| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Refractory or relapsed solid malignancies |
|
| E.1.1.1 | Medical condition in easily understood language |
| Different types of cancer that are not responding to treatment or have reappeared following an initial recovery |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Cohort 1 (Single-Agent Dose-Finding)
Identify the recommended dose (RD) of lenvatinib as a single agent in children and adolescents with relapsed or refractory solid malignant tumors
Cohort 2 (Single-Agent Expansion)
Evaluate the activity of lenvatinib in 2 separate malignancy groups:
o Cohort 2A: 131I- refractory differentiated thyroid cancer: by objective response rate (ORR) for subjects with measurable disease and by best overall response (BOR) for all subjects
o Cohort 2B: Relapsed or refractory osteosarcoma: by progression-free survival at 4 months (PFS)-4
Cohort 3 (Combination Dose-Finding and Expansion)
Cohort 3A (Combination Dose-Finding)
To identify the RD of lenvatinib in combination with ifosfamide and etoposide in osteosarcoma subjects
Cohort 3B (Combination Expansion)
o Evaluate the activity of lenvatinib in combination with ifosfamide and etoposide in osteosarcoma subjects by PFS-4 |
|
| E.2.2 | Secondary objectives of the trial |
Cohort 1
• Evaluate the activity of E7080 as assessed by BOR, ORR, DOR, PFS, time to progression (TTP), based on RECIST 1.1
• Assess the safety & toxicity profile of E7080 in children and adolescents and young adults
Cohort 2
• Assess the safety and toxicity of E7080 as for Cohort 1
• Evaluate the efficacy of E7080 as assessed by BOR, ORR (osteosarcoma only), DOR, TTP, PFS , DCR and CBR
Cohort 3
• Assess the safety & toxicity of E7080 in combination with IFO and etoposide in children, adolescents and young adults with relapsed or refractory osteosarcoma
• Evaluate the efficacy of E7080 as assessed by BOR, ORR, DOR, TTP, PFS , DCR and CBR
Cohorts 1,2&3
• Examine blood and tumor biomarkers and correlate with clinical response to E7080
• Assess bone growth and height during and after discontinuation of treatment with E7080
• Determine population-based PK parameters of E7080
Assess the palatability and acceptability of the suspension formulation of E7080 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Histologically or cytologically confirmed diagnosis of solid malignant tumor
a.Cohort 1: Any solid malignant tumor
b.Cohort 2A: DTC with one of the following histological subtypes:
i.Papillary thyroid cancer (PTC)
1.Follicular variant
2.Other variants (tall cell, columnar cell, cribriform-morular, solid, oxyphil, Warthin’s-like, trabecular, tumor with nodular fasciitis-, Hürthle cell variant of papillary, or poorly differentiated carcinomas)
ii.Follicular thyroid cancer (FTC)
1.Hürthle cell
2.Clear cell
3.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.
3.Evaluable or measurable disease that meets the following criteria
a. Subjects must have evaluable or measurable disease based on RECIST 1.1
b.Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies must have subsequently grown unequivocally to be deemed a target lesion
4.DTC subjects must be 131I-refractory/relapsed as defined by at least one of the following:
a.One or more evaluable or measurable lesions that do not demonstrate iodine uptake on any radioiodine scan OR
b.One or more evaluable or measurable lesions that have progressed based on RECIST 1.1, within 12 months of 131I therapy, despite demonstration of radioiodine avidity at the time of that treatment by pre- or post-treatment scanning. These subjects must not be eligible for possible curative surgery OR
c.Cumulative activity of 131I >400 millicuries (mCi) or 14.8 gigabecquerels (GBq), with the last dose administered at least 6 months prior to study entry
5.Subjects with DTC must be receiving thyroxine suppression therapy and levels of thyroid stimulating hormone (TSH) should not be elevated (TSH should be ≤5.50 mU/L). When tolerated by the subject, thyroxine dose should be changed to achieve TSH suppression (TSH <0.50 mU/L)
6.Subjects with known CNS primary tumors or metastases who have completed brain therapy (such as radiotherapy), stereotactic radiosurgery or complete surgical resection, will be eligible if they have remained clinically stable, asymptomatic and off of steroids for 4 weeks prior to Cycle 1 Day 1.
