Phase 1b Trial of Lenvatinib Plus Pembrolizumab in Participants With Selected Solid Tumors

Study Overview
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Brief Summary
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This is an open-label Phase 1b study designed to confirm the tolerability and safety of lenvatinib in combination with pembrolizumab in participants with selected solid tumors (non-small cell lung cancer, predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, or melanoma [excluding uveal melanoma]).

Official Title
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An Open-Label Phase 1b Trial of Lenvatinib Plus Pembrolizumab in Subjects With Selected Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: lenvatinib
* Drug: pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically and/or cytologically confirmed selected solid tumor types that have progressed after treatment with standard therapies or for which there are no other appropriate therapies available. The selected tumor types are: non-small cell lung cancer, predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, or melanoma (excluding uveal melanoma) At least 1 measurable target lesion according to modified Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 Participants must have an Eastern Cooperative Oncology Group (ECOG)-Performance Status (PS) of 0 to 1. Adequate liver function as evidenced by bilirubin ≤1.5×ULN and alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3×ULN (in the case of liver metastases ≤5×ULN). In case ALP is >3×ULN (in the absence of liver metastases) or >5×ULN (in the presence of liver metastases) AND the participant also is known to have bone metastases, the liver-specific ALP must be separated from the total and used to assess the liver function instead of the total ALP. Males or females age ≥20 years at the time of informed consent Life expectancy of 12 weeks or more Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol Exclusion Criteria: Prior anticancer treatment within 28 days (or 5 times the half-life time, whichever is shorter) or any investigational agent within 28 days prior to the first dose of study drugs. All toxicities related to prior treatments must be resolved to Grade ≤1 (except alopecia). Prior treatment with lenvatinib or any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, excluding cancer types such as melanoma and non-small cell lung cancer where prior treatment with one anti-PD-1, anti-PD-L1, or anti-PD-L2 agent is allowed Participants must have recovered adequately from any complications from major surgery prior to starting therapy. New York Heart Association congestive heart failure of grade II or above, unstable angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia associated with significant cardiovascular impairment within the past 6 months Prolongation of QTc (Fridericia formula) interval to >480 milliseconds (ms) Active infection (any infection requiring systemic treatment) Participant is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C Known intolerance to either of the study drugs (or any of the excipients) History of organ allograft Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis, or has a history of interstitial lung disease Females who are breastfeeding or pregnant at Screening or Baseline. Females of childbearing potential. Participants must be on a stable dose of the same oral hormonal contraceptive product for at least 4 weeks before dosing with study drug and for the duration of the study.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lenvatinib 20 mg plus pembrolizumab 200 mg<br>Participants with selected tumors will receive oral lenvatinib at a starting dose of 20 milligrams (mg) once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks (Q3W) on a 21-day treatment cycle until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study. | Drug: lenvatinib<br>* lenvatinib capsules<br>Drug: pembrolizumab<br>* pembrolizumab intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | A TEAE was defined as an adverse event (AE) that emerged during the time from the first dose of study drug to 30 days following the last dose of study drug, having been absent at pretreatment (Baseline) or reemerged during treatment, having been present at pretreatment (Baseline) but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the AE was continuous. A Serious AE is any untoward medical occurrence that at any dose: resulted in death; was life threatening (that is, the participant was at immediate risk of death from the AE as it occurred; this does not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death) required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or is medically important due to other reasons than the above mentioned criteria. | From the first dose until 30 days after the last dose (approximately 2 years 7 months) | 
| Number of Participants With Dose-limiting Toxicities | A DLT is defined as any of the following: any of the hematological or nonhematological toxicities specified in the protocol that are considered to be at least possibly related to lenvatinib and/or pembrolizumab occurring during Cycle 1; failed to administer greater than or equal to 75 percent (%) of the planned dosage of lenvatinib as a result of treatment-related toxicity during Cycle 1; participants who discontinued due to treatment-related toxicity in Cycle 1; greater than a 2-week delay in starting pembrolizumab in Cycle 2 because of a treatment-related toxicity, even if the toxicity does not meet DLT criteria. | Cycle 1 (Cycle length=21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Based on Modified Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 | ORR was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) for target and non-target lesions. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in the short axis to less than 10 millimeter (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The tumor assessment was done using number of lesions based on modified RECIST 1.1 for assessing tumor burden up to 10 target lesions with up to 5 target lesions per organ. | From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or up to approximately 2 years 7 months | 
