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

NCT ID: NCT02432274

Last Updated: 2023-07-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 117 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-12-29
• Study Completion Date: 2022-07-20

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).

Detailed Description

The study consists of 5 cohorts:

Cohort 1 (Single-Agent Dose-Finding) dose-escalation to find the recommended dose (RD) of lenvatinib using time-to-event continual reassessment method (TiTE-CRM) in children and adolescents with relapsed or refractory solid malignant tumors. When the RD is identified, Cohorts 2A, 2B, and 3A will enroll in parallel.

Cohort 2 (Single-Agent Expansion) will evaluate the efficacy of lenvatinib at the RD in children, adolescents, and young adults with

1. 131 iodine-refractory differentiated thyroid cancer (DTC) [Cohort 2A] or

2. Relapsed or refractory osteosarcoma [Cohort 2B]

Cohort 3A (Combination Dose-Finding) will determine the RD of lenvatinib in combination with ifosfamide and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma.

Cohort 3B (Combination Expansion) will evaluate the efficacy of lenvatinib at the RD from Cohort 3A in combination with ifosfamide and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma. Participants with osteosarcoma who have enrolled into Cohort 1 or 2B and experienced progressive disease will also be candidates for enrollment in Cohort 3B.

Lenvatinib will be provided as hard capsules containing 1, 4, or 10 mg lenvatinib. Lenvatinib capsules should be dissolved in water or apple juice for those who are unable to swallow capsules.

Conditions

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort 1: Single-Agent Dose-Finding

Children and adolescents with relapsed or refractory solid malignant tumors.

Group Type: EXPERIMENTAL

Lenvatinib

Intervention Type: 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.

Cohort 2A: Single-agent Expansion (DTC)

Children and adolescents with 131 iodine-refractory DTC.

Group Type: EXPERIMENTAL

Lenvatinib

Intervention Type: DRUG

Cohort 2A: Lenvatinib (RD determined in Cohort 1) will be administered orally, once daily on Days 1 to 28 of each 28-day cycle.

Cohort 2B: Single-agent Expansion (Osteosarcoma)

Participants with relapsed or refractory osteosarcoma.

Group Type: EXPERIMENTAL

Lenvatinib

Intervention Type: DRUG

Cohort 2B: Lenvatinib (RD determined in Cohort 1) will be administered orally, once daily on Days 1 to 28 of each 28-day cycle.

Cohort 3A: Combination Dose-finding

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

Group Type: EXPERIMENTAL

Lenvatinib

Intervention Type: DRUG

Cohort 3A: Lenvatinib will be administered orally, once daily on Days 1 to 21 of each 21-day cycle at 20% lower than RD determined in Cohort 1 (starting dose). Lenvatinib dose can be escalated to the RD from Cohort 1 or de-escalated to 40 and 60% lower than the RD from Cohort 1.

Ifosfamide

Intervention Type: 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.

Etoposide

Intervention Type: 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 3B: Combination Expansion

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

Group Type: EXPERIMENTAL

Lenvatinib

Intervention Type: DRUG

Cohort 3B: Lenvatinib will be administered orally, once daily on Days 1 to 21 of each 21-day cycle at the RD as determined in Cohort 3A.

Ifosfamide

Intervention Type: DRUG

Ifosfamide dose identified in Cohort 3A will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles.

Etoposide

Intervention Type: DRUG

Etoposide dose identified in Cohort 3A will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles.

Interventions

Lenvatinib

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.

Intervention Type: DRUG

Lenvatinib

Cohort 2A: Lenvatinib (RD determined in Cohort 1) will be administered orally, once daily on Days 1 to 28 of each 28-day cycle.

Intervention Type: DRUG

Lenvatinib

Cohort 2B: Lenvatinib (RD determined in Cohort 1) will be administered orally, once daily on Days 1 to 28 of each 28-day cycle.

Intervention Type: DRUG

Lenvatinib

Cohort 3A: Lenvatinib will be administered orally, once daily on Days 1 to 21 of each 21-day cycle at 20% lower than RD determined in Cohort 1 (starting dose). Lenvatinib dose can be escalated to the RD from Cohort 1 or de-escalated to 40 and 60% lower than the RD from Cohort 1.

