Relapsed or Refractory Solid Tumors
Conditions
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 were enrolled into Ewing sarcoma (EWS), rhabdomyosarcoma (RMS), high-grade glioma (HGG), diffuse midline glioma, medulloblastoma, ependymoma, and Other Solid Tumors Excluding Osteosarcoma, diffuse midline glioma, medulloblastoma, and ependymoma cohorts.
Interventions
DRUGLenvatinib
Lenvatinib capsules administered orally at 14 mg/m\^2 QD
Sponsors
Eisai Inc.
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open Label
Eligibility
Sex/Gender
ALL
Age
2 Years to 21 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Up to 16 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | Up to approximately 21 months | 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). |
| Best Overall Response (BOR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | Up to approximately 21 months | 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. |
| Duration of Response (DOR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | Up to approximately 21 months | 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. |
| Disease Control Rate (DCR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | Up to approximately 21 months | 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. |
| Clinical Benefit Rate (CBR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | Up to approximately 21 months | 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. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 50 months | 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. |
| ORR Per RECIST 1.1 or RANO Criteria (for HGG Only), by Investigator Assessment | Up to approximately 21 months | 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. |
| Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Taste Category | Cycle 1 Day 1 (cycle = 28 days) | 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. |
| Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Appearance Category | Cycle 1 Day 1 (cycle = 28 days) | 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. |
| Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Smell Category | Cycle 1 Day 1 (cycle = 28 days) | 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. |
| Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Mouth Feel Category | Cycle 1 Day 1 (cycle = 28 days) | 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. |
| Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Overall Acceptability Category | Cycle 1 Day 1 (cycle = 28 days) | 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. |
| Area Under the Concentration-Time Curve of Lenvatinib at Steady State (AUCss) | 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. | Blood samples were taken predose and at specified times postdose on Days 1-28 to determine the AUCss of Lenvatinib. |
| Number of Participants Who Discontinued Study Treatment Due to an AE | Up to approximately 38 months | 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. |
Countries
Argentina, Australia, Belgium, Croatia, Czechia, France, Guatemala, Hungary, Israel, Italy, New Zealand, Peru, Russia, Serbia, South Africa, South Korea, Spain, Sweden, Turkey (Türkiye), United States
Participant flow
Recruitment details
Participants were recruited to tumor cohorts of Ewing Sarcoma, Rhabdomyosarcoma, High Grade Glioma, and Other Solid Tumors Excluding Osteosarcoma. Enrollment to the protocol pre-specified tumor cohort of Other Solid Tumors Excluding Osteosarcoma was further expanded into categories of Diffuse midline glioma, Medulloblastoma, and Ependymoma.
Participants by arm
| Arm | Count |
|---|---|
| Ewing Sarcoma Participants with Ewing sarcoma received lenvatinib 14 mg/m\^2 once daily (QD) orally until progressive disease or unacceptable toxicity. | 9 |
| Rhabdomyosarcoma Participants with rhabdomyosarcoma received lenvatinib 14 mg/m\^2 QD orally until progressive disease or unacceptable toxicity. | 17 |
| High Grade Glioma Participants with high grade glioma received lenvatinib 14 mg/m\^2 QD orally until progressive disease or unacceptable toxicity. | 8 |
| Diffuse Midline Glioma Participants with diffuse midline glioma received lenvatinib 14 mg/m\^2 QD orally until progressive disease or unacceptable toxicity. | 9 |
| Medulloblastoma Participants with medulloblastoma received lenvatinib 14 mg/m\^2 QD orally until progressive disease or unacceptable toxicity. | 9 |
| Ependymoma Participants with ependymoma received lenvatinib 14 mg/m\^2 QD orally until progressive disease or unacceptable toxicity. | 9 |
| Other Solid Tumors Excluding Osteosarcoma, Diffuse Midline Glioma, Medulloblastoma and Ependymoma Participants with other solid tumors received lenvatinib 14 mg/m\^2 QD orally until progressive disease or unacceptable toxicity. | 66 |
| Total | 127 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 9 | 16 | 8 | 9 | 8 | 9 | 55 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Sponsor Decision | 0 | 0 | 0 | 0 | 1 | 0 | 10 |
| Overall Study | Withdrawal by Parent/Guardian | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Ewing Sarcoma | Rhabdomyosarcoma | High Grade Glioma | Diffuse Midline Glioma | Medulloblastoma | Ependymoma | Other Solid Tumors Excluding Osteosarcoma, Diffuse Midline Glioma, Medulloblastoma and Ependymoma | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 14.8 Years STANDARD_DEVIATION 4 | 13.1 Years STANDARD_DEVIATION 4.7 | 14.0 Years STANDARD_DEVIATION 3.1 | 10.0 Years STANDARD_DEVIATION 5.2 | 13.2 Years STANDARD_DEVIATION 4.5 | 8.7 Years STANDARD_DEVIATION 5.7 | 13.1 Years STANDARD_DEVIATION 5.6 | 12.7 Years STANDARD_DEVIATION 5.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 9 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 11 Participants | 6 Participants | 4 Participants | 2 Participants | 6 Participants | 43 Participants | 77 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 2 Participants | 5 Participants | 6 Participants | 3 Participants | 14 Participants | 37 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 13 Participants | 22 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 3 Participants | 4 Participants | 6 Participants | 2 Participants | 11 Participants | 32 Participants |
| Race (NIH/OMB) White | 3 Participants | 10 Participants | 4 Participants | 2 Participants | 2 Participants | 7 Participants | 35 Participants | 63 Participants |
| Sex: Female, Male Female | 2 Participants | 7 Participants | 4 Participants | 8 Participants | 3 Participants | 4 Participants | 32 Participants | 60 Participants |
| Sex: Female, Male Male | 7 Participants | 10 Participants | 4 Participants | 1 Participants | 6 Participants | 5 Participants | 34 Participants | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 9 | 17 / 17 | 8 / 8 | 9 / 9 | 8 / 9 | 9 / 9 | 55 / 66 |
| other Total, other adverse events | 9 / 9 | 17 / 17 | 6 / 8 | 9 / 9 | 9 / 9 | 7 / 9 | 66 / 66 |
| serious Total, serious adverse events | 4 / 9 | 5 / 17 | 6 / 8 | 4 / 9 | 4 / 9 | 4 / 9 | 39 / 66 |
Outcome results
Primary
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.
Time frame: Up to 16 weeks
Population: All participants who had measurable disease present at baseline and at least one efficacy assessment, unless they discontinued prior to the first efficacy assessment due to progressive disease.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ewing Sarcoma | 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 | 22.2 Percentage of Participants |
| Rhabdomyosarcoma | 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 | 11.8 Percentage of Participants |
| High Grade Glioma | 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 | 0.0 Percentage of Participants |
| Diffuse Midline Glioma | 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 | 0.0 Percentage of Participants |
| Medulloblastoma | 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 | 0.0 Percentage of Participants |
| Ependymoma | 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 | 0.0 Percentage of Participants |
| Other Solid Tumors Excluding Osteosarcoma, Diffuse Midline Glioma, Medulloblastoma and Ependymoma | 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 | 7.7 Percentage of Participants |
Secondary
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.
Time frame: 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.
Population: All participants who received at least one dose of study treatment and had at least one measurable postdose plasma concentration with an adequately documented dosing history were analyzed. Lenvatinib exposures are reported by the four protocol pre-specified cohorts at the time of enrollment (EWS, RMS, HGG, and Other Solid Tumors excluding Osteosarcoma). For the purposes of the analysis, AUCss was reported for participants with Other Solid Tumors irrespective of tumor type.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ewing Sarcoma | Area Under the Concentration-Time Curve of Lenvatinib at Steady State (AUCss) | 5896 ng*hr/ml | Geometric Coefficient of Variation 31.2 |
| Rhabdomyosarcoma | Area Under the Concentration-Time Curve of Lenvatinib at Steady State (AUCss) | 3915 ng*hr/ml | Geometric Coefficient of Variation 32.9 |
| High Grade Glioma | Area Under the Concentration-Time Curve of Lenvatinib at Steady State (AUCss) | 3660 ng*hr/ml | Geometric Coefficient of Variation 43.5 |
| Diffuse Midline Glioma | Area Under the Concentration-Time Curve of Lenvatinib at Steady State (AUCss) | 4990 ng*hr/ml | Geometric Coefficient of Variation 53.2 |
Secondary
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.
Time frame: Up to approximately 21 months
Population: All participants who had measurable disease present at baseline and at least one efficacy assessment, unless they discontinued prior to the first efficacy assessment due to progressive disease.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ewing Sarcoma | Best Overall Response (BOR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 22.2 Percentage of Participants |
| Rhabdomyosarcoma | Best Overall Response (BOR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 11.8 Percentage of Participants |
| High Grade Glioma | Best Overall Response (BOR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 0.0 Percentage of Participants |
| Diffuse Midline Glioma | Best Overall Response (BOR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 0.0 Percentage of Participants |
| Medulloblastoma | Best Overall Response (BOR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 0.0 Percentage of Participants |
| Ependymoma | Best Overall Response (BOR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 0.0 Percentage of Participants |
| Other Solid Tumors Excluding Osteosarcoma, Diffuse Midline Glioma, Medulloblastoma and Ependymoma | Best Overall Response (BOR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 7.7 Percentage of Participants |
Secondary
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.
