| 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 | 17.1 |
| 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)
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 cyclophosphamide (CPM) and etoposide in osteosarcoma subjects
Cohort 3B (Combination Expansion)
o Evaluate the activity of lenvatinib in combination with CPM and etoposide in osteosarcoma subjects by PFS-4 |
|
| E.2.2 | Secondary objectives of the trial |
Cohort 1
• Evaluate the activity of lenvatinib as assessed by best overall response (BOR), ORR, duration of response (DOR), time to progression (TTP), based on RECIST 1.1, and overall survival (OS)
• Assess the safety and toxicity profile of lenvatinib in children and adolescents
Cohort 2
• Assess the safety and toxicity profile of lenvatinib in children and adolescents
• Evaluate the efficacy of lenvatinib as assessed by BOR, ORR (osteosarcoma only), DOR, TTP, and OS
Cohort 3
• Assess the safety and toxicity of lenvatinib in combination with CPM and etoposide in children and adolescents with relapsed or refractory osteosarcoma
• Evaluate the efficacy of lenvatinib as assessed by BOR, ORR, DOR, TTP, and OS
Cohorts 1,2&3
• Examine blood and tumor biomarkers and correlate with clinical response to lenvatinib
• Assess bone growth and height during and after discontinuation of treatment with lenvatinib
• Determine population-based pharmacokinetic (PK) parameters of lenvatinib |
|
| 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 histological subtype:
i.Papillary thyroid cancer
1.Follicular variant 2.Other (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 1.Hürthle cell 2.Clear cell 3.Insular
2.Relapsed or refractory solid tumor malignancy that has progressed on standard anticancer therapy with no available curative options 3.Evidence of metastases
4.Measurable disease that meets the following criteria a.Subjects with osteosarcoma and other tumor types who are in the dose-finding cohorts (Cohort 1 and Cohort 3A) must have evaluable disease based on RECIST 1.1 b.Subjects with DTC in Cohort 2A: i.Must have disease meeting the following criteria: At least 1 lesion of ≥1.0 cm in the longest diameter for a non-lymph node or ≥1.5 cm in the short-axis diameter for a lymph node. For Cohort 2, if there is only 1 target lesion and it is a non-lymph node, it should have a longest diameter of ≥1.5 cm
ii.Lesions that have had external beam radiotherapy or locoregional therapies must have subsequently grown unequivocally to be deemed a target lesion
5.DTC subjects must be 131I-refractory/ relapsed as defined by
a.One or more measurable lesions that do not demonstrate iodine uptake on any radioiodine scan OR b.have progressed based on RECIST 1.1 within 12 months of 131I therapy OR c.Cumulative activity of 131I >600 millicuries or 22 gigabecquerels with the last dose administered at least 6 months prior to study entry
6.Subjects with DTC must be receiving thyroxine suppression therapy and levels of thyroid stimulating hormone should be ≤5.50 mU/L).
7.Subjects with known brain metastases who have completed whole brain radiotherapy, stereotactic radiosurgery or complete surgical resection, will be eligible if they have remained clinically stable, asymptomatic and off of steroids for 1 month prior to study entry
8.Male or female subjects age 12 years to <18 years
9.Lansky play score ≥70% or ECOG ≤1
10.Life expectancy ≥3 months
11.Adequate bone marrow function
12.Adequate liver function:
a.bilirubin ≤1.5 times the upper limit of normal (ULN)
b.alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase ≤ 3 × ULN (in the case of liver metastases ≤5 × ULN)
13.Adequate renal function:
a.Serum creatinine ≤1.5 × ULN for age.
b.Urine dipstick <2+ for proteinuria.
c.No clinical evidence of nephrotic syndrome
14.Adequate cardiac function as evidenced by Fractional Shortening ≥28% and left ventricular ejection fraction ≥50%)
15.Adequately controlled blood pressure
a.BP <95th percentile for sex, age, and height/length at screening and no change in antihypertensive medications within 1-week prior to Cycle 1/Day 1
16.Washout of 3 weeks in case of prior chemotherapy, 6 weeks if treatment included nitrosoureas; 4 weeks in case of prior radiotherapy, 3 months from high-dose chemotherapy and stem cell rescue
17.Females must not be lactating or pregnant at Screening or Baseline
18.All post pubertal females will be considered to be of childbearing potential unless they have early menopause due to prior treatment procedures or have been sterilized surgically
19.Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception throughout the entire study period and for 6 months after study drug discontinuation. Abstinence is acceptable only when this is in line with the preferred and usual lifestyle of the patient. If currently abstinent, the subject must agree to use a double barrier method as described above if she becomes sexually active during the study period or for 6 months after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and must continue to use the same contraceptive during the study and for 6 months after study drug discontinuation
20.If sexually active, male subjects and their female partners must use a highly effective method of contraception throughout the study period and for 6 months after study drug discontinuation. No sperm donation is allowed during the study period and for 6 months after study drug discontinuation
21.Written and signed informed consent from the parent(s) or legal guardian and assent from the minor subject
22.Able to comply with the protocol
Cohort 3B: Osteosarcoma subjects who progressed in
Cohort 2B and opt to receive combination therapy:
23.Osteosarcoma subjects receiving combination therapy of lenvatinib with CPM and etoposide should meet only Inclusion Criteria Numbers 9 through 22 (after progression in Cohort 2B) |
|
| E.4 | Principal exclusion criteria |
1. Any history or evidence of severe acute or chronic infection or infectious illness unless fully recovered for at least 4 weeks prior to screening
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, not already covered in the inclusion/exclusion criteria, which has not recovered to Grade <2 per 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 subjects previously enrolled into Cohort 3B of this study)
7. Two or more prior VEGF/VEGFR-targeted therapies
8. Currently enrolled in another clinical trial or used any investigational drug or device 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 melanoma, carcinoma in-situ, basal or squamous cell
carcinoma of the skin)
13. Osteosarcoma subjects receiving combination therapy of lenvatinib with CPM and etoposide 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 CRM design.
Cohort 2 (Single-Agent Expansion)
Cohort 2A: DTC Group: ORR (CR + PR) 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 + CPM)
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 CPM 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 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 ECOG performance scores, physical examination findings, and bone growth and height 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 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 ECOG performance scores, physical examination findings, and bone growth and height 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 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 ECOG performance scores, physical examination findings, and bone growth and height 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| 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 | 4 |
| 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 |
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