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

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ClinicalTrials.gov Identifier: NCT03006887
Recruitment Status : Active, not recruiting
First Posted : December 30, 2016
Last Update Posted : July 10, 2018
Sponsor:
Information provided by (Responsible Party):
Eisai Inc. ( Eisai Co., Ltd. )

Brief Summary:
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]).

Condition or disease Intervention/treatment Phase
Solid Tumors Drug: lenvatinib Drug: pembrolizumab Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label Phase 1b Trial of Lenvatinib Plus Pembrolizumab in Subjects With Selected Solid Tumors
Actual Study Start Date : January 19, 2017
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018


Arm Intervention/treatment
Experimental: lenvatinib 20 mg plus pembrolizumab 200 mg
Participants will receive oral lenvatinib at a starting dose of 20 milligrams (mg) once a day (QD) in combination with intravenous pembrolizumab 200 mg every 3 weeks (Q3W) on a 21-day treatment cycle
Drug: lenvatinib
lenvatinib capsules

Drug: pembrolizumab
pembrolizumab intravenous infusion




Primary Outcome Measures :
  1. Number of participants with any serious adverse event and number of participants with any non-serious adverse event [ Time Frame: For each participant, from the first participant first dose until 30 days after the last dose (up to approximately 2 years) ]
    An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with the medicinal product. An SAE is any untoward medical occurrence that at any dose: results in death; is life threatening (ie, 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); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug).

  2. Dose-limiting toxicity (DLT) of lenvatinib and pembrolizumab during Cycle 1 [ Time Frame: Up to Cycle 1 (21 days) ]
    A DLT (side effects that prevents a dose increase) is defined as any of the following: (1) 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; (2) failure to administer greater than or equal to 75% of the planned dosage of lenvatinib as a result of treatment-related toxicity during Cycle 1; (3) participants who discontinue treatment due to treatment-related toxicity in Cycle 1; (4) 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.


Secondary Outcome Measures :
  1. Objective response rate (ORR) based on Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) [ Time Frame: From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or up to approximately 2 years ]
    ORR is defined as the percentage of participants who have a Best Overall Response (BOR) of immune related (ir) complete response (CR) or (ir) partial response (PR). As per irRECIST, irCR is defined as follows: the complete disappearance of all measurable and nonmeasurable lesions (from baseline) and no unequivocal new lesions (unconfirmed irCR); lymph nodes must decrease to less than 10 millimeters (mm) in the short axis; and confirmation of response is required greater than or equal to 4 weeks later to be considered a confirmed irCR. icPR is defined as follows: at least a 30% decrease in the sum of the diameter of the target lesions (reference is the baseline value) and no unequivocal new lesions and no progression of nontarget disease, it is an irPR (unconfirmed) and confirmation is required greater than or equal to 4 weeks later to be considered a confirmed irPR.

  2. ORR based on Response Evaluation Criteria In Solid Tumors (RESIST) v1.1 [ Time Frame: From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or up to approximately 2 years ]
    ORR is defined as the percentage of participants with a BOR of CR or PR based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for target lesions. CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in the short axis to less than 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

  3. Duration of response (DOR) based on irRECIST [ Time Frame: From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or up to approximately 2 years ]
    DOR is defined as the time from the first documentation of (ir)CR or (ir)PR to the date of the first documentation of disease progression or death (whichever occurs first). Immune-related Progressive Disease (irPD) is defined as a minimum of a 20% increase and a minimum of 5 mm absolute increase in the sum of the diameter compared to nadir, or irPD for nontarget lesion(s) or unequivocal new lesion(s). Duration of response = End Date - Date of first CR or PR + 1.

  4. DOR based on RECIST v1.1 [ Time Frame: From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or up to approximately 2 years ]
    DOR is defined as the time from the first documentation of CR or PR to the date of the first documentation of disease progression or death (whichever occurs first). Disease progression is defined as at least a 20% increase in the sum of the longest diameter of target lesions (taking as reference the smallest sum on study), recorded since the treatment started or the appearance of 1 or more new lesions using RECIST 1.1. Duration of response = End Date - Date of first CR or PR + 1.

  5. Mean maximum concentration (Cmax) of lenvatinib [ Time Frame: Cycle 1, Day 1: predose of pembrolizumab; 1, 2, 4, 8, and 24 hours postdose of lenvatinib. Cycle 1, Day 15: predose of lenvatinib; 1, 2, 4, 8, and 24 hours postdose of lenvatinib ]
    Plasma samples will be collected at the designated time points. Cmax is the highest concentration of drug in the blood that is measured after a dose.

