominal pain |
1
14.3%
|
0
0%
|
0
0%
|
||||
Grade 2 fatigue with Grade 1 GI reflux & anorexia |
0
0%
|
1
9.1%
|
0
0%
|
||||
Grade 3 nausea |
0
0%
|
0
0%
|
1
50%
|
||||
Grade 2 stomatitis |
0
0%
|
0
0%
|
1
50%
|
Title | Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2) Dose |
---|---|
Description | The highest dose level resulting in 0 or 1 DLT in 6 participants was to be considered the MTD of Phase 1b. Once the MTD was established, the participant cohort was expanded to a minimum of 10 participants. The MTD was confirmed by assessing DLTs during Cycle 1 and intolerable toxicities (i.e., not manageable with dose interruption and/or reduction) during Cycle 2 of therapy. Once the dose of lenvatinib/everolimus combination to be used in the succeeding Phase 2 part of the study was established, enrollment into Phase 2 was started. The RP2 dose was the same as the confirmed MTD and was used for the Phase 2 Treatment Arm A of this study. |
Time Frame | First dose of study drug (Cycle 1 Day 1) to end of Cycle 2 (1 cycle = 28 days/4 weeks) |
Outcome Measure Data
Analysis Population Description |
---|
Safety analysis set included all participants who received at least one dose of study treatment. |
Arm/Group Title | Phase 1b: Dose Escalation and MTD Expansion Cohorts |
---|---|
Arm/Group Description | Oral everolimus (18 mg) and lenvatinib (5 mg) were taken once daily in the morning (consistently with or without food) with water. Any dietary habits around the time of study medication intake had to be kept as consistent as possible throughout the study. |
Measure Participants | 11 |
Number [mg/day] |
18.0
|
Title | Phase 2: Progression-Free Survival (PFS) |
---|---|
Description | PFS was defined as the time (in months) from the date of first dose of study drug to the first documentation of disease progression or death, whichever occurred first. Kaplan-Meier (K-M) estimates were used to estimate median PFS, presented with 2-sided 95% confidence intervals (CIs). Tumor assessments were performed every 8 weeks (or sooner if there was evidence of progressive disease using computed tomography (CT) or magnetic resonance imaging (MRI) and scan acquisition techniques (including use or nonuse of intravenous (IV) contrast). Tumor response was determined at the site by the investigator and radiologist using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 in the evaluation of the tumor assessment scans. The date of objective disease progression was defined as the earliest date of radiological disease progression. Participants removed from therapy due to clinical progression with no radiologic confirmation were censored at their last radiologic assessment date. |
Time Frame | Date of randomization into Phase 2 (Cycle 1 Day 1) to the date of first documentation of disease progression or death (whichever occurred first), assessed up to data cutoff date (13 Jun 2014), up to approximately 2 years and 3 months |
Outcome Measure Data
Analysis Population Description |
---|
Full analysis set included all randomized participants. |
Arm/Group Title | Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 2 (Arm B): 24 mg Lenvatinib | Phase 2 (Arm C): 10 mg Everolimus |
---|---|---|---|---|---|---|---|
Arm/Group Description | Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | The DLT was achieved and no participants were enrolled into this cohort. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days. | Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. | Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles. |
Measure Participants | 0 | 0 | 0 | 0 | 51 | 52 | 50 |
Median (95% Confidence Interval) [Months] |
14.6
|
7.4
|
5.5
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus, Phase 2 (Arm C): 10 mg Everolimus |
---|---|---|
Comments | Null hypothesis of no difference in PFS was analyzed using the stratified log-rank test with hemoglobin (less than or equal to 13 g/dL vs greater than 13 g/dL for males; and less than or equal to 11.5 g/dL vs greater than 11.5 g/dL for females) and corrected serum calcium (greater than or equal to 10 mg/dL vs less than 10 mg/dL) as stratification factors. Each null hypothesis was tested at a nominal alpha=0.05. | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | =0.0005 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.40 | |
Confidence Interval |
(2-Sided) 95% 0.24 to 0.68 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | Hazard ratio between treatment groups and corresponding 95% CI was estimated using the stratified Cox regression model (stratified by hemoglobin and corrected serum calcium) with treatment as a factor. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Phase 2 (Arm B): 24 mg Lenvatinib, Phase 2 (Arm C): 10 mg Everolimus |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0479 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.61 | |
Confidence Interval |
(2-Sided) 95% 0.38 to 0.98 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.1209 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.66 | |
Confidence Interval |
(2-Sided) 95% 0.39 to 1.10 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Phase 2: Overall Survival (OS) |
---|---|
Description | OS was defined as the time (in months) from the date of randomization until date of death from any cause. Median survival time was calculated using K-M estimate for each treatment arm and presented with 2-sided 95% CIs. Participants who were lost to follow-up or alive at the data cutoff date (10 Dec 2014) were censored at the date the participants were last known to be alive. |
Time Frame | Randomization (Cycle 1 Day 1) until date of death from any cause, assessed up to the data cutoff date (10 Dec 2014), up to approximately 2 years and 9 months |
Outcome Measure Data
Analysis Population Description |
---|
Full analysis set which included all randomized participants. |
Arm/Group Title | Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 2 (Arm B): 24 mg Lenvatinib | Phase 2 (Arm C): 10 mg Everolimus |
---|---|---|---|---|---|---|---|
Arm/Group Description | Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | The DLT was achieved and no participants were enrolled into this cohort. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days. | Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. | Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles. |
Measure Participants | 0 | 0 | 0 | 0 | 51 | 52 | 50 |
Median (95% Confidence Interval) [Months] |
25.5
|
19.1
|
15.4
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus, Phase 2 (Arm C): 10 mg Everolimus |
---|---|---|
Comments | Planned analyses were performed to test null hypothesis of treatment difference in OS at a nominal significance level of 0.05 (2-sided) using the stratified log-rank test using stratification factors. | |
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | =0.0242 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.514 | |
Confidence Interval |
(2-Sided) 95% 0.299 to 0.884 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | Hazard ratio between treatment groups and corresponding 95% CI was estimated using the stratified Cox regression model (stratified by hemoglobin and corrected serum calcium) with treatment as a factor. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Phase 2 (Arm B): 24 mg Lenvatinib, Phase 2 (Arm C): 10 mg Everolimus |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | =0.1181 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.684 | |
