Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including Central Nervous System Tumors
Status: Recruiting
Phase:
DFCI Protocol ID: 17-513
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:
Steven Dubois MD,
Dana Farber Cancer Institute
Site-responsible Investigators:
Contacts:
Dana-Farber Cancer Institute:
Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP,
ctip@partners.orgEligibility 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