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

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.

Conducting Institutions:

Brigham and Women's Hospital, Dana-Farber Cancer Institute

Overall PI:

Site-responsible Investigators:

Contacts:

Eligibility Criteria

Inclusion Criteria

  -  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.

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 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