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A Study to Compare the Efficacy and Safety of Ifosfamide and Etoposide With or Without Lenvatinib in Children, Adolescents and Young Adults With Relapsed and Refractory Osteosarcoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04154189
Recruitment Status : Recruiting
First Posted : November 6, 2019
Last Update Posted : November 27, 2020
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Eisai Inc.

Tracking Information
First Submitted Date  ICMJE November 1, 2019
First Posted Date  ICMJE November 6, 2019
Last Update Posted Date November 27, 2020
Actual Study Start Date  ICMJE March 23, 2020
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 12, 2020)
Progression-free Survival (PFS) [ Time Frame: From the date of randomization to the date of the first documentation of PD or death, whichever occurs first (up to approximately 36 months) ]
PFS by independent imaging review (IIR) is defined as the time from the date of randomization to the date of the first documentation of PD or death (whichever occurs first) as determined by IIR using RECIST 1.1.
Original Primary Outcome Measures  ICMJE
 (submitted: November 5, 2019)
Progression-free Survival Rate at Month 4 (PFS-4m Rate) [ Time Frame: Month 4 ]
PFS-4m by independent imaging review (IIR) is defined as the percentage of participants who will be alive and without PD at 4 months from the randomization date as determined by IIR of radiological imaging using RECIST 1.1.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 12, 2020)
  • Progression-free Survival Rate at Month 4 (PFS-4m Rate) [ Time Frame: Month 4 ]
    PFS-4m rate by IIR is defined as the percentage of participants who will be alive and without PD at 4 months from the randomization date as determined by IIR of radiological imaging using RECIST 1.1.
  • Progression-free Survival Rate at 1 Year or Month 12 (PFS-1y rate) [ Time Frame: Month 12 ]
    Progression-free survival rate at 1 year or 12 months (PFS-1y rate) by IIR is defined as the percentage of participants who will be alive and without PD at 1 year from the randomization date as determined by IIR of radiological imaging using RECIST 1.1.
  • Overall Survival (OS) [ Time Frame: From the date of randomization to the date of death from any cause (up to approximately 36 months) ]
    OS is defined as the time from the date of randomization to the date of death from any cause.
  • Objective Response Rate at Month 4 (ORR-4m) [ Time Frame: Month 4 ]
    ORR-4m is defined as the percentage of participants who will have best overall response of complete response (CR) or partial response (PR) as determined by IIR using RECIST 1.1 within the first 4 months.
  • Objective Response Rate (ORR) [ Time Frame: From the date of randomization to the date of the first documentation of CR or PR, whichever occurs first (up to approximately 36 months) ]
    ORR by IIR is defined as the percentage of participants who will have best overall response of CR or PR as determined by IIR using RECIST 1.1.
  • Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: From Baseline up to 30 days after the last dose of study drug or until resolution, whichever comes first (up to approximately 36 months) ]
  • Plasma Concentration of Lenvatinib - Arm A [ Time Frame: Cycle 1 Day 1: 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 15: Predose, 0.5-4 hours and 6-10 hours postdose; Cycle 2 Day 1: Predose (Cycle length = 21 days) ]
  • Change From Baseline in Score for all Pediatric Quality of Life Inventory (PedsQL) Scales Including Generic Core Scales and Cancer Modules [ Time Frame: Up to approximately 36 months ]
    Health-Related Quality of Life (HRQOL): The PedsQL is a modular instrument designed to measure HRQoL in pediatric and adults population. The PedsQL 4.0 Generic Core Scales are multidimensional child self-report and parent proxy-report scales developed as the generic core measure to be integrated with the PedsQL disease specific modules. The PedsQL 3.0 Cancer Module was designed to measure pediatric cancer specific HRQOL.
  • Palatability and Acceptability of the Suspension Formulation of Lenvatinib in Participants Receiving the Suspension Formulation, as Assessed Using Palatability Questionnaire [ Time Frame: Cycle 1 Day 1 (Cycle length = 21 days) ]
    The palatability and acceptability of the suspension formulation questionnaire will assess the following parameters: taste, appearance, smell, how does it feel in the mouth and overall acceptability. Each parameter will be measured using a 7-point facial Hedonic scale grading parameters according to the following values: super bad, really bad, bad, may be good or may be bad, good, really good, or super good. For each parameter, the percentage of responses per grading value will be described.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 5, 2019)
  • Progression-free Survival Rate at 1 Year or Month 12 (PFS-1y rate) [ Time Frame: Month 12 ]
    Progression-free survival rate at 1 year or 12 months (PFS-1y rate) by IIR is defined as the percentage of participants who will be alive and without PD at 1 year from the randomization date as determined by IIR of radiological imaging using RECIST 1.1.
  • Progression-free Survival (PFS) [ Time Frame: From the date of randomization to the date of the first documentation of PD or death, whichever occurs first (up to approximately 36 months) ]
    PFS by IIR is defined as the time from the date of randomization to the date of the first documentation of PD or death (whichever occurs first) as determined by IIR using RECIST 1.1.
  • Overall Survival (OS) [ Time Frame: From the date of randomization to the date of death from any cause (up to approximately 36 months) ]
    OS is defined as the time from the date of randomization to the date of death from any cause.
  • Objective Response Rate (ORR) [ Time Frame: Month 4 ]
    ORR by IIR at 4 months is defined as the percentage of participants who will have best overall response of complete response (CR) or partial response (PR) as determined by IIR using RECIST 1.1 within the first 4 months.
  • Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: From Baseline up to 30 days after the last dose of study drug or until resolution, whichever comes first (up to approximately 36 months) ]
  • Plasma Concentration of Lenvatinib - Arm A [ Time Frame: Cycle 1 Day 1: 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 15: Predose, 0.5-4 hours and 6-10 hours postdose; Cycle 2 Day 1: Predose (Cycle length = 21 days) ]
  • Change From Baseline in Score for all Pediatric Quality of Life Inventory (PedsQL) Scales Including Generic Core Scales and Cancer Modules [ Time Frame: Up to approximately 36 months ]
    Health-Related Quality of Life (HRQOL): The PedsQL is a modular instrument designed to measure HRQoL in pediatric and adults population. The PedsQL 4.0 Generic Core Scales are multidimensional child self-report and parent proxy-report scales developed as the generic core measure to be integrated with the PedsQL disease specific modules. The PedsQL 3.0 Cancer Module was designed to measure pediatric cancer specific HRQOL.
  • Palatability and Acceptability of the Suspension Formulation of Lenvatinib in Participants Receiving the Suspension Formulation, as Assessed Using Palatability Questionnaire [ Time Frame: Cycle 1 Day 1 (Cycle length = 21 days) ]
    The palatability and acceptability of the suspension formulation questionnaire will assess the following parameters: taste, appearance, smell, how does it feel in the mouth and overall acceptability. Each parameter will be measured using a 7-point Hedonic scale which is a Visual Analog Scale (VAS) grading parameters according to the following values: super bad, really bad, bad, may be good or may be bad, good, really good, or super good. For each parameter, the percentage of responses per grading value will be described.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Compare the Efficacy and Safety of Ifosfamide and Etoposide With or Without Lenvatinib in Children, Adolescents and Young Adults With Relapsed and Refractory Osteosarcoma
Official Title  ICMJE A Multicenter, Open-label, Randomized Phase 2 Study to Compare the Efficacy and Safety of Lenvatinib in Combination With Ifosfamide and Etoposide Versus Ifosfamide and Etoposide in Children, Adolescents and Young Adults With Relapsed or Refractory Osteosarcoma (OLIE)
Brief Summary This Is a Multicenter, Randomized, Open-Label, Parallel-Group, Phase 2 Study to Compare the Efficacy and Safety of Lenvatinib in Combination with Ifosfamide and Etoposide Versus Ifosfamide and Etoposide in Children, Adolescents, and Young Adults with Relapsed or Refractory Osteosarcoma.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Osteosarcoma
Intervention  ICMJE
  • Drug: Lenvatinib

