Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including Central Nervous System Tumors
- Conditions
- Recurrent and Refractory Solid Tumors
- Interventions
- Registration Number
- NCT03245151
- Lead Sponsor
- Eisai Inc.
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 64
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 1: Phase 1; Recurrent or refractory solid tumors Lenvatinib During 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 1: Phase 1; Recurrent or refractory solid tumors Everolimus During 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 Everolimus During 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 1, Ewing sarcoma Lenvatinib During 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 Lenvatinib During 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) Everolimus During 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. Phase 2: Cohort 2, Rhabdomyosarcoma Everolimus During 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) Lenvatinib During 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.
- Primary Outcome Measures
Name Time Method Phase 1: Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination With Everolimus Cycle 1 (Each cycle was of 28 days) 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.
Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months) 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.
Phase 1: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE) From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months) 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.
Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib in Combination With Everolimus Cycle 1 (Each cycle was of 28 days) 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.
Phase 2: Objective Response Rate (ORR) at Week 16 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.
- Secondary Outcome Measures
Name Time Method Phase 1: Maximum Plasma Concentration of Lenvatinib (Cmax) Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days) Cmax of lenvatinib was quantified using validated liquid LC-MS/MS methods.
Phase 1: Time to Reach Maximum Plasma Concentration (Cmax) of Lenvatinib (Tmax) Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days) Tmax of lenvatinib was quantified using validated liquid LC-MS/MS methods.
Phase 2: Disease Control Rate (DCR) From first dose of study drug until PD or death, whichever occurred first (up to 6.5 months) DCR was defined as percentage of participants with confirmed CR, PR, or SD (SD duration greater than or equal to \[\>=\] 7 weeks since first dose of study treatment) divided by number of participants in analysis set. DCR was assessed by investigator based on RECIST v1.1 for non-HGG cohorts or RANO for HGG cohort. CR: 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 \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
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) ORR was defined as the percentage of participants with BOR of CR or PR based on investigator assessment according to RECIST version 1.1 for non-HGG cohorts and 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 \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters.
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) ORR was defined as the percentage of participants with BOR of CR or PR based on investigator assessment according to RECIST version 1.1 for non-HGG cohorts and 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 \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters.
Phase 1: Clinical Benefit Rate (CBR) From first dose of study drug until PD or death, whichever occurred first (up to 16.5 months) CBR was defined as percentage of participants who had BOR of CR, PR, or durable SD (SD duration \>=23 weeks since the first dose of study treatment) divided by number of participants in analysis set. CBR was assessed by an investigator based on RECIST v1.1 for non-HGG participants or RANO for HGG participants. CR: 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 \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Phase 2: Duration of Response (DOR) 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) DOR was defined as the time (in months) from the date of first observation of confirmed response (PR or CR) to the date of the first observation of progression based on the investigator's assessment utilizing RECIST 1.1 for non-HGG cohorts and RANO for HGG cohort, or date of death, whatever the cause. CR: 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 \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Phase 1: Disease Control Rate (DCR) From first dose of study drug until PD or death, whichever occurred first (up to 16.5 months) DCR was defined as percentage of participants with a confirmed CR, PR, or stable disease (SD) (SD duration \>=7 weeks since the first dose of study treatment) divided by number of participants in analysis set. DCR was assessed by an investigator based on RECIST v1.1 for non-HGG participants or RANO for HGG participants. CR: 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 \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Phase 1: Trough Concentrations (Ctrough) of Everolimus When Administered in Combination With Lenvatinib Cycle 1 Days 1, 2, 15 and 22: Pre-dose (Cycle length=28 days) Trough concentrations of everolimus was quantified using validated liquid LC-MS/MS methods.
Phase 2: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) From date of first dose up to 28 days after the last dose of study treatment (up to 7.5 months) 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.
Phase 2: Clinical Benefit Rate (CBR) From first dose of study drug until PD or death, whichever occurred first (up to 6.5 months) CBR was defined as percentage of participants who had BOR of CR, PR, or durable SD (SD duration \>=23 weeks since the first dose of study treatment) divided by number of participants in analysis set. CBR was assessed by an investigator based on RECIST v1.1 for non-HGG cohorts or RANO for HGG cohort. CR: 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 \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Phase 1: Duration of Response (DOR) 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) DOR was defined as the time (in months) from the date of first observation of confirmed response (PR or CR) to the date of the first observation of progression based on the investigator's assessment utilizing RECIST 1.1 for non-HGG cohorts and RANO for HGG cohorts, or date of death, whatever the cause. CR: 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 \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Phase 1: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration of Lenvatinib (AUC[0-t Hours]) Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days) AUC0-t of lenvatinib was quantified using validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methods.
Phase 2: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE) From date of first dose up to 28 days after the last dose of study treatment (up to 7.5 months) 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.
Trial Locations
- Locations (50)
Children's Hospital of Pittsburgh of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
Children's Hospital of Los Angeles
🇺🇸Los Angeles, California, United States
Southern California Permanente Medical Group
🇺🇸Los Angeles, California, United States
Miller Children's and Women's Hospital
🇺🇸Long Beach, California, United States
Loma Linda University Medical Center
🇺🇸Loma Linda, California, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸Fort Myers, Florida, United States
Johns Hopkins
🇺🇸Baltimore, Maryland, United States
Cohen Children's Medical Center
🇺🇸New Hyde Park, New York, United States
Columbia University/Herbert Irving Cancer Center
🇺🇸New York, New York, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Montreal Children's Hospital
🇨🇦Montreal, Quebec, Canada
St Jude Midwest Affiliate
🇺🇸Peoria, Illinois, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Children's Hospital of The King's Daughters
🇺🇸Norfolk, Virginia, United States
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
New York Medical College
🇺🇸Valhalla, New York, United States
Children's Hospital of Orange County
🇺🇸Orange, California, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
UCSF Medical Center at Mission Bay - Pediatric Oncology
🇺🇸San Francisco, California, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Nicklaus Children's Hospital
🇺🇸Miami, Florida, United States
Riley Hospital for Children - Indiana University
🇺🇸Indianapolis, Indiana, United States
University of Minnesota/Masonic Cancer Center
🇺🇸Minneapolis, Minnesota, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
Texas Children's Hospital
🇺🇸Houston, Texas, United States
The Children's Hospital of San Antonio
🇺🇸San Antonio, Texas, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Kaiser Permenente
🇺🇸Oakland, California, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, United States
Phoenix Children's Hospital
🇺🇸Phoenix, Arizona, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
The University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Nemours/ Alfred I. duPont Hospital for Children
🇺🇸Wilmington, Delaware, United States
Rutgers cancer Institute of NJ
🇺🇸New Brunswick, New Jersey, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Alliance for Childhood Diseases
🇺🇸Las Vegas, Nevada, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
IWK Health Centre
🇨🇦Halifax, Nova Scotia, Canada
Morristown Medical Center
🇺🇸Morristown, New Jersey, United States
CS Mott Children's Hospital
🇺🇸Ann Arbor, Michigan, United States
Dell Children's Medical Center of Central Texas
🇺🇸Austin, Texas, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
University of Florida
🇺🇸Gainesville, Florida, United States
Kapi'olani Medical Center
🇺🇸Honolulu, Hawaii, United States
Children's Mercy Hospital and Clinics
🇺🇸Kansas City, Missouri, United States
University of Louisville and Norton Children's Hospital
🇺🇸Louisville, Kentucky, United States