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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03245151
Recruitment Status : Recruiting
First Posted : August 10, 2017
Last Update Posted : March 2, 2020
Sponsor:
Information provided by (Responsible Party):
Eisai Inc.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Recurrent and Refractory Solid Tumors Drug: Lenvatinib Drug: Everolimus Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including CNS Tumors
Actual Study Start Date : November 16, 2017
Estimated Primary Completion Date : May 31, 2022
Estimated Study Completion Date : May 31, 2022


Arm Intervention/treatment
Experimental: Phase 1: Phase 1; Recurrent or refractory solid tumors
During 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.
Drug: Lenvatinib
oral hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib, or an extemporaneous suspension

Drug: Everolimus
2 mg, 3 mg, or 5 mg tablets for oral suspension

Experimental: Phase 2: Cohort 1, Ewing sarcoma/pPNET
During 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.
Drug: Lenvatinib
oral hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib, or an extemporaneous suspension

Drug: Everolimus
2 mg, 3 mg, or 5 mg tablets for oral suspension

Experimental: Phase 2: Cohort 2, Rhabdomyosarcoma
During 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.
Drug: Lenvatinib
oral hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib, or an extemporaneous suspension

Drug: Everolimus
2 mg, 3 mg, or 5 mg tablets for oral suspension

Experimental: Phase 2: Cohort 3, High Grade Glioma (HGG)
During 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.
Drug: Lenvatinib
oral hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib, or an extemporaneous suspension

Drug: Everolimus
2 mg, 3 mg, or 5 mg tablets for oral suspension




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) of lenvatinib in combination with everolimus: Phase 1 [ Time Frame: Cycle 1 (Day 1 to Day 28) of the Treatment Phase ]
    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.

  2. Recommended Phase 2 dose (RP2D) of lenvatinib in combination with everolimus: Phase 1 [ Time Frame: Cycle 1 (Day 1 to Day 28) of the Treatment Phase ]
    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 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. The RP2D is determined based on the MTD and DLTs.

  3. Number of participants with any treatment-emergent (TE) serious adverse event (SAE) in Phase 1, 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 years ]
    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 adverse event [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.

  4. Number of participants with any TE adverse event (TEAE) in Phase 1, 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 years ]
    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.

  5. Overall Response Rate (ORR) at Week 16 for Phase 2 [ Time Frame: Week 16 ]
    ORR is defined as the proportion of participants who have the best overall response (BOR) of complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (for Ewing sarcoma/peripheral primitive neuroectodermal tumor [pPNET] and rhabdomyosarcoma) or Response Assessment in Neuro-Oncology (RANO) Criteria (for high grade glioma [HGG]).


Secondary Outcome Measures :
  1. 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 ]
    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).

  2. 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 ]
    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).

  3. Disease Control Rate (DCR): Phase 1 [ Time Frame: up to Week 4 of the Treatment Phase; up to 2 years in the Extension Phase ]
    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).

  4. DCR: Phase 2 [ Time Frame: up to Week 16 of the Treatment Phase; up to 2 years in the Extension Phase ]
    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).

  5. Clinical Benefit Rate (CBR): Phase 1 [ Time Frame: up to Week 4 of the Treatment Phase; up to 2 years in the Extension Phase ]
    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).

  6. CBR: Phase 2 [ Time Frame: up to Week 16 of the Treatment Phase; up to 2 years in the Extension Phase ]
    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).

  7. Duration of Response (DOR): Phase 1 [ Time Frame: up to Week 4 of the Treatment Phase; up to 2 years in the Extension Phase ]
    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).

  8. DOR: Phase 2 [ Time Frame: up to Week 16 of the Treatment Phase; up to 2 years in the Extension Phase ]
    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).

  9. 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 ]
    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.

  10. AUC: Phase 2 [ Time Frame: Lenvatinib and everolimus: C1D1, C1D15, Cycles 2 and 3 ]
    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.

  11. Maximum observed concentration (Cmax): Phase 1 [ Time Frame: Lenvatinib: Cycle 1 Day 1 (C1D1), C1D2, C1D15, C1D22, C2D1, C3D1; Everolimus: C1D1, C1D2, C1D15, C1D22 ]
    Cmax is the highest concentration of drug in the blood that is measured after a dose. Cmax will be estimated by non-compartmental methods.

  12. Cmax: Phase 2 [ Time Frame: Lenvatinib and everolimus: C1D1, C1D15, Cycles 2 and 3 ]
    Cmax is the highest concentration of drug in the blood that is measured after a dose. Cmax will be estimated by non-compartmental methods.

  13. 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 ]
    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.

  14. Tmax: Phase 2 [ Time Frame: Lenvatinib and everolimus: C1D1, C1D15, Cycles 2 and 3 ]
    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.

  15. 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 ]
    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.

  16. 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 ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   2 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 (exception: participants with primary CNS tumors and leptomeningeal disease)
  • 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

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): NCT03245151


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

Locations
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Sponsors and Collaborators
Eisai Inc.

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Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT03245151    
Other Study ID Numbers: E7080-A001-216
First Posted: August 10, 2017    Key Record Dates
Last Update Posted: March 2, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Eisai Inc.:
pediatrics
central nervous system tumors
lenvatinib
E7080
everolimus
Ewing sarcoma/peripheral primitive neuroectodermal tumor
rhabdomyosarcoma
high grade glioma
solid tumors
Additional relevant MeSH terms:
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Central Nervous System Neoplasms
Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases
Everolimus
Lenvatinib
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action