  6. Mean time to reach maximum concentration (Tmax) of lenvatinib [ Time Frame: Cycle 1, Day 1: predose of pembrolizumab; 1, 2, 4, 8, and 24 hours postdose of lenvatinib. Cycle 1, Day 15: predose of lenvatinib; 1, 2, 4, 8, and 24 hours postdose of lenvatinib ]
    Blood samples will be collected at the designated time points. Tmax is the time to the highest concentration of lenvatinib in the plasma that is measured after a dose.

  7. Mean terminal half-life (t1/2) of lenvatinib [ Time Frame: Cycle 1, Day 1: predose of pembrolizumab; 1, 2, 4, 8, and 24 hours postdose of lenvatinib. Cycle 1, Day 15: predose of lenvatinib; 1, 2, 4, 8, and 24 hours postdose of lenvatinib ]
    Blood samples will be collected at the designated time points."t1/2 is the time taken for the plasma concentration to fall to half its original value.

  8. Mean area under the drug concentration-time curve (AUC) of lenvatinib [ Time Frame: Cycle 1, Day 1: predose of pembrolizumab; 1, 2, 4, 8, and 24 hours postdose of lenvatinib. Cycle 1, Day 15: predose of lenvatinib; 1, 2, 4, 8, and 24 hours postdose of lenvatinib ]
    Plasma samples will be collected at the designated time points. AUC represents the overall amount of drug in the bloodstream after dosing.

  9. Mean apparent volume of distribution (Vz/F) of lenvatinib [ Time Frame: Cycle 1, Day 1: predose of pembrolizumab; 1, 2, 4, 8, and 24 hours postdose of lenvatinib. Cycle 1, Day 15: predose of lenvatinib; 1, 2, 4, 8, and 24 hours postdose of lenvatinib ]
    Blood samples will be collected at the designated time points. The apparent volume of distribution gives information about the amount of lenvatinib distributed in body tissue rather than the blood/plasma.

  10. Mean measured concentration at the end of a dosing interval (Ctrough) of pembrolizumab [ Time Frame: Day 1 of Cycles 1, 2, 4, 6, and 8 and Day 1 in every 4 cycles after Cycle 8: predose of pembrolizumab. End of treatment: within 30 days after discontinuation or until the initiation of other anticancer treatment, whichever is earlier ]
    Blood samples will be collected at the designated time points. Ctrough is the minimum concentration at the end of the dosing interval.

  11. Mean clearance (CL) of pembrolizumab [ Time Frame: Day 1 of Cycles 1, 2, 4, 6, and 8 and Day 1 in every 4 cycles after Cycle 8: predose of pembrolizumab. End of treatment: within 30 days after discontinuation or until the initiation of other anticancer treatment, whichever is earlier ]
    Blood samples will be collected at the designated time points. Apparent clearance is defined as the rate of pembrolizumab elimination divided by serum concentration, giving a volume of plasma from which drug is completely removed per unit of time.

  12. Number of participants with anti-drug antibodies (ADA) for pembrolizumab [ Time Frame: Day 1 of Cycles 1, 2, 4, 6, and 8 and Day 1 in every 4 cycles after Cycle 8: predose of pembrolizumab. End of treatment: within 30 days after discontinuation or until the initiation of other anticancer treatment, whichever is earlier ]
    Anti-pembrolizumab antibody samples will be collected within 24 hours before infusion. Serum concentrations of pembrolizumab will be measured by using validated methods.



Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03006887


Locations
Japan
Eisai Trial Site
Chuo-ku, Tokyo, Japan
Sponsors and Collaborators
Eisai Co., Ltd.

Responsible Party: Eisai Co., Ltd.
ClinicalTrials.gov Identifier: NCT03006887     History of Changes
Other Study ID Numbers: E7080-J081-115
KEYNOTE 523 ( Other Identifier: Merck )
First Posted: December 30, 2016    Key Record Dates
Last Update Posted: July 10, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Eisai Inc. ( Eisai Co., Ltd. ):
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
E7080
lenvatinib
pembrolizumab
Japan

Additional relevant MeSH terms:
Pembrolizumab
Lenvatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action