| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory pediatric solid tumors |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed/Refractory Solid Tumors |
|
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 1.To determine the Objective Response Rate (ORR) at Week 16, by each tumor type, per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or Response Assessment in Neuro-Oncology (RANO) (for High Grade Glioma [HGG] only) as assessed by the investigator. |
|
| E.2.2 | Secondary objectives of the trial |
1.To evaluate ORR, by each tumor type, per RECIST 1.1 or RANO (for HGG only) as assessed by the investigator.
2.To evaluate Progression-free Survival (PFS) per RECIST 1.1 or RANO (for HGG only), by each tumor type.
3.To evaluate the Best Overall Response (BOR), Duration of Response (DOR), Disease Control Rate (DCR), and Clinical Benefit Rate (CBR) by each tumor type.
4.To evaluate the safety of lenvatinib (MK-7902).
5.To assess the palatability and acceptability of the suspension formulation of lenvatinib.
6.To characterize the pharmacokinetics (PK) of lenvatinib. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has histologically or cytologically documented relapsed, or refractory pediatric solid malignancy excluding osteosarcoma. Participants with diffuse midline glioma (known as diffuse intrinsic pontine glioma), optic pathway glioma, or pineal tumors with elevated tumor markers do not require histological or cytological confirmation of diagnosis. Participants with diffuse intrinsic pontine glioma are not eligible for the HGG cohort and should only be enrolled in the other solid tumors cohort.
2. Has measurable disease as defined by RECIST 1.1 or RANO for HGG, meeting the criteria below:
- All tumor types except HGG and neuroblastoma: At least 1 lesion measuring ≥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 that is reproducibly measurable on CT or MRI scans.
- HGG: At least 1 contrast-enhancing lesion with clearly defined margins on T1-weighted MRI scan, measuring ≥1.0 cm in 2 perpendicular diameters, and visible on at least 2 axial slices.
- Participants with neuroblastoma who do not have measurable disease per RECIST 1.1 but have MIBG-positive evaluable disease may be enrolled.
- Tumor lesions situated in a previously irradiated area or in an area subjected to other locoregional therapy are considered measurable only if progression has been observed in such lesions since the completion of therapy.
3. Has a performance status as defined below:
- Lansky Play Score ≥50 for participants ≥ 16 years of age.
- KPS ≥50 for participants >16 years of age.
- Neurologic deficits in participants with primary CNS tumors must have been stable for at least 7 days prior to study enrollment. Participants who are unable to walk because of paralysis, but who can perform ADL while wheelchair bound, will be considered ambulatory for the purpose of assessing the performance score.
4. Demonstrate adequate organ function as defined in the protocol.
5. Has urine dipstick <2+ for proteinuria. Participants who have ≥2+ proteinuria on dipstick urinalysis should undergo a spot P/C ratio that should be Grade <2 per CTCAE v5.0, and if possible, perform a 24-hour urine collection.
6. Has no clinical evidence of nephrotic syndrome.
7. Has adequate BP control with or without antihypertensive medications, as described in the protocol.
8. Has adequate cardiac function, as described in the protocol.
9. Has adequate neurologic function:
- Participants with seizure disorder may be enrolled if on anticonvulsants and seizure disorder is well controlled.
10. Has fully recovered to CTCAE v5.0 Grade ≤1 (except for alopecia, ototoxicity, and Grade ≤2 peripheral neuropathy) from the acute toxic effects of all prior anticancer therapy and must meet the minimum duration from prior anticancer-directed therapy prior to enrollment, as described in the protocol. If after the required timeframe, the numerical eligibility criteria are met, eg, blood count criteria, the participant is considered to have recovered adequately.
11. Male or female ≥2 years to ≤21 years of age, on the day the main informed consent/assent is signed.
12. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 7 days after the last dose of study intervention:
- Be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent
OR
- Must agree to use contraception unless confirmed to be azoospermic as detailed below:
Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
13. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- Is not a WOCBP
OR
- Is a WOCBP and using a contraceptive method that is highly effective, as described in the protocol during the intervention period and for at least 30 days post lenvatinib.
