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Study Description

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 1 has been completed]

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.

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