Clinical trial NCT03245151: Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including Central Nervous System Tumors
Official title: A Phase 1/2 Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including CNS Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Recurrent and Refractory Solid Tumors
Keywords: pediatrics
central nervous system tumors
lenvatinib
E7080
everolimus
Ewing sarcoma/peripheral primitive neuroectodermal tumor
rhabdomyosarcoma
high grade glioma
solid tumors
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2017-08-10
Enrollment: 64
Sex: ALL
Minimum age (years): 2
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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, rhabdomyosarcoma, and high grade glioma (HGG) using objective response rate (ORR) at Week 16 as the outcome measure.


Eligibility criteria: 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, 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
* Adequate metabolic function
* Adequate glycemic control
* 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
* Participants having an active infection requiring systemic therapy.
* Participants with a known history of active hepatitis B (defined as hepatitis B surface antigen reactive or hepatitis B virus- deoxyribonucleic \[DNA\] detected) or known active hepatitis C virus (HCV, defined as HCV- Ribonucleic acid \[RNA\] detected). Note: No testing for hepatitis B and hepatitis C is required unless mandated by the local health authority.
* Known to be human immunodeficiency virus (HIV) positive. Note: HIV testing is required at screening only when mandated by the local health authority
* 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
* Males who have not had a successful vasectomy (confirmed azoospermia) or if they and their female partners do not meet the criteria above (that is, not of childbearing potential or practicing highly effective contraception throughout the study period and for 7 days after lenvatinib discontinuation or 4 weeks after discontinuation of everolimus). No sperm donation is allowed during the study period and for 7 days after lenvatinib discontinuation or 4 weeks after discontinuation of everolimus.

Primary outcomes:
measure: Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib in Combination With Everolimus
timeFrame: Cycle 1 (Each cycle was of 28 days)
measure: Phase 1: Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination With Everolimus
timeFrame: Cycle 1 (Each cycle was of 28 days)
measure: Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
timeFrame: From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months)
measure: Phase 1: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE)
timeFrame: From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months)
measure: Phase 2: Objective Response Rate (ORR) at Week 16
timeFrame: Week 16
Secondary outcomes:
measure: Phase 1: Objective Response Rate (ORR)
timeFrame: From the date of the first dose of study drug to the date of first documentation of disease progression or death, whichever occurred first (up to 16.5 months)
measure: Phase 2: Objective Response Rate (ORR)
timeFrame: From the date of the first dose of study drug to the date of first documentation of disease progression or death, which ever occurred first (up to 6.5 months)
measure: Phase 1: Disease Control Rate (DCR)
timeFrame: From first dose of study drug until PD or death, whichever occurred first (up to 16.5 months)
measure: Phase 2: Disease Control Rate (DCR)
timeFrame: From first dose of study drug until PD or death, whichever occurred first (up to 6.5 months)
measure: Phase 1: Clinical Benefit Rate (CBR)
timeFrame: From first dose of study drug until PD or death, whichever occurred first (up to 16.5 months)
measure: Phase 2: Clinical Benefit Rate (CBR)
timeFrame: From first dose of study drug until PD or death, whichever occurred first (up to 6.5 months)
measure: Phase 1: Duration of Response (DOR)
timeFrame: From date of the first observation of CR or PR until the date of first observation of progression or date of death (up to 16.5 months)
measure: Phase 2: Duration of Response (DOR)
timeFrame: From date of the first observation of CR or PR until the date of first observation of progression or date of death (up to 6.5 months)
measure: Phase 1: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration of Lenvatinib (AUC[0-t Hours])
timeFrame: Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days)
measure: Phase 1: Maximum Plasma Concentration of Lenvatinib (Cmax)
timeFrame: Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days)
measure: Phase 1: Time to Reach Maximum Plasma Concentration (Cmax) of Lenvatinib (Tmax)
timeFrame: Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days)
measure: Phase 1: Trough Concentrations (Ctrough) of Everolimus When Administered in Combination With Lenvatinib
timeFrame: Cycle 1 Days 1, 2, 15 and 22: Pre-dose (Cycle length=28 days)
measure: Phase 2: Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
timeFrame: From date of first dose up to 28 days after the last dose of study treatment (up to 7.5 months)
measure: Phase 2: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE)
timeFrame: From date of first dose up to 28 days after the last dose of study treatment (up to 7.5 months)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Long Beach
country: United States
facility: Miller Children's and Women's Hospital
state: California
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: Los Angeles
country: United States
facility: Southern California Permanente Medical Group
state: California
city: Oakland
country: United States
facility: Kaiser Permenente
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center at Mission Bay - Pediatric Oncology
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Wilmington
country: United States
facility: Nemours/ Alfred I. duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Fort Myers
country: United States
facility: Golisano Children's Hospital of Southwest Florida
state: Florida
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: Nicklaus Children's Hospital
state: Florida
city: Honolulu
country: United States
facility: Kapi'olani Medical Center
state: Hawaii
city: Peoria
country: United States
facility: St Jude Midwest Affiliate
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children - Indiana University
state: Indiana
city: Louisville
country: United States
facility: University of Louisville and Norton Children's Hospital
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: CS Mott Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota/Masonic Cancer Center
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Children's Mercy Hospital and Clinics
state: Missouri
city: Las Vegas
country: United States
facility: Alliance for Childhood Diseases
state: Nevada
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers cancer Institute of NJ
state: New Jersey
city: New Hyde Park
country: United States
facility: Cohen Children's Medical Center
state: New York
city: New York
country: United States
facility: Columbia University/Herbert Irving Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Austin
country: United States
facility: Dell Children's Medical Center of Central Texas
state: Texas
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: San Antonio
country: United States
facility: The Children's Hospital of San Antonio
state: Texas
city: Norfolk
country: United States
facility: Children's Hospital of The King's Daughters
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Halifax
country: Canada
facility: IWK Health Centre
state: Nova Scotia
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Montreal Children's Hospital
state: Quebec
Study officials:
References: