Metastatic Renal Cell Carcinoma
Conditions
Keywords
Unresectable advanced or metastatic renal cell carcinoma
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.
Interventions
DRUGLenvatinib
taken orally, once a day
DRUGEverolimus
taken orally, once a day
Sponsors
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Czechia, Poland, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 173 participants were enrolled into the study and treated.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus 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. | 7 |
| Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus 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. | 11 |
| Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus 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. | 2 |
| Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus The DLT was achieved and no participants were enrolled into this cohort. | 0 |
| Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus 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. | 51 |
| Phase 2 (Arm B): 24 mg Lenvatinib 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. | 52 |
| Phase 2 (Arm C): 10 mg Everolimus 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. | 50 |
| Total | 173 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Phase 1b | Administrative-Withdrew Consent | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Phase 1b | Adverse Event | 0 | 3 | 1 | 0 | 0 | 0 | 0 |
| Phase 1b | Clinical Progression | 1 | 1 | 0 | 0 | 0 | 0 | 0 |
| Phase 1b | Participant Choice | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Phase 2 | Administrative-Withdrew Consent | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Phase 2 | Adverse Event | 0 | 0 | 0 | 0 | 11 | 13 | 5 |
| Phase 2 | Disease Progression | 0 | 0 | 0 | 0 | 30 | 32 | 38 |
| Phase 2 | Other | 0 | 0 | 0 | 0 | 6 | 7 | 6 |
| Phase 2 | Participant Choice | 0 | 0 | 0 | 0 | 3 | 0 | 1 |
Baseline characteristics
| Characteristic | 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 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 |
|---|---|---|---|---|---|---|---|
| Age, Customized Phase 1b | 58.0 Years STANDARD_DEVIATION 3.92 | 58.1 Years STANDARD_DEVIATION 7.97 | 61.0 Years STANDARD_DEVIATION 2.83 | 0 Years STANDARD_DEVIATION 0 | 0 Years STANDARD_DEVIATION 0 | 0 Years STANDARD_DEVIATION 0 | 58.4 Years STANDARD_DEVIATION 6.29 |
| Age, Customized Phase 2 | 0 Years STANDARD_DEVIATION 0 | 0 Years STANDARD_DEVIATION 0 | 0 Years STANDARD_DEVIATION 0 | 61.7 Years STANDARD_DEVIATION 8.2 | 63.3 Years STANDARD_DEVIATION 8.6 | 58.9 Years STANDARD_DEVIATION 9.2 | 61.3 Years STANDARD_DEVIATION 8.8 |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 1 Participants | 16 Participants | 13 Participants | 12 Participants | 47 Participants |
| Sex: Female, Male Male | 4 Participants | 9 Participants | 1 Participants | 35 Participants | 39 Participants | 38 Participants | 126 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 7 | 9 / 11 | 0 / 2 | 0 / 0 | 43 / 51 | 40 / 52 | 45 / 50 |
| other Total, other adverse events | 7 / 7 | 11 / 11 | 2 / 2 | 0 / 0 | 51 / 51 | 51 / 52 | 50 / 50 |
| serious Total, serious adverse events | 6 / 7 | 8 / 11 | 0 / 2 | 0 / 0 | 30 / 51 | 28 / 52 | 21 / 50 |
Outcome results
Primary
Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2) Dose
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)
Population: Safety analysis set included all participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2) Dose | 18.0 mg/day |
Primary
Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT)
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)
Population: Safety analysis set included all participants who received at least one dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT) | Grade 2 fatigue with Grade 1 GI reflux & anorexia | 0 Participants |
| Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT) | Grade 3 abdominal pain | 1 Participants |
| Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT) | Grade 3 nausea | 0 Participants |
| Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT) | Grade 2 stomatitis | 0 Participants |
| Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT) | Grade 2 stomatitis | 0 Participants |
| Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT) | Grade 3 abdominal pain | 0 Participants |
| Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT) | Grade 2 fatigue with Grade 1 GI reflux & anorexia | 1 Participants |
| Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT) | Grade 3 nausea | 0 Participants |
| Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT) | Grade 2 stomatitis | 1 Participants |
| Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT) | Grade 3 nausea | 1 Participants |
| Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT) | Grade 3 abdominal pain | 0 Participants |
| Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT) | Grade 2 fatigue with Grade 1 GI reflux & anorexia | 0 Participants |
Primary
Phase 2: Progression-Free Survival (PFS)
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
Population: Full analysis set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 2: Progression-Free Survival (PFS) | 14.6 Months |
| Phase 2 (Arm B): 24 mg Lenvatinib | Phase 2: Progression-Free Survival (PFS) | 7.4 Months |
| Phase 2 (Arm C): 10 mg Everolimus | Phase 2: Progression-Free Survival (PFS) | 5.5 Months |
Comparison: 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.p-value: =0.000595% CI: [0.24, 0.68]Log Rank
p-value: 0.047995% CI: [0.38, 0.98]Log Rank
p-value: 0.120995% CI: [0.39, 1.1]Log Rank
Secondary
Area Under the Blood Concentration-Time Curve From 0 to 24 Hours for Everolimus When Administered Alone or in Combination With Lenvatinib
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)
Population: PK sub analysis set. n=8 for AUC(0-24)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Area Under the Blood Concentration-Time Curve From 0 to 24 Hours for Everolimus When Administered Alone or in Combination With Lenvatinib | 378 ng·hr/mL | Standard Deviation 88.1 |
| Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Area Under the Blood Concentration-Time Curve From 0 to 24 Hours for Everolimus When Administered Alone or in Combination With Lenvatinib | 463 ng·hr/mL | Standard Deviation 263 |
Secondary
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
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)
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | 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 | 3185 ng·hr/mL | Standard Deviation 1030 |
| Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | 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 | 5252 ng·hr/mL | Standard Deviation 2717 |
Secondary
Clinical Benefit Rate (CBR)
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
Population: Full analysis set which included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Clinical Benefit Rate (CBR) | 68.6 Percentage of participants |
| Phase 2 (Arm B): 24 mg Lenvatinib | Clinical Benefit Rate (CBR) | 65.4 Percentage of participants |
| Phase 2 (Arm C): 10 mg Everolimus | Clinical Benefit Rate (CBR) | 42.0 Percentage of participants |
Secondary
Disease Control Rate (DCR)
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
Population: Full analysis set which included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Disease Control Rate (DCR) | 84.3 Percentage of participants |
| Phase 2 (Arm B): 24 mg Lenvatinib | Disease Control Rate (DCR) | 78.8 Percentage of participants |
| Phase 2 (Arm C): 10 mg Everolimus | Disease Control Rate (DCR) | 68.0 Percentage of participants |
Secondary
Durable Stable Disease (SD) Rate
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
Population: Full analysis set which included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Durable Stable Disease (SD) Rate | 25.5 Percentage of participants |
| Phase 2 (Arm B): 24 mg Lenvatinib | Durable Stable Disease (SD) Rate | 38.5 Percentage of participants |
| Phase 2 (Arm C): 10 mg Everolimus | Durable Stable Disease (SD) Rate | 36.0 Percentage of participants |
Secondary
Maximum Concentration (Cmax) of Lenvatinib in Plasma When Administered Alone or in Combination With Everolimus
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
Population: PK sub analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Maximum Concentration (Cmax) of Lenvatinib in Plasma When Administered Alone or in Combination With Everolimus | 327 ng/mL | Standard Deviation 179 |
| Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Maximum Concentration (Cmax) of Lenvatinib in Plasma When Administered Alone or in Combination With Everolimus | 403 ng/mL | Standard Deviation 165 |
Secondary
Maximum Concentration of Everolimus (Cmax) in Blood When Administered Alone or in Combination With Lenvatinib
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
Population: PK sub analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Maximum Concentration of Everolimus (Cmax) in Blood When Administered Alone or in Combination With Lenvatinib | 38 ng/mL | Standard Deviation 14.5 |
| Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Maximum Concentration of Everolimus (Cmax) in Blood When Administered Alone or in Combination With Lenvatinib | 54 ng/mL | Standard Deviation 24.9 |
Secondary
Phase 2: Objective Response Rate (ORR)
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
Population: Full analysis set which included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 2: Objective Response Rate (ORR) | 43.1 Percentage of participants |
| Phase 2 (Arm B): 24 mg Lenvatinib | Phase 2: Objective Response Rate (ORR) | 26.9 Percentage of participants |