Confidence Interval |
(2-Sided) 95% 0.411 to 1.138 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | =0.3157 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.751 | |
Confidence Interval |
(2-Sided) 95% 0.433 to 1.301 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Phase 2: Objective Response Rate (ORR) |
---|---|
Description | The ORR was defined as the percentage of participants who had the best overall response (BOR) of complete response (CR) or partial response (PR) as determined by the investigator, using RECIST 1.1 in the evaluation of MRI or CT scans of targeted lesions. Tumor assessments were performed every 8 weeks (or sooner if there was evidence of progressive disease). The BOR was defined as the best response recorded from the start of the study treatment until discontinuation from the study. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have 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. ORR = CR + PR was calculated with exact 95% CIs using the method of Clopper and Pearson. |
Time Frame | Randomization (Cycle 1 Day 1) until first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months |
Outcome Measure Data
Analysis Population Description |
---|
Full analysis set which included all randomized participants. |
Arm/Group Title | Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 2 (Arm B): 24 mg Lenvatinib | Phase 2 (Arm C): 10 mg Everolimus |
---|---|---|---|---|---|---|---|
Arm/Group Description | Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | The DLT was achieved and no participants were enrolled into this cohort. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days. | Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. | Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles. |
Measure Participants | 0 | 0 | 0 | 0 | 51 | 52 | 50 |
Number (95% Confidence Interval) [Percentage of participants] |
43.1
615.7%
|
26.9
244.5%
|
6.0
300%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus, Phase 2 (Arm C): 10 mg Everolimus |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | Analysis performed after database lock. P-value was based on the 2-sided Fisher's exact P-value. | |
Method | Fisher Exact | |
Comments | ||
Method of Estimation | Estimation Parameter | Rate ratio |
Estimated Value | 7.2 | |
Confidence Interval |
(2-Sided) 95% 2.3 to 22.5 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | Rate ratio was based on the normal approximation. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Phase 2 (Arm B): 24 mg Lenvatinib, Phase 2 (Arm C): 10 mg Everolimus |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0067 |
Comments | Analysis performed after database lock. P-value was based on the 2-sided Fisher's exact P-value. | |
Method | Fisher Exact | |
Comments | ||
Method of Estimation | Estimation Parameter | Rate ratio |
Estimated Value | 4.5 | |
Confidence Interval |
(2-Sided) 95% 1.4 to 14.7 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority or Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | =0.1007 |
Comments | Analysis performed after database lock. P-value was based on the 2-sided Fisher's exact P-value. | |
Method | Fisher Exact | |
Comments | ||
Method of Estimation | Estimation Parameter | Rate ratio |
Estimated Value | 1.6 | |
Confidence Interval |
(2-Sided) 95% 0.9 to 2.8 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Disease Control Rate (DCR) |
---|---|
Description | The DCR was defined as the percentage of participants who had a BOR of CR or PR or SD (minimum duration from randomization to SD greater than or equal to 7 weeks). Assessments were performed every 8 weeks and were based on investigator review data using RECIST 1.1. The 95% CI was constructed using the method of Clopper and Pearson. DCR = CR + PR + SD greater than or equal to 7 weeks. |
Time Frame | Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months |
Outcome Measure Data
Analysis Population Description |
---|
Full analysis set which included all randomized participants. |
Arm/Group Title | Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 2 (Arm B): 24 mg Lenvatinib | Phase 2 (Arm C): 10 mg Everolimus |
---|---|---|---|---|---|---|---|
Arm/Group Description | Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day withwater, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | The DLT was achieved and no participants were enrolled into this cohort. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days. | Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. | Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles. |
Measure Participants | 0 | 0 | 0 | 0 | 51 | 52 | 50 |
Number (95% Confidence Interval) [Percentage of participants] |
84.3
1204.3%
|
78.8
716.4%
|
68.0
3400%
|
Title | Durable Stable Disease (SD) Rate |
---|---|
Description | The durable SD rate was defined as the percentage of participants whose BOR was SD and the duration of SD was greater than or equal to 23 weeks. The durable SD was based on investigator review data using RECIST 1.1. The 95% CI was constructed using the method of Clopper and Pearson. |
Time Frame | Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months |
Outcome Measure Data
Analysis Population Description |
---|
Full analysis set which included all randomized participants. |
Arm/Group Title | Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 2 (Arm B): 24 mg Lenvatinib | Phase 2 (Arm C): 10 mg Everolimus |
---|---|---|---|---|---|---|---|
Arm/Group Description | Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | The DLT was achieved and no participants were enrolled into this cohort. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days. | Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. | Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles. |
Measure Participants | 0 | 0 | 0 | 0 | 51 | 52 | 50 |
Number (95% Confidence Interval) [Percentage of participants] |
25.5
364.3%
|
38.5
350%
|
36.0
1800%
|
Title | Clinical Benefit Rate (CBR) |
---|---|
Description | The CBR was defined as the percentage of participants who had BOR of CR, PR, or durable SD (duration of SD was greater than or equal to 23 weeks) and was based on investigator review data using RECIST 1.1. The BOR was defined as the best response recorded from the start of study treatment until discontinuation from the study. There was no requirement for confirmatory measurement of PR or CR to deem either one the BOR. The 95% CI was constructed using the method of Clopper and Pearson. CBR = CR + PR + SD greater than or equal to 23 weeks. |
Time Frame | Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months |
Outcome Measure Data
Analysis Population Description |
---|
Full analysis set which included all randomized participants. |
Arm/Group Title | Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 2 (Arm B): 24 mg Lenvatinib | Phase 2 (Arm C): 10 mg Everolimus |
---|---|---|---|---|---|---|---|
Arm/Group Description | Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | The DLT was achieved and no participants were enrolled into this cohort. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days. | Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. | Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4 week) cycles. |
Measure Participants | 0 | 0 | 0 | 0 | 51 | 52 | 50 |
