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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT04154189




Registration number
NCT04154189
Ethics application status
Date submitted
1/11/2019
Date registered
6/11/2019
Date last updated
26/04/2021

Titles & IDs
Public title
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
Scientific title
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)
Secondary ID [1] 0 0
2019-003696-19
Secondary ID [2] 0 0
E7080-G000-230
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Osteosarcoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Bone
Cancer 0 0 0 0
Sarcoma (also see 'Bone') - soft tissue
Cancer 0 0 0 0
Children's - Other

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Lenvatinib
Treatment: Drugs - Ifosfamide
Treatment: Drugs - Etoposide
Treatment: Drugs - Lenvatinib

Experimental: Randomization Phase: Lenvatinib + Ifosfamide + Etoposide - Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and 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.


Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression-free Survival (PFS) - 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.
Timepoint [1] 0 0
From the date of randomization to the date of the first documentation of PD or death, whichever occurs first (up to approximately 36 months)
Secondary outcome [1] 0 0
Progression-free Survival Rate at Month 4 (PFS-4m Rate) - 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.
Timepoint [1] 0 0
Month 4
Secondary outcome [2] 0 0
Progression-free Survival Rate at 1 Year or Month 12 (PFS-1y rate) - 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.
Timepoint [2] 0 0
Month 12
Secondary outcome [3] 0 0
Overall Survival (OS) - OS is defined as the time from the date of randomization to the date of death from any cause.
Timepoint [3] 0 0
From the date of randomization to the date of death from any cause (up to approximately 36 months)
Secondary outcome [4] 0 0
Objective Response Rate at Month 4 (ORR-4m) - 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.
Timepoint [4] 0 0
Month 4
Secondary outcome [5] 0 0
Objective Response Rate (ORR) - 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.
Timepoint [5] 0 0
From the date of randomization to the date of the first documentation of CR or PR, whichever occurs first (up to approximately 36 months)
Secondary outcome [6] 0 0
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Timepoint [6] 0 0
From Baseline up to 30 days after the last dose of study drug or until resolution, whichever comes first (up to approximately 36 months)
Secondary outcome [7] 0 0
Plasma Concentration of Lenvatinib - Arm A
Timepoint [7] 0 0
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)
Secondary outcome [8] 0 0
Change From Baseline in Score for all Pediatric Quality of Life Inventory (PedsQL) Scales Including Generic Core Scales and Cancer Modules - 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.
Timepoint [8] 0 0
Up to approximately 36 months
Secondary outcome [9] 0 0
Palatability and Acceptability of the Suspension Formulation of Lenvatinib in Participants Receiving the Suspension Formulation, as Assessed Using Palatability Questionnaire - 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.
Timepoint [9] 0 0
Cycle 1 Day 1 (Cycle length = 21 days)