7.Male or female subjects age 2 years to <18, (≤25 years for osteosarcoma subjects) at the time of informed consent
8.Lansky play score ≥50% or Karnofsky Performance Status score ≥50%
9.Life expectancy ≥ 3 monthss
10.Adequate bone marrow function
11.Adequate liver function:
a.bilirubin ≤1.5 times the upper limit of normal (ULN)
b.alkaline phosphatase, ALT, and AST ≤ 3 × ULN (in the case of liver metastases ≤5 × ULN)
12.Adequate renal function:
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 >70 mL/min/1.73 m2 (Appendix 6).
Age Max. Serum Creatinine (mg/dL)
Male Female
2 to < 6 years 0.8 0.8
6 to < 10 years 1 1
10 to < 13 years 1.2 1.2
13 to < 16 years 1.5 1.4
≥ 16 years 1.7 1.4
b.Urine dipstick <2+ for proteinuria.
c.No clinical evidence of nephrotic syndrome
13. Adequate cardiac function as evidenced by Fractional Shortening ≥28% (≥35% for children <3 yrs of age) or left ventricular ejection fraction ≥50%)
14. Adequately controlled blood pressure (BP) with or without antihypertensive medications:
BP <95th percentile for sex, age, and height/length at screening (as per National Heart Lung and Blood Institute guidelines; see Appendix 7 and Appendix 8) and no change in antihypertensive medications within 1-week prior to Cycle 1/Day 1. Osteosarcoma subjects age 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. Subjects 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 guardian and assent from the minor subject. 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):
18.Osteosarcoma subjects receiving combination therapy of lenvatinib with ifosfamide and etoposide should meet only Inclusion Criteria Numbers 6 through 17 (after progression in Cohort 2B)
|
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will be excluded from this study:
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 subject’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 <2 per CTCAE v4.03
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 subjects previously enrolled into Cohorts 1 or 2B of this study)
7.Two or more prior 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 >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 ½ 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 ≥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.
Females of childbearing potential who:
•Within 28 days before study entry, did not use a highly effective method of contraception, which includes any of the following:
ototal abstinence (if it is their preferred and usual lifestyle)
o an intrauterine device or intrauterine hormone-releasing system (IUS)
o an oral contraceptive. Subject must be on a stable dose of the same oral contraceptive product for at least 28 days before dosing and throughout the study and for 6 months after study drug discontinuation.) .
o have a vasectomized partner with confirmed azoospermia.
•Do not agree to use a highly effective method of contraception (as described above) throughout the entire study period and for 6 months after study drug discontinuation.
Cohort 3B (Combination Expansion): Osteosarcoma subjects who progressed in Cohorts 1 or 2B and opt to receive combination therapy:
15.Osteosarcoma subjects receiving combination therapy of lenvatinib with etoposide and ifosfamide should meet all the exclusion criteria, with the exception of Criterion Number 6.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Cohort 1 (Single-Agent Dose-Finding)
RD based on the TiTE-CRM design.
Cohort 2 (Single-Agent Expansion)
Cohort 2A: DTC ORR (CR + PR) for subjects with measurable disease and BOR for all subjects based on RECIST 1.1
Cohort 2B: Osteosarcoma Group: PFS-4, ie, the percentage of subjects who are alive and free of disease progression 4 months after the first dose based on RECIST 1.1
Cohort 3A (Combination Dose-Finding)
RD of the combination treatment (lenvatinib + etoposide + ifosfamide)
Cohort 3B (Combination Expansion)
PFS-4, ie, the percentage of subjects who are alive and free of disease progression 4 months after the first dose based on RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Cohort 1: determination of the RD (either when approximately 18 subjects have been tested, or when futility is declared or when 10 subjects have been treated at the same dose).
Cohort 2A: all ORR will be based on RECIST 1.1 assessed every 8 weeks.
Cohort 2B: PFS-4 based on RECIST 1.1.
Cohort 3A: the DLT will be assessed to determine the RD of lenvatinib in combination with ifosfamide plus etoposide.
