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Phase 1b/2 Trial of Lenvatinib (E7080) Plus Pembrolizumab in Subjects With Selected Solid Tumors

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ClinicalTrials.gov Identifier: NCT02501096
Recruitment Status : Recruiting
First Posted : July 17, 2015
Last Update Posted : February 5, 2018
Sponsor:
Information provided by (Responsible Party):
Eisai Inc.

Brief Summary:
This is an open-label Phase 1b/2 trial of lenvatinib (E7080) plus pembrolizumab in participants with selected solid tumors. Phase 1b will determine and confirm the maximum tolerated dose (MTD) for lenvatinib in combination with 200 milligrams (mg) (intravenous [IV], every 3 weeks [Q3W]) pembrolizumab in participants with selected solid tumors (i.e. non-small cell lung cancer, renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, or melanoma). Phase 2 (Expansion) will evaluate the safety and efficacy of the combination in 6 cohorts at the MTD from Phase 1b (lenvatinib 20 mg/day orally + pembrolizumab 200 mg Q3W, IV).

Condition or disease Intervention/treatment Phase
Tumors Drug: Lenvatinib Drug: Pembrolizumab Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 191 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter, Open-Label Phase 1b/2 Trial of Lenvatinib (E7080) Plus Pembrolizumab in Subjects With Selected Solid Tumors
Actual Study Start Date : July 22, 2015
Estimated Primary Completion Date : August 31, 2019
Estimated Study Completion Date : February 28, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Lenvatinib + pembrolizumab
Participants with one of the tumors: non-small cell lung cancer, renal cell carcinoma, endometrial cancer, urothelial cancer, squamous cell carcinoma of the head and neck, or melanoma.
Drug: Lenvatinib
Lenvatinib will be administered with water orally once a day (with or without food) continuously in 21-day treatment cycle.
Other Name: Lenvima, E7080

Drug: Pembrolizumab
Pembrolizumab will be administered as a dose of 200 mg Q3W, IV in 21-day treatment cycle.




Primary Outcome Measures :
  1. MTD (Phase 1b) [ Time Frame: Cycle 1 (21 Days) ]
  2. Objective response rate (ORR) at Week 24 [ Time Frame: Week 24 ]
  3. Dose Limiting Toxicity (DLT) [ Time Frame: Cycle 1 (21 Days) ]

Secondary Outcome Measures :
  1. Number of participants with Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (SAEs) [ Time Frame: For each participant, from the first dose till 90 days after the last dose, unless participant starts new anticancer drug then 30 days, or up to approximately 2 years ]
  2. ORR [ 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 ]
  3. Progression-free survival (PFS) [ Time Frame: From the date of first dose of study drug to the date of first documentation of confirmed disease progression or death (whichever occurs first) or up to approximately 2 years ]
  4. Overall survival (OS) [ Time Frame: From the date of first dose of study drug until date of death from any cause or up to approximately 2 years ]
  5. Duration of response (DOR) [ 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 ]
  6. Disease control rate (DCR) [ 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 ]
  7. Durable Stable Disease rate (DSDR) [ 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 ]
  8. Clinical benefit rate (CBR) [ 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 ]
  9. Area under the curve (AUC) of lenvatinib [ Time Frame: 0.5-4 hours (hrs), and 6-10 hrs post lenvatinib dose on C1D1, pre-dose, 0.5-4 hrs, and 6-10 hrs post lenvatinib dose on C1D15, and pre-pembrolizumab dose and 2-12 hrs post lenvatinib dose on C2D1. Pre-pembrolizumab dose only on Day 1 of Cycles 3 to 6. ]
  10. Apparent clearance of lenvatinib [ Time Frame: 0.5-4 hours (hrs), and 6-10 hrs post lenvatinib dose on C1D1, pre-dose, 0.5-4 hrs, and 6-10 hrs post lenvatinib dose on C1D15, and pre-pembrolizumab dose and 2-12 hrs post lenvatinib dose on C2D1. Pre-pembrolizumab dose only on Day 1 of Cycles 3 to 6. ]


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Phase 1b: Histologically and/or cytologically confirmed metastatic selected solid tumor types that have progressed after treatment with approved therapies or for which there are no standard effective therapies available. If nivolumab or pembrolizumab is an approved therapy for the participant's tumor type, but the participant has not been treated with it, the Investigator may enroll the participant in this study. Phase 2: Histologically and/or cytologically confirmed metastatic selected solid tumor types with 0-2 prior lines of systemic therapy (unless discussed with the sponsor) For the non-small cell lung cancer (NSCLC) and melanoma cohorts, participants must have progressed on or after prior treatment with one anti-PD-1, anti-PD-L1, or anti-PDL2 agent Selected tumor types of both phases: NSCLC, predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, or melanoma (excluding uveal melanoma)
  2. Life expectancy of 12 weeks or more
  3. Phase 2: Measurable disease meeting the following criteria:

