Why are we doing this research?
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.
- Maximum tolerated dose (MTD) of lenvatinib in combination with everolimus [ 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.
- Recommended Phase 2 dose (RP2D) of lenvatinib in combination with everolimus [ 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.
- 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.
- 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.
- 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]).
Study Type: Interventional
Intervention Model: Parallel Assignment
Masking: None - Open Label
Primary Purpose: Treatment
Who can participate?
AGES ELIGIBLE FOR STUDY: 2 Years to 21 Years
- 2 years to 21 years of age
- 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
- 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
- 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, with the exception of one study arm which requires a minimum BSA of 1.33 m^2.
- 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 enrollment
- 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 enrollment.
- Surgical or other wounds must be adequately healed prior to enrollment.
- 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 enrollment
- Clinical evidence of nephrotic syndrome prior to enrollment
- Gastrointestinal bleeding or active hemoptysis (bright red blood of at least half teaspoon) within 21 days prior to enrollment
- 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.