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