    Lenvatinib 14 milligrams per square meter (mg/m^2) capsules will be administered once daily on Days 1 to 21 of each 21-day cycle until disease progression (PD), development of unacceptable toxicity, participant request, withdrawal of consent, or discontinuation of study by the sponsor.

    An extemporaneous suspension of lenvatinib capsules may be used for participants unable to swallow capsules.

    Other Name: E7080
  • Drug: Ifosfamide
    Ifosfamide 3000 milligrams per square meter per day (mg/m^2/day) intravenous infusion will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles.
  • Drug: Etoposide
    Etoposide 100 mg/m^2/day intravenous infusion will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles.
  • Drug: Lenvatinib
    Lenvatinib 14 mg/m^2 capsules will be administered once daily on Days 1 to 21 of each 21-day cycle until the next PD (per response evaluation criteria in solid tumors [RECIST] 1.1 as assessed by investigator), development of unacceptable toxicity, participant request, or withdrawal of consent, whichever occurs first.
    Other Name: E7080
Study Arms  ICMJE
  • Experimental: Randomization Phase: Lenvatinib + Ifosfamide + Etoposide
    Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide.
    Interventions:
    • Drug: Lenvatinib
    • Drug: Ifosfamide
    • Drug: Etoposide
  • Active Comparator: Randomization Phase: Ifosfamide + Etoposide and Lenvatinib (Optional)
    Participants with relapsed or refractory osteosarcoma will receive ifosfamide with etoposide. Participants with relapsed or refractory osteosarcoma may receive optional lenvatinib plus or minus chemotherapy (Ifosfamide and Etoposide) if disease progression is observed in study.
    Interventions:
    • Drug: Ifosfamide
    • Drug: Etoposide
    • Drug: Lenvatinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 5, 2019)
72
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Histologically or cytologically confirmed diagnosis of high grade osteosarcoma
  2. Refractory or relapsed osteosarcoma after 1 to 2 prior lines of systemic treatments
  3. Measurable or evaluable disease per RECIST 1.1.
  4. Life expectancy of 12 weeks or more
  5. Lansky play score greater than or equal to (>=) 50 Percent (%) or Karnofsky Performance Status score >=50%. Use Karnofsky for participants >=16 years of age and Lansky for participants less than (<)16 years of age. Participants who are unable to walk because of paralysis, but who are able to perform activities of daily living while wheelchair bound, will be considered ambulatory for the purpose of assessing the performance score
  6. Adequate organ function per blood work
  7. Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF) >=50% at baseline as determined by echocardiography or multigated acquisition (MUGA) scan
  8. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as:

    BP <95th percentile for sex, age, and height/length at screening (as per National Heart Lung and Blood Institute guidelines) and no change in antihypertensive medications within 1 week prior to Cycle 1 Day 1. Participants >18 years of age should have BP less than or equal to (<=) 150/90 millimeters of Mercury at screening and no change in antihypertensive therapy within 1 week prior to Cycle 1 Day 1

  9. Washout before Cycle 1 Day 1 of 3 weeks in case of prior chemotherapy, 6 weeks if treatment included nitrosoureas; 4 weeks for definitive radiotherapy, 2 weeks for palliative radiotherapy; and 3 months from high-dose chemotherapy and stem cell rescue. For all other anti-cancer therapies, washout before Cycle 1 Day 1 of at least 5 half-lives (or at least 28 days, whichever is shorter). Participants must have recovered [to Grade <=1, except for alopecia, ototoxicity, and Grade <=2 peripheral neuropathy, per common terminology criteria for adverse events (CTCAE) v5.0] from the acute toxic effects of all prior anticancer therapy before Cycle 1 Day 1
  10. Must have no prior history of lenvatinib treatment

Eligibility for optional lenvatinib crossover:

  1. Disease progression per RECIST 1.1 (as confirmed by IIR for all participants who crossover prior to the study data-cut)
  2. No new systemic anti-cancer medication administered after the last dose of study drugs
  3. Meets all safety parameters listed in the inclusion criteria and none listed in the exclusion criteria
  4. Study is ongoing

Exclusion Criteria:

  1. Any active infection or infectious illness unless fully recovered prior to Cycle 1 Day 1 (that is, no longer requiring systemic treatment)
  2. Participants with central nervous system metastases are not eligible, unless they have completed local therapy (example, whole brain radiation therapy, surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 2 weeks before Cycle 1 Day 1
  3. Active second malignancy within 2 years prior to enrollment ([in addition to osteosarcoma], but not including definitively treated superficial melanoma, carcinoma-in-situ, basal or squamous cell carcinoma of the skin)
  4. Has had major surgery within 3 weeks prior to Cycle 1 Day 1. Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility
  5. A clinically significant electrocardiogram (ECG) abnormality, including a marked baseline prolonged QT or corrected QT (QTc) interval (example, a repeated demonstration of a QTc interval greater than [>] 480 millisecond [msec])
  6. Has clinically significant cardiovascular disease within 6 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability. Note: Medically controlled arrhythmia would be permitted
  7. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that in the opinion of the investigator might affect the absorption of lenvatinib
  8. Pre-existing Grade >=3 gastrointestinal or non-gastrointestinal fistula
  9. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least 1 divided [/] by 2 teaspoon) within 3 weeks prior to Cycle 1 Day 1
  10. Radiographic evidence of intratumoral cavitation, encasement, or invasion of a major blood vessel. Additionally, the degree of proximity to major blood vessels should be considered for exclusion because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after lenvatinib therapy
  11. History of ifosfamide-related Grade >=3 nephrotoxicity or encephalopathy
  12. Known to be human immunodeficiency virus (HIV) positive
  13. Known active Hepatitis B (example, Hepatitis B surface antigen [HBsAg] reactive) or Hepatitis C (example, hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected). Note: Testing for Hepatitis B or Hepatitis C is required at screening only when mandated by local health authority
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 25 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Eisai Medical Information 1-888-274-2378 esi_oncmedinfo@eisai.com
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Finland,   France,   Hong Kong,   Ireland,   Israel,   Korea, Republic of,   Netherlands,   New Zealand,   Singapore,   Spain,   Sweden,   Switzerland,   Taiwan,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04154189
Other Study ID Numbers  ICMJE E7080-G000-230
2019-003696-19 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Eisai's data sharing commitment and further information on how to request data can be found on our website http://eisaiclinicaltrials.com/.
Responsible Party Eisai Inc.
Study Sponsor  ICMJE Eisai Inc.
Collaborators  ICMJE Merck Sharp & Dohme Corp.
Investigators  ICMJE Not Provided
PRS Account Eisai Inc.
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP