A Phase 1/2 interventional study of Lenvatinib and Everolimus in Metastatic Renal Cell Carcinoma, sponsored by Eisai Inc.. Completed at 37 sites in 5 countries. Open to participants aged 18 Years to 99 Years. Per ClinicalTrials.gov, last updated 2019-02-27.
Sponsored by Eisai Inc. · Phase 1/2, Interventional, and Treatment
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.
1,992 studies on the registry are indexed under Carcinoma, Renal Cell; 387 are open to participants now.
This study's enrollment of 173 is above the median of 42 across 1,501 interventional studies indexed under Carcinoma, Renal Cell.
Browse Carcinoma, Renal Cell studies →Eisai Inc. is the lead sponsor of 368 studies on the registry; 7 are open to participants now.
Of its 83 completed or terminated interventional studies of FDA-regulated products, 56 (67%) have results posted.
Counted across the registry records on this site, refreshed daily.
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Phase 1b or Phase 2 specific per below:
Phase 1b or Phase 2 specific per below:
Drug: Lenvatinib
Drug: Lenvatinib · Drug: Everolimus
Drug: Everolimus
taken orally, once a day
Also known as: E7080, Lenvima, Kisplyx
taken orally, once a day
Also known as: Afinitor
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)
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)
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
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
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
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
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
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
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)
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)
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)
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
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
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)
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
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
| Milestone | 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 |
|---|---|---|---|---|---|---|---|
| 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 |
| Withdrew: Adverse event | 0 | 3 | 1 | 0 | 0 | 0 | 0 |
| Withdrew: Participant choice | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Withdrew: Administrative-withdrew consent | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Clinical progression | 1 | 1 | 0 | 0 | 0 | 0 | 0 |
| Milestone | 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 |
|---|---|---|---|---|---|---|---|
| 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 |
| Withdrew: Disease progression | 0 | 0 | 0 | 0 | 30 | 32 | 38 |
| Withdrew: Adverse event | 0 | 0 | 0 | 0 | 11 | 13 | 5 |
| Withdrew: Participant choice | 0 | 0 | 0 | 0 | 3 | 0 | 1 |
| Withdrew: Administrative-withdrew consent | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Withdrew: Other | 0 | 0 | 0 | 0 | 6 | 7 | 6 |
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.
| Participants | 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 |
|---|---|---|---|---|---|---|---|
| Grade 3 abdominal pain | 1 | 0 | 0 | — | — | — | — |
| Grade 2 fatigue with Grade 1 GI reflux & anorexia | 0 | 1 | 0 | — | — | — | — |
| Grade 3 nausea | 0 | 0 | 1 | — | — | — | — |
| Grade 2 stomatitis | 0 | 0 | 1 | — | — | — | — |
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.
| mg/day | Phase 1b: Dose Escalation and MTD Expansion Cohorts |
|---|---|
| Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2) Dose | 18.0 |
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.
| Months | 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 |
|---|---|---|---|---|---|---|---|
| Phase 2: Progression-Free Survival (PFS) | — | — | — | — | 14.6 (5.9 to 20.1) | 7.4 (5.6 to 10.2) | 5.5 (3.5 to 7.1) |
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.
| Months | 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 |
|---|---|---|---|---|---|---|---|
| Phase 2: Overall Survival (OS) | — | — | — | — | 25.5 (16.4 to NA) | 19.1 (13.6 to 26.2) | 15.4 (11.8 to 19.6) |
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.
| Percentage of participants | 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 |
|---|---|---|---|---|---|---|---|
| Phase 2: Objective Response Rate (ORR) | — | — | — | — | 43.1 (29.3 to 57.8) | 26.9 (15.6 to 41.0) | 6.0 (1.3 to 16.5) |
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.
| Percentage of participants | 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 |
|---|---|---|---|---|---|---|---|
| Disease Control Rate (DCR) | — | — | — | — | 84.3 (71.4 to 93.0) | 78.8 (65.3 to 88.9) | 68.0 (53.3 to 80.5) |
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.
