| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory Osteosarcoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Osteosarcoma (a cancer in the bone) which is not responding to treatment or has 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 |
To evaluate whether lenvatinib in combination with ifosfamide and etoposide (Arm A) is superior to ifosfamide and etoposide (Arm B) in improving progression-free survival (PFS) by independent imaging review (IIR) using Response Evaluation Criteria In Solid Tumors (RECIST 1.1), in children, adolescents, and young adults with relapsed or refractory osteosarcoma.
|
|
| E.2.2 | Secondary objectives of the trial |
1. Compare difference in PFS rate at 4 months (PFS-4m) between the 2 treatment arms per IIR
2. Compare difference in PFS rate at 1 year (PFS-1y) between the 2 treatment arms per IIR
3. Compare difference in overall survival (OS) and OS rate at 1 year (OS-1y) between the 2 treatment arms
4. Compare difference in objective response rate at 4 months (ORR-4m) between the 2 treatment arms per IIR
5. Compare difference in objective response rate (ORR) between the 2 treatment arms per IIR
6. Compare difference in safety and tolerability between the 2 treatment arms
7. Characterize the pharmacokinetics (PK) of lenvatinib, when administered in combination with ifosfamide and etoposide
8. Compare difference in HRQoL as assessed by using the PedsQL Generic Core Scales and Cancer Module between the 2 treatment arms
9. Assess the palatability and acceptability of the suspension formulation of lenvatinib in subjects receiving the suspension formulation in the study |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed diagnosis of high grade osteosarcoma.
2. Refractory or relapsed osteosarcoma after 1 to 2 prior lines of systemic treatments.
3. Measurable or evaluable disease per RECIST 1.1 that meets the following criteria:
- Measurable disease is defined as a lesion with a minimum size (by long axis) of 10 mm using computed tomography/magnetic resonance imaging (CT/MRI) (lymph nodes must be accurately measurable with a minimum size [by short axis] of 15 mm).
- 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.
- Any other non-measurable lesions will be considered evaluable disease.
4. Aged 2 years to ≤25 years at the time of informed consent.
5. Life expectancy of 12 weeks or more.
6. Lansky play score ≥50% or Karnofsky Performance Status score ≥50%. Use Karnofsky for subjects ≥16 years of age and Lansky for subjects <16 years of age. Subjects who are unable to walk because of paralysis, but who are able to perform Activities of Daily Living (ADL) while wheelchair bound, will be considered ambulatory for the purpose of assessing the performance score.
7. Adequate bone marrow function as evidenced by:
a. absolute neutrophil count (ANC) ≥1.5×10^9/L. (subjects with bone marrow involvement should have ANC ≥0.8×10^9/L and leucocyte count ≥1×10^9/L).
b. hemoglobin ≥8.0 g/dL (a hemoglobin of <8.0 g/dL is acceptable if it is corrected by growth factor or transfusion before Cycle 1 Day 1).
c. platelet count ≥100×10^9/L.
8. Adequate blood coagulation function defined by International Normalized ratio or prothrombin time (INR/PT) and activated partial thromboplastin time or partial thromboplastin time (aPTT/PTT) ≤1.5 unless participant is receiving anticoagulant therapy, as long as INR/PT and aPTT/PTT are within therapeutic range of intended use of anticoagulants.
9. Adequate liver function as evidenced by:
a. Bilirubin ≤1.5 times the upper limit of normal (ULN).
b. Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3×ULN (in the case of liver metastases ≤5×ULN).
10. 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 within the protocol page 5, then creatinine clearance (or radioisotope glomerular filtration rate [GFR]) must be >70 mL/min/1.73 m2.
b. Urine dipstick <2+ for proteinuria. Subjects who have ≥2+ proteinuria on dipstick urinalysis should undergo a spot protein-creatinine (P/C) ratio test that should be Grade <2 per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and if possible perform a 24-hour urine collection (children and adolescents ≤12 years of age must have ≤500 mg of protein/24 hours and subjects >12 years of age must have ≤1 g of protein/24 hours).
c. No clinical evidence of nephrotic syndrome.
11. Adequate cardiac function as evidenced by left ventricular ejection fraction ≥50% at baseline as determined by echocardiography or multigated acquisition (MUGA) scan.
12. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as:
a. BP <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.
Subjects >18 years of age should have BP ≤150/90 mm Hg at screening and no change in antihypertensive therapy within 1 week prior to Cycle 1 Day 1.
13. Washout before Cycle 1 Day 1 of 3 weeks in case of prior chemotherapy, 6 weeks if treatment
included nitrosoureas; 4 weeks for definitive radiotherapy, 2 weeks for palliative radiotherapy; and 3 months from high-dose chemotherapy and stem cell rescue. For all other anti-cancer therapies, washout before Cycle 1 Day 1 of at least 5 half-lives (or at least 28 days, whichever is shorter). Subjects must have recovered (to Grade ≤1, except for alopecia, ototoxicity, and Grade ≤2 peripheral neuropathy, per CTCAE v5.0) from the acute toxic effects of all prior anticancer therapy before Cycle 1 Day 1.
14. Must have no prior history of lenvatinib treatment.
15. 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.
16. Willing and able to comply with the protocol, scheduled follow-up, and management of toxicity as judged by the investigator. |
|
| E.4 | Principal exclusion criteria |
1. Any active infection or infectious illness unless fully recovered prior to Cycle 1 Day 1.
2. Subjects with central nervous system metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication at least 2 weeks before C1D1
3. Active second malignancy within 2 years prior to enrollment
4. Any medical or other condition that in the opinion of the investigator(s) would preclude the subject's participation in a clinical study.
