Study of Lenvatinib in Children and Adolescents With Refractory or Relapsed Solid Malignancies and Young Adults With Osteosarcoma

NCT02432274 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: E7080-G000-2072013-005534-38
• Study Type: interventional
• Target: 117
• Locations: 6 countries
• Sites: 19

Brief Summary

This is a phase 1/2 study evaluating safety, tolerability, and efficacy of lenvatinib as single-agent, and in combination with chemotherapy (ifosfamide and etoposide) in children and adolescents with refractory or relapsed solid malignancies including differentiated thyroid carcinoma (single agent lenvatinib) and osteosarcoma (single agent and combination lenvatinib).

Conditions

Tumors; Solid Malignant Tumors; Osteosarcoma; Differentiated Thyroid Cancer (DTC)

Keywords

E7080; Lenvatinib; Solid malignancies; Osteosarcoma; Differentiated Thyroid Cancer

Outcome Measures

Primary Outcomes (5)

• Cohort 1: Recommended Dose (RD) of Lenvatinib

  RD was defined as the dose that had a dose limiting toxicity (DLT) rate closest to the targeted 20% rate. DLT was an adverse drug reaction and was assessed according to common terminology criteria for adverse events (CTCAE) version (v) 4.03 defined as 1) Grade 4 neutropenia for greater than or equal to (\>=) 7 days, 2) Grade \>=3 thrombocytopenia with bleeding, or lasting greater than (\>) 7 days, 3) Grade \>=3 febrile neutropenia, 4) Next course of chemotherapy delayed for \>=7 days, 5) Grade \>=3 non-hematologic toxicity persisting \>7 days optimal supportive care, 6) Grade 4 hypertension, confirmed systolic or diastolic blood pressure \>25 millimeters of mercury (mmHg) above the 95th percentile for age, or an elevated diastolic blood pressure (that is, \>95th percentile for age) not controlled by a single antihypertensive medication within 14 days of use, 7) Grade 3 proteinuria, 8) Any recurrent Grade 2 non-hematological toxicity requiring \>=2 interruption and dose reductions.

  Cycle 1 (28 days)

• Cohort 2A: Number of Participants With Objective Response (OR) of Complete Response (CR) or Partial Response (PR)

  OR was defined as participants with best overall response (BOR) of CR or PR as assessed by investigator based on response evaluation criteria in solid tumors (RECIST) version (v) 1.1. For OR, the BOR was defined as the best response (CR or PR for \>4 weeks) recorded from the start of the treatment until PD or death whichever occurred first. CR was 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 \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.

  From date of first dose of study drug until first documentation of PD or death, whichever occurred first (until the data cut-off date, 31 May 2019)

• Cohort 2A: Number of Participants With Best Overall Response (BOR)

  BOR was defined as the best response of CR or PR for \>4 weeks or SD for \>=7 weeks recorded from the start of the treatment until PD or death, whichever occurred first based on RECIST v1.1. CR: 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 \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.

  From first dose of study drug until PD or death, whichever occurred first (until the data cut-off date, 31 May 2019)

• Cohorts 2B and 3B: Progression-free Survival (PFS) Rate at Month 4

  Progression free survival at Month 4 (PFS-4) rate was defined as the percentage of participants who were alive and without PD at Month 4 after the first dose of study drug, based on RECIST v1.1, using a binomial proportion with corresponding 95% confidence interval (CI). PD: \>= 20% increase in sum of diameters of target lesions, reference-smallest sum recorded in study (sum at baseline if that was smallest). Sum of diameters must have absolute increase of \>=5 mm. Appearance of \>=1 new lesions also considered PD.

  At Month 4

• Cohort 3A: Recommended Dose (RD) of Lenvatinib When Given in Combination With Etoposide and Ifosfamide

  RD of lenvatinib when given in combination with ifosfamide and etoposide was defined as dose that resulted in no more than 1 DLT per 6 participants,or hematologic DLT in 1 participant and nonhematologic DLT in another participant per 6 participants,upon repeating same dose level.DLT was adverse drug reaction and assessed per CTCAE v4.03 defined as 1)Grade 4 neutropenia for \>=10 days,2)Grade \>=3 thrombocytopenia with bleeding,or lasting \>=10 days,3)Grade \>=3 febrile neutropenia lasting \>=7 days,4)Next course of chemotherapy delayed for \>=7 days,5)Grade \>=3 nonhematologic toxicity persisting \>7 days despite optimal supportive care,6)Grade 4 hypertension,confirmed systolic or diastolic blood pressure \>25 mmHg above 95th percentile for age,or elevated diastolic blood pressure(\>95th percentile for age)not controlled by single antihypertensive medication within 14 days use,7)Grade 3 proteinuria,8)Any recurrent Grade 2 nonhematological toxicity requiring \>=2 interruption and dose reductions.

