Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including Central Nervous System Tumors
A Phase 1/2 Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including CNS Tumors
1 other identifier
interventional
64
2 countries
50
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Nov 2017
Longer than P75 for phase_1
50 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
August 3, 2017
CompletedFirst Posted
Study publicly available on registry
August 10, 2017
CompletedStudy Start
First participant enrolled
November 16, 2017
CompletedPrimary Completion
Last participant's last visit for primary outcome
September 30, 2022
CompletedStudy Completion
Last participant's last visit for all outcomes
September 30, 2022
CompletedResults Posted
Study results publicly available
August 30, 2023
CompletedAugust 30, 2023
November 1, 2022
4.9 years
August 3, 2017
August 7, 2023
August 7, 2023
Conditions
Keywords
Outcome Measures
Primary Outcomes (5)
Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib in Combination With Everolimus
MTD was defined as the highest dose level at which no more than 1/6 participants experienced a dose limiting toxicity (DLTs), with the next higher dose having at least 0 of 3 or 1 of 6 participants experiencing DLTs. DLT was graded according to common terminology criteria for adverse events (CTCAE) version 4.03.
Cycle 1 (Each cycle was of 28 days)
Phase 1: Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination With Everolimus
The RP2D of lenvatinib in combination with everolimus was determined by Dose Escalation Committee (DEC) based on safety (including DLTs), pharmacokinetic and clinical data. DLT was graded according to CTCAE v4.03.
Cycle 1 (Each cycle was of 28 days)
Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
A TEAE was defined as an adverse event that emerged during treatment, having been absent at pretreatment or reemerged during treatment, having been present at pretreatment but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the adverse event is continuous. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product.
From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months)
Phase 1: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE)
A TESAE was any untoward medical occurrence that at any dose: resulted in death; life threatening condition; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically important due to other reasons than the above mentioned criteria. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product.
From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months)
Phase 2: Objective Response Rate (ORR) at Week 16
ORR at Week 16 was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) at Week 16 based on investigator assessment according to response evaluation criteria in solid tumors (RECIST) version 1.1 for non-HGG cohorts and response assessment in neuro-oncology (RANO) for HGG cohort. CR was defined as disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis less than (\<) 10 millimeter (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters.
Week 16
Secondary Outcomes (14)
Phase 1: Objective Response Rate (ORR)
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)
Phase 2: Objective Response Rate (ORR)
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)
Phase 1: Disease Control Rate (DCR)
From first dose of study drug until PD or death, whichever occurred first (up to 16.5 months)
Phase 2: Disease Control Rate (DCR)
From first dose of study drug until PD or death, whichever occurred first (up to 6.5 months)
Phase 1: Clinical Benefit Rate (CBR)
From first dose of study drug until PD or death, whichever occurred first (up to 16.5 months)
- +9 more secondary outcomes
Study Arms (4)
Phase 1: Phase 1; Recurrent or refractory solid tumors
EXPERIMENTALDuring Phase 1 (Treatment Phase: 1 cycle; 28 days of treatment), utilizing a rolling 6 design, participants with recurrent or refractory solid tumors will receive escalating doses of lenvatinib in combination with everolimus for determination of the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D). Participants who complete 1 cycle of treatment will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
Phase 2: Cohort 1, Ewing sarcoma
EXPERIMENTALDuring Phase 2 (four 28-day cycles \[up to 16 weeks of treatment\]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory Ewing sarcoma (Cohort 1) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1. Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
Phase 2: Cohort 2, Rhabdomyosarcoma
EXPERIMENTALDuring Phase 2 (four 28-day cycles \[up to 16 weeks of treatment\]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory rhabdomyosarcoma (Cohort 2) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1 (1 cycle; 4 weeks of treatment). Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
Phase 2: Cohort 3, High Grade Glioma (HGG)
EXPERIMENTALDuring Phase 2 (four 28-day cycles \[up to 16 weeks of treatment\]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory HGG (Cohort 3) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1 (1 cycle; 4 weeks). Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
Interventions
oral hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib, or an extemporaneous suspension
