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

NCT04154189 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: E7080-G000-2302019-003696-19
• Study Type: interventional
• Target: 81
• Locations: 20 countries
• Sites: 79

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.

Conditions

Osteosarcoma

Keywords

Osteosarcoma; Lenvatinib; Ifosfamide; Etoposide; E7080; Relapsed or Refractory Osteosarcoma; Pediatrics; Chemotherapy

Outcome Measures

Primary Outcomes (1)

• 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 20.5 months)

Secondary Outcomes (11)

• Percentage of Participants With PFS at Month 4 (PFS-4m Rate) by IIR Assessment

  Month 4

• Percentage of Participants With PFS at 1 Year or Month 12 (PFS-1y Rate) by IIR Assessment

  Month 12 or 1 Year

• Overall Survival (OS)

  From the date of randomization to the date of death from any cause (up to 37.1 months)

• Percentage of Participants With Overall Survival at 1 Year or Month 12 (OS-1y)

  Month 12 or 1 Year

• Objective Response Rate at Month 4 (ORR-4m) by IIR Assessment

  Month 4

Study Arms (2)

Randomization Phase: Lenvatinib + Ifosfamide + Etoposide

EXPERIMENTAL

Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide.

Drug: Lenvatinib; Drug: Ifosfamide; Drug: Etoposide

Randomization Phase: Ifosfamide + Etoposide

ACTIVE COMPARATOR

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.

Drug: Ifosfamide; Drug: Etoposide; Drug: Lenvatinib

Interventions

Lenvatinib DRUG

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.

Also known as: E7080

Randomization Phase: Lenvatinib + Ifosfamide + Etoposide

Ifosfamide DRUG

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.

Randomization Phase: Ifosfamide + Etoposide; Randomization Phase: Lenvatinib + Ifosfamide + Etoposide

Etoposide DRUG

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.

Randomization Phase: Ifosfamide + Etoposide; Randomization Phase: Lenvatinib + Ifosfamide + Etoposide

Eligibility Criteria

• Age: 2 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Histologically or cytologically confirmed diagnosis of high grade osteosarcoma
• Refractory or relapsed osteosarcoma after 1 to 2 prior lines of systemic treatments
• Measurable or evaluable disease per RECIST 1.1.
• Life expectancy of 12 weeks or more
• 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
• Adequate organ function per blood work
• Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF) \>=50% at baseline as determined by echocardiography or multigated acquisition (MUGA) scan
• 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
• 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
• Must have no prior history of lenvatinib treatment
• Eligibility for optional lenvatinib crossover:
• Disease progression per RECIST 1.1 (as confirmed by IIR for all participants who crossover prior to the study data-cut)
• No new systemic anti-cancer medication administered after the last dose of study drugs

You may not qualify if:

• Study is ongoing
• Any active infection or infectious illness unless fully recovered prior to Cycle 1 Day 1 (that is, no longer requiring systemic treatment)
• 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
• 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)
• 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
• 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 \[msec\])
• 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
• Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that in the opinion of the investigator might affect the absorption of lenvatinib
• Pre-existing Grade \>=3 gastrointestinal or non-gastrointestinal fistula
• 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
• History of ifosfamide-related Grade \>=3 nephrotoxicity or encephalopathy
• Known to be human immunodeficiency virus (HIV) positive
• 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

Sponsors & Collaborators

• Eisai Inc.: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (84)

Children's of Alabama

Birmingham, Alabama, 35233, United States

Location

Loma Linda University Medical Center

Loma Linda, California, 92354, United States

Location

Children's Hospital of Orange County

Orange, California, 92868, United States

Location

UCSF Benioff Children's Hospitals

San Francisco, California, 94143, United States

Location

Childrens Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Riley Hospital For Children

Indianapolis, Indiana, 46202, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

University of Mississippi Medical Center

Jackson, Mississippi, 39216, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Children's Medical Center Dallas

Dallas, Texas, 75235, United States

Location

Cook Children's Health Care System

Fort Worth, Texas, 76104, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Chris O'Brien Lifehouse Hospital