  Cycle 1 (21 days)

Secondary Outcomes (16)

• Cohorts 1, 2B, 3A, and 3B: Number of Participants With Best Overall Response (BOR)

  From date of first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)

• Cohorts 1, 2B, 3A, and 3B: Objective Response Rate (ORR)

  From date of first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)

• Cohorts 1, 2A, 2B, 3A and 3B: Duration of Response (DOR)

  First documentation of CR/PR until first documentation of PD (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)

• Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Who Experienced Disease Control

  From first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)

• Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Experienced Clinical Benefit

  From first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)

Study Arms (5)

Cohort 1: Single-Agent Dose-Finding

EXPERIMENTAL

Children and adolescents with relapsed or refractory solid malignant tumors.

Drug: Lenvatinib

Cohort 2A: Single-agent Expansion (DTC)

EXPERIMENTAL

Children and adolescents with 131 iodine-refractory DTC.

Drug: Lenvatinib

Cohort 2B: Single-agent Expansion (Osteosarcoma)

EXPERIMENTAL

Participants with relapsed or refractory osteosarcoma.

Drug: Lenvatinib

Cohort 3A: Combination Dose-finding

EXPERIMENTAL

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

Drug: Lenvatinib; Drug: Ifosfamide; Drug: Etoposide

Cohort 3B: Combination Expansion

EXPERIMENTAL

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

Drug: Lenvatinib; Drug: Ifosfamide; Drug: Etoposide

Interventions

Lenvatinib DRUG

Cohort 1: Lenvatinib will be administered orally, once daily on Days 1 to 28 of each 28-day cycle at a starting dose of 11 mg/m2. Dose can be de-escalated to 9 mg/m2 or escalated to 14 and 17 mg/m2.

Also known as: E7080, lenvatinib

Cohort 1: Single-Agent Dose-Finding

Ifosfamide DRUG

Ifosfamide 3000 mg/m2/day (starting dose) will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles. Ifosfamide dose can be de-escalated to 2400 mg/m2/day and 1800 mg/m2/day.

Cohort 3A: Combination Dose-finding

Etoposide DRUG

Etoposide 100 mg/m2/day (starting dose) will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles. Etoposide dose can be de-escalated to 80 mg/m2/day and 60 mg/m2/day.

Cohort 3A: Combination Dose-finding

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 solid malignant tumor.
• Cohort 1: Any solid malignant tumor.
• Cohort 2A: Differentiated Thyroid Cancer (DTC) with one of the following histological subtypes:
• i) Papillary thyroid cancer (PTC). i.a) Follicular variant. i.b) Other variants (including but not limited to tall cell, columnar cell, cribriform-morular, solid, oxyphil, Warthin's-like, trabecular, tumor with nodular fasciitis-like stroma, Hurthle cell variant of papillary carcinoma, or poorly differentiated carcinomas).
• ii) Follicular thyroid cancer (FTC). ii.a) Hurthle cell. ii.b) Clear cell. ii.c) Insular.
• c) Cohort 2B, 3A, and 3B: Relapsed or refractory osteosarcoma.
• Relapsed or refractory solid tumor malignancy that has progressed on standard anticancer therapy with no available curative options. (Note: Osteosarcoma participants must be in first or subsequent relapse \[greater than or equal to first relapse\]). Only the osteosarcoma participants enrolled to Cohorts 3A and 3B must be deemed candidates for ifosfamide and etoposide chemotherapy).
• Evaluable or measurable disease that meets the following criteria:
• Participants must have evaluable or measurable disease based on RECIST 1.1 using computed tomography (CT)/magnetic resonance imaging (MRI).
• Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as radiofrequency (RF) ablation must have subsequently grown unequivocally to be deemed a target lesion.
• DTC participants must be 131 iodine-refractory/ relapsed as defined by at least one of the following:
• One or more evaluable or measurable lesions that do not demonstrate iodine uptake on any radioiodine scan; or
• One or more evaluable or measurable lesions that have progressed based on RECIST 1.1, within 12 months of 131 iodine therapy, despite demonstration of radioiodine avidity at the time of that treatment by pre- or post-treatment scanning. These participants must not be eligible for possible curative surgery; or
• Cumulative activity of 131 iodine greater than 400 millicuries (mCi) or 14.8 gigabecquerels (GBq), with the last dose administered at least 6 months prior to study entry.
• Participants with DTC must be receiving thyroxine suppression therapy and levels of thyroid stimulating hormone (TSH) should not be elevated (TSH should be less than or equal to 5.50 milliunits per liter (mU/L)). When tolerated by the participant, thyroxine dose should be changed to achieve TSH suppression (TSH less than 0.50 mU/L).