Cohort 3B: PFS-4 based on RECIST 1.1. |
|
| E.5.2 | Secondary end point(s) |
Cohort 1 (Single-Agent Dose-Finding):
Efficacy
o BOR over the treatment period
o ORR
o DOR
o PFS
o Disease Control Rate (DCR) defined as the percentage of subjects who have a BOR of CR or PR or stable disease (SD). To be assigned a best overall response of SD, the time from the first administration of study drug until the date of documented SD should be ≥7 weeks.
o Durable SD rate defined as the percentage of subjects who have the duration of SD lasting ≥ 23 weeks
o Clinical Benefit Rate (CBR) defined as the percentage of subjects who have a BOR of CR or PR or durable SD
o TTP defined as the time from the date of the first administration of study drug until the date of first documentation of disease progression
o Time to OS defined as the time from the date of the first administration of study drug until the date of death from any cause. Subjects who are lost to follow-up and those who are alive at the date of data cutoff will be censored at the date the subject was last known to be alive (or the data cutoff date)
Safety
o AEs, clinical laboratory values, vital signs, 12-lead ECG, Lansky Play Scores or Karnofsky Performance Status scores, physical examination findings, and bone growth and height (including proximal tibial growth plates)during treatment and follow-up
Plasma lenvatinib exposure
Assessment of blood or tumor biomarkers that correlate with clinical response to lenvatinib treatment or AEs associated with lenvatinib treatment
Cohort 2:
Efficacy
o BOR over the treatment period
o ORR (osteosarcoma group)
o DOR
o PFS
o DCR defined as the percentage of subjects who have a BOR of CR or PR or SD. To be assigned a best overall response of SD, the time from the first administration of study drug until the date of documented SD should be ≥7 weeks.
o Durable SD rate defined as the percentage of subjects who have the duration of SD lasting ≥ 23 weeks
o CBR defined as the percentage of subjects who have a BOR of CR or PR or durable SD
o TTP defined as the time from the date of the first administration of study drug until the date of first documentation of disease progression
o Time to OS defined as the time from the date of the first administration of study drug until the date of death from any cause. Subjects who are lost to follow-up and those who are alive at the date of data cutoff will be censored at the date the subject was last known to be alive (or the data cutoff date).
Safety
o AEs, clinical laboratory values, vital signs, 12-lead ECGs, Lansky play scores or Karnofsky Performance Status, physical examination findings, and bone growth and height (including proximal tibial growth plates) during treatment and follow-up
Plasma lenvatinib exposure parameters
Assessment of blood or tumor biomarkers that correlate with clinical response to lenvatinib treatment or AEs associated with lenvatinib treatment.
Cohort 3A and 3B:
Efficacy
o BOR over the treatment period
o ORR (osteosarcoma group)
o DOR
o PFS
o DCR defined as the percentage of subjects who have a BOR of CR or PR or SD. To be assigned a best overall response of SD, the time from the first administration of study drug until the date of documented SD should be ≥7 weeks.
o Durable SD rate defined as the percentage of subjects who have the duration of SD lasting ≥ 23 weeks
o CBR defined as the percentage of subjects who have a BOR of CR or PR or durable SD
o TTP defined as the time from the date of the first administration of study drug until the date of first documentation of disease progression
o Time to OS defined as the time from the date of the first administration of study drug until the date of death from any cause. Subjects who are lost to follow-up and those who are alive at the date of data cutoff will be censored at the date the subject was last known to be alive (or the data cutoff date).
Safety
o AEs, clinical laboratory values, vital signs, 12-lead ECGs, Lansky play scores or Karnofsky Performance Status scores, physical examination findings, and bone growth and height (including proximal tibial growth plates)during treatment and follow-up
Plasma lenvatinib exposure parameters
Assessment of blood or tumor biomarkers that correlate with clinical response to
lenvatinib treatment or AEs associated with lenvatinib treatment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Median PFS, median OS, and the cumulative probability of PFS at 4, 12, and 24 months and OS at 12 and 24 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase 1/2 paediatric study |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