Camperdown, Australia

Location

Perth Childrens Hospital

Nedlands, Australia

Location

Royal Children's Hospital Melbourne

Parkville, Australia

Location

Queensland Children's Hospital

South Brisbane, Australia

Location

Children's Hospital at Westmead

Westmead, Australia

Location

St. Anna Kinderspital

Vienna, Austria

Location

UZ Gent

Ghent, Belgium

Location

Hospital For Sick Children

Toronto, Canada

Location

FN Brno 2 Detska Klinika

Brno, Czechia

Location

Fakultní nemocnice v Motole

Prague, Czechia

Location

Tampereen yliopistollinen sairaala

Tampere, Länsi-Suomen Lääni, FI-33520, Finland

Location

Centre Hospitalier Universitaire de Bordeaux, Hopital Pellegrin

Bordeaux, France

Location

Centre Oscar Lambret

Lille, France

Location

Centre Léon Berard

Lyon, France

Location

Hopitaux de La Timone

Marseille, France

Location

Hôpital de La Mère Et de L'enfant

Nantes, France

Location

CHU de Nice

Nice, France

Location

Hôpital Armand Trousseau

Paris, France

Location

Institut Curie

Paris, France

Location

Hopital de Hautepierre

Strasbourg, France

Location

Hôpital Des Enfants

Toulouse, France

Location

CHRU Nancy

Vandœuvre-lès-Nancy, France

Location

Institut Gustave Roussy

Villejuif, France

Location

Hong Kong Children's Hospital

Hong Kong, Hong Kong

Location

Prince of Wales Hospital

Hong Kong, Hong Kong

Location

Children's Health Ireland at Crumlin

Dublin, Ireland

Location

Schneider Children's Medical Center of Israel

Petah Tikva, Israel

Location

Istituti Ortopedici Rizzoli

Bologna, Italy

Location

Azienda Ospedaliera A Meyer

Florence, Italy

Location

Istituto Giannina Gaslini

Genova, Italy

Location

Istituto Nazionale Dei Tumori

Milan, Italy

Location

IRCCS Ospedale Pediatrico Bambino Gesù

Roma, Italy

Location

Princess Maxima Center for Pediatric Oncology

Utrecht, Netherlands

Location

Auckland City Hospital

Auckland, New Zealand

Location

Starship Children's Hospital

Auckland, New Zealand

Location

KK Women's and Children's Hospital

Singapore, Singapore

Location

National Cancer Centre

Singapore, Singapore

Location

National University Hospital

Singapore, Singapore

Location

National Cancer Center

Goyang-si, South Korea

Location

Asan Medical Center

Seoul, South Korea

Location

Samsung Medical Center

Seoul, South Korea

Location

Seoul National University Hospital

Seoul, South Korea

Location

Severance Hospital Yonsei University Health System

Seoul, South Korea

Location

Hospital Universitario de Cruces

Barakaldo, Spain

Location

Hospital Sant Joan de Deu

Barcelona, Spain

Location

Hospital Universitario Vall d'Hebrón

Barcelona, Spain

Location

Hospital Infantil Universitario Niño Jesus

Madrid, Spain

Location

Hospital Universitario Fundacion Jimenez Diaz

Madrid, Spain

Location

Hospital Universitario La Paz

Madrid, Spain

Location

Hospital Universitario Virgen del Rocio

Seville, Spain

Location

Hospital Universitari i Politecnic La Fe de Valencia

Valencia, Spain

Location

Drottning Silvias Barn Och Ungdomssjukhus

Gothenburg, Sweden

Location

Skanes Universitetssjukhus Lund

Lund, Sweden

Location

Karolinska Universitetssjukhuset Solna

Stockholm, Sweden

Location

Centre Hospitalier Universitaire Vaudois

Lausanne, Switzerland

Location

Kinderspital Zürich - Eleonorenstiftung

Zurich, Switzerland

Location

National Taiwan University Hospital

Taipei, Taiwan

Location

Taipei Veterans General Hospital

Taipei, Taiwan

Location

Birmingham Children's Hospital

Birmingham, United Kingdom

Location

The Royal Hospital for Children

Bristol, United Kingdom

Location

Royal Hospital for Children

Glasgow, United Kingdom

Location

Leeds Children Hospital

Leeds, United Kingdom

Location

Alder Hey Children's Hospital

Liverpool, United Kingdom

Location

UCL Cancer Institute

London, United Kingdom

Location

Royal Manchester Childrens Hospital

Manchester, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, United Kingdom

Location

Royal Victoria Infirmary

Newcastle, United Kingdom

Location

John Radcliffe Hospital

Oxford, United Kingdom

Location

Related Publications (3)

• Gaspar N, Hung GY, Strauss SJ, Campbell-Hewson Q, Dela Cruz FS, Glade Bender JL, Koh KN, Whittle SB, Chan GC, Gerber NU, Palmu S, Morgenstern DA, Longhi A, Baecklund F, Lee JA, Locatelli F, Marquez Vega C, Janeway KA, McCowage G, McCabe MG, Bidadi B, Huang J, McKenzie J, Okpara CE, Bautista F; OLIE Study Investigators. Lenvatinib Plus Ifosfamide and Etoposide in Children and Young Adults With Relapsed Osteosarcoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2024 Dec 1;10(12):1645-1653. doi: 10.1001/jamaoncol.2024.4381.

  PMID: 39418029 DERIVED

• 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.

  PMID: 34416158 DERIVED

• 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.

  PMID: 34382412 DERIVED

MeSH Terms

Conditions

Osteosarcoma; Recurrence

Interventions

lenvatinib; Ifosfamide; Etoposide

Condition Hierarchy (Ancestors)

Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cyclophosphamide; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates

Results Point of Contact

• Title: Eisai Medical Information
• Organization: Eisai Inc.

esi_oncmedinfo@eisai.com

1-888-274-2378

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 2019
• First Posted: November 6, 2019
• Study Start: March 23, 2020
• Primary Completion: June 22, 2022
• Study Completion: August 17, 2023
• Last Updated: July 22, 2024
• Results First Posted: August 7, 2023

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share

Locations

SG (3); FI (1); AU (1); CZ (2); BE (1); FR (12); IT (5); NZ (2); IE (1); KR (5); NL (1); ES (8); GB (10); IL (1); SE (3); HK (2); CA (1); CH (2); TW (2); US (16)