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

This study is currently recruiting participants.
Verified December 2017 by Eisai Inc. ( Eisai Limited )
Sponsor:
ClinicalTrials.gov Identifier:
NCT02432274
First Posted: May 4, 2015
Last Update Posted: December 14, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Eisai Inc. ( Eisai Limited )
  Purpose
This is a phase 1/2 study evaluating safety, tolerability, and efficacy of lenvatinib in children and adolescents with refractory or relapsed solid malignancies and young adults with Osteosarcoma.

Condition Intervention Phase
Tumors Solid Malignant Tumors Osteosarcoma Differentiated Thyroid Cancer (DTC) Drug: Lenvatinib Drug: Ifosfamide Drug: Etoposide Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2 Study of Lenvatinib in Children and Adolescents With Refractory or Relapsed Solid Malignancies and Young Adults With Osteosarcoma

Resource links provided by NLM:


Further study details as provided by Eisai Inc. ( Eisai Limited ):

Primary Outcome Measures:
  • Recommended dose (RD) of lenvatinib using TiTE-CRM [Cohort 1] [ Time Frame: Cycle 1 (Day 1 to Day 28) ]
    The RD in this study will be defined as the dose that has a Dose limiting toxicities (DLT) rate closest to the targeted 20% rate.

  • Objective response rate (ORR) [Cohort 2A (subjects with measurable disease)] [ Time Frame: Up to approximately 3 years ]
    The objective response rate is defined as complete response (CR) + partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

  • Progression-free survival (PFS) at Month 4 [Cohort 2B and Cohort 3B] [ Time Frame: At Month 4 ]
    The percentage of participants who are alive and free of disease progression at 4 months after the first dose of study drug based on RECIST 1.1.

  • RD of lenvatinib in combination with ifosfamide and etoposide [Cohort 3A] [ Time Frame: Cycle 1 (Day 1 to Day 21) ]

Secondary Outcome Measures:
  • Best overall response (BOR) [all Cohorts] [ Time Frame: Up to approximately 3 years ]
  • Objective response rate (ORR) [Cohorts1, 2B, 3A, and 3B] [ Time Frame: Up to approximately 3 years ]
  • Duration of response (DOR) [all Cohorts] [ Time Frame: Up to approximately 3 years ]
  • Disease control rate (DCR) [all Cohorts] [ Time Frame: Up to approximately 3 years ]
  • Clinical benefit rate (CBR) [all Cohorts] [ Time Frame: Up to approximately 3 years ]
  • Time to progression (TTP) [all Cohorts] [ Time Frame: Up to approximately 3 years ]
  • Overall survival (OS) [all Cohorts] [ Time Frame: From date of the first administration of study drug until the date of death or up to approximately 3 years ]
  • Number of participants with Adverse Events (AEs) / Serious Adverse Events (SAEs) as a measure of safety and tolerability. [ Time Frame: From the date of signing informed consent up to 30 days after the participant's last dose or up to approximately 3 years ]
  • Plasma concentrations of lenvatinib: Area under the concentration x time curve (AUC) [all Cohorts] [ Time Frame: Run-in Day 15 (predose), Day 1 (postdose 0.5-4 and 6-10 hours) and Day 15 of Cycle 1 (predose, postdose 0.5-4 and 6-10 hours) , and Day 1 of Cycle 2 (predose and postdose 2-12 hours) ]
  • PD biomarker: VEGFR and FGFR [Cohort 1, Cohort 2A, and Cohort 2B] [ Time Frame: Baseline (Day -1), Day 1 of Cycle 1 (predose for participants 2 to <6 years)), Day 15 of Cycle 1, Day 1 of all subsequent cycles and at the off-treatment visit or up to approximately 3 years ]
  • PD biomarker: VEGFR and FGFR [Cohort 3A and Cohort 3B] [ Time Frame: Baseline (Day -1), Day 8 of Cycle 1, and Day 1 of all subsequent cycles and at the off-treatment visit ]