5. Has had major surgery within 3 weeks prior to Cycle 1 Day 1.
6. Known hypersensitivity to any component(s) of the study drugs (lenvatinib, ifosfamide, and etoposide, or their ingredients).
7. Currently receiving any investigational drug or device in another clinical study or within 28 days prior to C1D1.
8. A clinically significant ECG abnormality, including a marked baseline prolonged QT or QTc interval (eg, a repeated demonstration of a QTc interval >480 msec).
9. Has clinically significant cardiovascular disease within 6 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability. Note: Medically controlled arrhythmia would be permitted.
10. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that in the
opinion of the investigator might affect the absorption of lenvatinib.
11. Pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
12. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least ½ teaspoon) within 3 weeks prior to Cycle 1 Day 1.
13. Radiographic evidence of intratumoral cavitation, encasement, or invasion of a major blood vessel. Additionally, the degree of proximity to major blood vessels should be considered for exclusion because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after lenvatinib therapy.
14. History of ifosfamide-related Grade ≥3 nephrotoxicity or encephalopathy.
15. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the subject's safety or interfere with the study assessments.
16. Known to be human immunodeficiency virus (HIV) positive. Note: HIV testing is required at screening only when mandated by local authority.
17. Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA [qualitative] is detected). Note: Testing for Hepatitis B or Hepatitis C is required at screening only when mandated by local health authority.
18. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ßhCG]) (human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG /hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of any study drug.
19. Females of childbearing potential* who:
- Do not agree to use a highly effective method of contraception for the entire study period and for 28 days after lenvatinib discontinuation or 12 months after etoposide and ifosfamide discontinuation, ie:
◦ total abstinence (if it is their preferred and usual lifestyle)
◦ an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
◦ a contraceptive implant
◦ an oral contraceptive **(with additional barrier method)
OR
- Do not have a vasectomized partner with confirmed azoospermia.
* All post pubertal females will be considered to be of childbearing potential unless they have early menopause (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing), or are pre-menarcheal (Tanner Stage 1-3).
**Must be on stable dose of the same oral hormonal contraceptive product for at least 4 weeks before dosing with study drug(s) and for the duration of the study.
20. Males who have not had a successful vasectomy (confirmed azoospermia) or if they and their female partners do not meet the criteria above (ie, not of childbearing potential or practicing highly effective contraception throughout the study period and for 28 days after lenvatinib discontinuation or 6 months after discontinuation of etoposide and ifosfamide). No sperm donation is allowed during the study period and for 28 days after lenvatinib discontinuation or 6 months after discontinuation of etoposide and ifosfamide
21. A contraindication to any of the study drugs (lenvatinib, ifosfamide, and etoposide) per local prescribing information |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) by independent imaging review (IIR) is defined as the time from the date of randomization to the date of the first documentation of progressive disease (PD) or death (whichever occurs first) as determined by IIR using RECIST 1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From the date of randomization to the date of the first documentation of progressive disease/death |
|
| E.5.2 | Secondary end point(s) |
1. Progression-free survival rate at 4 months (PFS-4m) by IIR is defined as the percentage of subjects who are alive and without PD at 4 months from the randomization date as determined by IIR of radiological imaging using RECIST 1.1. The PFS-4m rate is estimated using the Kaplan-Meier (K-M) method.
2. Progression-free survival rate at 1 year (PFS-1y rate) by IIR is defined as the percentage of subjects who are alive and without PD at 1 year from the randomization date as determined by IIR of radiological imaging using RECIST 1.1. The PFS-1y rate is estimated using the K-M method.
3. Overall survival (OS) is defined as the time from the date of randomization to 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 for the primary analysis, will be censored at the date the subject was last known to be alive, or date of data cutoff for the primary analysis, whichever occurs first. Overall survival rate at 1 year will be estimated using the K-M method.
4. Objective response rate by IIR at 4 months (ORR-4m) is defined as the proportion of subjects who have best overall response of complete response (CR) or partial response (PR) as determined by IIR using RECIST 1.1 within the first 4 months.
5. Objective response rate (ORR) by IIR is defined as the proportion of subjects who have best overall response of complete response (CR) or partial response (PR) as determined by IIR using RECIST 1.1.
6. Safety will be assessed summarising the incidence of TEAEs and SAEs together with all other safety parameters.
7. Assessment of population-based PK parameters of lenvatinib.
8. Score changes from baseline for all PedsQL scales including Generic Core Scales and Cancer Module. Scores will be calculated for total generic score, total cancer score, each physical function subscale including physical health, psychosocial health, emotional function, social function, school/work function in the Generic Core Scales, and each subscales in the cancer module.
9. Palatability and acceptability of the suspension formulation of lenvatinib in subjects receiving the suspension formulation in the study will be assessed using the Palatability Questionnaire (see Appendix 4 within the protocol). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At 4 months
2. At 1 year
3. From randomization to death
4. During 4 months up to complete response or partial response
5. During the trial up to complete response or partial response
6. Throught the trial
7. PK C1D1 postdose 0.5-4; C1D15 predose, postdose 0.5-4 and 6-10; C2D1 predose
8. Baseline, C2D1, C3D1, W18, C8D1, C18D1
9. C1D1 |
|
| 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 | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 53 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Hong Kong |
| Israel |
| Korea, Republic of |
| New Zealand |
| Singapore |
| Taiwan |
| United States |
| Austria |
| Belgium |
| Croatia |
| Finland |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| Czechia |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The definition of the end of the study is the date of the data cutoff for the final analysis or last subject/last visit, including discontinuation from the study for any reason, whichever occurs later. |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 6 |
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