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

Osteosarcoma Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04154189
• Other study ID #: E7080-G000-230
• Secondary ID: 2019-003696-19
• Status: Completed
• Phase: Phase 2
• Start date: March 23, 2020
• Est. completion date: August 17, 2023

Study information

• Verified date: May 2023
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 81
• Est. completion date: August 17, 2023
• Est. primary completion date: June 22, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 25 Years

Eligibility

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

Related Conditions & MeSH terms

• Osteosarcoma

Intervention

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.
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
Australia	Chris O'Brien Lifehouse Hospital	Camperdown
Australia	Perth Childrens Hospital	Nedlands
Australia	Royal Children's Hospital Melbourne	Parkville
Australia	Queensland Children's Hospital	South Brisbane
Australia	Children's Hospital at Westmead	Westmead
Austria	St. Anna Kinderspital	Wien
Belgium	UZ Gent	Gent
Canada	Hospital For Sick Children	Toronto
Czechia	FN Brno 2 Detska Klinika	Brno
Czechia	Fakultní nemocnice v Motole	Prague
Finland	Tampereen yliopistollinen sairaala	Tampere	Länsi-Suomen Lääni
France	Centre Hospitalier Universitaire de Bordeaux, Hopital Pellegrin	Bordeaux
France	Centre Oscar Lambret	Lille
France	Centre Léon Berard	Lyon
France	Hopitaux de La Timone	Marseille
France	Hôpital de La Mère Et de L'enfant	Nantes
France	CHU de Nice	Nice
France	Hôpital Armand Trousseau	Paris
France	Institut Curie	Paris
France	Hopital de Hautepierre	Strasbourg
France	Hôpital Des Enfants	Toulouse
France	CHRU Nancy	Vandœuvre-lès-Nancy
France	Institut Gustave Roussy	Villejuif
Hong Kong	Hong Kong Children's Hospital	Hong Kong
Hong Kong	Prince of Wales Hospital	Hong Kong
Ireland	Children's Health Ireland at Crumlin	Dublin
Israel	Schneider Children's Medical Center of Israel	Petach Tikva
Italy	Istituti Ortopedici Rizzoli	Bologna
Italy	Azienda Ospedaliera A Meyer	Firenze
Italy	Istituto Giannina Gaslini	Genova
Italy	Istituto Nazionale Dei Tumori	Milan
Italy	IRCCS Ospedale Pediatrico Bambino Gesù	Roma
Korea, Republic of	National Cancer Center	Goyang-si
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital Yonsei University Health System	Seoul
Netherlands	Princess Maxima Center for Pediatric Oncology	Utrecht
New Zealand	Auckland City Hospital	Auckland
New Zealand	Starship Children's Hospital	Auckland
Singapore	KK Women's and Children's Hospital	Singapore
Singapore	National Cancer Centre	Singapore
Singapore	National University Hospital	Singapore
Spain	Hospital Universitario de Cruces	Barakaldo
Spain	Hospital Sant Joan de Deu	Barcelona
Spain	Hospital Universitario Vall d'Hebrón	Barcelona
Spain	Hospital Infantil Universitario Niño Jesus	Madrid
Spain	Hospital Universitario Fundacion Jimenez Diaz	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Universitari i Politecnic La Fe de Valencia	Valencia
Sweden	Drottning Silvias Barn Och Ungdomssjukhus	Göteborg
Sweden	Skanes Universitetssjukhus Lund	Lund
Sweden	Karolinska Universitetssjukhuset Solna	Stockholm
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne
Switzerland	Kinderspital Zürich - Eleonorenstiftung	Zürich
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
United Kingdom	Birmingham Children's Hospital	Birmingham
United Kingdom	The Royal Hospital for Children	Bristol
United Kingdom	Royal Hospital for Children	Glasgow
United Kingdom	Leeds Children Hospital	Leeds
United Kingdom	Alder Hey Children's Hospital	Liverpool
United Kingdom	UCL Cancer Institute	London
United Kingdom	Royal Manchester Childrens Hospital	Manchester
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Royal Victoria Infirmary	Newcastle
United Kingdom	John Radcliffe Hospital	Oxford
United States	Childrens Hospital Colorado	Aurora	Colorado
United States	Children's of Alabama	Birmingham	Alabama
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Children's Medical Center Dallas	Dallas	Texas
United States	Cook Children's Health Care System	Fort Worth	Texas
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Texas Children's Hospital	Houston	Texas
United States	Riley Hospital For Children	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Children's Hospital of Orange County	Orange	California
United States	UCSF Benioff Children's Hospitals	San Francisco	California
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Eisai Inc.	Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czechia,  Finland,  France,  Hong Kong,  Ireland,  Israel,  Italy,  Korea, Republic of,  Netherlands,  New Zealand,  Singapore,  Spain,  Sweden,  Switzerland,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS) by Independent Imaging Review (IIR) Assessment	PFS as assessed by IIR was defined as the time from the date of randomization to the date of the first documentation of PD or date of death (whichever occurred first), as determined using RECIST v1.1. PD was defined as at least a 20 percent (%) increase or 5 millimeter (mm) increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was analyzed using Kaplan-Meier method.	From the date of randomization to the date of the first documentation of PD or date of death, whichever occurred first (up to 14.2 months)
Secondary	Percentage of Participants With PFS at Month 4 (PFS-4m Rate) by IIR Assessment	PFS rate at 4 months as assessed by IIR was defined as the percentage of participants who were alive and without PD at 4 months from the randomization date using RECIST v1.1. PD was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. The PFS-4m was estimated using the Kaplan-Meier method. Final analysis data was reported for this outcome measure.	Month 4