Number (95% Confidence Interval) [Percentage of participants] |
68.6
980%
|
65.4
594.5%
|
42.0
2100%
|
Title | Summary of Plasma Concentrations of Lenvatinib for Sparse Pharmacokinetic (PK) Sampling for Phase 1b and Phase 2 |
---|---|
Description | Blood samples were collected during the Randomization Phase. Most participants had 6 samples taken over 3 cycles of treatment (sparse sampling - 2 samples taken per cycle, one at predose and one at 2 to 8 hours postdose). Plasma concentrations of lenvatinib were measured and concentration data were summarized. The summary statistics at time points with one or more below the limit of quantitation (BLQ) values were calculated by assigning zero for each BLQ value. |
Time Frame | Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1) |
Outcome Measure Data
Analysis Population Description |
---|
Pharmacokinetic analysis set included all participants who have received at least one dose of study drug (lenvatinib or everolimus) and have evaluable concentration data. |
Arm/Group Title | Cycle 1, Day 1 (0 Hours) | Cycle 1, Day 1 (2-8 Hours) | Cycle 2, Day 1 (0 Hours) | Cycle 2, Day 1 (2-8 Hours) | Cycle 3, Day 1 (0 Hours) | Cycle 3, Day 1 (2-8 Hours) |
---|---|---|---|---|---|---|
Arm/Group Description | Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected immediately prior to study drug administration. | Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected 2 to 8 hours after study drug administration. | Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected immediately prior to study drug administration. | Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected 2 to 8 hours after study drug administration. | Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected immediately prior to study drug administration. | Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected 2 to 8 hours after study drug administration. |
Measure Participants | 57 | 55 | 45 | 41 | 42 | 40 |
Geometric Mean (Standard Deviation) [ng/mL] |
5.6
(29.8)
|
197
(140)
|
66.9
(52.7)
|
237
(154)
|
37.0
(35.5)
|
180
(118)
|
Title | Summary of Blood Concentrations of Everolimus for Sparse PK Sampling for Phase 1b and Phase 2 |
---|---|
Description | Blood samples were collected during the Randomization Phase. Most participants had 6 samples taken over 3 cycles of treatment (sparse sampling - 2 samples taken per cycle, one at predose and one at 2 to 8 hours postdose). Whole blood concentrations of everolimus were measured and concentration data were summarized. The summary statistics at time points with one or more BLQ values were calculated by assigning zero for each BLQ value. |
Time Frame | Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1) |
Outcome Measure Data
Analysis Population Description |
---|
Pharmacokinetic analysis set included all participants who received at least one dose of study drug (lenvatinib or everolimus) and had evaluable concentration data. |
Arm/Group Title | Cycle 1, Day 1 (0 Hours) | Cycle 1, Day 1 (2-8 Hours) | Cycle 2, Day 1 (0 Hours) | Cycle 2, Day 1 (2-8 Hours) | Cycle 3, Day 1 (0 Hours) | Cycle 3, Day 1 (2-8 Hours) |
---|---|---|---|---|---|---|
Arm/Group Description | Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected immediately prior to study drug administration. | Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected 2 to 8 hours after study drug administration. | Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected immediately prior to study drug administration. | Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected 2 to 8 hours after study drug administration. | Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected immediately prior to study drug administration. | Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected 2 to 8 hours after study drug administration. |
Measure Participants | 37 | 35 | 29 | 28 | 27 | 25 |
Geometric Mean (Standard Deviation) [ng/mL] |
0.0
(0.00)
|
19.4
(9.16)
|
10.0
(7.28)
|
24.3
(14.2)
|
6.8
(6.06)
|
26.4
(14.8)
|
Title | Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours (AUC(0-24)) for Lenvatinib When Administered Alone or in Combination With Everolimus |
---|---|
Description | Between 9 and 12 participants in each of the 3 treatment arms participated in an optional substudy where instead of the sparse sampling, 9 samples were to be taken over 1 single 24-hour period (i.e., intensive sampling) for full PK profiling. Blood samples were analyzed for study drug using standardized methods. PK parameters for lenvatinib were derived from lenvatinib concentration data using non-compartmental methods. Data were compared via descriptive statistics between single agent and combination therapy. |
Time Frame | Phase 2: Cycle 1 Day 15 immediately predose, and 30 minutes, 1, 2, 3, 4, 8, 12 (optional), and 24 hours postdose (predose on Day 16) |
Outcome Measure Data
Analysis Population Description |
---|
Pharmacokinetic sub analysis set consisted of all participants who agreed to participate in the intensive PK sampling portion of Phase 2 of the study, had received at least 1 dose of study drug (lenvatinib or everolimus), and had evaluable concentration data. |
Arm/Group Title | Phase 2: 18 mg Lenvatinib + 5 mg Everolimus | Phase 2: 24 mg Lenvatinib |
---|---|---|
Arm/Group Description | Oral lenvatinib (18mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days. | Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. |
Measure Participants | 8 | 9 |
Mean (Standard Deviation) [ng·hr/mL] |
3185
(1030)
|
5252
(2717)
|
Title | Maximum Concentration (Cmax) of Lenvatinib in Plasma When Administered Alone or in Combination With Everolimus |
---|---|
Description | Cmax for lenvatinib was defined as the maximum observed concentration of lenvatinib in plasma following administration of study treatment on Cycle 1 Day 15 and was obtained directly from the measured plasma concentration-time curves. |
Time Frame | Phase 2: Cycle 1 Day 15 |
Outcome Measure Data
Analysis Population Description |
---|
PK sub analysis set |
Arm/Group Title | Phase 2: 18 mg Lenvatinib + 5 mg Everolimus | Phase 2: 24 mg Lenvatinib |
---|---|---|
Arm/Group Description | Oral lenvatinib (18mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days. | Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. |
Measure Participants | 8 | 9 |
Mean (Standard Deviation) [ng/mL] |
327
(179)
|
403
(165)
|
Title | Time to Cmax (Tmax) for Lenvatinib When Administered Alone or in Combination With Everolimus |
---|---|
Description | Tmax for lenvatinib was the amount of time taken after administration of study treatment on Cycle 1 Day 15 to reach maximum concentration (Cmax) of lenvatinib in plasma. |
Time Frame | Phase 2: Cycle 1 Day 15 |
Outcome Measure Data
Analysis Population Description |
---|
PK sub analysis set |
Arm/Group Title | Phase 2: 18 mg Lenvatinib + 5 mg Everolimus | Phase 2: 24 mg Lenvatinib |
---|---|---|
Arm/Group Description | Oral lenvatinib (18mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days. | Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. |
Measure Participants | 8 | 9 |
Median (Full Range) [Hours] |
2.0
|
4.0
|
Title | Area Under the Blood Concentration-Time Curve From 0 to 24 Hours for Everolimus When Administered Alone or in Combination With Lenvatinib |
---|---|