| Phase 2 (Arm C): 10 mg Everolimus | Phase 2: Objective Response Rate (ORR) | 6.0 Percentage of participants |
p-value: <0.000195% CI: [2.3, 22.5]Fisher Exact
p-value: 0.006795% CI: [1.4, 14.7]Fisher Exact
p-value: =0.100795% CI: [0.9, 2.8]Fisher Exact
Secondary
Phase 2: Overall Survival (OS)
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
Population: Full analysis set which included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Phase 2: Overall Survival (OS) | 25.5 Months |
| Phase 2 (Arm B): 24 mg Lenvatinib | Phase 2: Overall Survival (OS) | 19.1 Months |
| Phase 2 (Arm C): 10 mg Everolimus | Phase 2: Overall Survival (OS) | 15.4 Months |
Comparison: 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.p-value: =0.024295% CI: [0.299, 0.884]Log Rank
p-value: =0.118195% CI: [0.411, 1.138]Log Rank
p-value: =0.315795% CI: [0.433, 1.301]Log Rank
Secondary
Summary of Blood Concentrations of Everolimus for Sparse PK Sampling for Phase 1b and Phase 2
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)
Population: Pharmacokinetic analysis set included all participants who received at least one dose of study drug (lenvatinib or everolimus) and had evaluable concentration data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Summary of Blood Concentrations of Everolimus for Sparse PK Sampling for Phase 1b and Phase 2 | 0.0 ng/mL | Standard Deviation 0 |
| Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Summary of Blood Concentrations of Everolimus for Sparse PK Sampling for Phase 1b and Phase 2 | 19.4 ng/mL | Standard Deviation 9.16 |
| Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Summary of Blood Concentrations of Everolimus for Sparse PK Sampling for Phase 1b and Phase 2 | 10.0 ng/mL | Standard Deviation 7.28 |
| Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus | Summary of Blood Concentrations of Everolimus for Sparse PK Sampling for Phase 1b and Phase 2 | 24.3 ng/mL | Standard Deviation 14.2 |
| Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Summary of Blood Concentrations of Everolimus for Sparse PK Sampling for Phase 1b and Phase 2 | 6.8 ng/mL | Standard Deviation 6.06 |
| Phase 2 (Arm B): 24 mg Lenvatinib | Summary of Blood Concentrations of Everolimus for Sparse PK Sampling for Phase 1b and Phase 2 | 26.4 ng/mL | Standard Deviation 14.8 |
Secondary
Summary of Plasma Concentrations of Lenvatinib for Sparse Pharmacokinetic (PK) Sampling for Phase 1b and Phase 2
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)
Population: 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 | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Summary of Plasma Concentrations of Lenvatinib for Sparse Pharmacokinetic (PK) Sampling for Phase 1b and Phase 2 | 5.6 ng/mL | Standard Deviation 29.8 |
| Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Summary of Plasma Concentrations of Lenvatinib for Sparse Pharmacokinetic (PK) Sampling for Phase 1b and Phase 2 | 197 ng/mL | Standard Deviation 140 |
| Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | Summary of Plasma Concentrations of Lenvatinib for Sparse Pharmacokinetic (PK) Sampling for Phase 1b and Phase 2 | 66.9 ng/mL | Standard Deviation 52.7 |
| Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus | Summary of Plasma Concentrations of Lenvatinib for Sparse Pharmacokinetic (PK) Sampling for Phase 1b and Phase 2 | 237 ng/mL | Standard Deviation 154 |
| Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | Summary of Plasma Concentrations of Lenvatinib for Sparse Pharmacokinetic (PK) Sampling for Phase 1b and Phase 2 | 37.0 ng/mL | Standard Deviation 35.5 |
| Phase 2 (Arm B): 24 mg Lenvatinib | Summary of Plasma Concentrations of Lenvatinib for Sparse Pharmacokinetic (PK) Sampling for Phase 1b and Phase 2 | 180 ng/mL | Standard Deviation 118 |
Secondary
Time to Cmax (Tmax) for Everolimus When Administered Alone or in Combination With Lenvatinib
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
Population: PK sub analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Time to Cmax (Tmax) for Everolimus When Administered Alone or in Combination With Lenvatinib | 1.0 Hours |
| Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Time to Cmax (Tmax) for Everolimus When Administered Alone or in Combination With Lenvatinib | 1.0 Hours |
Secondary
Time to Cmax (Tmax) for Lenvatinib When Administered Alone or in Combination With Everolimus
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
Population: PK sub analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | Time to Cmax (Tmax) for Lenvatinib When Administered Alone or in Combination With Everolimus | 2.0 Hours |
| Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | Time to Cmax (Tmax) for Lenvatinib When Administered Alone or in Combination With Everolimus | 4.0 Hours |