| Percentage of participants | 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 |
|---|---|---|---|---|---|---|---|
| Durable Stable Disease (SD) Rate | — | — | — | — | 25.5 (14.3 to 39.6) | 38.5 (25.3 to 53.0) | 36.0 (22.9 to 50.8) |
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.
| Percentage of participants | 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 |
|---|---|---|---|---|---|---|---|
| Clinical Benefit Rate (CBR) | — | — | — | — | 68.6 (54.1 to 80.9) | 65.4 (50.9 to 78.0) | 42.0 (28.2 to 56.8) |
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.
| ng/mL | 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) |
|---|---|---|---|---|---|---|
| Summary of Plasma Concentrations of Lenvatinib for Sparse Pharmacokinetic (PK) Sampling for Phase 1b and Phase 2 | 5.6 ± 29.8 | 197 ± 140 | 66.9 ± 52.7 | 237 ± 154 | 37.0 ± 35.5 | 180 ± 118 |
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.
| ng/mL | 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) |
|---|---|---|---|---|---|---|
| Summary of Blood Concentrations of Everolimus for Sparse PK Sampling for Phase 1b and Phase 2 | 0.0 ± 0.00 | 19.4 ± 9.16 | 10.0 ± 7.28 | 24.3 ± 14.2 | 6.8 ± 6.06 | 26.4 ± 14.8 |
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.
| ng·hr/mL | Phase 2: 18 mg Lenvatinib + 5 mg Everolimus | Phase 2: 24 mg Lenvatinib |
|---|---|---|
| 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 ± 1030 | 5252 ± 2717 |
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.
| ng/mL | Phase 2: 18 mg Lenvatinib + 5 mg Everolimus | Phase 2: 24 mg Lenvatinib |
|---|---|---|
| Maximum Concentration (Cmax) of Lenvatinib in Plasma When Administered Alone or in Combination With Everolimus | 327 ± 179 | 403 ± 165 |
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.
| Hours | Phase 2: 18 mg Lenvatinib + 5 mg Everolimus | Phase 2: 24 mg Lenvatinib |
|---|---|---|
| Time to Cmax (Tmax) for Lenvatinib When Administered Alone or in Combination With Everolimus | 2.0 (2.0 to 8.2) | 4.0 (0.5 to 8.0) |
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.
| ng·hr/mL | Phase 2: 18 mg Lenvatinib + 5 mg Everolimus | Phase 2: 10 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 ± 88.1 | 463 ± 263 |
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.
| ng/mL | Phase 2: 18 mg Lenvatinib + 5 mg Everolimus | Phase 2: 10 mg Everolimus |
|---|---|---|
| Maximum Concentration of Everolimus (Cmax) in Blood When Administered Alone or in Combination With Lenvatinib | 38 ± 14.5 | 54 ± 24.9 |
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.
| Hours | Phase 2: 18 mg Lenvatinib + 5 mg Everolimus | Phase 2: 10 mg Everolimus |
|---|---|---|
| Time to Cmax (Tmax) for Everolimus When Administered Alone or in Combination With Lenvatinib | 1.0 (0.5 to 8.0) | 1.0 (0.5 to 25.9) |
Collected over 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.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus | 6/7 (85.7%) | 6/7 (85.7%) | 7/7 (100%) |
| Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus | 9/11 (81.8%) | 8/11 (72.7%) | 11/11 (100%) |
| Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus | 0/2 (0%) | 0/2 (0%) | 2/2 (100%) |
| Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus | — | — | — |
| Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus | 43/51 (84.3%) | 30/51 (58.8%) | 51/51 (100%) |
| Phase 2 (Arm B): 24 mg Lenvatinib | 40/52 (76.9%) | 28/52 (53.8%) | 51/52 (98.1%) |
| Phase 2 (Arm C): 10 mg Everolimus | 45/50 (90%) | 21/50 (42%) | 50/50 (100%) |
| Event | 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 |
|---|---|---|---|---|---|---|---|
| HyponatraemiaMetabolism and nutrition disorders | 2/7 | 0/11 | 0/2 | — | 0/51 | 0/52 | 0/50 |
| DehydrationMetabolism and nutrition disorders | 0/7 | 2/11 | 0/2 | — | 4/51 | 0/52 | 0/50 |
| Renal Failure AcuteRenal and urinary disorders | 1/7 | 2/11 | 0/2 | — | 3/51 | 4/52 | 0/50 |
| Abdominal PainGastrointestinal disorders | 1/7 | 0/11 | 0/2 | — | 0/51 | 2/52 | 0/50 |
| FatigueGeneral disorders | 1/7 | 0/11 | 0/2 | — | 1/51 | 1/52 | 0/50 |
| General Physical Health DeteriorationGeneral disorders | 1/7 | 0/11 | 0/2 | — | 2/51 | 0/52 | 0/50 |
| Non-Cardiac Chest PainGeneral disorders | 1/7 | 0/11 | 0/2 | — | 0/51 | 0/52 | 1/50 |
| CholangitisHepatobiliary disorders | 1/7 | 0/11 | 0/2 | — | 1/51 | 0/52 | 0/50 |
| Metastatic PainNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/7 | 0/11 | 0/2 | — | 0/51 | 1/52 | 0/50 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 1/7 | 1/11 | 0/2 | — | 2/51 | 1/52 | 2/50 |
| Event | 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 |
|---|---|---|---|---|---|---|---|
| StomatitisGastrointestinal disorders | 4/7 | 7/11 | 2/2 | — | 15/51 | 13/52 | 21/50 |
| FatigueGeneral disorders | 4/7 | 11/11 | 2/2 | — | 26/51 | 21/52 | 16/50 |
| NauseaGastrointestinal disorders | 6/7 | 6/11 | 1/2 | — | 22/51 | 32/52 | 8/50 |
| CoughRespiratory, thoracic and mediastinal disorders | 6/7 | 3/11 | 0/2 | — | 20/51 | 9/52 | 16/50 |
| DiarrhoeaGastrointestinal disorders | 3/7 | 7/11 | 1/2 | — | 43/51 | 37/52 | 17/50 |
| VomitingGastrointestinal disorders | 5/7 | 5/11 | 1/2 | — | 24/51 | 20/52 | 6/50 |
| ProteinuriaRenal and urinary disorders | 5/7 | 6/11 | 0/2 | — | 13/51 | 16/52 | 7/50 |
| HypertensionVascular disorders | 5/7 | 4/11 | 0/2 | — | 21/51 | 26/52 | 5/50 |
| HypertriglyceridaemiaMetabolism and nutrition disorders | 1/7 | 7/11 | 0/2 | — | 18/51 | 7/52 | 12/50 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 1/7 | 7/11 | 1/2 | — | 11/51 | 11/52 | 11/50 |
Full analysis set included all randomized participants.
| Age, Customized(Years) | 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 |
|---|---|---|---|---|---|---|---|---|
| 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(Participants) | 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 |
|---|---|---|---|---|---|---|---|---|
| Female | 3 | 2 | 1 | — | 16 | 13 | 12 | 47 |
| Male | 4 | 9 | 1 | — | 35 | 39 | 38 | 126 |
Ran from Aug 2010 to primary completion in Jun 2014, 46 months.
Results were first posted in Feb 2019, 4 years 8 months after primary completion. A results delay was requested in Apr 2016.
Of 63 industry-sponsored phase 1/2 interventional studies under Carcinoma, Renal Cell, half reached primary completion within 67 months of starting (the median), counting those still running; a quarter within 46 and three quarters within 75. This study's 46 months is below that.
Counting every sponsor, half of 106 studies reached it within 67 months; a quarter within 45 and three quarters within 114.
How these figures are worked out, and which studies are left out of them.
This study is completed, as verified in Jan 2018. You cannot join it, but the record below documents what was studied.
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Studies of the drugs tested here: Lenvatinib · Everolimus