Description | Between 9 and 12 participants in each of the 3 treatment arms participated in an optional substudy where instead of the sparse sampling, 9 samples were to be taken over 1 single 24-hour period (i.e., intensive sampling) for full PK profiling. Blood samples were analyzed for study drug using standardized methods. PK parameters for everolimus were derived from everolimus concentration data using non-compartmental methods. Data were compared via descriptive statistics between single agent and combination therapy. |
Time Frame | Phase 2: Cycle 1 Day 15 immediately predose, and 30 minutes, 1, 2, 3, 4, 8, 12 (optional), and 24 hours postdose (predose on Day 16) |
Outcome Measure Data
Analysis Population Description |
---|
PK sub analysis set. n=8 for AUC(0-24) |
Arm/Group Title | Phase 2: 18 mg Lenvatinib + 5 mg Everolimus | Phase 2: 10 mg Everolimus |
---|---|---|
Arm/Group Description | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days. | Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles. |
Measure Participants | 4 | 8 |
Mean (Standard Deviation) [ng·hr/mL] |
378
(88.1)
|
463
(263)
|
Title | Maximum Concentration of Everolimus (Cmax) in Blood When Administered Alone or in Combination With Lenvatinib |
---|---|
Description | Cmax for everolimus was defined as the maximum observed concentration of everolimus in blood following administration of study treatment on Cycle 1 Day 15 and was obtained directly from the measured blood concentration-time curves. |
Time Frame | Phase 2: Cycle 1 Day 15 |
Outcome Measure Data
Analysis Population Description |
---|
PK sub analysis set |
Arm/Group Title | Phase 2: 18 mg Lenvatinib + 5 mg Everolimus | Phase 2: 10 mg Everolimus |
---|---|---|
Arm/Group Description | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days. | Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles. |
Measure Participants | 4 | 11 |
Mean (Standard Deviation) [ng/mL] |
38
(14.5)
|
54
(24.9)
|
Title | Time to Cmax (Tmax) for Everolimus When Administered Alone or in Combination With Lenvatinib |
---|---|
Description | Tmax for everolimus was the amount of time taken after administration of study treatment on Cycle 1 Day 15 to reach the maximum concentration (Cmax) of everolimus in blood. |
Time Frame | Phase 2: Cycle 1 Day 15 |
Outcome Measure Data
Analysis Population Description |
---|
PK sub analysis set |
Arm/Group Title | Phase 2: 18 mg Lenvatinib + 5 mg Everolimus | Phase 2: 10 mg Everolimus |
---|---|---|
Arm/Group Description | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days. | Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles. |
Measure Participants | 4 | 11 |
Median (Full Range) [Hours] |
1.0
|
1.0
|
Adverse Events
Time Frame | Treatment-emergent adverse events (AEs) were collected and defined as those AEs that occurred after the first dose of study medication and up to 30 days after the last dose of study medication. AEs were collected for approximately 4 years. | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Adverse Event Reporting Description | Safety analysis set included all participants who received at least one dose of study drug/s and had at least one postbaseline safety evaluation. AE severity was assessed using Common Terminology for Adverse Events (CTCAE). Serious AEs were followed until the event resolved or the event or sequelae stabilized. | |||||||||||||
Arm/Group Title | Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 2 (Arm B): 24 mg Lenvatinib | Phase 2 (Arm C): 10 mg Everolimus | |||||||
Arm/Group Description | Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped. | Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort. | The DLT was achieved and no participants were enrolled into this cohort. | Oral lenvatinib (18mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days. | Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. | Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4 week) cycles. | |||||||
All Cause Mortality |
||||||||||||||
Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 2 (Arm B): 24 mg Lenvatinib | Phase 2 (Arm C): 10 mg Everolimus | ||||||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 6/7 (85.7%) | 9/11 (81.8%) | 0/2 (0%) | 0/0 (NaN) | 43/51 (84.3%) | 40/52 (76.9%) | 45/50 (90%) | |||||||
Serious Adverse Events |
||||||||||||||
Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 2 (Arm B): 24 mg Lenvatinib | Phase 2 (Arm C): 10 mg Everolimus | ||||||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 6/7 (85.7%) | 8/11 (72.7%) | 0/2 (0%) | 0/0 (NaN) | 30/51 (58.8%) | 28/52 (53.8%) | 21/50 (42%) | |||||||
Blood and lymphatic system disorders | ||||||||||||||
Anaemia | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 1/52 (1.9%) | 4/50 (8%) | |||||||
Sideroblastic Anaemia | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Thrombocytopenia | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 3/51 (5.9%) | 0/52 (0%) | 0/50 (0%) | |||||||
Cardiac disorders | ||||||||||||||
Cardiomyopathy | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Myocardial Infarction | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Acute Myocardial Infarction | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 3/52 (5.8%) | 1/50 (2%) | |||||||
Cardiac Failure | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Cardiac Failure Congestive | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Tachycardia | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Ear and labyrinth disorders | ||||||||||||||
Vertigo Positional | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Endocrine disorders | ||||||||||||||
Inappropriate Antidiuretic Hormone Secretion | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Gastrointestinal disorders | ||||||||||||||
Abdominal Pain | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 2/52 (3.8%) | 0/50 (0%) | |||||||
Gastritis | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Vomiting | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 0/52 (0%) | 0/50 (0%) | |||||||
Diarrhoea | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 3/51 (5.9%) | 0/52 (0%) | 0/50 (0%) | |||||||
Dysphagia | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Gastric Haemorrhage | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Ileus | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Haemorrhoids | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
General disorders | ||||||||||||||
Fatigue | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
General Physical Health Deterioration | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 0/52 (0%) | 0/50 (0%) | |||||||
Non-Cardiac Chest Pain | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Asthenia | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 1/50 (2%) | |||||||
Chest Discomfort | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Pain | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 1/50 (2%) | |||||||
Pyrexia | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 0/52 (0%) | 1/50 (2%) | |||||||
Hepatobiliary disorders | ||||||||||||||
Cholangitis | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Cholecystitis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 2/52 (3.8%) | 0/50 (0%) | |||||||
Cholecystitis Acute | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Immune system disorders | ||||||||||||||
Drug Hypersensitivity | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Infections and infestations | ||||||||||||||
