A Study of Lenvatinib (MK-7902) in Pediatric Participants With Relapsed or Refractory Solid Malignancies (MK-7902-013/E7080)

Study Overview
=================
Brief Summary
-----------------
The main purpose of this study is to evaluate the antitumor activity and safety of Lenvatinib (MK-7902/E7080) in children, adolescents, and young adults with relapsed or refractory solid malignancies after administration. Participants will be enrolled into initial tumor-specific cohorts which will be expanded based on observed response.

Official Title
-----------------
An Open-Label, Multicenter Phase 2 Basket Study to Evaluate the Antitumor Activity and Safety of Lenvatinib in Children, Adolescents, and Young Adults With Relapsed or Refractory Solid Malignancies

Conditions
-----------------
Relapsed or Refractory Solid Tumors

Intervention / Treatment
-----------------
* Drug: Lenvatinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has histologically or cytologically documented relapsed, or refractory pediatric solid malignancy excluding osteosarcoma Has measurable disease as defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) or Response Assessment in Neuro-Oncology (RANO) for High Grade Glioma (HGG) Has a performance status defined as follows: 1) Lansky Play Score ≥50 for participants up to and including 16 years of age 2) Karnofsky performance status (KPS) ≥50 for participants >16 years of age 3) Neurologic deficits in participants with primary central nervous system (CNS) tumors must have been stable for at least 7 days prior to study enrollment Demonstrate adequate organ function No clinical evidence of nephrotic syndrome. Has adequate blood pressure (BP) control with or without antihypertensive medications Has adequate cardiac function Has adequate neurologic function Participant must have fully recovered to Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE v5.0) Grade ≤1 (except for alopecia, ototoxicity, and Grade ≤2 peripheral neuropathy) from the acute toxic effects of all prior anticancer therapy Male participants must agree to use approved contraception during the treatment period and for at least 7 days after the last dose of study intervention and refrain from donating sperm during this period Female participants are not pregnant and not breastfeeding, and are not a woman of childbearing potential (WOCBP) or are a WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 30 days after the last dose of study intervention Exclusion Criteria: Has had major surgery within 3 weeks prior to Cycle 1 Day 1 (C1D1) Has gastrointestinal (GI) bleeding or active hemoptysis (bright red blood of at least half teaspoon) within 21 days prior to enrollment Has CNS tumors with a history of symptomatic tumor hemorrhage Has evidence of new intracranial hemorrhage of more than punctate size on MRI assessment obtained within 28 days prior to study enrollment Has radiographic evidence of encasement or invasion of a major blood vessel or of intratumoral cavitation Has evidence of untreated CNS metastases (exception: participants with primary CNS tumors and leptomeningeal disease. Has GI malabsorption, GI anastomosis, or any other condition that in the opinion of the investigator might affect the absorption of lenvatinib Has preexisting ≥Grade 3 GI or non-GI fistula Has any active infection requiring systemic therapy Known to be Human immunodeficiency virus (HIV) positive Known active viral hepatitis (B or C) as demonstrated by positive serology. Testing for hepatitis B or hepatitis C is required at screening only when mandated by local health authority 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 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 Has known hypersensitivity to any component of the investigational product (lenvatinib or ingredients) Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the stud 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 Has non-healing wound, tumor ulceration, unhealed or incompletely healed fracture, or a compound (open) bone fracture at the time of enrollment

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ewing Sarcoma<br>Participants with Ewing sarcoma will receive lenvatinib 14 mg/m^2 once daily (QD) orally until progressive disease or unacceptable toxicity. | Drug: Lenvatinib<br>* Lenvatinib capsules administered orally at 14 mg/m^2 QD<br>* Other names: LENVIMA;|
| Experimental: Rhabdomyosarcoma<br>Participants with rhabdomyosarcoma will receive lenvatinib 14 mg/m^2 QD orally until progressive disease or unacceptable toxicity. | Drug: Lenvatinib<br>* Lenvatinib capsules administered orally at 14 mg/m^2 QD<br>* Other names: LENVIMA;|
| Experimental: High Grade Glioma<br>Participants with high grade glioma will receive lenvatinib 14 mg/m^2 QD orally until progressive disease or unacceptable toxicity. | Drug: Lenvatinib<br>* Lenvatinib capsules administered orally at 14 mg/m^2 QD<br>* Other names: LENVIMA;|
| Experimental: Diffuse Midline Glioma<br>Participants with diffuse midline glioma will receive lenvatinib 14 mg/m^2 QD orally until progressive disease or unacceptable toxicity. | Drug: Lenvatinib<br>* Lenvatinib capsules administered orally at 14 mg/m^2 QD<br>* Other names: LENVIMA;|
| Experimental: Medulloblastoma<br>Participants with medulloblastoma will receive lenvatinib 14 mg/m^2 QD orally until progressive disease or unacceptable toxicity. | Drug: Lenvatinib<br>* Lenvatinib capsules administered orally at 14 mg/m^2 QD<br>* Other names: LENVIMA;|
| Experimental: Ependymoma<br>Participants with ependymoma will receive lenvatinib 14 mg/m^2 QD orally until progressive disease or unacceptable toxicity. | Drug: Lenvatinib<br>* Lenvatinib capsules administered orally at 14 mg/m^2 QD<br>* Other names: LENVIMA;|
| Experimental: Other Solid Tumors Excluding Osteosarcoma, Diffuse Midline Glioma, Medulloblastoma and Ependymoma<br>Participants with other solid tumors will receive lenvatinib 14 mg/m^2 QD orally until progressive disease or unacceptable toxicity. | Drug: Lenvatinib<br>* Lenvatinib capsules administered orally at 14 mg/m^2 QD<br>* Other names: LENVIMA;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | ORR at Week 16 was defined as the percentage of participants with a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters [SOD] of target lesions, taking as reference the baseline SOD) as assessed by the investigator per RECIST 1.1 at 16 Weeks. For participants with HGG, response was assessed according to RANO criteria whereby overall response is based on both radiographic response (CR: disappearance of all target lesions, PR: sum of products of diameters [SPD] decreased by ≥ 50% from baseline value) and clinical performance status with steroid dose information. | Up to 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR Per RECIST 1.1 or RANO Criteria (for HGG Only), by Investigator Assessment | ORR was defined as the percentage of participants with a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD) as assessed by the investigator per RECIST 1.1. For participants with HGG, response was assessed according to RANO criteria whereby overall RANO response is based on both radiographic response (CR: disappearance of all target lesions, PR: SPD decreased by ≥ 50% from baseline value) and clinical performance status with steroid dose information. | Up to approximately 21 months | 
| Progression Free Survival (PFS) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | PFS was defined as the time from the date of the first administration of study drug until the date of first documentation of progressive disease (PD) per RECIST 1.1 or RANO (for HGG) or death (whichever occurs first). | Up to approximately 21 months | 
| Best Overall Response (BOR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | BOR is defined as the participant's best confirmed response (CR or PR) over the treatment period as assessed by the investigator per RECIST 1.1 or RANO. As per RECIST 1.1, CR is defined as disappearance of all target lesions and PR is defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. For participants with HGG, response will be assessed according to RANO criteria whereby overall RANO response is based on both radiographic response (CR: disappearance of all target lesions, PR: SPD decreased by ≥ 50% from baseline value) and clinical performance status with steroid dose information. | Up to approximately 21 months | 
| Duration of Response (DOR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | DOR was defined as the time from the date of the first documented CR or PR to the date first documentation of progressive disease or death (whichever occurs first). As per RECIST 1.1, CR was defined as disappearance of all target lesions and PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. For participants with HGG, response will be assessed according to RANO criteria whereby overall RANO response is based on both radiographic response (CR: disappearance of all target lesions, PR: SPD decreased by ≥ 50% from baseline value) and clinical performance status with steroid dose information. | Up to approximately 21 months | 
