| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent and Refractory Solid Tumors |
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| 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
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
| Phase 1 of this study, utilizing a rolling 6 design, will be conducted to determine a maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), and to describe the toxicities of lenvatinib administered in combination with everolimus once daily to pediatric subjects with recurrent/refractory solid tumors. Phase 2, utilizing Simon's optimal 2-stage design, will be conducted to estimate the antitumor activity of lenvatinib in combination with everolimus in pediatric subjects with selected recurrent/refractory solid tumors including Ewing sarcoma, rhabdomyosarcoma, and high grade glioma (HGG) using objective response rate (ORR) at Week 16 as the outcome measure. |
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| E.2.2 | Secondary objectives of the trial |
Phase 1: To preliminarily define the antitumor activity of lenvatinib in combination with everolimus in pediatric subjects with recurrent/refractory solid tumors. To characterize the pharmacokinetics (PK) of oral lenvatinib and everolimus, when administered in combination to pediatric subjects with recurrent/refractory solid tumors.
Phase 2: To assess other response variables including ORR at the time of data cutoff, disease
control rate (DCR), clinical benefit rate (CBR), and duration of response (DOR). To evaluate the tolerability and safety profile of lenvatinib in combination with everolimus in pediatric subjects with recurrent/refractory Ewing sarcoma, rhabdomyosarcoma, and HGG. To characterize the PK of lenvatinib and everolimus, when administered in combination to children with recurrent/refractory Ewing sarcoma, rhabdomyosarcoma, and HGG. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Histologically or cytologically confirmed diagnosis:
-Phase 1: Recurrent or refractory solid tumors (excluding hepatoblastoma and lymphomas), including primary central nervous system (CNS) tumors; subjects must have either measurable or evaluable disease. Subjects with diffuse intrinsic pontine glioma, optic pathway glioma, or pineal tumors with elevated tumor markers (alpha-fetoprotein [AFP] and beta-human chorionic gonadotropin [ß-hCG][or human chorionic gonadotropin [hCG]) do not require histological or cytological confirmation of diagnosis
-Phase 2: Ewing sarcoma, Rhabdomyosarcoma, High Grade Glioma (HGG) (all must have measurable disease); exclusion of Diffuse Intrinsic Pontine Glioma
2) Measurable disease that meets the criteria (Phase 2): RECIST 1.1 (for all tumor types except HGG); Response Assessment in Neuro-Oncology (RANO) for high grade glioma (HGG)
Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as radiofrequency (RF) ablation must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion
3) Karnofsky performance score >=50 for subjects >16 year of age and Lansky play score >=50 for subjects <=16 years of age. Neurologic deficits in subjects with CNS tumors must have been relatively stable for at least 7 days prior to study enrollment. Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
4) Prior Therapy
a) Subjects must have fully recovered from the acute toxic effects of all prior anti-cancer therapy
b) Cytotoxic chemotherapy or other chemotherapy known to be myelosuppressive: >=21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
c) Anti-cancer agents not known to be myelosuppressive (eg, not associated with reduced platelet or absolute neutrophil counts): >=7 days after the last dose of agent
d) Monoclonal antibodies: >=21 days or 3 half-lives (whichever is shorter) of the antibody must have elapsed after the last dose of a monoclonal antibody (including checkpoint inhibitors). Toxicity related to prior antibody therapy must be recovered to Grade <=1
e) Corticosteroids: If used to modify immune adverse events related to prior therapy, >=14 days must have elapsed since last dose of corticosteroid. Subjects receiving corticosteroids, who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment, are not eligible
f) Hematopoietic growth factors: >=14 days after the last dose of a long-acting growth factor or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
g) Interleukins, interferons, and cytokines (other than hematopoietic growth factors): >=21 days after the completion of interleukins, interferons or cytokines (other than hematopoietic growth factors)
h) Stem cell infusions (with or without total body irradiation): Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor leukocytes infusion or boost infusion: >=84 days after infusion and no evidence of graft versus host disease; Autologous stem cell infusion including boost infusion: >=42 days
i) Cellular Therapy: >=42 days after the completion of any type of cellular therapy (example, modified T cells, natural killer cells, dendritic cells)
j) Radiotherapy (XRT)/External Beam Irradiation including Protons: >=14 days after local XRT; >=150 days after total body irradiation, craniospinal XRT or if radiation to >=50% of the pelvis; >=42 days if other substantial bone marrow radiation.
k) Radiopharmaceutical therapy: >=42 days after systemically administered therapy.
l) Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-targeted or mammalian target of rapamycin (mTOR)-targeted therapies: Must not have received prior exposure to lenvatinib; May have previously progressed on an mTOR inhibitor; No more than 2 prior VEGF/VEGFR-targeted therapies (For Phase 2 only); Must not have received prior VEGF/VEGFR-targeted therapy in combination with an mTOR inhibitor (For Phase 2 only)
5) Phase 1: >=2 years and <18 years and Phase 2: >=2 years and <=21 years of age for enrolment
6) Adequate bone marrow function for subjects with solid tumors without known bone marrow involvement and with known bone marrow metastatic disease; Adequate renal function; Adequate liver function; Adequate cardiac function; Adequate neurologic function; Adequate blood pressure (BP) control with or without antihypertensive medications; Adequate coagulation; Adequate pancreatic function; Adequate metabolic function; Adequate glycemic control
7) Subjects must have a minimum body surface area of 0.6 m^2 at study entry. |
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| E.4 | Principal exclusion criteria |
1) Subjects who have had or are planning to have the following invasive procedures
-Major surgical procedure, laparoscopic procedure, open biopsy or significant traumatic injury within 28 days prior to enrolment
-Central line placement or subcutaneous port placement is not considered major surgery. External central lines must be placed at least 3 days prior to enrollment and subcutaneous ports must be placed at least 7 days prior to enrollment
-Fine needle aspirate within 7 days prior to enrolment
-Surgical or other wounds must be adequately healed prior to enrolment
-For purposes of this study, bone marrow aspirate and biopsy are not considered surgical procedures and therefore are permitted within 14 days prior to start of protocol therapy
2) Subjects who have non-healing wound, unhealed or incompletely healed fracture, or a compound (open) bone fracture at the time of enrolment
3) Subjects having an active infection requiring systemic therapy.
4) Subjects with a known history of active hepatitis B (defined as hepatitis B surface antigen reactive or hepatitis B virus- deoxyribonucleic [DNA] detected) or known active hepatitis C virus (HCV, defined as HCV- Ribonucleic acid [RNA] detected). Note: No testing for hepatitis B and hepatitis C is required unless mandated by the local health authority.
5) Known to be human immunodeficiency virus (HIV) positive. Note: HIV testing is required at screening only when mandated by the local health authority
6) Clinical evidence of nephrotic syndrome prior to enrolment
7) Gastrointestinal bleeding or active hemoptysis (bright red blood of at least half teaspoon) within 21 days prior to enrolment
8) Thrombotic/ thromboembolic event requiring systemic anticoagulation within 90 days prior to enrollment
9) Evidence of new intracranial hemorrhage of more than punctate size on MRI assessment obtained within 28 days prior to study enrollment for subjects with HGG
10) Diagnosis of lymphoma
11) Radiographic evidence of major blood vessel invasion/infiltration.
12) Evidence of untreated CNS metastases (exception: subjects with primary CNS tumors and leptomeningeal disease)
13) Subjects who are currently receiving enzyme-inducing anticonvulsants |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1) Maximum tolerated dose (MTD) of lenvatinib in combination with everolimus: Phase 1
2) Recommended Phase 2 dose (RP2D) of lenvatinib in combination with everolimus
3) Number of subjects with any treatment-emergent (TE) serious adverse event (SAE) in Phase 1, as a measure of the safety and toxicity of lenvatinib in combination with everolimus
4) Number of subjects with any TE adverse event (TEAE) in Phase 1, as a measure of the safety and toxicity of lenvatinib in combination with everolimus
5) Overall Response Rate (ORR) at Week 16 for Phase 2 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Cycle 1 (Day 1 to Day 28) of the Treatment Phase
2) Cycle 1 (Day 1 to Day 28) of the Treatment Phase
3) From date of first dose up to 28 days after the last dose of study treatment, up to approximately 2 years
4) From date of first dose up to 28 days after the last dose of study treatment, up to approximately 2 years
5) Week 16 |
|
| E.5.2 | Secondary end point(s) |
1) ORR at the time of data cutoff: Phase 1
2) ORR at the time of data cutoff: Phase 2
3) Disease Control Rate (DCR): Phase 1
4) DCR: Phase 2
5) Clinical Benefit Rate (CBR): Phase 1
6) CBR: Phase 2
7) Duration of Response (DOR): Phase 1
8) DOR: Phase 2
9) Area under the plasma concentration time course profile (AUC): Phase 1
10) Maximum observed concentration (Cmax): Phase 1
11) Time from dosing to the maximum observed concentration (Tmax): Phase 1
12) Number of subjects with any TE SAE in Phase 2, as a measure of the safety and toxicity of lenvatinib in combination with everolimus
13) Number of subjects with any TEAE in Phase 2, as a measure of the safety and toxicity of lenvatinib in combination with everolimus
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1)upto Week 4 of Treatment Phase(TP);upto 2 years in Extension Phase(EP)
2)upto Week 16(TP);upto 2 years(EP)
3)upto Week 4 (TP);upto 2 years (EP)
4)upto Week 16 (TP);upto 2 years (EP)
5)upto Week 4 (TP);upto 2 years (EP)
6)upto Week 16 (TP);upto 2 years (EP)
7)upto Week 4 (TP);upto 2 years (EP)
8)upto Week 16 (TP);upto 2 years (EP)
9)Lenvatinib: Cycle 1 Day 1(C1D1),C1D15;Everolimus:C1D1,C1D15
10)Lenvatinib: Cycle 1 Day 1(C1D1),C1D15;Everolimus:C1D1,C1D15
11)Lenvatinib: Cycle 1 Day 1(C1D1),C1D15;Everolimus:C1D1,C1D15
12 and 13) upto 2.5 years
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| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Phase 1/2 paediatric study
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| 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 | 4 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
|
| 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
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| The definition for end of the study is the date of data cutoff for the final analysis or last subject/last visit including discontinuation from the study for any reason, whichever occurs later. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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