Cellulitis | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Lung Infection | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Appendicitis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Appendicitis Perforated | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Bronchopneumonia | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Diabetic Foot Infection | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Escherichia Sepsis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 1/50 (2%) | |||||||
Infection | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Infectious Pleural Effusion | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Lower Respiratory Tract Infection | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 2/50 (4%) | |||||||
Osteomyelitis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 1/50 (2%) | |||||||
Parotitis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Pneumonia | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 2/52 (3.8%) | 1/50 (2%) | |||||||
Rectal Abscess | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Sepsis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 1/52 (1.9%) | 1/50 (2%) | |||||||
Upper Respiratory Tract Infection | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Injury, poisoning and procedural complications | ||||||||||||||
Joint Dislocation | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Spinal Compression Fracture | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Toxicity to Various Agents | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Investigations | ||||||||||||||
Ejection Fraction Decreased | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
White Blood Cell Count Decreased | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Blood Bilirubin Increased | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Blood Creatinine Phosphokinase Increased | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Body Temperature Increased | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Electrocardiogram Repolarisation Abnormality | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Fibrin D Dimer Increased | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Transaminases Increased | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Lipase Increased | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Metabolism and nutrition disorders | ||||||||||||||
Dehydration | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 0/52 (0%) | 0/50 (0%) | |||||||
Hypercholesterolaemia | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Hyponatraemia | 2/7 (28.6%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Decreased Appetite | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Failure to Thrive | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Glucose Tolerance Impaired | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Hyperkalaemia | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 0/52 (0%) | 0/50 (0%) | |||||||
Hypomagnesaemia | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Malnutrition | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Hypokalaemia | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Musculoskeletal and connective tissue disorders | ||||||||||||||
Arthralgia | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Back Pain | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Flank Pain | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 2/52 (3.8%) | 0/50 (0%) | |||||||
Haemarthrosis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Musculoskeletal Chest Pain | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Psoriatic Arthropathy | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Pathological Fracture | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Spinal Pain | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||
Metastatic Pain | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Malignant Pleural Effusion | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Nervous system disorders | ||||||||||||||
Cerebral Haemorrhage | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Convulsion | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 1/50 (2%) | |||||||
Haemorrhage Intracranial | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Headache | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 3/52 (5.8%) | 1/50 (2%) | |||||||
Ischaemic Stroke | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Paresis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Posterior Reversible Encephalopathy Syndrome | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Somnolence | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Spinal Cord Compression | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Trigeminal Neuralgia | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Carotid Artery Occlusion | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Psychiatric disorders | ||||||||||||||
Anxiety | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Confusional State | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Renal and urinary disorders | ||||||||||||||
Proteinuria | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Renal Failure Acute | 1/7 (14.3%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 3/51 (5.9%) | 4/52 (7.7%) | 0/50 (0%) | |||||||
Haematuria | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Renal Impairment | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 0/52 (0%) | 0/50 (0%) | |||||||
Reproductive system and breast disorders | ||||||||||||||
Benign Prostatic Hyperplasia | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Respiratory, thoracic and mediastinal disorders | ||||||||||||||
Dyspnoea | 1/7 (14.3%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 1/52 (1.9%) | 2/50 (4%) | |||||||
Pleural Effusion | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Acute Respiratory Failure | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 1/50 (2%) | |||||||
Haemoptysis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Pneumonitis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 3/50 (6%) | |||||||
Pulmonary Embolism | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 1/52 (1.9%) | 1/50 (2%) | |||||||
Vascular disorders | ||||||||||||||
Deep Vein Thrombosis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Hot Flush | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Subclavian Vein Thrombosis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Venous Thrombosis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Other (Not Including Serious) Adverse Events |
||||||||||||||
Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus | Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 2 (Arm B): 24 mg Lenvatinib | Phase 2 (Arm C): 10 mg Everolimus | ||||||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 7/7 (100%) | 11/11 (100%) | 2/2 (100%) | 0/0 (NaN) | 51/51 (100%) | 51/52 (98.1%) | 50/50 (100%) | |||||||
Blood and lymphatic system disorders | ||||||||||||||
Anaemia | 2/7 (28.6%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 7/51 (13.7%) | 3/52 (5.8%) | 11/50 (22%) | |||||||
Haemorrhagic Disorder | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Lymphadenopathy | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Neutropenia | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Thrombocytopenia | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 5/51 (9.8%) | 1/52 (1.9%) | 4/50 (8%) | |||||||
