Clinical Trials /

Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including Central Nervous System Tumors

NCT03245151

Description:

Phase 1 of this study, utilizing a rolling 6 design, will be conducted to determine a maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), and to describe the toxicities of lenvatinib administered in combination with everolimus once daily to pediatric participants with recurrent/refractory solid tumors. Phase 2, utilizing Simon's optimal 2-stage design, will be conducted to estimate the antitumor activity of lenvatinib in combination with everolimus in pediatric participants with selected recurrent/refractory solid tumors including Ewing sarcoma/peripheral primitive neuroectodermal tumor (pPNET), rhabdomyosarcoma, and high grade glioma (HGG) using objective response rate (ORR) at Week 16 as the outcome measure.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including Central Nervous System Tumors
  • Official Title: A Phase 1/2 Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including CNS Tumors

Clinical Trial IDs

  • ORG STUDY ID: E7080-A001-216
  • NCT ID: NCT03245151

Conditions

  • Recurrent and Refractory Solid Tumors

Interventions

DrugSynonymsArms
LenvatinibPhase 1: Phase 1; Recurrent or refractory solid tumors
EverolimusPhase 1: Phase 1; Recurrent or refractory solid tumors

Purpose

Phase 1 of this study, utilizing a rolling 6 design, will be conducted to determine a maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), and to describe the toxicities of lenvatinib administered in combination with everolimus once daily to pediatric participants with recurrent/refractory solid tumors. Phase 2, utilizing Simon's optimal 2-stage design, will be conducted to estimate the antitumor activity of lenvatinib in combination with everolimus in pediatric participants with selected recurrent/refractory solid tumors including Ewing sarcoma/peripheral primitive neuroectodermal tumor (pPNET), rhabdomyosarcoma, and high grade glioma (HGG) using objective response rate (ORR) at Week 16 as the outcome measure.

Trial Arms

NameTypeDescriptionInterventions
Phase 1: Phase 1; Recurrent or refractory solid tumorsExperimentalDuring Phase 1 (Treatment Phase: 1 cycle; 28 days of treatment), utilizing a rolling 6 design, participants with recurrent or refractory solid tumors will receive escalating doses of lenvatinib in combination with everolimus for determination of the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D). Participants who complete 1 cycle of treatment will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
  • Lenvatinib
  • Everolimus
Phase 2: Cohort 1, Ewing sarcoma/pPNETExperimentalDuring Phase 2 (four 28-day cycles [up to 16 weeks of treatment]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory Ewing sarcoma/peripheral primitive neuroectodermal tumor (pPNET) (Cohort 1) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1. Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
  • Lenvatinib
  • Everolimus
Phase 2: Cohort 2, RhabdomyosarcomaExperimentalDuring Phase 2 (four 28-day cycles [up to 16 weeks of treatment]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory rhabdomyosarcoma (Cohort 2) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1 (1 cycle; 4 weeks of treatment). Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
  • Lenvatinib
  • Everolimus
Phase 2: Cohort 3, High Grade Glioma (HGG)ExperimentalDuring Phase 2 (four 28-day cycles [up to 16 weeks of treatment]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory HGG (Cohort 3) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1 (1 cycle; 4 weeks). Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
  • Lenvatinib
  • Everolimus

Eligibility Criteria

        Inclusion Criteria

          -  ≥2 years and <18 years of age for enrolment in Phase 1 or ≥2 years and ≤21 years of
             age for enrolment in Phase 2.

          -  Recurrent or refractory solid tumors

               -  Phase 1: All solid tumors (measurable or evaluable disease), including primary
                  central nervous system (CNS) tumors; exclusion of hepatoblastoma and lymphomas.
                  Participants with diffuse intrinsic pontine glioma, optic pathway glioma, or
                  pineal tumors with elevated tumor markers (alpha-fetoprotein [AFP] and beta-human
                  chorionic gonadotropin [ß-hCG][or human chorionic gonadotropin [hCG])do not
                  require histological or cytological confirmation of diagnosis

               -  Phase 2: Ewing sarcoma/peripheral primitive neuroectodermal tumor (pPNET),
                  Rhabdomyosarcoma, High Grade Glioma (HGG) (all must have measurable disease);
                  exclusion of Diffuse Intrinsic Pontine Glioma

          -  Histologically or cytologically confirmed diagnosis

          -  Measurable disease that meets the following criteria (Phase 2):

