Carcinoma, Renal Cell
Conditions
Keywords
lenvatinib, Everolimus, Carcinoma, Unresectable advanced renal cell carcinoma, Metastatic renal cell carcinoma
Brief summary
Phase 1 study to investigate the tolerability and safety of lenvatinib in combination with Everolimus in participants with unresectable advanced or metastatic RCC.
Interventions
DRUGLenvatinib
DRUGEverolimus
Sponsors
Eisai Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Voluntary agreement to provide written informed consent of this study. 2. Willing and able to comply with all aspects of the protocol after being fully informed of the content. 3. Males or females aged greater than or equal to 20 years at the time of informed consent. 4. Histological or cytological confirmation of RCC. 5. Participants must have confirmed diagnosis of unresectable advanced and/or metastatic RCC. 6. Disease progression following vascular endothelial growth factor (VEGF) targeted therapy. 7. Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 to 1. 8. Adequately controlled blood pressure with or without the use of antihypertensive agents. 9. Participants with adequate function of major organs. 10. Adequate blood coagulation function, defined as international normalized ratio (INR) less than or equal to 1.5. 11. Survival expectation of 3 months or longer after study enrollment. 12. Participants with adequate washout period from the end of prior treatment to the start of study drug administration. 13. Females of childbearing potential must not have had unprotected sexual intercourse within 28 days before participant registration and must agree to use a highly effective method of contraception throughout the entire study period and for 30 days after final administration of investigational drug. If currently abstinent, the participant must agree to use a double-barrier method as described above if she becomes sexually active during this study period or for 30 days after investigational drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before administration and must continue to use the same contraceptive during this study and for 30 days after investigational drug discontinuation. 14. Male participants and their female partners must meet the criteria above.
Exclusion criteria
1. Participants with central nervous system (CNS) metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (example, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment. 2. Prior exposure to lenvatinib. 3. Participants who have not recovered from toxicities to less than or equal to Grade 1 as a result of prior anticancer therapy, except alopecia. 4. Major surgery within 3 weeks prior to the first dose of lenvatinib. 5. Participants with a urine protein greater than or equal to 1 gram per 24 hours (g/24 hours). 6. Uncontrollable diabetes as defined by fasting glucose greater than 1.5\* upper limit of normal (ULN). 7. Fasting total cholesterol greater than 7.75 millimole per liter (mmol/L) (greater than 300 milligram per decilitre \[mg/dL\]). 8. Fasting triglycerides greater than 2.5 \* ULN. 9. Any condition that might affect the absorption of lenvatinib and/or everolimus. 10. Significant cardiovascular impairment. 11. Bleeding or thrombotic disorders or use of anticoagulants requiring therapeutic INR monitoring. 12. Active hemoptysis. 13. Active infections that require systemic treatment. 14. Human immunodeficiency virus (HIV) positive. 15. Hepatitis B virus (HBV). 16. A history of interstitial pneumonia with clinical manifestation or as confirmed by means of diagnostic imaging. 17. Medical need for the continued use of potent or moderate inhibitors of cytochrome P450 3A (CYP3A) or P-gp, or potent or moderate inducer of CYP3A. 18. Known intolerance to lenvatinib (or any of the excipients) or known hypersensitivity to everolimus (or any of the excipients) or rapmycins (sirolimus, temsirolimus and so on). 19. Alcohol or drug dependency or abuse, inability to comply with every aspects of the study protocol, or any physical or mental conditions that in the opinion of the investigators would preclude the participant's participation in the study. 