Cardiac disorders | ||||||||||||||
Angina Pectoris | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Aortic Valve Incompetence | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Coronary Artery Disease | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Coronary Artery Occlusion | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Mitral Valve Incompetence | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Palpitations | 1/7 (14.3%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 2/50 (4%) | |||||||
Tachycardia | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 2/52 (3.8%) | 0/50 (0%) | |||||||
Ventricular Hypokinesia | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Left ventricular dysfunction | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Ear and labyrinth disorders | ||||||||||||||
Ear Pain | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Vertigo | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 3/52 (5.8%) | 0/50 (0%) | |||||||
Endocrine disorders | ||||||||||||||
Hypothyroidism | 1/7 (14.3%) | 3/11 (27.3%) | 0/2 (0%) | 0/0 (NaN) | 12/51 (23.5%) | 19/52 (36.5%) | 1/50 (2%) | |||||||
Inappropriate Antidiuretic Hormone Secretion | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Eye disorders | ||||||||||||||
Diplopia | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Eye Swelling | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Ocular Hyperaemia | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Vision Blurred | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Gastrointestinal disorders | ||||||||||||||
Abdominal Pain | 1/7 (14.3%) | 3/11 (27.3%) | 0/2 (0%) | 0/0 (NaN) | 12/51 (23.5%) | 11/52 (21.2%) | 1/50 (2%) | |||||||
Abdominal Pain Upper | 2/7 (28.6%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 8/51 (15.7%) | 7/52 (13.5%) | 3/50 (6%) | |||||||
Anal Pruritus | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Anorectal Discomfort | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Aphthous Stomatitis | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Constipation | 3/7 (42.9%) | 4/11 (36.4%) | 1/2 (50%) | 0/0 (NaN) | 6/51 (11.8%) | 19/52 (36.5%) | 9/50 (18%) | |||||||
Diarrhoea | 3/7 (42.9%) | 7/11 (63.6%) | 1/2 (50%) | 0/0 (NaN) | 43/51 (84.3%) | 37/52 (71.2%) | 17/50 (34%) | |||||||
Dry Mouth | 1/7 (14.3%) | 0/11 (0%) | 1/2 (50%) | 0/0 (NaN) | 2/51 (3.9%) | 6/52 (11.5%) | 3/50 (6%) | |||||||
Dyspepsia | 0/7 (0%) | 4/11 (36.4%) | 0/2 (0%) | 0/0 (NaN) | 6/51 (11.8%) | 6/52 (11.5%) | 6/50 (12%) | |||||||
Flatulence | 1/7 (14.3%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 3/52 (5.8%) | 0/50 (0%) | |||||||
Gastric Haemorrhage | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Gastritis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 3/51 (5.9%) | 0/52 (0%) | 0/50 (0%) | |||||||
Gastrooesophageal Reflux Disease | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 2/52 (3.8%) | 0/50 (0%) | |||||||
Gingival Bleeding | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 2/52 (3.8%) | 0/50 (0%) | |||||||
Glossitis | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Glossodynia | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 2/52 (3.8%) | 0/50 (0%) | |||||||
Haemorrhoidal Haemorrhage | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Haemorrhoids | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Lip Discolouration | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Nausea | 6/7 (85.7%) | 6/11 (54.5%) | 1/2 (50%) | 0/0 (NaN) | 22/51 (43.1%) | 32/52 (61.5%) | 8/50 (16%) | |||||||
Oral Mucosal Blistering | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Oral Pain | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 6/51 (11.8%) | 5/52 (9.6%) | 1/50 (2%) | |||||||
Paraesthesia Oral | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Stomatitis | 4/7 (57.1%) | 7/11 (63.6%) | 2/2 (100%) | 0/0 (NaN) | 15/51 (29.4%) | 13/52 (25%) | 21/50 (42%) | |||||||
Vomiting | 5/7 (71.4%) | 5/11 (45.5%) | 1/2 (50%) | 0/0 (NaN) | 24/51 (47.1%) | 20/52 (38.5%) | 6/50 (12%) | |||||||
Abdominal Pain Lower | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 3/51 (5.9%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Anal Fissure | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 3/51 (5.9%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Cheilitis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 3/51 (5.9%) | 1/52 (1.9%) | 1/50 (2%) | |||||||
Toothache | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 5/51 (9.8%) | 3/52 (5.8%) | 1/50 (2%) | |||||||
Mouth Ulceration | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 5/51 (9.8%) | 0/52 (0%) | 5/50 (10%) | |||||||
Abdominal Discomfort | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 3/51 (5.9%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Abdominal Distension | 0/7 (0%) | 1/11 (9.1%) | 1/2 (50%) | 0/0 (NaN) | 4/51 (7.8%) | 2/52 (3.8%) | 0/50 (0%) | |||||||
General disorders | ||||||||||||||
Asthenia | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 13/51 (25.5%) | 8/52 (15.4%) | 3/50 (6%) | |||||||
Chills | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 3/52 (5.8%) | 1/50 (2%) | |||||||
Fatigue | 4/7 (57.1%) | 11/11 (100%) | 2/2 (100%) | 0/0 (NaN) | 26/51 (51%) | 21/52 (40.4%) | 16/50 (32%) | |||||||
Gait Disturbance | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 2/52 (3.8%) | 1/50 (2%) | |||||||
Localised Oedema | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Non-Cardiac Chest Pain | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 2/52 (3.8%) | 1/50 (2%) | |||||||
Oedema Peripheral | 1/7 (14.3%) | 6/11 (54.5%) | 0/2 (0%) | 0/0 (NaN) | 15/51 (29.4%) | 9/52 (17.3%) | 9/50 (18%) | |||||||
Pyrexia | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 9/51 (17.6%) | 5/52 (9.6%) | 5/50 (10%) | |||||||
Influenza Like Illness | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 2/52 (3.8%) | 0/50 (0%) | |||||||
Pain | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 3/51 (5.9%) | 2/52 (3.8%) | 1/50 (2%) | |||||||
Malaise | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 3/52 (5.8%) | 1/50 (2%) | |||||||
Peripheral Swelling | 1/7 (14.3%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 5/51 (9.8%) | 1/52 (1.9%) | 2/50 (4%) | |||||||
Hepatobiliary disorders | ||||||||||||||
Dilatation Intrahepatic Duct Acquired | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Infections and infestations | ||||||||||||||
Bronchitis | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 4/52 (7.7%) | 1/50 (2%) | |||||||
Cellulitis | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Infectious Pleural Effusion | 0/7 (0%) | 3/11 (27.3%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Influenza | 2/7 (28.6%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Lymph Gland Infection | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Nasopharyngitis | 1/7 (14.3%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 7/51 (13.7%) | 4/52 (7.7%) | 7/50 (14%) | |||||||
Oral Herpes | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 1/52 (1.9%) | 3/50 (6%) | |||||||
Osteomyelitis | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Paronychia | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Pneumonia | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 1/52 (1.9%) | 1/50 (2%) | |||||||