               1. RECIST 1.1 (for all tumor types except HGG): At least 1 lesion of ≥1.0 cm in the
                  longest diameter for a non lymph node or ≥1.5 cm in the short-axis diameter for a
                  lymph node which is serially measurable according to RECIST 1.1 using computed
                  tomography /magnetic resonance imaging (CT/MRI)

               2. Response Assessment in Neuro-Oncology (RANO) for high grade glioma (HGG): At
                  least one lesion must be measurable as defined as a bi dimensionally contrast
                  enhancing lesion with clearly defined margins by CT or MRI scan, with a minimal
                  diameter of 1 cm, and visible on 2 axial slices which are preferably at most 5 mm
                  apart with 0 mm skip

        Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as
        radiofrequency (RF) ablation must show evidence of progressive disease based on RECIST 1.1
        to be deemed a target lesion

          -  Karnofsky performance score ≥50 for participants>16 year of age and Lansky play score
             ≥50 for participants ≤16 years of age. Neurologic deficits in participants with CNS
             tumors must have been relatively stable for at least 7 days prior to study enrollment.
             Participants who are unable to walk because of paralysis, but who are up in a
             wheelchair, will be considered ambulatory for the purpose of assessing the performance
             score

          -  Prior Therapy

               -  Participants must have fully recovered from the acute toxic effects of all prior
                  anti-cancer therapy

               -  Cytotoxic chemotherapy or other chemotherapy known to be myelosuppressive: ≥21
                  days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days
                  if prior nitrosourea)

               -  Anti-cancer agents not known to be myelosuppressive (eg, not associated with
                  reduced platelet or absolute neutrophil counts): ≥7 days after the last dose of
                  agent

               -  Monoclonal antibodies: ≥21 days or 3 half-lives (whichever is shorter) of the
                  antibody must have elapsed after the last dose of a monoclonal antibody
                  (including checkpoint inhibitors). Toxicity related to prior antibody therapy
                  must be recovered to Grade ≤1

               -  Corticosteroids: If used to modify immune adverse events related to prior
                  therapy, ≥14 days must have elapsed since last dose of corticosteroid.
                  Participants receiving corticosteroids, who have not been on a stable or
                  decreasing dose of corticosteroid for at least 7 days prior to enrollment, are
                  not eligible

               -  Hematopoietic growth factors: ≥14 days after the last dose of a long-acting
                  growth factor or 7 days for short-acting growth factor. For agents that have
                  known adverse events occurring beyond 7 days after administration, this period
                  must be extended beyond the time during which adverse events are known to occur

               -  Interleukins, interferons, and cytokines (other than hematopoietic growth
                  factors): ≥21 days after the completion of interleukins, interferons or cytokines
                  (other than hematopoietic growth factors)

               -  Stem cell infusions (with or without total body irradiation): Allogeneic
                  (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion
                  including donor leukocytes infusion or boost infusion: ≥84 days after infusion
                  and no evidence of graft versus host disease; Autologous stem cell infusion
                  including boost infusion: ≥42 days

               -  Cellular Therapy: ≥42 days after the completion of any type of cellular therapy
                  (eg, modified T cells, natural killer cells, dendritic cells, etc)

               -  Radiotherapy (XRT)/External Beam Irradiation including Protons: ≥14 days after
                  local XRT; ≥150 days after total body irradiation, craniospinal XRT or if
                  radiation to ≥50% of the pelvis; ≥42 days if other substantial bone marrow
                  radiation.

               -  Radiopharmaceutical therapy: ≥42 days after systemically administered therapy.

               -  Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-targeted or
                  mammalian target of rapamycin (mTOR)-targeted therapies: Must not have received
                  prior exposure to lenvatinib; May have previously progressed on an mTOR
                  inhibitor; No more than 2 prior VEGF/VEGFR-targeted therapies (For Phase 2 only);
                  Must not have received prior VEGF/VEGFR-targeted therapy in combination with an
                  mTOR inhibitor (For Phase 2 only)

          -  Adequate bone marrow function for participants with solid tumors without known bone
             marrow involvement

          -  Adequate bone marrow function for participants with known bone marrow metastatic
             disease

          -  Adequate renal function

          -  Adequate liver function

          -  Adequate cardiac function

          -  Adequate neurologic function

          -  Adequate blood pressure (BP) control with or without antihypertensive medications

          -  Adequate coagulation

          -  Adequate pancreatic function

          -  Participants must have a minimum body surface area (BSA) of 0.6 m^2 at study entry.

        Exclusion Criteria

          -  Participants who have had or are planning to have the following invasive procedures

               -  Major surgical procedure, laparoscopic procedure, open biopsy or significant
                  traumatic injury within 28 days prior to enrolment

               -  Central line placement or subcutaneous port placement is not considered major
                  surgery. External central lines must be placed at least 3 days prior to
                  enrollment and subcutaneous ports must be placed at least 7 days prior to
                  enrollment

               -  Fine needle aspirate within 7 days prior to enrolment

               -  Surgical or other wounds must be adequately healed prior to enrolment

               -  For purposes of this study, bone marrow aspirate and biopsy are not considered
                  surgical procedures and therefore are permitted within 14 days prior to start of
                  protocol therapy

          -  Participants who have non-healing wound, unhealed or incompletely healed fracture, or
             a compound (open) bone fracture at the time of enrolment

          -  Clinical evidence of nephrotic syndrome prior to enrolment

          -  Gastrointestinal bleeding or active hemoptysis (bright red blood of at least half
             teaspoon) within 21 days prior to enrolment

          -  Thrombotic/ thromboembolic event requiring systemic anticoagulation within 90 days
             prior to enrollment

          -  Evidence of new intracranial hemorrhage of more than punctate size on MRI assessment
             obtained within 28 days prior to study enrollment for Participants with HGG

          -  Diagnosis of lymphoma

          -  Radiographic evidence of major blood vessel invasion/infiltration.

          -  Evidence of untreated CNS metastases

          -  Participants who are currently receiving enzyme-inducing anticonvulsants

          -  Participants chronically receiving strong cytochrome P450 3A4 (CYP3A4)/P-glycoprotein
             (P-gp) inhibitors or inducers within 7 days prior to study enrollment

          -  Females who are breastfeeding or pregnant. For females of childbearing potential, a
             negative screening pregnancy test must be obtained within 72 hours before the first
             dose of study drug
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of lenvatinib in combination with everolimus
Time Frame:Cycle 1 (Day 1 to Day 28) of the Treatment Phase
Safety Issue:
Description:The sponsor and Protocol Steering Committee will review all participants' safety and clinical data to determine the MTD of the combination of lenvatinib with everolimus. If 2 or more of a cohort of up to 6 participants experience dose-limiting toxicities (DLTs: side effects that prevent a dose increase) at a given dose level, then the MTD has been exceeded and dose escalation will be stopped.

Secondary Outcome Measures

Measure:ORR at the time of data cutoff: Phase 1
Time Frame:up to Week 4 of the Treatment Phase; up to 2 years in the Extension Phase
Safety Issue:
Description:ORR is defined as the proportion of participants with a BOR of CR or PR per RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO Criteria (for HGG).
Measure:ORR at the time of data cutoff: Phase 2
Time Frame:up to Week 16 of the Treatment Phase; up to 2 years in the Extension Phase
Safety Issue:
Description:ORR is defined as the proportion of participants with a BOR of CR or PR per RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO Criteria (for HGG only).
Measure:Disease Control Rate (DCR): Phase 1
Time Frame:up to Week 4 of the Treatment Phase; up to 2 years in the Extension Phase
Safety Issue:
Description:DCR is defined as the proportion of participants with a BOR of CR, PR, or stable disease (SD) (SD duration ≥7 weeks since the first dose of the study treatment) per RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO Criteria (for HGG only).
Measure:DCR: Phase 2
Time Frame:up to Week 16 of the Treatment Phase; up to 2 years in the Extension Phase
Safety Issue:
Description:DCR is defined as the proportion of participants with a BOR of CR, PR, or SD (SD duration ≥7 weeks since the first dose of the study treatment) per RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO Criteria (for HGG only).
Measure:Clinical Benefit Rate (CBR): Phase 1
Time Frame:up to Week 4 of the Treatment Phase; up to 2 years in the Extension Phase
Safety Issue:
Description:CBR is defined as the proportion of participants with a BOR of CR, PR, or durable SD (SD duration ≥23 weeks since the first dose of the study treatment) per RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO Criteria (for HGG only).
Measure:CBR: Phase 2
Time Frame:up to Week 16 of the Treatment Phase; up to 2 years in the Extension Phase
Safety Issue:
Description:CBR is defined as the proportion of participants with a BOR of CR, PR, or durable SD (SD duration ≥23 weeks since the first dose of the study treatment) per RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO Criteria (for HGG only).
Measure:Duration of Response (DOR): Phase 1
Time Frame:up to Week 4 of the Treatment Phase; up to 2 years in the Extension Phase
Safety Issue:
Description:DOR is defined as the time from the date of the first documented CR or PR to the date of the disease progression objectively documented or death (whichever occurs first). CR, PR, and disease progression will be defined per RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO Criteria (for HGG only).
Measure:DOR: Phase 2
Time Frame:up to Week 16 of the Treatment Phase; up to 2 years in the Extension Phase
Safety Issue:
Description:DOR is defined as the time from the date of the first documented CR or PR to the date of the disease progression objectively documented or death (whichever occurs first). CR, PR, and disease progression will be defined per RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO Criteria (for HGG only).
Measure:Area under the plasma concentration time course profile (AUC): Phase 1
Time Frame:Lenvatinib: Cycle 1 Day 1 (C1D1), C1D2, C1D15, C1D22, C2D1, C3D1; Everolimus: C1D1, C1D2, C1D15, C1D22
Safety Issue:
Description:AUC represents the overall amount of drug in the bloodstream after dosing. AUC will be estimated by non-compartmental methods. Blood samples for plasma concentrations of lenvatinib and whole blood concentrations of everolimus will be collected from all participants.
Measure:AUC: Phase 2
Time Frame:Lenvatinib and everolimus: C1D1, C1D15, Cycles 2 and 3
Safety Issue:
Description:AUC represents the overall amount of drug in the bloodstream after dosing. AUC will be estimated by non-compartmental methods. Blood samples for plasma concentrations of lenvatinib and whole blood concentrations of everolimus will be collected from all participants.
Measure:Maximum observed concentration (Cmax): Phase 1
Time Frame:Lenvatinib: Cycle 1 Day 1 (C1D1), C1D2, C1D15, C1D22, C2D1, C3D1; Everolimus: C1D1, C1D2, C1D15, C1D22
Safety Issue:
Description:Cmax is the highest concentration of drug in the blood that is measured after a dose. Cmax will be estimated by non-compartmental methods.
Measure:Cmax: Phase 2
Time Frame:Lenvatinib and everolimus: C1D1, C1D15, Cycles 2 and 3
Safety Issue:
Description:Cmax is the highest concentration of drug in the blood that is measured after a dose. Cmax will be estimated by non-compartmental methods.
Measure:Time from dosing to the maximum observed concentration (Tmax): Phase 1
Time Frame:Lenvatinib: Cycle 1 Day 1 (C1D1), C1D2, C1D15, C1D22, C2D1, C3D1; Everolimus: C1D1, C1D2, C1D15, C1D22
Safety Issue:
Description:Tmax is the time to the highest concentration of drug in the blood that is measured after a dose. Tmax will be estimated by non-compartmental methods.
Measure:Tmax: Phase 2
Time Frame:Lenvatinib and everolimus: C1D1, C1D15, Cycles 2 and 3
Safety Issue:
Description:Tmax is the time to the highest concentration of drug in the blood that is measured after a dose. Tmax will be estimated by non-compartmental methods.
Measure:Number of participants with any TE SAE in Phase 2, as a measure of the safety and toxicity of lenvatinib in combination with everolimus
Time Frame:From date of first dose up to 28 days after the last dose of study treatment, up to approximately 2.5 years
Safety Issue:
Description: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). A TEAE is defined as an AE that emerges during treatment, having been absent at pretreatment (baseline) or (1) reemerges during treatment, having been present at pretreatment (baseline) but stopped before treatment, or (2) worsens in severity during treatment relative to the pretreatment state, when the AE is continuous.
Measure:Number of participants with any TEAE in Phase 2, as a measure of the safety and toxicity of lenvatinib in combination with everolimus
Time Frame:From date of first dose up to 28 days after the last dose of study treatment, up to approximately 2.5 years
Safety Issue:
Description:An 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. A TEAE is defined as an AE that emerges during treatment, having been absent at pretreatment (baseline) or (1) reemerges during treatment, having been present at pretreatment (baseline) but stopped before treatment, or (2) worsens in severity during treatment relative to the pretreatment state, when the AE is continuous.

Details

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

Trial Keywords

  • pediatrics
  • central nervous system tumors
  • lenvatinib
  • E7080
  • everolimus
  • Ewing sarcoma/peripheral primitive neuroectodermal tumor
  • rhabdomyosarcoma
  • high grade glioma
  • solid tumors

Last Updated

April 16, 2019