Clinical trial NCT04154189: 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: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Osteosarcoma
Keywords: Osteosarcoma
Lenvatinib
Ifosfamide
Etoposide
E7080
Relapsed or Refractory Osteosarcoma
Pediatrics
Chemotherapy
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2019-11-06
Enrollment: 81
Sex: ALL
Minimum age (years): 2
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Progression-free Survival (PFS) by Independent Imaging Review (IIR) Assessment
timeFrame: From the date of randomization to the date of the first documentation of PD or date of death, whichever occurred first (up to 20.5 months)
Secondary outcomes:
measure: Percentage of Participants With PFS at Month 4 (PFS-4m Rate) by IIR Assessment
timeFrame: Month 4
measure: Percentage of Participants With PFS at 1 Year or Month 12 (PFS-1y Rate) by IIR Assessment
timeFrame: Month 12 or 1 Year
measure: Overall Survival (OS)
timeFrame: From the date of randomization to the date of death from any cause (up to 37.1 months)
measure: Percentage of Participants With Overall Survival at 1 Year or Month 12 (OS-1y)
timeFrame: Month 12 or 1 Year
measure: Objective Response Rate at Month 4 (ORR-4m) by IIR Assessment
timeFrame: Month 4
measure: ORR by IIR Assessment
timeFrame: From the date of randomization to the date of the first documentation of CR or PR (up to 20.5 months)
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: From first dose up to 30 days after the last dose of study drug (up to 40.8 months)
measure: Treatment Arm A: Plasma Concentration of Lenvatinib
timeFrame: Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: Pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: Pre-dose (each Cycle length = 21 days)
measure: Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Scale: Generic Core Scale Score at Month 4
timeFrame: Baseline and Month 4
measure: Change From Baseline in PedsQL Scale: Cancer Module Scale Score at Month 4
timeFrame: Baseline and Month 4
measure: Number of Participants Categorized Based on Overall Palatability and Acceptability Questionnaire Responses for Suspension of Lenvatinib
timeFrame: Cycle 1 Day 1 (Cycle length = 21 days)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's of Alabama
state: Alabama
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: UCSF Benioff Children's Hospitals
state: California
city: Aurora
country: United States
facility: Childrens Hospital Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Indianapolis
country: United States
facility: Riley Hospital For Children
state: Indiana
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Children's Medical Center Dallas
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Health Care System
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse Hospital
city: Nedlands
country: Australia
facility: Perth Childrens Hospital
city: Parkville
country: Australia
facility: Royal Children's Hospital Melbourne
city: South Brisbane
country: Australia
facility: Queensland Children's Hospital
city: Westmead
country: Australia
facility: Children's Hospital at Westmead
city: Wien
country: Austria
facility: St. Anna Kinderspital
city: Gent
country: Belgium
facility: UZ Gent
city: Toronto
country: Canada
facility: Hospital For Sick Children
city: Brno
country: Czechia
facility: FN Brno 2 Detska Klinika
city: Prague
country: Czechia
facility: Fakultní nemocnice v Motole
city: Tampere
country: Finland
facility: Tampereen yliopistollinen sairaala
state: Länsi-Suomen Lääni
city: Bordeaux
country: France
facility: Centre Hospitalier Universitaire de Bordeaux, Hopital Pellegrin
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Léon Berard
city: Marseille
country: France
facility: Hopitaux de La Timone
city: Nantes
country: France
facility: Hôpital de La Mère Et de L'enfant
city: Nice
country: France
facility: CHU de Nice
city: Paris
country: France
facility: Hôpital Armand Trousseau
city: Paris
country: France
facility: Institut Curie
city: Strasbourg
country: France
facility: Hopital de Hautepierre
city: Toulouse
country: France
facility: Hôpital Des Enfants
city: Vandœuvre-lès-Nancy
country: France
facility: CHRU Nancy
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Hong Kong
country: Hong Kong
facility: Hong Kong Children's Hospital
city: Hong Kong
country: Hong Kong
facility: Prince of Wales Hospital
city: Dublin
country: Ireland
facility: Children's Health Ireland at Crumlin
city: Petach Tikva
country: Israel
facility: Schneider Children's Medical Center of Israel
city: Bologna
country: Italy
facility: Istituti Ortopedici Rizzoli
city: Firenze
country: Italy
facility: Azienda Ospedaliera A Meyer
city: Genova
country: Italy
facility: Istituto Giannina Gaslini
city: Milan
country: Italy
facility: Istituto Nazionale Dei Tumori
city: Roma
country: Italy
facility: IRCCS Ospedale Pediatrico Bambino Gesù
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System
city: Utrecht
country: Netherlands
facility: Princess Maxima Center for Pediatric Oncology
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Auckland
country: New Zealand
facility: Starship Children's Hospital
city: Singapore
country: Singapore
facility: KK Women's and Children's Hospital
city: Singapore
country: Singapore
facility: National Cancer Centre
city: Singapore
country: Singapore
facility: National University Hospital
city: Barakaldo
country: Spain
facility: Hospital Universitario de Cruces
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Deu
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebrón
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Niño Jesus
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe de Valencia
city: Göteborg
country: Sweden
facility: Drottning Silvias Barn Och Ungdomssjukhus
city: Lund
country: Sweden
facility: Skanes Universitetssjukhus Lund
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset Solna
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
city: Zürich
country: Switzerland
facility: Kinderspital Zürich - Eleonorenstiftung
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: Bristol
country: United Kingdom
facility: The Royal Hospital for Children
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Children
city: Leeds
country: United Kingdom
facility: Leeds Children Hospital
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's Hospital
city: London
country: United Kingdom
facility: UCL Cancer Institute
city: Manchester
country: United Kingdom
facility: Royal Manchester Childrens Hospital
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Newcastle
country: United Kingdom
facility: Royal Victoria Infirmary
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
Study officials:
References:
citation: Gaspar N, Venkatramani R, Hecker-Nolting S, Melcon SG, Locatelli F, Bautista F, Longhi A, Lervat C, Entz-Werle N, Casanova M, Aerts I, Strauss SJ, Thebaud E, Morland B, Nieto AC, Marec-Berard P, Gambart M, Rossig C, Okpara CE, He C, Dutta L, Campbell-Hewson Q. Lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma (ITCC-050): a multicentre, open-label, multicohort, phase 1/2 study. Lancet Oncol. 2021 Sep;22(9):1312-1321. doi: 10.1016/S1470-2045(21)00387-9. Epub 2021 Aug 17.
citation: Gaspar N, Campbell-Hewson Q, Huang J, Okpara CE, Bautista F. OLIE, ITCC-082: a Phase II trial of lenvatinib plus ifosfamide and etoposide in relapsed/refractory osteosarcoma. Future Oncol. 2021 Nov;17(32):4249-4261. doi: 10.2217/fon-2021-0743. Epub 2021 Aug 12.