| Duration of Response (DOR) Based on Modified Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 | DOR was defined as time from the first documented of CR or PR to the date of first documentation of disease progression (PD) (based on modified RECIST 1.1) or death (whichever occurs first). CR was defined as the disappearance of all target lesions and non-target lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD for target lesion, was defined as a minimum 20% increase and a minimum 5 mm absolute increase in sum of diameters compared to nadir, or PD for non-target lesion(s) or unequivocal new lesion(s). Nadir was defined as lowest measure sum of diameters of target lesions at any time point from baseline onward. The tumor assessment was done using number of lesions based on modified RECIST 1.1 for assessing tumor burden up to 10 target lesions with up to 5 target lesions per organ. DOR = Date of PD/death (whichever occurs first) - Date of first CR or PR + 1. | From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or up to approximately 2 years 7 months. | 
| Cmax: Maximum Plasma Concentration of Lenvatinib in Combination With Pembrolizumab |  | Cycle 1 Day 1: 0-24 hours | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Lenvatinib in Combination With Pembrolizumab |  | Cycle 1 Day 1: 0-24 hours | 
| T1/2: Terminal Half-life of Lenvatinib in Combination With Pembrolizumab |  | Cycle 1 Day 1: 0-24 hours; Cycle 1 Day 15: 0-24 hours | 
| AUC(0-t): Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration of Lenvatinib in Combination With Pembrolizumab |  | Cycle 1 Day 1: 0-24 hours; Cycle 1 Day 15: 0-24 hours | 
| AUC(0-inf): Area Under the Concentration-time Curve From Zero (Pre-dose) Extrapolated to Infinite Time of Lenvatinib in Combination With Pembrolizumab |  | Cycle 1 Day 1: 0-24 hours | 
| Vz/F: Apparent Volume of Distribution at Terminal Phase of Lenvatinib in Combination With Pembrolizumab |  | Cycle 1 Day 1: 0-24 hours; Cycle 1 Day 15: 0-24 hours | 
| CL/F: Apparent Total Clearance Following Oral Dosing of Lenvatinib in Combination With Pembrolizumab |  | Cycle 1 Day 1: 0-24 hours | 
| MRT: Mean Residence Time of Lenvatinib in Combination With Pembrolizumab |  | Cycle 1 Day 1: 0-24 hours; Cycle 1 Day 15: 0-24 hours | 
| Css,Max: Maximum Observed Plasma Concentration at Steady State of Lenvatinib in Combination With Pembrolizumab |  | Cycle 1 Day 15: 0-24 hours | 
| Css,Min: Minimum Observed Plasma Concentration at Steady State of Lenvatinib in Combination With Pembrolizumab |  | Cycle 1 Day 15: 0-24 hours | 
| Tss,Max: Time to Reach the Maximum Plasma Concentration (Cmax) at Steady State of Lenvatinib in Combination With Pembrolizumab |  | Cycle 1 Day 15: 0-24 hours | 
| AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval of Lenvatinib in Combination With Pembrolizumab |  | Cycle 1 Day 15: 0-24 hours | 
| Clss/F: Apparent Total Clearance Following Oral Administration at Steady State of Lenvatinib in Combination With Pembrolizumab |  | Cycle 1 Day 15: 0-24 hours | 
| Css,Av: Average Steady State Plasma Concentration of Lenvatinib in Combination With Pembrolizumab |  | Cycle 1 Day 15: 0-24 hours | 
| Rac (Cmax): Accumulation Index of Cmax for Lenvatinib in Combination With Pembrolizumab | Rac (Cmax) was calculated as the ratio of drug concentrations observed during a dosing interval at steady state divided by drug concentrations seen during the dosing interval after a single (first) dose. Rac (Cmax) = Css,max on Cycle 1 Day 15 / Cmax on Cycle 1 Day 1 | Cycle 1 Day 1: 0-24 hours and Cycle 1 Day 15: 0-24 hours | 
| Rac (AUC): Accumulation Index of AUC for Lenvatinib in Combination With Pembrolizumab | Rac (AUC) was calculated as the ratio of drug concentrations observed during a dosing interval at steady state divided by drug concentrations seen during the dosing interval after a single (first) dose. Rac (AUC) = AUC(0-t) on Cycle 1 Day 15 / AUC(0-t) on Cycle 1 Day 1. | Cycle 1 Day 1: 0-24 hours and Cycle 1 Day 15: 0-24 hours | 
| Lambda z: Terminal Phase Elimination Rate Constant of Lenvatinib in Combination With Pembrolizumab |  | Cycle 1 Day 1: 0-24 hours; Cycle 1 Day 15: 0-24 hours | 
| PTF: Peak-trough Fluctuation Ratio of Lenvatinib in Combination With Pembrolizumab | The peak trough fluctuation within complete dosing interval at steady state, calculated as PTF (%) = ([Cmax - Cmin]/Cav ) multiplied by 100 | Cycle 1 Day 15: 0-24 hours | 
| Number of Participants Positive for Serum Anti-drug Antibodies (ADA) Status for Pembrolizumab |  | Day 1 of Cycles 1, 2, 4, 6, and 8 and every 4 cycles thereafter; within 30 days after discontinuation or until the initiation of other anticancer treatment, whichever is earlier (Cycle length=21 days); up to 31 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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E7080, lenvatinib, pembrolizumab, Japan, solid tumors, non-small cell lung cancer, predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, non-uveal melanoma