Time frame: Up to approximately 21 months
Population: All participants who had measurable disease present at baseline and at least one efficacy assessment, unless they discontinued prior to the first efficacy assessment due to progressive disease.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ewing Sarcoma | Clinical Benefit Rate (CBR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 33.3 Percentage of Participants |
| Rhabdomyosarcoma | Clinical Benefit Rate (CBR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 29.4 Percentage of Participants |
| High Grade Glioma | Clinical Benefit Rate (CBR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 0.0 Percentage of Participants |
| Diffuse Midline Glioma | Clinical Benefit Rate (CBR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 11.1 Percentage of Participants |
| Medulloblastoma | Clinical Benefit Rate (CBR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 44.4 Percentage of Participants |
| Ependymoma | Clinical Benefit Rate (CBR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 33.3 Percentage of Participants |
| Other Solid Tumors Excluding Osteosarcoma, Diffuse Midline Glioma, Medulloblastoma and Ependymoma | Clinical Benefit Rate (CBR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 40.0 Percentage of Participants |
Secondary
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.
Time frame: Up to approximately 21 months
Population: All participants who had measurable disease present at baseline and at least one efficacy assessment, unless they discontinued prior to the first efficacy assessment due to progressive disease.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ewing Sarcoma | Disease Control Rate (DCR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 66.7 Percentage of Participants |
| Rhabdomyosarcoma | Disease Control Rate (DCR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 52.9 Percentage of Participants |
| High Grade Glioma | Disease Control Rate (DCR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 33.3 Percentage of Participants |
| Diffuse Midline Glioma | Disease Control Rate (DCR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 22.2 Percentage of Participants |
| Medulloblastoma | Disease Control Rate (DCR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 55.6 Percentage of Participants |
| Ependymoma | Disease Control Rate (DCR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 55.6 Percentage of Participants |
| Other Solid Tumors Excluding Osteosarcoma, Diffuse Midline Glioma, Medulloblastoma and Ependymoma | Disease Control Rate (DCR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 64.6 Percentage of Participants |
Secondary
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.
Time frame: Up to approximately 21 months
Population: All participants who had measurable disease present at baseline and at least one efficacy assessment, unless they discontinued prior to the first efficacy assessment due to progressive disease, and demonstrated CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ewing Sarcoma | Duration of Response (DOR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | NA Months |
| Rhabdomyosarcoma | Duration of Response (DOR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 4.6 Months |
| Other Solid Tumors Excluding Osteosarcoma, Diffuse Midline Glioma, Medulloblastoma and Ependymoma | Duration of Response (DOR) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 4.6 Months |
Secondary
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.
Time frame: Up to approximately 38 months
Population: All participants who received at least one dose of study treatment were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ewing Sarcoma | Number of Participants Who Discontinued Study Treatment Due to an AE | 1 Participants |
| Rhabdomyosarcoma | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| High Grade Glioma | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| Diffuse Midline Glioma | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| Medulloblastoma | Number of Participants Who Discontinued Study Treatment Due to an AE | 1 Participants |
| Ependymoma | Number of Participants Who Discontinued Study Treatment Due to an AE | 2 Participants |
| Other Solid Tumors Excluding Osteosarcoma, Diffuse Midline Glioma, Medulloblastoma and Ependymoma | Number of Participants Who Discontinued Study Treatment Due to an AE | 6 Participants |
Secondary
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.
Time frame: Up to approximately 50 months
Population: All participants who received at least one dose of study treatment were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ewing Sarcoma | Number of Participants Who Experienced an Adverse Event (AE) | 9 Participants |
| Rhabdomyosarcoma | Number of Participants Who Experienced an Adverse Event (AE) | 17 Participants |
| High Grade Glioma | Number of Participants Who Experienced an Adverse Event (AE) | 8 Participants |
| Diffuse Midline Glioma | Number of Participants Who Experienced an Adverse Event (AE) | 9 Participants |
| Medulloblastoma | Number of Participants Who Experienced an Adverse Event (AE) | 9 Participants |
| Ependymoma | Number of Participants Who Experienced an Adverse Event (AE) | 8 Participants |
| Other Solid Tumors Excluding Osteosarcoma, Diffuse Midline Glioma, Medulloblastoma and Ependymoma | Number of Participants Who Experienced an Adverse Event (AE) | 66 Participants |
Secondary
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.