20. Females who are pregnant or breastfeeding (not eligible even she discontinues breastfeeding). 21. Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT) | From first dose of study drug up to Cycle 1 Day 28 (Cycle length=28 days) | DLT was defined as toxicity related to the combination therapy and was graded according to Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03). |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Baseline up to 30 days after the last dose of study drug (up to approximately 21.5 months) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Levatinib and Everolimus | Cycle 1 Day 1 predose and at 1, 2, 4 ,8, and 24 hours postdose (Cycle length=28 days) | — |
| Tss,Max: Time to Reach the Maximum Plasma Concentration (Cmax) at Steady State for Levatinib and Everolimus | Cycle 1 Day 15 predose and at 1, 2, 4 ,8, and 24 hours postdose (Cycle length=28 days) | — |
| AUC 0-t: Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration for Levatinib and Everolimus | Cycle 1 Day 1 and Cycle 1 Day 15 predose and at 1, 2, 4 ,8, and 24 hours postdose (Cycle length=28 days) | — |
| Cmax: Maximum Observed Plasma Concentration for Levatinib and Everolimus | Cycle 1 Day 1 predose and at 1, 2, 4 ,8, and 24 hours postdose (Cycle length=28 days) | — |
| Objective Response Rate (ORR) | From first dose of study drug until PD, development of unacceptable toxicity, participant requests to discontinue, withdrawal of consent or study termination (up to approximately 23 months) | ORR was defined as the percentage of participants who achieved BOR of CR or PR. ORR was assessed using RECIST 1.1. |
| Disease Control Rate (DCR) | From first dose of study drug until PD, development of unacceptable toxicity, participant requests to discontinue, withdrawal of consent or study termination (up to approximately 23 months) | DCR was defined as the percentage of participants who achieved BOR of CR, PR, or SD. DCR was assessed based on RECIST 1.1. |
| Number of Participants With the Minimum Percent Change From Baseline in the Sum of Diameters of Target Lesions | Baseline up to first tumor assessment at which diameter of target lesions were available (up to approximately 23 months) | — |
| Number of Participants With Best Overall Response (BOR) | From first dose of study drug until PD, development of unacceptable toxicity, participant requests to discontinue, withdrawal of consent or study termination (up to approximately 23 months) | BOR included complete response (CR), partial response (PR), stable disease (SD), and PD (progressive disease). BOR was assessed using Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 |
| Css,Max: Maximum Observed Plasma Concentration at Steady State for Levatinib and Everolimus | Cycle 1 Day 15 predose and at 1, 2, 4 ,8, and 24 hours postdose (Cycle length=28 days) | — |
Countries
Japan
Participant flow
Recruitment details
Participants took part in the study at 3 sites in Japan from 01 July 2015 to 29 May 2017.
Pre-assignment details
A total of 9 participants were screened, of which 7 were enrolled and treated in the study.
Participants by arm
| Arm | Count |
|---|---|
| Lenvatinib 18 mg + Everolimus 5 mg Participants received lenvatinib 18 mg capsules along with everolimus 5 mg tablets, orally, once daily in 28-days treatment cycles up to disease progression, development of unacceptable toxicity, participant's request to discontinue, withdrawal of consent, or study termination by sponsor (up to 23 cycles). | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Incomplete DLT Evaluation | 1 |
Baseline characteristics
| Characteristic | Lenvatinib 18 mg + Everolimus 5 mg |
|---|---|
| Age, Continuous | 65.7 years STANDARD_DEVIATION 6.29 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 7 |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 3 / 7 |
Outcome results
Primary
Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT)
DLT was defined as toxicity related to the combination therapy and was graded according to Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Time frame: From first dose of study drug up to Cycle 1 Day 28 (Cycle length=28 days)