You may not qualify if:

• Any active infection or infectious illness unless fully recovered prior to dosing.
• Any medical or other condition that in the opinion of the investigator(s) would preclude the participant's participation in a clinical study.
• Known hypersensitivity to any component of the product (lenvatinib or ingredients).
• Concurrent administration of any other antitumor therapy.
• Previous treatment with lenvatinib (except for participants previously enrolled into Cohorts 1 or 2B of this study).
• Two or more prior vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) targeted therapies.
• Currently receiving any investigational drug or device in another clinical trial or within 30 days preceding informed consent.
• A clinically significant ECG abnormality, including a marked baseline prolonged QT or QTc interval (eg, a repeated demonstration of a QTc interval greater than 480 msec).
• Gastrointestinal malabsorption or any other condition that in the opinion of the investigator might affect the absorption of lenvatinib.
• Gastrointestinal bleeding or active hemoptysis (bright red blood of at least half teaspoon) within 3 weeks prior to the first dose of study drug.
• Previous treatment with ifosfamide and Grade greater than or equal to 3 nephrotoxicity or encephalopathy (Cohorts 3A and 3B).
• Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin \[ß-hCG\] (or human chorionic gonadotropin \[hCG\]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG \[or hCG\]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
• Cohort 3B (Combination Expansion): Osteosarcoma participants who progressed in Cohorts 1 or 2B and opt to receive combination therapy.

Sponsors & Collaborators

• Eisai Limited: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (19)

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

CHU Strasbourg - Hopital Hautepierre

Strasbourg, Bas Rhin, France

Location

Centre Oscar Lambret Lille

Lille, Rhone, France

Location

Centre Leon Berard

Lyon, Rhone, France

Location

CHU Nantes - Hopital Mere-Enfant

Nantes, France

Location

Institut Curie - Centre de Lutte Contre le Cancer (CLCC) de Paris

Paris, France

Location

Institut Gustave Roussy

Paris, France

Location

CHU de Toulouse - Hopital des Enfants

Toulouse, France

Location

Universitaetsklinikum Muenster

Münster, Germany

Location

Kinderklinik des Olga hospitals

Stuttgart, Germany

Location

Istituto Ortopedico Rizzoli

Bologna, Italy

Location

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Italy

Location

Ospedale Pediatrico Bambino Gesu

Roma, Italy

Location

Hospital Universitari Vall d'Hebron

Barcelona, Spain

Location

Hospital Infantil Universitario Nino Jesus

Madrid, Spain

Location

Hospital Universitario y Politecnico La Fe Hospital La Fe Valencia

Valencia, Spain

Location

Birmingham Children's Hospital

Birmingham, United Kingdom

Location

University College London Hospital

London, United Kingdom

Location

Royal Victoria Infirmary

Newcastle, United Kingdom

Location

Related Publications (4)

• Gaspar N, Campbell-Hewson Q, Gallego Melcon S, Locatelli F, Venkatramani R, Hecker-Nolting S, Gambart M, Bautista F, Thebaud E, Aerts I, Morland B, Rossig C, Canete Nieto A, Longhi A, Lervat C, Entz-Werle N, Strauss SJ, Marec-Berard P, Okpara CE, He C, Dutta L, Casanova M. Phase I/II study of single-agent lenvatinib in children and adolescents with refractory or relapsed solid malignancies and young adults with osteosarcoma (ITCC-050)☆. ESMO Open. 2021 Oct;6(5):100250. doi: 10.1016/j.esmoop.2021.100250. Epub 2021 Sep 22.

  PMID: 34562750 DERIVED

• Rutkowski P. Antiangiogenic agents combined with systemic chemotherapy in refractory osteosarcoma. Lancet Oncol. 2021 Sep;22(9):1206-1207. doi: 10.1016/S1470-2045(21)00422-8. Epub 2021 Aug 17. No abstract available.

  PMID: 34416160 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

• Hattinger CM, Patrizio MP, Magagnoli F, Luppi S, Serra M. An update on emerging drugs in osteosarcoma: towards tailored therapies? Expert Opin Emerg Drugs. 2019 Sep;24(3):153-171. doi: 10.1080/14728214.2019.1654455. Epub 2019 Aug 14.

  PMID: 31401903 DERIVED

MeSH Terms

Conditions

Neoplasms; Osteosarcoma

Interventions

lenvatinib; Ifosfamide; Etoposide

Condition Hierarchy (Ancestors)

Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Sarcoma

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 Ltd.

esi_oncmedinfo@eisai.com

1-888-274-2378

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 22, 2015
• First Posted: May 4, 2015
• Study Start: December 29, 2014
• Primary Completion: July 18, 2019
• Study Completion: July 20, 2022
• Last Updated: July 11, 2023
• Results First Posted: September 17, 2020

Record last verified: 2021-08

Locations

IT (3); ES (3); DE (2); GB (3); US (1); FR (7)