Clinical trial NCT02432274: Study of Lenvatinib in Children and Adolescents With Refractory or Relapsed Solid Malignancies and Young Adults With Osteosarcoma
Official title: Phase 1/2 Study of Lenvatinib in Children and Adolescents With Refractory or Relapsed Solid Malignancies and Young Adults With Osteosarcoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Tumors
Solid Malignant Tumors
Osteosarcoma
Differentiated Thyroid Cancer (DTC)
Keywords: E7080
Lenvatinib
Solid malignancies
Osteosarcoma
Differentiated Thyroid Cancer
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2015-05-04
Enrollment: 117
Sex: ALL
Minimum age (years): 2
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.
18. Osteosarcoma participants receiving combination therapy of lenvatinib with ifosfamide and etoposide should meet only Inclusion Criteria Numbers 6 through 17 (after progression in Cohort 2B).

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.
3. Other organ toxicity due to prior anticancer therapy (investigational agent, chemotherapy, or radiation therapy) except alopecia, and ototoxicity due to cisplatin not already covered in the inclusion/exclusion criteria, which has not recovered to Grade less than 2 per Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
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.
15. Osteosarcoma participants receiving combination therapy of lenvatinib with ifosfamide and etoposide should meet all the exclusion criteria, with the exception of Criterion Number 6.

Primary outcomes:
measure: Cohort 1: Recommended Dose (RD) of Lenvatinib
timeFrame: Cycle 1 (28 days)
measure: Cohort 2A: Number of Participants With Objective Response (OR) of Complete Response (CR) or Partial Response (PR)
timeFrame: 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)
measure: Cohort 2A: Number of Participants With Best Overall Response (BOR)
timeFrame: From first dose of study drug until PD or death, whichever occurred first (until the data cut-off date, 31 May 2019)
measure: Cohorts 2B and 3B: Progression-free Survival (PFS) Rate at Month 4
timeFrame: At Month 4
measure: Cohort 3A: Recommended Dose (RD) of Lenvatinib When Given in Combination With Etoposide and Ifosfamide
timeFrame: Cycle 1 (21 days)
Secondary outcomes:
measure: Cohorts 1, 2B, 3A, and 3B: Number of Participants With Best Overall Response (BOR)
timeFrame: 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)
measure: Cohorts 1, 2B, 3A, and 3B: Objective Response Rate (ORR)
timeFrame: 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)
measure: Cohorts 1, 2A, 2B, 3A and 3B: Duration of Response (DOR)
timeFrame: 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)
measure: Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Who Experienced Disease Control
timeFrame: 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)
measure: Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Experienced Clinical Benefit
timeFrame: 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)
measure: Cohorts 1, 2A, 2B, 3A and 3B: Progression-free Survival (PFS)
timeFrame: 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)
measure: Cohorts 1, 2A, 2B, 3A and 3B: Time to Progression (TTP)
timeFrame: From first dose of study drug until 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)
measure: Cohorts 1, 2A, 2B, 3A and 3B: Overall Survival (OS)
timeFrame: From first dose of study drug until death (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)
measure: Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From the date of first dose of study drug up to 30 days after the last dose (up to approximately 7 years)
measure: Cohorts 1, 2A, 2B, 3A, and 3B: Number of Participants With Shift From Baseline to Worst Post Baseline Measurements on Urine DipStick for Proteinuria
timeFrame: Baseline up to approximately 4 years 7 months
measure: Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants With Shift From Baseline to Worst Post Baseline Score in Lansky Performance Play Score
timeFrame: Baseline up to approximately 4 years 7 months
measure: Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants With Shift From Baseline to Worst Post Baseline Score in Karnofsky Performance Status (KPS) Scores
timeFrame: Baseline up to approximately 4 years 7 months
measure: Cohorts 1, 2A, 2B, 3A, and 3B: Plasma Concentrations of Lenvatinib
timeFrame: Cohorts 1, 2A, 2B: Cycle(C)1 Day(D)1: 0.5-4 hours (h), 6-10 h post-dose, C1D15: pre-dose, 0.5-4 h, 6-10 h post-dose, C2D1: pre-dose, 2-12 h post-dose; Cohorts 3A, 3B: C1D1: 0.5-4 h, 6-10 h post-dose, C2D1: pre-dose, 2-12 h post-dose
measure: Cohort 2B, 3B: Percent Change From Baseline in Serum Biomarkers Level
timeFrame: Cohort 2B: Baseline, Cycle 2-3 Day 1 (Duration of each cycle=28 days); Cohort 3B: Baseline, Cycle 2 Day 1, Cycle 4 Day 1 (Duration of each cycle=21 days)
measure: Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants With Most Frequent Treatment-emergent Adverse Events (TEAEs) Related to Lenvatinib Exposure
timeFrame: First dose of study drug until 30 days after last dose of study drug (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)
measure: Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Categorized Based on Overall Acceptability Questionnaire Responses for Suspension of Lenvatinib
timeFrame: Cycle 1 Day 1 (Cycle length=28 days for Cohorts 1, 2A, 2B; Cycle length=21 days for Cohorts 3A, 3B)
Other outcomes:
Locations:
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Strasbourg
country: France
facility: CHU Strasbourg - Hopital Hautepierre
state: Bas Rhin
city: Lille
country: France
facility: Centre Oscar Lambret Lille
state: Rhone
city: Lyon
country: France
facility: Centre Leon Berard
state: Rhone
city: Nantes
country: France
facility: CHU Nantes - Hopital Mere-Enfant
city: Paris
country: France
facility: Institut Curie - Centre de Lutte Contre le Cancer (CLCC) de Paris
city: Paris
country: France
facility: Institut Gustave Roussy
city: Toulouse
country: France
facility: CHU de Toulouse - Hopital des Enfants
city: Muenster
country: Germany
facility: Universitaetsklinikum Muenster
city: Stuttgart
country: Germany
facility: Kinderklinik des Olga hospitals
city: Bologna
country: Italy
facility: Istituto Ortopedico Rizzoli
city: Milan
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesu
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Nino Jesus
city: Valencia
country: Spain
facility: Hospital Universitario y Politecnico La Fe Hospital La Fe Valencia
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: London
country: United Kingdom
facility: University College London Hospital
city: Newcastle
country: United Kingdom
facility: Royal Victoria Infirmary
Study officials:
References:
citation: 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.
citation: 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.
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: 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.