| Disease Control Rate (DCR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | DCR was defined as a BOR of CR or PR, or stable disease (SD). To be assigned a BOR of SD, the time from the first administration of study drug until the date of documented SD should be ≥7 weeks. As per RECIST 1.1, CR was defined as disappearance of all target lesions, PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, and SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. For participants with HGG, response was assessed according to RANO criteria whereby overall response was based on both radiographic response (CR: disappearance of all target lesions, PR: SPD decreased by ≥ 50% from baseline value and SD: SPD <50% decreased from baseline, but <25% increased from nadir) and clinical performance status with steroid dose information. | Up to approximately 21 months | 
| Clinical Benefit Rate (CBR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | CBR was defined as a BOR of CR or PR, or durable SD (Duration of SD should be ≥23 weeks since the first dose of the study treatment. As per RECIST 1.1, CR was defined as disappearance of all target lesions, PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD and SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. For participants with HGG, response is assessed according to RANO criteria whereby overall response was based on both radiographic response (CR: disappearance of all target lesions, PR: SPD decreased by ≥ 50% from baseline value and SD: SPD <50% decreased from baseline, but <25% increased from nadir) and clinical performance status with steroid dose information. | Up to approximately 21 months | 
| Number of Participants Who Experienced an Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experienced at least one AE is reported. | Up to approximately 21 months | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinued study treatment due to an AE is reported. | Up to approximately 20 months | 
| Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Taste Category | A hedonic Visual Analog Scale (VAS) was used to assess taste likability or palatability of a lenvatinib suspension formulated with water or apple juice. Participants scored each category on a scale from 1-7 ranging from super bad (score = 1) to super good (score = 7). As pre-specified by the supplemental Statistical Analysis Plan (sSAP), all participants who received suspension formulation were evaluated for palatability and acceptability of the suspension formulation, and data were summarized in an overall safety analysis set irrespective of tumor type. The palatability score based on the taste category is presented. | Cycle 1 Day 1 (cycle = 28 days) | 
| Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Appearance Category | A hedonic VAS was used to assess taste likability or palatability of a lenvatinib suspension formulated with water or apple juice. Participants scored each category on a scale from 1-7 ranging from super bad (score = 1) to super good (score = 7). As pre-specified by the sSAP, all participants who received suspension formulation were evaluated for palatability and acceptability of the suspension formulation, and data were summarized in an overall safety analysis set irrespective of tumor type. The palatability score based on the appearance category is presented. | Cycle 1 Day 1 (cycle = 28 days) | 
| Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Smell Category | A hedonic VAS was used to assess taste likability or palatability of a lenvatinib suspension formulated with water or apple juice. Participants scored each category on a scale from 1-7 ranging from super bad (score = 1) to super good (score = 7). As pre-specified by the sSAP, all participants who received suspension formulation were evaluated for palatability and acceptability of the suspension formulation, and data were summarized in an overall safety analysis set irrespective of tumor type. The palatability score based on the smell category is presented. | Cycle 1 Day 1 (cycle = 28 days) | 
| Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Mouth Feel Category | A hedonic VAS was used to assess taste likability or palatability of a lenvatinib suspension formulated with water or apple juice. Participants scored each category on a scale from 1-7 ranging from super bad (score = 1) to super good (score = 7). As pre-specified by the sSAP, all participants who received suspension formulation were evaluated for palatability and acceptability of the suspension formulation, and data were summarized in an overall safety analysis set irrespective of tumor type. The palatability score based on the mouth feel category is presented. | Cycle 1 Day 1 (cycle = 28 days) | 
| Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Overall Acceptability Category | A hedonic VAS was used to assess taste likability or palatability of a lenvatinib suspension formulated with water or apple juice. Participants scored each category on a scale from 1-7 ranging from super bad (score = 1) to super good (score = 7). As pre-specified by the sSAP, all participants who received suspension formulation were evaluated for palatability and acceptability of the suspension formulation, and data were summarized in an overall safety analysis set irrespective of tumor type. The palatability score based on the overall acceptability category is presented. | Cycle 1 Day 1 (cycle = 28 days) | 
| Area Under the Concentration-Time Curve of Lenvatinib at Steady State (AUCss) | Blood samples were taken predose and at specified times postdose on Days 1-28 to determine the AUCss of Lenvatinib. | Cycle 1 Day 1 (0.5-4 and 6-10 hours post-dose), Cycle 1 Day 15 (pre-dose, 0.5-4, and 6-10 hours post-dose), and Cycle 2 Day 1 (pre-dose and 2-12 hours post-dose). A cycle is 28 days. |