- A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within 24 hours before the first dose of study intervention.
- If a urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
Contraceptive use by women and men should be consistent with local regulations for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than
the requirements above, the local label requirements are to be followed.
14. Is willing and able to provide (and/or their parents or legal guardians) documented informed consent/assent for the study. Documented informed consent is required from participants ≥18 years.
15. Is 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. Has had major surgery within 3 weeks prior to C1D1.
2. Has GI bleeding or active hemoptysis (bright red blood of at least half teaspoon) within 21 days prior to enrollment.
3. Has CNS tumors with a history of symptomatic tumor hemorrhage.
4. Has evidence of new intracranial hemorrhage of more than punctate size on MRI assessment obtained within 28 days prior to study enrollment.
5. Has radiographic evidence of encasement or invasion of a major blood vessel or of intratumoral cavitation.
6. Has evidence of untreated CNS metastases (exception: participants with primary CNS tumors and leptomeningeal disease).
7. Has GI malabsorption, GI anastomosis, or any other condition that in the opinion of the investigator might affect the absorption of lenvatinib.
8. Has preexisting ≥Grade 3 GI or non-GI fistula.
9. Has any active infection requiring systemic therapy.
10. Is known to be HIV positive.
11. Has known active viral hepatitis B virus (eg, HBsAg reactive) or Hepatitis C virus (eg, HCV RNA [qualitative] is detected) infection.
12. 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.
13. Has non-healing would, tumor ulceration, unhealed or incompletely healed fracture, or a compound (open) bone fracture at the time of enrollment.
14. Is currently participating and receiving study therapy, or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the date of allocation.
15. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
16. Has known hypersensitivity to any component of the investigational product (lenvatinib or ingredients).
17. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Objective Response Rate (ORR) At Week 16 per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) or Response Assessment in Neuro-Oncology (RANO) Criteria (for High Grade Glioma [HGG] only), by Investigator Assessment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. ORR per RECIST 1.1 or RANO Criteria (for HGG only), by Investigator Assessment
2. Progression Free Survival (PFS) per RECIST 1.1 or RANO (for HGG only), by Investigator Assessment
3. Best Overall Response (BOR) per RECIST 1.1 or RANO (for HGG only), by Investigator Assessment
4. Duration of Response (DOR) per RECIST 1.1 or RANO (for HGG only), by Investigator Assessment
5. Disease Control Rate (DCR) per RECIST 1.1 or RANO (for HGG only), by Investigator Assessment
6. Clinical Benefit Rate (CBR) per RECIST 1.1 or RANO (for HGG only), by Investigator Assessment
7. Number of Participants who Experience an Adverse Event (AE)
8. Number of Participants who Discontinue Study Treatment Due to an AE
9. Palatability Questionnaire Score For Lenvatinib Suspension Formulation
10. Area Under the Concentration-Time Curve of lenvatinib From Time 0 to Infinity (AUC 0-inf) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 43 months
2. Up to approximately 43 months
3. Up to approximately 43 months
4. Up to approximately 43 months
5. Up to approximately 43 months
6. Up to approximately 43 months
7. Up to approximately 43 months
8. Up to approximately 43 months
9. Cycle 1 Day 1 (cycle = 28 days)
10. At designated time points on Cycle 1 Day 1 (post-dose), Cycle 1 Day 15 (pre-dose and post-dose), and Cycle 2 Day 1 (pre-dose and post-dose). A cycle is 28 days. |
|
| 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 | Yes |
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Guatemala |
| Israel |
| Korea, Republic of |
| New Zealand |
| Peru |
| Russian Federation |
| Serbia |
| South Africa |
| Turkey |
| United States |
| Belgium |
| Croatia |
| France |
| Hungary |
| Italy |
| Spain |
| Sweden |
| Czechia |
| Argentina |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 42 |
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