Intervention Type: DRUG

Lenvatinib

Cohort 3B: Lenvatinib will be administered orally, once daily on Days 1 to 21 of each 21-day cycle at the RD as determined in Cohort 3A.

Intervention Type: DRUG

Ifosfamide

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.

Intervention Type: DRUG

Etoposide

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.

Intervention Type: DRUG

Ifosfamide

Ifosfamide dose identified in Cohort 3A will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles.

Intervention Type: DRUG

Etoposide

Etoposide dose identified in Cohort 3A will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles.

Intervention Type: DRUG

Other Intervention Names

E7080, lenvatinib; E7080, lenvatinib; E7080, lenvatinib; E7080, lenvatinib; E7080, lenvatinib

Eligibility Criteria

Inclusion Criteria

1. Histologically or cytologically confirmed diagnosis of solid malignant tumor.

1. Cohort 1: Any solid malignant tumor.

2. 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.

2. 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).

3. Evaluable or measurable disease that meets the following criteria:

1. Participants must have evaluable or measurable disease based on RECIST 1.1 using computed tomography (CT)/magnetic resonance imaging (MRI).

2. 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.

4. DTC participants must be 131 iodine-refractory/ relapsed as defined by at least one of the following:

1. One or more evaluable or measurable lesions that do not demonstrate iodine uptake on any radioiodine scan; or

2. 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

3. 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.

5. 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).

6. Participants with known central nervous system (CNS) primary tumors or metastases who have completed brain therapy (such as radiotherapy, stereotactic radiosurgery, or surgical resection) and have remained clinically stable, asymptomatic, and off of steroids for 2 weeks prior to Cycle 1 Day 1 will be eligible.

7. Male or female participants age 2 years to less than18 years and less than or equal to 25 years for osteosarcoma subjects at the time of informed consent.

8. Lansky play score greater than or equal to 50% or Karnofsky Performance Status score greater than or equal to 50%. Use Karnofsky for participants greater than or equal to 16 years of age and Lansky for participants less than 16 years of age.

9. Life expectancy greater than or equal to 3 months.

10. Adequate bone marrow function as evidenced by:

1. absolute neutrophil count (ANC) greater than or equal to 1.0 x 10^9/L (for Cohorts 3A and 3B leucocyte count greater than or equal to 2 x 10^9/L; participants with bone marrow involvement should have ANC greater than or equal to 0.8 x 10^9/L and leucocyte count greater than or equal to 1 x 10^9/L).

2. hemoglobin greater than or equal to 8.0 grams/deciliter (g/dL) (a hemoglobin less than 8.0 g/dL is acceptable if it is corrected by growth factor or transfusion before starting lenvatinib).

3. platelet count greater than or equal to 75 x 10^9/L.

11. Adequate liver function as evidenced by:

1. bilirubin less than or equal 1.5 times the upper limit of normal (ULN).

2. alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 times ULN.

12. Adequate renal function as evidenced by:

a) Serum creatinine based on age/gender as below. If serum creatinine is greater than maximum serum creatinine for age/gender as shown in the table below, then creatinine clearance (or radioisotope glomerular filtration rate [GFR]) must be greater than 70 milliliter/minute/1.73 square meter (mL/min/1.73 m2).

Maximum Serum Creatinine in milligrams/deciliter (mg/dL) for male:

i. Age 2 to less than 6 years = 0.8

ii. Age 6 to less than 10 years = 1.0

iii. Age 10 to less than 13 years = 1.2

iv. Age 13 to less than 16 years = 1.5

v. Age greater than or equal to 16 years = 1.7

Maximum Serum Creatinine (mg/dL) for Female:

vi. Age 2 to less than 6 years = 0.8

vii. Age 6 to less than 10 years = 1.0

viii. Age 10 to less than 13 years = 1.2

ix. Age 13 to less than 16 years = 1.4

x. Age greater than or equal to 16 years = 1.4

The threshold creatinine values in this Table were derived from the Schwartz formula for estimating glomerular filtration rate using child length and stature data published by the CDC.

b) Urine dipstick less than 2+ for proteinuria. Participants who have greater than or equal to 2+ proteinuria on dipstick urinalysis should undergo a spot protein-creatinine (P/C) ratio that should be Grade less than 2.

c) No clinical evidence of nephrotic syndrome.

13. Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF) greater than or equal to 50%) at baseline as determined by echocardiography.

14. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as:

BP less than 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. Osteosarcoma subjects 18 to 25 years should have BP ≤150/90 mm Hg at screening and no change in antihypertensive therapy within 1 week prior to Cycle 1/Day 1.

15. Washout of 3 weeks in case of prior chemotherapy, 6 weeks if treatment included nitrosoureas; 4 weeks for definitive radiotherapy, and 2 weeks for palliative radiotherapy; 3 months from high-dose chemotherapy and stem cell rescue; 3 weeks from major surgery. Participants must have recovered from the acute toxic effects of all prior anticancer therapy before enrollment into the study.

16. Written and signed informed consent from the parent(s) or legal representative (guardian) and assent from the minor participant. Written informed consent from subjects ≥18 years.

17. Willing and able to comply with the protocol, scheduled follow-up, and management of toxicity as judged by the Investigator.

Cohort 3B (Combination Expansion): Osteosarcoma subjects who progressed in Cohorts 1 or 2B and opt to receive combination therapy.

Exclusion Criteria

1. Any active infection or infectious illness unless fully recovered prior to dosing.

2. Any medical or other condition that in the opinion of the investigator(s) would preclude the participant's participation in a clinical study.

4. Known hypersensitivity to any component of the product (lenvatinib or ingredients).

5. Concurrent administration of any other antitumor therapy.

6. Previous treatment with lenvatinib (except for participants previously enrolled into Cohorts 1 or 2B of this study).

7. Two or more prior vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) targeted therapies.

8. Currently receiving any investigational drug or device in another clinical trial or within 30 days preceding informed consent.

9. 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).

10. Gastrointestinal malabsorption or any other condition that in the opinion of the investigator might affect the absorption of lenvatinib.

11. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least half teaspoon) within 3 weeks prior to the first dose of study drug.

12. Active second malignancy within 2 years prior to enrollment ([in addition to the primary tumor types specified by cohort in Inclusion Criterion Number 1], but not including definitively treated superficial melanoma, in-situ, basal or squamous cell carcinoma of the skin).

13. Previous treatment with ifosfamide and Grade greater than or equal to 3 nephrotoxicity or encephalopathy (Cohorts 3A and 3B).

14. 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.

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 25 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Eisai Limited

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Texas Children's Hospital

Houston, Texas, United States

CHU Strasbourg - Hopital Hautepierre

Strasbourg, Bas Rhin, France

Centre Oscar Lambret Lille

Lille, Rhone, France

Centre Leon Berard

Lyon, Rhone, France

CHU Nantes - Hopital Mere-Enfant

Nantes, , France

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

Paris, , France

Institut Gustave Roussy

Paris, , France

CHU de Toulouse - Hopital des Enfants

Toulouse, , France

Universitaetsklinikum Muenster

Münster, , Germany

Kinderklinik des Olga hospitals

Stuttgart, , Germany

Istituto Ortopedico Rizzoli

Bologna, , Italy

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, , Italy

Ospedale Pediatrico Bambino Gesu

Roma, , Italy

Hospital Universitari Vall d'Hebron

Barcelona, , Spain

Hospital Infantil Universitario Nino Jesus

Madrid, , Spain

Hospital Universitario y Politecnico La Fe Hospital La Fe Valencia

Valencia, , Spain

Birmingham Children's Hospital

Birmingham, , United Kingdom

University College London Hospital

London, , United Kingdom

Royal Victoria Infirmary

Newcastle, , United Kingdom

Countries

United States; France; Germany; Italy; Spain; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 34562750 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34416160 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34416158 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31401903 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2013-005534-38

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

E7080-G000-207

Identifier Type: -

Identifier Source: org_study_id