Eligibility
Key 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
Minimum age
2 Years
Maximum age
25 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Chris O'Brien Lifehouse Hospital - Camperdown
Recruitment hospital [2] 0 0
Perth Childrens Hospital - Nedlands
Recruitment hospital [3] 0 0
Royal Children's Hospital Melbourne - Parkville
Recruitment hospital [4] 0 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [5] 0 0
Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 0 0
- Camperdown
Recruitment postcode(s) [2] 0 0
- Nedlands
Recruitment postcode(s) [3] 0 0
- Parkville
Recruitment postcode(s) [4] 0 0
- South Brisbane
Recruitment postcode(s) [5] 0 0
- Westmead
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Colorado
Country [4] 0 0
United States of America
State/province [4] 0 0
District of Columbia
Country [5] 0 0
United States of America
State/province [5] 0 0
Indiana
Country [6] 0 0
United States of America
State/province [6] 0 0
Massachusetts
Country [7] 0 0
United States of America
State/province [7] 0 0
Mississippi
Country [8] 0 0
United States of America
State/province [8] 0 0
New Jersey
Country [9] 0 0
United States of America
State/province [9] 0 0
New York
Country [10] 0 0
United States of America
State/province [10] 0 0
Ohio
Country [11] 0 0
United States of America
State/province [11] 0 0
Texas
Country [12] 0 0
Austria
State/province [12] 0 0
Wien
Country [13] 0 0
Belgium
State/province [13] 0 0
Gent
Country [14] 0 0
Canada
State/province [14] 0 0
Toronto
Country [15] 0 0
Finland
State/province [15] 0 0
Länsi-Suomen Lääni
Country [16] 0 0
France
State/province [16] 0 0
Bordeaux
Country [17] 0 0
France
State/province [17] 0 0
Lille
Country [18] 0 0
France
State/province [18] 0 0
Lyon
Country [19] 0 0
France
State/province [19] 0 0
Marseille
Country [20] 0 0
France
State/province [20] 0 0
Nantes
Country [21] 0 0
France
State/province [21] 0 0
Nice
Country [22] 0 0
France
State/province [22] 0 0
Paris
Country [23] 0 0
France
State/province [23] 0 0
Strasbourg
Country [24] 0 0
France
State/province [24] 0 0
Toulouse
Country [25] 0 0
France
State/province [25] 0 0
VandÅ“uvre-lès-Nancy
Country [26] 0 0
France
State/province [26] 0 0
Villejuif
Country [27] 0 0
Hong Kong
State/province [27] 0 0
Hong Kong
Country [28] 0 0
Ireland
State/province [28] 0 0
Dublin
Country [29] 0 0
Israel
State/province [29] 0 0
Petach Tikva
Country [30] 0 0
Italy
State/province [30] 0 0
Bologna
Country [31] 0 0
Italy
State/province [31] 0 0
Firenze
Country [32] 0 0
Italy
State/province [32] 0 0
Milan
Country [33] 0 0
Italy
State/province [33] 0 0
Roma
Country [34] 0 0
Korea, Republic of
State/province [34] 0 0
Goyang-si
Country [35] 0 0
Korea, Republic of
State/province [35] 0 0
Seoul
Country [36] 0 0
Netherlands
State/province [36] 0 0
Utrecht
Country [37] 0 0
New Zealand
State/province [37] 0 0
Auckland
Country [38] 0 0
Singapore
State/province [38] 0 0
Singapore
Country [39] 0 0
Spain
State/province [39] 0 0
Barakaldo
Country [40] 0 0
Spain
State/province [40] 0 0
Barcelona
Country [41] 0 0
Spain
State/province [41] 0 0
Madrid
Country [42] 0 0
Spain
State/province [42] 0 0
Sevilla
Country [43] 0 0
Spain
State/province [43] 0 0
Valencia
Country [44] 0 0
Sweden
State/province [44] 0 0
Göteborg
Country [45] 0 0
Sweden
State/province [45] 0 0
Lund
Country [46] 0 0
Sweden
State/province [46] 0 0
Stockholm
Country [47] 0 0
Switzerland
State/province [47] 0 0
Lausanne
Country [48] 0 0
Switzerland
State/province [48] 0 0
Zürich
Country [49] 0 0
Taiwan
State/province [49] 0 0
Taipei
Country [50] 0 0
United Kingdom
State/province [50] 0 0
Birmingham
Country [51] 0 0
United Kingdom
State/province [51] 0 0
Glasgow
Country [52] 0 0
United Kingdom
State/province [52] 0 0
Liverpool
Country [53] 0 0
United Kingdom
State/province [53] 0 0
London
Country [54] 0 0
United Kingdom
State/province [54] 0 0
Manchester
Country [55] 0 0
United Kingdom
State/province [55] 0 0
Newcastle

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Eisai Inc.
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Merck Sharp & Dohme Corp.
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT04154189
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Eisai Medical Information
Address 0 0
Country 0 0
Phone 0 0
1-888-274-2378
Fax 0 0
Email 0 0
esi_oncmedinfo@eisai.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT04154189