Population: The DLT analysis set was the group of participants who had completed treatment Cycle 1 without major protocol deviation with a treatment compliance of at least 75 percent (%) and had been assessed for DLT, and participants who had experienced DLT during Cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib 18 mg + Everolimus 5 mg | Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT) | 0 participants |
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time frame: Baseline up to 30 days after the last dose of study drug (up to approximately 21.5 months)
Population: The safety analysis set was the group of participants who received at least 1 dose of lenvatinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenvatinib 18 mg + Everolimus 5 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 7 participants |
| Lenvatinib 18 mg + Everolimus 5 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAE | 3 participants |
Secondary
AUC 0-t: Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration for Levatinib and Everolimus
Time frame: Cycle 1 Day 1 and Cycle 1 Day 15 predose and at 1, 2, 4 ,8, and 24 hours postdose (Cycle length=28 days)
Population: The PK analysis set was group of participants who received at least 1 dose of lenvatinib and had sufficient data from which at least one PK parameter could be calculated. The PK analysis set where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lenvatinib 18 mg + Everolimus 5 mg | AUC 0-t: Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration for Levatinib and Everolimus | Lenvatinib: Cycle 1 Day 1 | 2770 hour * nanogram per milliliter (h*ng/mL) | Standard Deviation 1090 |
| Lenvatinib 18 mg + Everolimus 5 mg | AUC 0-t: Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration for Levatinib and Everolimus | Everolimus: Cycle 1 Day 1 | 211 hour * nanogram per milliliter (h*ng/mL) | Standard Deviation 115 |
| Lenvatinib 18 mg + Everolimus 5 mg | AUC 0-t: Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration for Levatinib and Everolimus | Lenvatinib: Cycle 1 Day 15 | 3220 hour * nanogram per milliliter (h*ng/mL) | Standard Deviation 1080 |
| Lenvatinib 18 mg + Everolimus 5 mg | AUC 0-t: Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration for Levatinib and Everolimus | Everolimus: Cycle 1 Day 15 | 401 hour * nanogram per milliliter (h*ng/mL) | Standard Deviation 128 |
Secondary
Cmax: Maximum Observed Plasma Concentration for Levatinib and Everolimus
Time frame: Cycle 1 Day 1 predose and at 1, 2, 4 ,8, and 24 hours postdose (Cycle length=28 days)
Population: The pharmacokinetic (PK) analysis was group of participants who received at least 1 dose of lenvatinib and had sufficient data from which at least one PK parameter could be calculated.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lenvatinib 18 mg + Everolimus 5 mg | Cmax: Maximum Observed Plasma Concentration for Levatinib and Everolimus | Lenvatinib: Cycle 1 Day 1 | 289 nanogram per milliliter (ng/mL) | Standard Deviation 136 |
| Lenvatinib 18 mg + Everolimus 5 mg | Cmax: Maximum Observed Plasma Concentration for Levatinib and Everolimus | Everolimus: Cycle 1 Day 1 | 39.1 nanogram per milliliter (ng/mL) | Standard Deviation 18.7 |
Secondary
Css,Max: Maximum Observed Plasma Concentration at Steady State for Levatinib and Everolimus
Time frame: Cycle 1 Day 15 predose and at 1, 2, 4 ,8, and 24 hours postdose (Cycle length=28 days)
Population: The PK analysis was group of participants who received at least 1 dose of lenvatinib and had sufficient data from which at least one PK parameter could be calculated. The PK analysis set where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lenvatinib 18 mg + Everolimus 5 mg | Css,Max: Maximum Observed Plasma Concentration at Steady State for Levatinib and Everolimus | Lenvatinib: Cycle 1 Day 15 | 257 ng/mL | Standard Deviation 112 |
| Lenvatinib 18 mg + Everolimus 5 mg | Css,Max: Maximum Observed Plasma Concentration at Steady State for Levatinib and Everolimus | Everolimus: Cycle 1 Day 15 | 41.5 ng/mL | Standard Deviation 19.3 |
Secondary
Disease Control Rate (DCR)
DCR was defined as the percentage of participants who achieved BOR of CR, PR, or SD. DCR was assessed based on RECIST 1.1.
Time frame: From first dose of study drug until PD, development of unacceptable toxicity, participant requests to discontinue, withdrawal of consent or study termination (up to approximately 23 months)
Population: The efficacy analysis set was the group of participants who received at least 1 dose of lenvatinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib 18 mg + Everolimus 5 mg | Disease Control Rate (DCR) | 85.7 percentage of participants |
Secondary
Number of Participants With Best Overall Response (BOR)
BOR included complete response (CR), partial response (PR), stable disease (SD), and PD (progressive disease). BOR was assessed using Response Evaluation Criteria in Solid Tumor (RECIST) 1.1
Time frame: From first dose of study drug until PD, development of unacceptable toxicity, participant requests to discontinue, withdrawal of consent or study termination (up to approximately 23 months)
Population: The efficacy analysis set was the group of participants who received at least 1 dose of lenvatinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenvatinib 18 mg + Everolimus 5 mg | Number of Participants With Best Overall Response (BOR) | CR | 0 participants |
| Lenvatinib 18 mg + Everolimus 5 mg | Number of Participants With Best Overall Response (BOR) | PR | 5 participants |
| Lenvatinib 18 mg + Everolimus 5 mg | Number of Participants With Best Overall Response (BOR) | SD | 1 participants |
| Lenvatinib 18 mg + Everolimus 5 mg | Number of Participants With Best Overall Response (BOR) | PD | 1 participants |
Secondary
Number of Participants With the Minimum Percent Change From Baseline in the Sum of Diameters of Target Lesions
Time frame: Baseline up to first tumor assessment at which diameter of target lesions were available (up to approximately 23 months)
Population: The efficacy analysis set was the group of participants who received at least 1 dose of lenvatinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenvatinib 18 mg + Everolimus 5 mg | Number of Participants With the Minimum Percent Change From Baseline in the Sum of Diameters of Target Lesions | Less than or equal to (<=) -30% | 5 participants |
| Lenvatinib 18 mg + Everolimus 5 mg | Number of Participants With the Minimum Percent Change From Baseline in the Sum of Diameters of Target Lesions | Greater than (>) -30% to less than (<) 20% | 1 participants |
| Lenvatinib 18 mg + Everolimus 5 mg | Number of Participants With the Minimum Percent Change From Baseline in the Sum of Diameters of Target Lesions | Greater than or equal to (>=) 20% | 1 participants |
Secondary
Objective Response Rate (ORR)
ORR was defined as the percentage of participants who achieved BOR of CR or PR. ORR was assessed using RECIST 1.1.
Time frame: From first dose of study drug until PD, development of unacceptable toxicity, participant requests to discontinue, withdrawal of consent or study termination (up to approximately 23 months)
Population: The efficacy analysis set was the group of participants who received at least 1 dose of lenvatinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib 18 mg + Everolimus 5 mg | Objective Response Rate (ORR) | 71.4 percentage of participants |
Secondary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Levatinib and Everolimus
Time frame: Cycle 1 Day 1 predose and at 1, 2, 4 ,8, and 24 hours postdose (Cycle length=28 days)
Population: The PK analysis was group of participants who received at least 1 dose of lenvatinib and had sufficient data from which at least one PK parameter could be calculated.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Lenvatinib 18 mg + Everolimus 5 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Levatinib and Everolimus | Lenvatinib: Cycle 1 Day 1 | 3.87 hour |
| Lenvatinib 18 mg + Everolimus 5 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Levatinib and Everolimus | Everolimus: Cycle 1 Day 1 | 0.92 hour |
Secondary
Tss,Max: Time to Reach the Maximum Plasma Concentration (Cmax) at Steady State for Levatinib and Everolimus
Time frame: Cycle 1 Day 15 predose and at 1, 2, 4 ,8, and 24 hours postdose (Cycle length=28 days)
Population: The PK analysis was group of participants who received at least 1 dose of lenvatinib and had sufficient data from which at least one PK parameter could be calculated. The PK analysis set where data at specified time points was available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Lenvatinib 18 mg + Everolimus 5 mg | Tss,Max: Time to Reach the Maximum Plasma Concentration (Cmax) at Steady State for Levatinib and Everolimus | Lenvatinib: Cycle 1 Day 15 | 3.77 hour |
| Lenvatinib 18 mg + Everolimus 5 mg | Tss,Max: Time to Reach the Maximum Plasma Concentration (Cmax) at Steady State for Levatinib and Everolimus | Everolimus: Cycle 1 Day 15 | 0.97 hour |