Estimated Enrollment: 108
Actual Study Start Date: December 29, 2014
Estimated Study Completion Date: September 30, 2018
Estimated Primary Completion Date: June 30, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1: Single-Agent Dose-Finding
Children and adolescents with relapsed or refractory solid malignant tumors.
Drug: 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.
Other Name: E7080, lenvatinib
Experimental: Cohort 2A: Single-agent Expansion (DTC)
Children and adolescents with 131 iodine-refractory DTC.
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.
Other Name: E7080, lenvatinib
Experimental: Cohort 2B: Single-agent Expansion (Osteosarcoma)
Participants with relapsed or refractory osteosarcoma.
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.
Other Name: E7080, lenvatinib
Experimental: Cohort 3A: Combination Dose-finding
Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide.
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).
Other Name: E7080, lenvatinib
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.
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.
Experimental: Cohort 3B: Combination Expansion
Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide.
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.
Other Name: E7080, lenvatinib
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.
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.

Detailed Description:

The study consists of 5 cohorts:

Cohort 1 (Single-Agent Dose-Finding) will use dose-escalation to find the recommended dose (RD) of lenvatinib using a time-to-event continual reassessment method (TiTE-CRM) design in children and adolescents with relapsed or refractory solid malignant tumors. When the RD is identified, Cohorts 2A, 2B, and 3A will start 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 participants 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 participants with relapsed or refractory osteosarcoma. Participants with osteosarcoma who have enrolled into Cohort 1 or 2B and experienced progressive disease on lenvatinib as well as lenvatinib-naive participants with relapsed or refractory osteosarcoma will 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 children unable to swallow capsules.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   2 Years to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02432274


Contacts
Contact: Eisai Medical Information 1-888-274-2378

Locations
United States, Texas
Texas Children Hospital Recruiting
Houston, Texas, United States
France
CHU Strasbourg - Hopital Hautepierre Recruiting
Strasbourg Cedex 2, Bas Rhin, France
Centre Oscar Lambret Recruiting
Lille Cedex, Rhone, France
Centre Leon Berard Recruiting
Lyon Cedex 08, Rhone, France
CHU Nantes - Hopital Mere-Enfant Recruiting
Nantes cedex 1, France
Institut Curie - Centre de Lutte Contre le Cancer (CLCC) de Paris Recruiting
Paris Cedex 05, France
CHU de Toulouse - Hopital des Enfants Recruiting
Toulouse cedex 9, France
Institut Gustave Roussy Recruiting
Villejuif cedex, France
Germany
Universitaetsklinikum Muenster Recruiting
Muenster, Germany
Kinderklinik des Olga hospitals Recruiting
Stuttgart, Germany
Italy
Istituto Ortopedico Rizzoli Not yet recruiting
Bologna, Italy
Fondazione IRCCS Istituto Nazionale dei Tumori Recruiting
Milano, Italy
Ospedale Pediatrico Bambino Gesu Recruiting
Romana, Italy
Spain
Hospital Universitari Vall d'Hebron Recruiting
Barcelona, Spain
Hospital Infantil Universitario Nino Jesus Recruiting
Madrid, Spain
Hospital Universitari i Politecnic La Fe Not yet recruiting
Valencia, Spain
United Kingdom
Birmingham Children's Hospital Recruiting
Birmingham, United Kingdom
UCL Cancer Centre Recruiting
London, United Kingdom
Royal Victoria Infirmary Recruiting
Newcastle upon Tyne, United Kingdom
Sponsors and Collaborators
Eisai Limited
  More Information

Responsible Party: Eisai Limited
ClinicalTrials.gov Identifier: NCT02432274     History of Changes
Other Study ID Numbers: E7080-G000-207
2013-005534-38 ( EudraCT Number )
First Submitted: April 22, 2015
First Posted: May 4, 2015
Last Update Posted: December 14, 2017
Last Verified: December 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Eisai Inc. ( Eisai Limited ):
E7080
Lenvatinib
Solid malignancies
Osteosarcoma
Differentiated Thyroid Cancer

Additional relevant MeSH terms:
Neoplasms
Thyroid Neoplasms
Osteosarcoma
Endocrine Gland Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Endocrine System Diseases
Thyroid Diseases
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Sarcoma
Etoposide
Etoposide phosphate
Isophosphamide mustard
Lenvatinib
Ifosfamide
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating
Alkylating Agents
Protein Kinase Inhibitors