Time frame: Up to approximately 21 months
Population: All participants who had measurable disease present at baseline and at least one efficacy assessment, unless they discontinued prior to the first efficacy assessment due to progressive disease.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ewing Sarcoma | ORR Per RECIST 1.1 or RANO Criteria (for HGG Only), by Investigator Assessment | 22.2 Percentage of Participants |
| Rhabdomyosarcoma | ORR Per RECIST 1.1 or RANO Criteria (for HGG Only), by Investigator Assessment | 11.8 Percentage of Participants |
| High Grade Glioma | ORR Per RECIST 1.1 or RANO Criteria (for HGG Only), by Investigator Assessment | 0.0 Percentage of Participants |
| Diffuse Midline Glioma | ORR Per RECIST 1.1 or RANO Criteria (for HGG Only), by Investigator Assessment | 0.0 Percentage of Participants |
| Medulloblastoma | ORR Per RECIST 1.1 or RANO Criteria (for HGG Only), by Investigator Assessment | 0.0 Percentage of Participants |
| Ependymoma | ORR Per RECIST 1.1 or RANO Criteria (for HGG Only), by Investigator Assessment | 0.0 Percentage of Participants |
| Other Solid Tumors Excluding Osteosarcoma, Diffuse Midline Glioma, Medulloblastoma and Ependymoma | ORR Per RECIST 1.1 or RANO Criteria (for HGG Only), by Investigator Assessment | 7.7 Percentage of Participants |
Secondary
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.
Time frame: Cycle 1 Day 1 (cycle = 28 days)
Population: Per protocol, all participants who received suspension formulation were analyzed. Data were summarized in an overall safety analysis set irrespective of tumor type.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Appearance Category | Super Bad | 0 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Appearance Category | Really Bad | 0 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Appearance Category | Bad | 1 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Appearance Category | Maybe Good or Maybe Bad | 5 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Appearance Category | Good | 2 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Appearance Category | Really Good | 0 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Appearance Category | Super Good | 2 Participants |
Secondary
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.
Time frame: Cycle 1 Day 1 (cycle = 28 days)
Population: Per protocol, all participants who received suspension formulation were analyzed. Data were summarized in an overall safety analysis set irrespective of tumor type.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Mouth Feel Category | Super Bad | 0 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Mouth Feel Category | Really Bad | 1 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Mouth Feel Category | Bad | 2 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Mouth Feel Category | Maybe Good or Maybe Bad | 4 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Mouth Feel Category | Good | 1 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Mouth Feel Category | Really Good | 2 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Mouth Feel Category | Super Good | 0 Participants |
Secondary
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.
Time frame: Cycle 1 Day 1 (cycle = 28 days)
Population: Per protocol, all participants who received suspension formulation were analyzed. Data were summarized in an overall safety analysis set irrespective of tumor type.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Overall Acceptability Category | Super Bad | 0 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Overall Acceptability Category | Really Bad | 1 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Overall Acceptability Category | Bad | 1 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Overall Acceptability Category | Maybe Good or Maybe Bad | 3 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Overall Acceptability Category | Good | 3 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Overall Acceptability Category | Really Good | 1 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Overall Acceptability Category | Super Good | 1 Participants |
Secondary
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.
Time frame: Cycle 1 Day 1 (cycle = 28 days)
Population: Per protocol, all participants who received suspension formulation were analyzed. Data were summarized in an overall safety analysis set irrespective of tumor type.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Smell Category | Super Bad | 0 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Smell Category | Really Bad | 0 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Smell Category | Bad | 0 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Smell Category | Maybe Good or Maybe Bad | 8 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Smell Category | Good | 1 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Smell Category | Really Good | 0 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Smell Category | Super Good | 1 Participants |
Secondary
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.
Time frame: Cycle 1 Day 1 (cycle = 28 days)
Population: Per protocol, all participants who received suspension formulation were analyzed. Data were summarized in an overall safety analysis set irrespective of tumor type.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Taste Category | Super Bad | 1 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Taste Category | Really Bad | 0 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Taste Category | Bad | 2 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Taste Category | Maybe Good or Maybe Bad | 5 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Taste Category | Good | 1 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Taste Category | Really Good | 0 Participants |
| Ewing Sarcoma | Palatability Questionnaire For Lenvatinib Suspension Formulation: Participant Responses by Taste Category | Super Good | 1 Participants |
Secondary
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).
Time frame: Up to approximately 21 months
Population: All participants who had measurable disease present at baseline and at least one efficacy assessment, unless they discontinued prior to the first efficacy assessment due to progressive disease.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ewing Sarcoma | Progression Free Survival (PFS) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 3.0 Months |
| Rhabdomyosarcoma | Progression Free Survival (PFS) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 2.6 Months |
| High Grade Glioma | Progression Free Survival (PFS) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 1.9 Months |
| Diffuse Midline Glioma | Progression Free Survival (PFS) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 1.8 Months |
| Medulloblastoma | Progression Free Survival (PFS) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 3.4 Months |
| Ependymoma | Progression Free Survival (PFS) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 2.5 Months |
| Other Solid Tumors Excluding Osteosarcoma, Diffuse Midline Glioma, Medulloblastoma and Ependymoma | Progression Free Survival (PFS) Per RECIST 1.1 or RANO (for HGG Only), by Investigator Assessment | 3.8 Months |