Sinusitis | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 0/52 (0%) | 0/50 (0%) | |||||||
Skin Infection | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Upper Respiratory Tract Infection | 2/7 (28.6%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 7/52 (13.5%) | 7/50 (14%) | |||||||
Urinary Tract Infection | 1/7 (14.3%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 4/52 (7.7%) | 3/50 (6%) | |||||||
Lower Respiratory Tract Infection | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 4/52 (7.7%) | 4/50 (8%) | |||||||
Respiratory Tract Infection | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 4/52 (7.7%) | 1/50 (2%) | |||||||
Gingivitis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 3/51 (5.9%) | 0/52 (0%) | 0/50 (0%) | |||||||
Injury, poisoning and procedural complications | ||||||||||||||
Arthropod Bite | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Contusion | 1/7 (14.3%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Fall | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 1/50 (2%) | |||||||
Periorbital Contusion | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Toxicity to Various Agents | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Investigations | ||||||||||||||
Alanine Aminotransferase Increased | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 5/51 (9.8%) | 3/52 (5.8%) | 3/50 (6%) | |||||||
Amylase Increased | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 2/52 (3.8%) | 0/50 (0%) | |||||||
Aspartate Aminotransferase Increased | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 2/52 (3.8%) | 3/50 (6%) | |||||||
Blood Alkaline Phosphatase Increased | 1/7 (14.3%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 1/52 (1.9%) | 2/50 (4%) | |||||||
Blood Bilirubin Increased | 1/7 (14.3%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Blood Cholesterol Increased | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 2/52 (3.8%) | 3/50 (6%) | |||||||
Blood Creatine Phosphokinase Increased | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 0/52 (0%) | 1/50 (2%) | |||||||
Blood Glucose Increased | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 0/52 (0%) | 1/50 (2%) | |||||||
Blood Phosphorus Increased | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 2/52 (3.8%) | 0/50 (0%) | |||||||
Blood Potassium Increased | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Blood Triglycerides Increased | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 2/52 (3.8%) | 1/50 (2%) | |||||||
Cardiac Murmur | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Computerised Tomogram Thorax Abnormal | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Ejection Fraction Decreased | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 4/52 (7.7%) | 0/50 (0%) | |||||||
Electrocardiogram QT Prolonged | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 2/52 (3.8%) | 0/50 (0%) | |||||||
Haemoglobin Decreased | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 2/52 (3.8%) | 5/50 (10%) | |||||||
Lipase Increased | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 5/52 (9.6%) | 3/50 (6%) | |||||||
Liver Function Test Abnormal | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Murphy's Sign Positive | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Platelet Count Increased | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Protein Urine Present | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Transaminases Increased | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Weight Decreased | 2/7 (28.6%) | 5/11 (45.5%) | 0/2 (0%) | 0/0 (NaN) | 16/51 (31.4%) | 26/52 (50%) | 4/50 (8%) | |||||||
White Blood Cell Count Decreased | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
White Blood Cell Count Increased | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Blood Thyroid Stimulating Hormone Increased | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 7/51 (13.7%) | 2/52 (3.8%) | 1/50 (2%) | |||||||
Blood Creatinine Increased | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 3/51 (5.9%) | 2/52 (3.8%) | 4/50 (8%) | |||||||
Metabolism and nutrition disorders | ||||||||||||||
Decreased Appetite | 3/7 (42.9%) | 6/11 (54.5%) | 1/2 (50%) | 0/0 (NaN) | 27/51 (52.9%) | 30/52 (57.7%) | 10/50 (20%) | |||||||
Dehydration | 1/7 (14.3%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 1/52 (1.9%) | 1/50 (2%) | |||||||
Failure to Thrive | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Hypercalcaemia | 2/7 (28.6%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Hypercholesterolaemia | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 18/51 (35.3%) | 6/52 (11.5%) | 8/50 (16%) | |||||||
Hyperglycaemia | 2/7 (28.6%) | 3/11 (27.3%) | 0/2 (0%) | 0/0 (NaN) | 8/51 (15.7%) | 3/52 (5.8%) | 12/50 (24%) | |||||||
Hyperkalaemia | 1/7 (14.3%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 3/52 (5.8%) | 1/50 (2%) | |||||||
Hyperlipidaemia | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Hypernatraemia | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Hypertriglyceridaemia | 1/7 (14.3%) | 7/11 (63.6%) | 0/2 (0%) | 0/0 (NaN) | 18/51 (35.3%) | 7/52 (13.5%) | 12/50 (24%) | |||||||
Hypophagia | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Hypophosphataemia | 3/7 (42.9%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 1/50 (2%) | |||||||
Hypovolaemia | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Malnutrition | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Metabolic Acidosis | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Hypomagnesaemia | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 4/52 (7.7%) | 0/50 (0%) | |||||||
Hypocalcaemia | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 3/52 (5.8%) | 2/50 (4%) | |||||||
Hypokalaemia | 1/7 (14.3%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 7/51 (13.7%) | 0/52 (0%) | 1/50 (2%) | |||||||
Hyponatraemia | 1/7 (14.3%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Musculoskeletal and connective tissue disorders | ||||||||||||||
Arthralgia | 4/7 (57.1%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 14/51 (27.5%) | 13/52 (25%) | 7/50 (14%) | |||||||
Back Pain | 3/7 (42.9%) | 4/11 (36.4%) | 0/2 (0%) | 0/0 (NaN) | 11/51 (21.6%) | 11/52 (21.2%) | 7/50 (14%) | |||||||
Flank Pain | 0/7 (0%) | 3/11 (27.3%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 2/52 (3.8%) | 2/50 (4%) | |||||||
Intervertebral Disc Protrusion | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Muscle Spasms | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 1/52 (1.9%) | 2/50 (4%) | |||||||
Muscular Weakness | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 3/52 (5.8%) | 0/50 (0%) | |||||||
Musculoskeletal Chest Pain | 1/7 (14.3%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 8/51 (15.7%) | 7/52 (13.5%) | 2/50 (4%) | |||||||
Musculoskeletal Pain | 3/7 (42.9%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 8/52 (15.4%) | 1/50 (2%) | |||||||
Myalgia | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 7/52 (13.5%) | 1/50 (2%) | |||||||
Neck Pain | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 0/52 (0%) | 1/50 (2%) | |||||||
Pain in Extremity | 2/7 (28.6%) | 4/11 (36.4%) | 0/2 (0%) | 0/0 (NaN) | 6/51 (11.8%) | 6/52 (11.5%) | 3/50 (6%) | |||||||
Spinal Osteoarthritis | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Bone Pain | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 4/52 (7.7%) | 2/50 (4%) | |||||||
Groin Pain | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Pain In Jaw | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 3/51 (5.9%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Nervous system disorders | ||||||||||||||
Disturbance In Attention | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Dizziness | 1/7 (14.3%) | 5/11 (45.5%) | 1/2 (50%) | 0/0 (NaN) | 2/51 (3.9%) | 4/52 (7.7%) | 2/50 (4%) | |||||||
Dysgeusia | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 4/52 (7.7%) | 1/50 (2%) | |||||||
Headache | 4/7 (57.1%) | 3/11 (27.3%) | 0/2 (0%) | 0/0 (NaN) | 10/51 (19.6%) | 13/52 (25%) | 4/50 (8%) | |||||||
Hyperaesthesia | 0/7 (0%) | 0/11 (0%) | 1/2 (50%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Hypoaesthesia | 1/7 (14.3%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 1/52 (1.9%) | 1/50 (2%) | |||||||
Paraesthesia | 1/7 (14.3%) | 1/11 (9.1%) | 1/2 (50%) | 0/0 (NaN) | 2/51 (3.9%) | 1/52 (1.9%) | 1/50 (2%) | |||||||
Peripheral Sensory Neuropathy | 2/7 (28.6%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 4/52 (7.7%) | 0/50 (0%) | |||||||
Sensory Disturbance | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Sinus Headache | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Tremor | 0/7 (0%) | 2/11 (18.2%) | 1/2 (50%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Lethargy | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 7/52 (13.5%) | 2/50 (4%) | |||||||
Psychiatric disorders | ||||||||||||||
Anxiety | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 3/52 (5.8%) | 1/50 (2%) | |||||||
Confusional State | 2/7 (28.6%) | 0/11 (0%) | 1/2 (50%) | 0/0 (NaN) | 1/51 (2%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Depression | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 3/51 (5.9%) | 1/52 (1.9%) | 2/50 (4%) | |||||||
Insomnia | 1/7 (14.3%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 10/51 (19.6%) | 8/52 (15.4%) | 1/50 (2%) | |||||||
Renal and urinary disorders | ||||||||||||||
Haematuria | 0/7 (0%) | 1/11 (9.1%) | 1/2 (50%) | 0/0 (NaN) | 2/51 (3.9%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Nocturia | 0/7 (0%) | 3/11 (27.3%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 2/52 (3.8%) | 3/50 (6%) | |||||||
Proteinuria | 5/7 (71.4%) | 6/11 (54.5%) | 0/2 (0%) | 0/0 (NaN) | 13/51 (25.5%) | 16/52 (30.8%) | 7/50 (14%) | |||||||
Renal Failure Acute | 1/7 (14.3%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Renal Failure Chronic | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Renal Mass | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Pollakiuria | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 2/52 (3.8%) | 4/50 (8%) | |||||||
Reproductive system and breast disorders | ||||||||||||||
Vaginal Haemorrhage | 0/7 (0%) | 0/11 (0%) | 1/2 (50%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Respiratory, thoracic and mediastinal disorders | ||||||||||||||
Cough | 6/7 (85.7%) | 3/11 (27.3%) | 0/2 (0%) | 0/0 (NaN) | 20/51 (39.2%) | 9/52 (17.3%) | 16/50 (32%) | |||||||
Dysphonia | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 10/51 (19.6%) | 19/52 (36.5%) | 2/50 (4%) | |||||||
Dyspnoea | 1/7 (14.3%) | 7/11 (63.6%) | 1/2 (50%) | 0/0 (NaN) | 11/51 (21.6%) | 11/52 (21.2%) | 11/50 (22%) | |||||||
Dyspnoea Exertional | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 1/52 (1.9%) | 5/50 (10%) | |||||||
Epistaxis | 2/7 (28.6%) | 5/11 (45.5%) | 1/2 (50%) | 0/0 (NaN) | 9/51 (17.6%) | 4/52 (7.7%) | 12/50 (24%) | |||||||
Haemoptysis | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 3/52 (5.8%) | 2/50 (4%) | |||||||
Lung Infiltration | 0/7 (0%) | 1/11 (9.1%) | 1/2 (50%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Nasal Congestion | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 1/52 (1.9%) | 1/50 (2%) | |||||||
Oropharyngeal Pain | 1/7 (14.3%) | 3/11 (27.3%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 2/52 (3.8%) | 2/50 (4%) | |||||||
Pleural Effusion | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 3/50 (6%) | |||||||
Pneumonitis | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 0/52 (0%) | 4/50 (8%) | |||||||
Productive Cough | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 2/52 (3.8%) | 2/50 (4%) | |||||||
Rhinorrhoea | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 2/52 (3.8%) | 2/50 (4%) | |||||||
Sinus Congestion | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Sputum Discoloured | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Upper-Airway Cough Syndrome | 1/7 (14.3%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Wheezing | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 2/52 (3.8%) | 2/50 (4%) | |||||||
Paranasal sinus discomfort | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 0/52 (0%) | 0/50 (0%) | |||||||
Skin and subcutaneous tissue disorders | ||||||||||||||
Dermatitis Acneiform | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 1/50 (2%) | |||||||
Dry Skin | 3/7 (42.9%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 5/51 (9.8%) | 3/52 (5.8%) | 3/50 (6%) | |||||||
Ecchymosis | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Erythema | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 2/50 (4%) | |||||||
Erythema Multiforme | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Hyperhidrosis | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 0/52 (0%) | 1/50 (2%) | |||||||
Hyperkeratosis | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 0/52 (0%) | 1/50 (2%) | |||||||
Night Sweats | 1/7 (14.3%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 2/52 (3.8%) | 2/50 (4%) | |||||||
Palmar-Plantar Erythrodysaesthesia Syndrome | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 4/51 (7.8%) | 8/52 (15.4%) | 2/50 (4%) | |||||||
Petechiae | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Pruritus | 2/7 (28.6%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 7/51 (13.7%) | 3/52 (5.8%) | 7/50 (14%) | |||||||
Rash | 3/7 (42.9%) | 5/11 (45.5%) | 1/2 (50%) | 0/0 (NaN) | 9/51 (17.6%) | 8/52 (15.4%) | 11/50 (22%) | |||||||
Rash Erythematous | 0/7 (0%) | 2/11 (18.2%) | 0/2 (0%) | 0/0 (NaN) | 2/51 (3.9%) | 3/52 (5.8%) | 4/50 (8%) | |||||||
Rash Macular | 1/7 (14.3%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 2/52 (3.8%) | 5/50 (10%) | |||||||
Skin Mass | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Skin Ulcer | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 2/52 (3.8%) | 1/50 (2%) | |||||||
Onychoclasis | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 3/50 (6%) | |||||||
Acne | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 3/51 (5.9%) | 1/52 (1.9%) | 3/50 (6%) | |||||||
Vascular disorders | ||||||||||||||
Aortic Dilatation | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 0/52 (0%) | 0/50 (0%) | |||||||
Deep Vein Thrombosis | 0/7 (0%) | 1/11 (9.1%) | 0/2 (0%) | 0/0 (NaN) | 0/51 (0%) | 3/52 (5.8%) | 0/50 (0%) | |||||||
Hypertension | 5/7 (71.4%) | 4/11 (36.4%) | 0/2 (0%) | 0/0 (NaN) | 21/51 (41.2%) | 26/52 (50%) | 5/50 (10%) | |||||||
Hypotension | 1/7 (14.3%) | 3/11 (27.3%) | 0/2 (0%) | 0/0 (NaN) | 3/51 (5.9%) | 1/52 (1.9%) | 0/50 (0%) | |||||||
Hot Flush | 0/7 (0%) | 0/11 (0%) | 0/2 (0%) | 0/0 (NaN) | 1/51 (2%) | 3/52 (5.8%) | 0/50 (0%) |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Eisai Medical Services |
---|---|
Organization | Eisai Medical Inc. |
Phone | 1-888-422-4743 |
- E7080-G000-205