    1. At least 1 lesion of greater than or equal to 10 mm in the longest diameter for a non-lymph node or greater than or equal to 15 mm in the short-axis diameter for a lymph node that is serially measurable according to irRECIST (immune-related RECIST) using computerized tomography/magnetic resonance imaging (CT/MRI)
    2. Lesions that have had external beam radiotherapy (EBRT) or loco-regional therapies such as radiofrequency (RF) ablation must show subsequent evidence of substantial size increase to be deemed a target lesion
  4. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1
  5. 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 Cycle 1 Day 1
  6. Adequate renal function defined as creatinine less than or equal to 1.5 X ULN (upper limit of normal) or calculated creatinine clearance greater than or equal to 40 mL/min per the Cockcroft and Gault formula with creatinine levels greater than 1.5 X ULN
  7. Adequate bone marrow function:

    1. Absolute neutrophil count (ANC) greater than or equal to 1500/mm3 (greater than or equal to 1.5 X 103/uL)
    2. Platelets greater than or equal to 100,000/mm3 (greater than or equal to 100 X 109/L)
    3. Hemoglobin greater than or equal to 9.0 g/dL
  8. Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) less than or equal to 1.5
  9. Adequate liver function as evidenced by bilirubin less than or equal to 1.5 times the ULN and alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 X ULN (in the case of liver metastases less than or equal to 5 X ULN). In case ALP is greater than 3 X ULN (in the absence of liver metastases) or greater than 5 X 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
  10. Males or females age greater than or equal to 18 years at the time of informed consent
  11. Participants with known brain metastases will be eligible if they have completed the primary brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery or complete surgical resection) and if they have remained clinically stable, asymptomatic and off of steroids for at least 28 days before starting study treatment.
  12. All females must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human chorionic gonadotropin [β-hCG]) at the Screening Visit and the Baseline Visit. A pregnancy test needs to be performed within 72 hours of the first dose of study drug. Females of childbearing potential must agree to use a highly effective method of contraception for the entire study period and for 120 days after study discontinuation, ie

    • total abstinence (if it is their preferred and usual lifestyle)
    • an intrauterine device (IUD) or hormone-releasing system (IUS)
    • a contraceptive implant
    • an oral contraceptive** (with additional barrier method) OR
    • have a vasectomized partner with confirmed azoospermia.

    NOTES:

    • All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
    • 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
  13. Male participants who are partners of women of childbearing potential must use a condom + spermicide and their female partners if of childbearing potential must use a highly effective method of contraception (see methods described in Inclusion Criterion #12) beginning at least 1 menstrual cycle prior to starting study drug(s), throughout the entire study period, and for 120 days after the last dose of study drug, unless the male participants are totally sexually abstinent or have undergone a successful vasectomy with confirmed azoospermia or unless the female partners have been sterilized surgically or are otherwise proven sterile.
  14. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol
  15. Archival tumor tissue or a newly obtained biopsy must be available prior to the first dose of study drug for biomarker analysis. In the case archival tissue cannot be provided, participants with inaccessible tumors for biopsy specimens can be enrolled without a biopsy upon consultation and agreement by the sponsor Note: In case of submitting unstained cut slides, freshly cut slides should be submitted to the testing laboratory within 14 days from when the slides are cut

Exclusion Criteria:

  1. Prior anticancer treatment within 28 days (or 5 times the half-life time, whichever is shorter) or any investigational agent within 30 days prior to the first dose of study drugs. All acute toxicities related to prior treatments must be resolved to Grade less than or equal to 1
  2. Participants must have recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy
  3. Participants having greater than 1+ proteinuria on urinalysis will undergo 24-h urine collection for quantitative assessment of proteinuria. Participants with urine protein greater than or equal to 1 g/24-hour will be ineligible.
  4. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib
  5. 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
  6. Prolongation of QTc interval to greater than 480 msec
  7. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug
  8. Active infection (any infection requiring systemic treatment)
  9. Participant is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C
  10. Serious nonhealing wound, ulcer, or bone fracture
  11. Known intolerance to either of the study drugs (or any of the excipients)
  12. History of organ allograft
  13. Biologic response modifiers (eg, granulocyte colony-stimulating factor) within 4 weeks before study entry. Chronic erythropoietin therapy is permitted provided that no dose adjustments were made within 2 months before first dose of study treatment
  14. Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial
  15. Females who are pregnant or breastfeeding
  16. Excluding the primary tumor leading to enrollment in this study, any other active malignancy (except for definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the bladder or cervix) within the past 24 months
  17. Prior treatment with lenvatinib or any PD-1, anti-PD-L1, or anti-PD-L2 agent, excluding melanoma and NSCLC where prior treatment with one PD-1, anti-PD-L1, or anti-PD-L2 agent is allowed
  18. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids (up to 7.5mg/d of prednisone or equivalent) may be approved after consultation with the sponsor.
  19. No active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  20. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
  21. Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.

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): NCT02501096


Contacts
Contact: Eisai Medical Information 1-888-274-2378 esi_medinfo@eisai.com

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Sponsors and Collaborators
Eisai Inc.

Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT02501096     History of Changes
Other Study ID Numbers: E7080-A001-111
First Posted: July 17, 2015    Key Record Dates
Last Update Posted: February 5, 2018
Last Verified: February 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Eisai Inc.:
Lenvatinib
Lenvima
E7080
Phase 1b/2
Pembrolizumab
Solid tumors

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