Clinical Trials /

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

NCT02501096

Description:

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).

Related Conditions:
  • Endometrial Carcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Melanoma
  • Non-Small Cell Lung Carcinoma
  • Renal Cell Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase 1b/2 Trial of Lenvatinib (E7080) Plus Pembrolizumab in Subjects With Selected Solid Tumors
  • Official Title: A Multicenter, Open-Label Phase 1b/2 Trial of Lenvatinib (E7080) Plus Pembrolizumab in Subjects With Selected Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: E7080-A001-111
  • NCT ID: NCT02501096

Conditions

  • Tumors

Interventions

DrugSynonymsArms
LenvatinibLenvima, E7080Lenvatinib + pembrolizumab
PembrolizumabLenvatinib + pembrolizumab

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Lenvatinib + pembrolizumabExperimentalParticipants 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.
  • Lenvatinib
  • Pembrolizumab

Eligibility 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: Up to two prior lines of systemic therapy in the selected tumor types
             described above (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

         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 [B-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, if not
             practicing total abstinence or having a vasectomized partner with confirmed
             azoospermia, must agree to use two highly effective methods of contraception, eg, 1)
             an intrauterine device [IUD], or intrauterine system (IUS); 2) a barrier method such
             as condom or occlusive cup (diaphragm or cervical/vault caps) + spermicide (foam,
             gel, cream, etc.); 3) oral, injected, or implanted hormonal contraceptives throughout
             the entire study period and for 30 days after study treatment discontinuation. Use of
             a double-barrier method (ie, use at the same time of a condom + occlusive cup
             [diaphragm or cervical/vault caps] + spermicide [foam, gel, cream, etc.]) is accepted
             as two highly effective methods of contraception. The only participants who will be
             exempt from this requirement are postmenopausal women (defined as women who have been
             amenorrheic for at least 12 consecutive months, in the appropriate age group, without
             other known or suspected primary cause) or participants who have been sterilized
             surgically or who are otherwise proven sterile (ie, bilateral tubal ligation with
             surgery at least 1 month prior to dosing, total hysterectomy, or bilateral
             oophorectomy with surgery at least 1 month prior to dosing). All women who are of
             reproductive potential and who are using hormonal contraceptives must have been on a
             stable dose of the same hormonal contraceptive product for at least 4 weeks prior to
             dosing and must continue to use the same contraceptive during the study. Females of
             childbearing potential must be willing to use contraception (as described above) for
             the duration of the study through 120 days after the last dose and for 120 days after
             study drug discontinuation.

         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.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:MTD (Phase 1b)
Time Frame:Cycle 1 (21 Days)
Safety Issue:
Description:

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Eisai Inc.

Trial Keywords

  • Lenvatinib
  • Lenvima
  • E7080
  • Phase 1b/2
  • Pembrolizumab
  • Solid tumors

Last Updated

April 17, 2017