2 mg, 3 mg, or 5 mg tablets for oral suspension
Eligibility Criteria
You may qualify if:
- ≥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
- Histologically or cytologically confirmed diagnosis
- Measurable disease that meets the following criteria (Phase 2):
- 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)
- 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
- +18 more criteria
You may not qualify if:
- 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
- +6 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Eisai Inc.lead
- Merck Sharp & Dohme LLCcollaborator
Study Sites (50)
Children's Hospital of Alabama
Birmingham, Alabama, 35233, United States
Phoenix Children's Hospital
Phoenix, Arizona, 85016, United States
Loma Linda University Medical Center
Loma Linda, California, 92350, United States
Miller Children's and Women's Hospital
Long Beach, California, 90806, United States
Children's Hospital of Los Angeles
Los Angeles, California, 90027, United States
Southern California Permanente Medical Group
Los Angeles, California, 90027, United States
Kaiser Permenente
Oakland, California, 94611, United States
Children's Hospital of Orange County
Orange, California, 92868, United States
UCSF Medical Center at Mission Bay - Pediatric Oncology
San Francisco, California, 94158, United States
Children's Hospital Colorado
Aurora, Colorado, 80045, United States
Nemours/ Alfred I. duPont Hospital for Children
Wilmington, Delaware, 19803, United States
Children's National Medical Center
Washington D.C., District of Columbia, 20010, United States
Golisano Children's Hospital of Southwest Florida
Fort Myers, Florida, 33908, United States
University of Florida
Gainesville, Florida, 32610, United States
Nicklaus Children's Hospital
Miami, Florida, 33155, United States
Kapi'olani Medical Center
Honolulu, Hawaii, 96826, United States
St Jude Midwest Affiliate
Peoria, Illinois, 61637, United States
Riley Hospital for Children - Indiana University
Indianapolis, Indiana, 46202, United States
University of Louisville and Norton Children's Hospital
Louisville, Kentucky, 40202, United States
Johns Hopkins
Baltimore, Maryland, 21287, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215, United States
CS Mott Children's Hospital
Ann Arbor, Michigan, 48109, United States
University of Minnesota/Masonic Cancer Center
Minneapolis, Minnesota, 55455, United States
University of Mississippi Medical Center
Jackson, Mississippi, 39216, United States
Children's Mercy Hospital and Clinics
Kansas City, Missouri, 64108, United States
Alliance for Childhood Diseases
Las Vegas, Nevada, 89135, United States
Hackensack University Medical Center
Hackensack, New Jersey, 07601, United States
Morristown Medical Center
Morristown, New Jersey, 07960, United States
Rutgers cancer Institute of NJ
New Brunswick, New Jersey, 08901, United States
Cohen Children's Medical Center
New Hyde Park, New York, 11040, United States
Columbia University/Herbert Irving Cancer Center
New York, New York, 10032, United States
Memorial Sloan Kettering Cancer Center
New York, New York, 10065, United States
New York Medical College
Valhalla, New York, 10595, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229, United States
Nationwide Children's Hospital
Columbus, Ohio, 43205, United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104, United States
Oregon Health & Science University
Portland, Oregon, 97239, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104, United States
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, 15224, United States
Vanderbilt University Medical Center
Nashville, Tennessee, 37232, United States
Dell Children's Medical Center of Central Texas
Austin, Texas, 78723, United States
The University of Texas Southwestern Medical Center
Dallas, Texas, 75390, United States
Cook Children's Medical Center
Fort Worth, Texas, 76104, United States
Texas Children's Hospital
Houston, Texas, 77030, United States
The Children's Hospital of San Antonio
San Antonio, Texas, 78207, United States
Children's Hospital of The King's Daughters
Norfolk, Virginia, 23507, United States
Seattle Children's Hospital
Seattle, Washington, 98105, United States
IWK Health Centre
Halifax, Nova Scotia, B3K 6R8, Canada
Hospital for Sick Children
Toronto, Ontario, M5G 1X8, Canada
Montreal Children's Hospital
Montreal, Quebec, H4A3J1, Canada
Related Publications (1)
Dela Cruz FS, Fox E, DuBois SG, Friedman GK, Croop JM, Kim A, Morgenstern DA, Balis FM, Macy ME, Pressey JG, Watt T, Krystal JI, Vo KT, Mody R, Laetsch TW, Weigel BJ, O'Hara K, He CS, Aluri J, Okpara CE, Glade Bender JL. A Phase 1/2 Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric and Young Adult Solid Tumors. Pediatr Blood Cancer. 2025 Jul;72(7):e31692. doi: 10.1002/pbc.31692. Epub 2025 May 1.
PMID: 40313040DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Eisai Medical Information
- Organization
- Eisai Inc.
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
August 3, 2017
First Posted
August 10, 2017
Study Start
November 16, 2017
Primary Completion
September 30, 2022
Study Completion
September 30, 2022
Last Updated
August 30, 2023
Results First Posted
August 30, 2023
Record last verified: 2022-11