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

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