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

Study Overview
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Brief Summary
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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, rhabdomyosarcoma, and high grade glioma (HGG) using objective response rate (ORR) at Week 16 as the outcome measure.

Official Title
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A Phase 1/2 Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including CNS Tumors

Conditions
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Recurrent and Refractory Solid Tumors

Intervention / Treatment
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* Drug: Lenvatinib
* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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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, 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): 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) 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 Adequate metabolic function Adequate glycemic control 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 Participants having an active infection requiring systemic therapy. Participants with a known history of active hepatitis B (defined as hepatitis B surface antigen reactive or hepatitis B virus- deoxyribonucleic [DNA] detected) or known active hepatitis C virus (HCV, defined as HCV- Ribonucleic acid [RNA] detected). Note: No testing for hepatitis B and hepatitis C is required unless mandated by the local health authority. Known to be human immunodeficiency virus (HIV) positive. Note: HIV testing is required at screening only when mandated by the local health authority 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 Males who have not had a successful vasectomy (confirmed azoospermia) or if they and their female partners do not meet the criteria above (that is, not of childbearing potential or practicing highly effective contraception throughout the study period and for 7 days after lenvatinib discontinuation or 4 weeks after discontinuation of everolimus). No sperm donation is allowed during the study period and for 7 days after lenvatinib discontinuation or 4 weeks after discontinuation of everolimus.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Phase 1; Recurrent or refractory solid tumors<br>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<br>* oral hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib, or an extemporaneous suspension<br>Drug: Everolimus<br>* 2 mg, 3 mg, or 5 mg tablets for oral suspension<br>|
| Experimental: Phase 2: Cohort 1, Ewing sarcoma<br>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 (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<br>* oral hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib, or an extemporaneous suspension<br>Drug: Everolimus<br>* 2 mg, 3 mg, or 5 mg tablets for oral suspension<br>|
| Experimental: Phase 2: Cohort 2, Rhabdomyosarcoma<br>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<br>* oral hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib, or an extemporaneous suspension<br>Drug: Everolimus<br>* 2 mg, 3 mg, or 5 mg tablets for oral suspension<br>|
| Experimental: Phase 2: Cohort 3, High Grade Glioma (HGG)<br>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<br>* oral hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib, or an extemporaneous suspension<br>Drug: Everolimus<br>* 2 mg, 3 mg, or 5 mg tablets for oral suspension<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib in Combination With Everolimus | MTD was defined as the highest dose level at which no more than 1/6 participants experienced a dose limiting toxicity (DLTs), with the next higher dose having at least 0 of 3 or 1 of 6 participants experiencing DLTs. DLT was graded according to common terminology criteria for adverse events (CTCAE) version 4.03. | Cycle 1 (Each cycle was of 28 days) | 
| Phase 1: Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination With Everolimus | The RP2D of lenvatinib in combination with everolimus was determined by Dose Escalation Committee (DEC) based on safety (including DLTs), pharmacokinetic and clinical data. DLT was graded according to CTCAE v4.03. | Cycle 1 (Each cycle was of 28 days) | 
| Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | A TEAE was defined as an adverse event that emerged during treatment, having been absent at pretreatment or reemerged during treatment, having been present at pretreatment but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the adverse event is continuous. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product. | From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months) | 
| Phase 1: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE) | A TESAE was any untoward medical occurrence that at any dose: resulted in death; life threatening condition; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically important due to other reasons than the above mentioned criteria. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product. | From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months) | 
| Phase 2: Objective Response Rate (ORR) at Week 16 | ORR at Week 16 was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) at Week 16 based on investigator assessment according to response evaluation criteria in solid tumors (RECIST) version 1.1 for non-HGG cohorts and response assessment in neuro-oncology (RANO) for HGG cohort. CR was defined as disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis less than (<) 10 millimeter (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters. | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Objective Response Rate (ORR) | ORR was defined as the percentage of participants with BOR of CR or PR based on investigator assessment according to RECIST version 1.1 for non-HGG cohorts and RANO for HGG cohort. CR was defined as disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis <10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. | From the date of the first dose of study drug to the date of first documentation of disease progression or death, whichever occurred first (up to 16.5 months) | 
| Phase 2: Objective Response Rate (ORR) | ORR was defined as the percentage of participants with BOR of CR or PR based on investigator assessment according to RECIST version 1.1 for non-HGG cohorts and RANO for HGG cohort. CR was defined as disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis <10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. | From the date of the first dose of study drug to the date of first documentation of disease progression or death, which ever occurred first (up to 6.5 months) | 
| Phase 1: Disease Control Rate (DCR) | DCR was defined as percentage of participants with a confirmed CR, PR, or stable disease (SD) (SD duration >=7 weeks since the first dose of study treatment) divided by number of participants in analysis set. DCR was assessed by an investigator based on RECIST v1.1 for non-HGG participants or RANO for HGG participants. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. | From first dose of study drug until PD or death, whichever occurred first (up to 16.5 months) | 
| Phase 2: Disease Control Rate (DCR) | DCR was defined as percentage of participants with confirmed CR, PR, or SD (SD duration greater than or equal to [>=] 7 weeks since first dose of study treatment) divided by number of participants in analysis set. DCR was assessed by investigator based on RECIST v1.1 for non-HGG cohorts or RANO for HGG cohort. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. | From first dose of study drug until PD or death, whichever occurred first (up to 6.5 months) | 
| Phase 1: Clinical Benefit Rate (CBR) | CBR was defined as percentage of participants who had BOR of CR, PR, or durable SD (SD duration >=23 weeks since the first dose of study treatment) divided by number of participants in analysis set. CBR was assessed by an investigator based on RECIST v1.1 for non-HGG participants or RANO for HGG participants. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. | From first dose of study drug until PD or death, whichever occurred first (up to 16.5 months) | 
| Phase 2: Clinical Benefit Rate (CBR) | CBR was defined as percentage of participants who had BOR of CR, PR, or durable SD (SD duration >=23 weeks since the first dose of study treatment) divided by number of participants in analysis set. CBR was assessed by an investigator based on RECIST v1.1 for non-HGG cohorts or RANO for HGG cohort. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. | From first dose of study drug until PD or death, whichever occurred first (up to 6.5 months) | 
| Phase 1: Duration of Response (DOR) | DOR was defined as the time (in months) from the date of first observation of confirmed response (PR or CR) to the date of the first observation of progression based on the investigator's assessment utilizing RECIST 1.1 for non-HGG cohorts and RANO for HGG cohorts, or date of death, whatever the cause. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. | From date of the first observation of CR or PR until the date of first observation of progression or date of death (up to 16.5 months) | 
| Phase 2: Duration of Response (DOR) | DOR was defined as the time (in months) from the date of first observation of confirmed response (PR or CR) to the date of the first observation of progression based on the investigator's assessment utilizing RECIST 1.1 for non-HGG cohorts and RANO for HGG cohort, or date of death, whatever the cause. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. | From date of the first observation of CR or PR until the date of first observation of progression or date of death (up to 6.5 months) | 
| Phase 1: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration of Lenvatinib (AUC[0-t Hours]) | AUC0-t of lenvatinib was quantified using validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. | Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days) | 
| Phase 1: Maximum Plasma Concentration of Lenvatinib (Cmax) | Cmax of lenvatinib was quantified using validated liquid LC-MS/MS methods. | Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days) | 
| Phase 1: Time to Reach Maximum Plasma Concentration (Cmax) of Lenvatinib (Tmax) | Tmax of lenvatinib was quantified using validated liquid LC-MS/MS methods. | Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days) | 
| Phase 1: Trough Concentrations (Ctrough) of Everolimus When Administered in Combination With Lenvatinib | Trough concentrations of everolimus was quantified using validated liquid LC-MS/MS methods. | Cycle 1 Days 1, 2, 15 and 22: Pre-dose (Cycle length=28 days) | 
| Phase 2: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | A TEAE was defined as an adverse event that emerged during treatment, having been absent at pretreatment or reemerged during treatment, having been present at pretreatment but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the adverse event is continuous. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product. | From date of first dose up to 28 days after the last dose of study treatment (up to 7.5 months) | 
| Phase 2: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE) | A TESAE was any untoward medical occurrence that at any dose: resulted in death; life threatening condition; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically important due to other reasons than the above mentioned criteria. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product. | From date of first dose up to 28 days after the last dose of study treatment (up to 7.5 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pediatrics, central nervous system tumors, lenvatinib, E7080, everolimus, Ewing sarcoma/peripheral primitive neuroectodermal tumor, rhabdomyosarcoma, high grade glioma, solid tumors