Secondary	Percentage of Participants With PFS at 1 Year or Month 12 (PFS-1y Rate) by IIR Assessment	PFS-1y rate as assessed by IIR was defined as the percentage of participants who were alive and without PD at 1 year from randomization date using RECIST v1.1. PD was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS-1y rate was estimated using Kaplan-Meier method. Final analysis data was reported for this outcome measure.	Month 12 or 1 Year
Secondary	Overall Survival (OS)	OS is defined as the time from the date of randomization to the date of death from any cause. Data for this outcome measure will be reported after study completion (anticipated study completion date is March 2025).	From the date of randomization to the date of death from any cause (up to approximately 59 months)
Secondary	Percentage of Participants With Overall Survival at 1 Year or Month 12 (OS-1y)	OS-1y was defined as the time from the date of randomization to the date of death from any cause assessed up to 1 year. OS was calculated using the Kaplan-Meier method. Final analysis data was reported for this outcome measure.	Month 12 or 1 Year
Secondary	Objective Response Rate at Month 4 (ORR-4m) by IIR Assessment	ORR-4m was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) as determined by IIR using RECIST v1.1 within the first 4 months. CR: defined as the 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 to less than (<) 10 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. 95% confidence interval (CI) of ORR was calculated using the method of Clopper and Pearson. Final analysis data was reported for this outcome measure.	Month 4
Secondary	ORR by IIR Assessment	ORR by IIR was defined as the percentage of participants with best overall response of CR or PR determined using RECIST v1.1. CR: defined as the 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 to <10 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. 95% CI of ORR was calculated using the method of Clopper and Pearson. Final analysis data was reported for this outcome measure.	From the date of randomization to the date of the first documentation of CR or PR, whichever occurred first (up to approximately 14.2 months)
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs)	TEAE was defined as an adverse event (AE) that emerged during time from first dose to 30 days following last dose of drug, 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 pretreatment state, when AE was continuous. SAE was defined as untoward medical occurrence that at any dose resulted in death; was life threatening; resulted in persistent or significant disability; was congenital anomaly or medically important due to other reasons than above mentioned criteria. Data for this outcome measure will be reported after study completion (anticipated study completion date is March 2025).	From date of first dose up to 30 days after the last dose of study drug (up to approximately 60 months)
Secondary	Treatment Arm A: Plasma Concentration of Lenvatinib	Plasma concentration of lenvatinib in participants from Treatment Arm A (Lenvatinib + Ifosfamide + Etoposide) at different time points were reported. As planned, data for this outcome measure was analyzed for treatment arm A only. Lenvatinib concentration in plasma was quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Final analysis data was reported for this outcome measure.	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)
Secondary	Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Scale: Generic Core Scale Score at Month 4	Health-Related Quality of Life (HRQoL): PedsQL 4.0 Generic Core Scale is a multidimensional scale. It included assessment of 4 dimensions: physical functioning (8 items), emotional functioning (8 items), social functioning (8 items), and school functioning (5 items - children greater than or equal to [>=] 5 years, adults; 3 items - toddlers [aged 2-4 years]). Each item was reported using a 5-point Likert scale, items were then reverse-scored and linearly transformed to a 0 to 100 scale. Generic Core Scale total score: sum of all the items divided by the number of items answered across all the scales. Total score ranges from 0 to 100, where higher scores=better HRQoL, lower scores=worse HRQoL. Final analysis data was reported for this outcome measure.	Baseline and Month 4
Secondary	Change From Baseline in PedsQL Scale: Cancer Module Scale Score at Month 4	HRQoL: PedsQL 3.0 Cancer Module Scale measured pediatric cancer-specific HRQoL. It included assessment of 8 dimensions: pain and hurt (2 items), nausea (5 items), procedural anxiety (3 items), treatment anxiety (3 items), worry (3 items), cognitive problems (3 items - toddlers [aged 2-4], 4 items - young children [aged 5-7]; 5 items for children aged >=8 years, adults), perceived physical appearance (3 items), communication (3 items). Each item was reported using a 5-point Likert scale, items were then reverse-scored and linearly transformed to a 0 to 100 scale. Cancer Module total score: sum of all items divided by the number of items answered on all the scales. Total score ranges from 0 to 100, where higher scores=better HRQoL, lower scores=worse HRQoL. Final analysis data was reported for this outcome measure.	Baseline and Month 4
Secondary	Number of Participants Categorized Based on Overall Palatability and Acceptability Questionnaire Responses for Suspension of Lenvatinib	The palatability and acceptability of lenvatinib oral suspension formulation was assessed using the Palatability Questionnaire. In the questionnaire, participants were asked to answer palatability and acceptability of lenvatinib suspension considering the following elements: taste, appearance, smell, how does it feel in the mouth and overall acceptability in terms of 7 responses: Super good, really good, good, may be good or may be bad, bad, really bad, super bad. In this outcome measure, number of participants have been reported per their overall palatability and acceptability responses. Final analysis data was reported for this outcome measure.	Cycle 1 Day 1 (Cycle length = 21 days)