Recurrent and Refractory Solid Tumors
Conditions
Keywords
pediatrics, central nervous system tumors, lenvatinib, E7080, everolimus, Ewing sarcoma/peripheral primitive neuroectodermal tumor, rhabdomyosarcoma, high grade glioma, solid tumors
Brief summary
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 participants 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 participants 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.
Interventions
DRUGLenvatinib
oral hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib, or an extemporaneous suspension
DRUGEverolimus
2 mg, 3 mg, or 5 mg tablets for oral suspension
Sponsors
Merck Sharp & Dohme LLC
Eisai Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
* ≥2 years and \<18 years of age for enrolment in Phase 1 or ≥2 years and ≤21 years of age for enrolment in Phase 2. * Recurrent or refractory solid tumors * Phase 1: All solid tumors (measurable or evaluable disease), including primary central nervous system (CNS) tumors; exclusion of hepatoblastoma and lymphomas. Participants 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 * Histologically or cytologically confirmed diagnosis * Measurable disease that meets the following criteria (Phase 2): 1. RECIST 1.1 (for all tumor types except HGG): At least 1 lesion of ≥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 which is serially measurable according to RECIST 1.1 using computed tomography /magnetic resonance imaging (CT/MRI) 2. Response Assessment in Neuro-Oncology (RANO) for high grade glioma (HGG): At least one lesion must be measurable as defined as a bi dimensionally contrast enhancing lesion with clearly defined margins by CT or MRI scan, with a minimal diameter of 1 cm, and visible on 2 axial slices which are preferably at most 5 mm apart with 0 mm skip 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 * Karnofsky performance score ≥50 for participants\>16 year of age and Lansky play score ≥50 for participants ≤16 years of age. Neurologic deficits in participants with CNS tumors must have been relatively stable for at least 7 days prior to study enrollment. Participants 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 * Prior Therapy * Participants must have fully recovered from the acute toxic effects of all prior anti-cancer therapy * 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) * 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 * 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 * Corticosteroids: If used to modify immune adverse events related to prior therapy, ≥14 days must have elapsed since last dose of corticosteroid. Participants 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 * 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 * Interleukins, interferons, and cytokines (other than hematopoietic growth factors): ≥21 days after the completion of interleukins, interferons or cytokines (other than hematopoietic growth factors) * 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 * Cellular Therapy: ≥42 days after the completion of any type of cellular therapy (eg, modified T cells, natural killer cells, dendritic cells, etc) * 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. * Radiopharmaceutical therapy: ≥42 days after systemically administered therapy. * 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) * Adequate bone marrow function for participants with solid tumors without known bone marrow involvement * Adequate bone marrow function for participants 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 * Participants must have a minimum body surface area (BSA) of 0.6 m\^2 at study entry.
Exclusion criteria
* Participants 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 * Participants who have non-healing wound, unhealed or incompletely healed fracture, or a compound (open) bone fracture at the time of enrolment * Participants having an active infection requiring systemic therapy. * Participants 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. * Known to be human immunodeficiency virus (HIV) positive. Note: HIV testing is required at screening only when mandated by the local health authority * Clinical evidence of nephrotic syndrome prior to enrolment * Gastrointestinal bleeding or active hemoptysis (bright red blood of at least half teaspoon) within 21 days prior to enrolment * Thrombotic/ thromboembolic event requiring systemic anticoagulation within 90 days prior to enrollment * Evidence of new intracranial hemorrhage of more than punctate size on MRI assessment obtained within 28 days prior to study enrollment for Participants with HGG * Diagnosis of lymphoma * Radiographic evidence of major blood vessel invasion/infiltration. * Evidence of untreated CNS metastases (exception: participants with primary CNS tumors and leptomeningeal disease) * Participants who are currently receiving enzyme-inducing anticonvulsants * Participants chronically receiving strong cytochrome P450 3A4 (CYP3A4)/P-glycoprotein (P-gp) inhibitors or inducers within 7 days prior to study enrollment * Females who are breastfeeding or pregnant. For females of childbearing potential, a negative screening pregnancy test must be obtained within 72 hours before the first dose of study drug * Males who have not had a successful vasectomy (confirmed azoospermia) or if they and their female partners do not meet the criteria above (that is, not of childbearing potential or practicing highly effective contraception throughout the study period and for 7 days after lenvatinib discontinuation or 4 weeks after discontinuation of everolimus). No sperm donation is allowed during the study period and for 7 days after lenvatinib discontinuation or 4 weeks after discontinuation of everolimus.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib in Combination With Everolimus | Cycle 1 (Each cycle was of 28 days) | MTD was defined as the highest dose level at which no more than 1/6 participants experienced a dose limiting toxicity (DLTs), with the next higher dose having at least 0 of 3 or 1 of 6 participants experiencing DLTs. DLT was graded according to common terminology criteria for adverse events (CTCAE) version 4.03. |
| Phase 1: Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination With Everolimus | Cycle 1 (Each cycle was of 28 days) | The RP2D of lenvatinib in combination with everolimus was determined by Dose Escalation Committee (DEC) based on safety (including DLTs), pharmacokinetic and clinical data. DLT was graded according to CTCAE v4.03. |
| Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months) | A TEAE was defined as an adverse event that emerged during treatment, having been absent at pretreatment or reemerged during treatment, having been present at pretreatment but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the adverse event is continuous. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product. |
| Phase 1: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE) | From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months) | A TESAE was any untoward medical occurrence that at any dose: resulted in death; life threatening condition; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically important due to other reasons than the above mentioned criteria. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product. |
| Phase 2: Objective Response Rate (ORR) at Week 16 | Week 16 | ORR at Week 16 was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) at Week 16 based on investigator assessment according to response evaluation criteria in solid tumors (RECIST) version 1.1 for non-HGG cohorts and response assessment in neuro-oncology (RANO) for HGG cohort. CR was defined as disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis less than (\<) 10 millimeter (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Clinical Benefit Rate (CBR) | From first dose of study drug until PD or death, whichever occurred first (up to 6.5 months) | CBR was defined as percentage of participants who had BOR of CR, PR, or durable SD (SD duration \>=23 weeks since the first dose of study treatment) divided by number of participants in analysis set. CBR was assessed by an investigator based on RECIST v1.1 for non-HGG cohorts or RANO for HGG cohort. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. |
| Phase 1: Duration of Response (DOR) | From date of the first observation of CR or PR until the date of first observation of progression or date of death (up to 16.5 months) | DOR was defined as the time (in months) from the date of first observation of confirmed response (PR or CR) to the date of the first observation of progression based on the investigator's assessment utilizing RECIST 1.1 for non-HGG cohorts and RANO for HGG cohorts, or date of death, whatever the cause. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. |
| Phase 2: Duration of Response (DOR) | From date of the first observation of CR or PR until the date of first observation of progression or date of death (up to 6.5 months) | DOR was defined as the time (in months) from the date of first observation of confirmed response (PR or CR) to the date of the first observation of progression based on the investigator's assessment utilizing RECIST 1.1 for non-HGG cohorts and RANO for HGG cohort, or date of death, whatever the cause. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. |
| Phase 1: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration of Lenvatinib (AUC[0-t Hours]) | Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days) | AUC0-t of lenvatinib was quantified using validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. |
| Phase 1: Objective Response Rate (ORR) | From the date of the first dose of study drug to the date of first documentation of disease progression or death, whichever occurred first (up to 16.5 months) | ORR was defined as the percentage of participants with BOR of CR or PR based on investigator assessment according to RECIST version 1.1 for non-HGG cohorts and RANO for HGG cohort. CR was defined as disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. |
| Phase 1: Time to Reach Maximum Plasma Concentration (Cmax) of Lenvatinib (Tmax) | Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days) | Tmax of lenvatinib was quantified using validated liquid LC-MS/MS methods. |
| Phase 1: Trough Concentrations (Ctrough) of Everolimus When Administered in Combination With Lenvatinib | Cycle 1 Days 1, 2, 15 and 22: Pre-dose (Cycle length=28 days) | Trough concentrations of everolimus was quantified using validated liquid LC-MS/MS methods. |
| Phase 2: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | From date of first dose up to 28 days after the last dose of study treatment (up to 7.5 months) | A TEAE was defined as an adverse event that emerged during treatment, having been absent at pretreatment or reemerged during treatment, having been present at pretreatment but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the adverse event is continuous. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product. |
| Phase 2: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE) | From date of first dose up to 28 days after the last dose of study treatment (up to 7.5 months) | A TESAE was any untoward medical occurrence that at any dose: resulted in death; life threatening condition; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically important due to other reasons than the above mentioned criteria. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product. |
| Phase 1: Maximum Plasma Concentration of Lenvatinib (Cmax) | Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days) | Cmax of lenvatinib was quantified using validated liquid LC-MS/MS methods. |
| Phase 2: Objective Response Rate (ORR) | From the date of the first dose of study drug to the date of first documentation of disease progression or death, which ever occurred first (up to 6.5 months) | ORR was defined as the percentage of participants with BOR of CR or PR based on investigator assessment according to RECIST version 1.1 for non-HGG cohorts and RANO for HGG cohort. CR was defined as disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. |
| Phase 1: Disease Control Rate (DCR) | From first dose of study drug until PD or death, whichever occurred first (up to 16.5 months) | DCR was defined as percentage of participants with a confirmed CR, PR, or stable disease (SD) (SD duration \>=7 weeks since the first dose of study treatment) divided by number of participants in analysis set. DCR was assessed by an investigator based on RECIST v1.1 for non-HGG participants or RANO for HGG participants. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. |
| Phase 2: Disease Control Rate (DCR) | From first dose of study drug until PD or death, whichever occurred first (up to 6.5 months) | DCR was defined as percentage of participants with confirmed CR, PR, or SD (SD duration greater than or equal to \[\>=\] 7 weeks since first dose of study treatment) divided by number of participants in analysis set. DCR was assessed by investigator based on RECIST v1.1 for non-HGG cohorts or RANO for HGG cohort. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. |
| Phase 1: Clinical Benefit Rate (CBR) | From first dose of study drug until PD or death, whichever occurred first (up to 16.5 months) | CBR was defined as percentage of participants who had BOR of CR, PR, or durable SD (SD duration \>=23 weeks since the first dose of study treatment) divided by number of participants in analysis set. CBR was assessed by an investigator based on RECIST v1.1 for non-HGG participants or RANO for HGG participants. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. |
Countries
Canada, United States
Participant flow
Recruitment details
Participants took part in the study at 24 investigative sites in the United States and Canada from 16 November 2017 to 30 September 2022.
Pre-assignment details
A total of 86 participants were screened, out of which 64 were enrolled and 9 participants completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2 Participants with recurrent or refractory solid tumors received lenvatinib 8 mg/m\^2, capsules, orally, once daily in combination with everolimus 3 mg/m\^2, tablets, orally, once daily in cycle 1 (each cycle was 28 days) until the occurrence of PD, clinical benefit, development of unacceptable toxicity leading to withdrawal from the study, study discontinuation or for a maximum of 18 cycles (each cycle was 28 days) whichever occurred first. | 5 |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 Participants with recurrent or refractory solid tumors received lenvatinib 11 mg/m\^2, capsules, orally, once daily in combination with everolimus 3 mg/m\^2, tablets, orally, once daily in cycle 1 (each cycle was 28 days) until the occurrence of PD, clinical benefit, development of unacceptable toxicity leading to withdrawal from the study, study discontinuation or for a maximum of 18 cycles (each cycle was 28 days) whichever occurred first. | 18 |
| Phase 2: Cohort 1, Ewing Sarcoma Participants with recurrent or refractory ewing sarcoma received lenvatinib 11 mg/m\^2, capsules, orally, once daily in combination with everolimus 3 mg/m\^2, tablets, orally, once daily for up to 7 cycles (each cycle was 28 days) unless participant discontinued early from the study. | 10 |
| Phase 2: Cohort 2, Rhabdomyosarcoma Participants with recurrent or refractory rhabdomyosarcoma received lenvatinib 11 mg/m\^2, capsules, orally, once daily in combination with everolimus 3 mg/m\^2, tablets, orally, once daily for up to 7 cycles (each cycle was 28 days) unless participant discontinued early from the study. | 20 |
| Phase 2: Cohort 3, HGG Participants with recurrent or refractory HGG received lenvatinib 11 mg/m\^2, capsules, orally, once daily in combination with everolimus 3 mg/m\^2, tablets, orally, once daily for up to 7 cycles (each cycle was 28 days) unless participant discontinued early from the study. | 11 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 3 | 14 | 9 | 16 | 7 |
| Overall Study | Sponsor's decision | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2 | Total | Phase 2: Cohort 3, HGG | Phase 2: Cohort 2, Rhabdomyosarcoma | Phase 2: Cohort 1, Ewing Sarcoma | Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 |
|---|---|---|---|---|---|---|
| Age, Customized 12-17 years | 4 Participants | 21 Participants | 7 Participants | 6 Participants | 3 Participants | 1 Participants |
| Age, Customized 18-64 years | 1 Participants | 12 Participants | 1 Participants | 5 Participants | 4 Participants | 1 Participants |
| Age, Customized 2-11 years | 0 Participants | 31 Participants | 3 Participants | 9 Participants | 3 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 12 Participants | 0 Participants | 2 Participants | 2 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 52 Participants | 11 Participants | 18 Participants | 8 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 6 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 10 Participants | 2 Participants | 3 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 3 Participants | 45 Participants | 6 Participants | 16 Participants | 9 Participants | 11 Participants |
| Sex: Female, Male Female | 2 Participants | 31 Participants | 8 Participants | 8 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Male | 3 Participants | 33 Participants | 3 Participants | 12 Participants | 7 Participants | 8 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 5 | 14 / 18 | 9 / 10 | 17 / 20 | 8 / 11 |
| other Total, other adverse events | 5 / 5 | 18 / 18 | 10 / 10 | 19 / 20 | 11 / 11 |
| serious Total, serious adverse events | 2 / 5 | 12 / 18 | 6 / 10 | 8 / 20 | 8 / 11 |
Outcome results
Primary
Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib in Combination With Everolimus
MTD was defined as the highest dose level at which no more than 1/6 participants experienced a dose limiting toxicity (DLTs), with the next higher dose having at least 0 of 3 or 1 of 6 participants experiencing DLTs. DLT was graded according to common terminology criteria for adverse events (CTCAE) version 4.03.
Time frame: Cycle 1 (Each cycle was of 28 days)
Population: SAS included all participants who received at least one dose of study drug (Lenvatinib or Everolimus).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib in Combination With Everolimus | 11 milligram per square meter (mg/m^2) |
Primary
Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
A TEAE was defined as an adverse event that emerged during treatment, having been absent at pretreatment or reemerged during treatment, having been present at pretreatment but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the adverse event is continuous. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product.
Time frame: From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months)
Population: SAS included all participants who received at least one dose of study drug (Lenvatinib or Everolimus).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 5 Participants |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 18 Participants |
Primary
Phase 1: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE)
A TESAE was any untoward medical occurrence that at any dose: resulted in death; life threatening condition; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically important due to other reasons than the above mentioned criteria. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product.
Time frame: From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months)
Population: SAS included all participants who received at least one dose of study drug (Lenvatinib or Everolimus).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE) | 2 Participants |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 1: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE) | 12 Participants |
Primary
Phase 1: Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination With Everolimus
The RP2D of lenvatinib in combination with everolimus was determined by Dose Escalation Committee (DEC) based on safety (including DLTs), pharmacokinetic and clinical data. DLT was graded according to CTCAE v4.03.
Time frame: Cycle 1 (Each cycle was of 28 days)
Population: SAS included all participants who received at least one dose of study drug (Lenvatinib or Everolimus).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination With Everolimus | 11 mg/m^2 |
Primary
Phase 2: Objective Response Rate (ORR) at Week 16
ORR at Week 16 was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) at Week 16 based on investigator assessment according to response evaluation criteria in solid tumors (RECIST) version 1.1 for non-HGG cohorts and response assessment in neuro-oncology (RANO) for HGG cohort. CR was defined as disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis less than (\<) 10 millimeter (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters.
Time frame: Week 16
Population: Evaluable analysis set included all evaluable participants who have measurable disease present at baseline, and at least one postbaseline efficacy assessment, unless they have discontinued prior to the first efficacy assessment due to progressive disease.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 2: Objective Response Rate (ORR) at Week 16 | 0.0 percentage of participants | 95% Confidence Interval 0 |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 2: Objective Response Rate (ORR) at Week 16 | 10.0 percentage of participants | 95% Confidence Interval 1.2 |
| Phase 2: Cohort 3, HGG | Phase 2: Objective Response Rate (ORR) at Week 16 | 0 percentage of participants | 95% Confidence Interval 0 |
Secondary
Phase 1: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration of Lenvatinib (AUC[0-t Hours])
AUC0-t of lenvatinib was quantified using validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methods.
Time frame: Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days)
Population: Pharmacokinetic analysis set included participants who had at least one measurable postdose plasma concentration with an adequately documented drug administration history. Here, 'number analyzed' signifies participants who were evaluable for given timepoints of this outcome measure. Pharmacokinetic data was planned to be analyzed for Phase 1 only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration of Lenvatinib (AUC[0-t Hours]) | Cycle 1 Day 1 | 2338.0 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 1633.41 |
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration of Lenvatinib (AUC[0-t Hours]) | Cycle 1 Day 15 | 1328.0 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 520.69 |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 1: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration of Lenvatinib (AUC[0-t Hours]) | Cycle 1 Day 1 | 3281.1 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 1064.72 |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 1: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration of Lenvatinib (AUC[0-t Hours]) | Cycle 1 Day 15 | 2139.8 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 1156.48 |
Secondary
Phase 1: Clinical Benefit Rate (CBR)
CBR was defined as percentage of participants who had BOR of CR, PR, or durable SD (SD duration \>=23 weeks since the first dose of study treatment) divided by number of participants in analysis set. CBR was assessed by an investigator based on RECIST v1.1 for non-HGG participants or RANO for HGG participants. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Time frame: From first dose of study drug until PD or death, whichever occurred first (up to 16.5 months)
Population: SAS included all participants who received at least 1 dose of study drug (lenvatinib or everolimus).
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Clinical Benefit Rate (CBR) | 20.0 percentage of participants | 95% Confidence Interval 0.5 |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 1: Clinical Benefit Rate (CBR) | 22.2 percentage of participants | 95% Confidence Interval 6.4 |
Secondary
Phase 1: Disease Control Rate (DCR)
DCR was defined as percentage of participants with a confirmed CR, PR, or stable disease (SD) (SD duration \>=7 weeks since the first dose of study treatment) divided by number of participants in analysis set. DCR was assessed by an investigator based on RECIST v1.1 for non-HGG participants or RANO for HGG participants. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Time frame: From first dose of study drug until PD or death, whichever occurred first (up to 16.5 months)
Population: SAS included all participants who received at least 1 dose of study drug (lenvatinib or everolimus).
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Disease Control Rate (DCR) | 20.0 percentage of participants | 95% Confidence Interval 0.5 |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 1: Disease Control Rate (DCR) | 50.0 percentage of participants | 95% Confidence Interval 26 |
Secondary
Phase 1: Duration of Response (DOR)
DOR was defined as the time (in months) from the date of first observation of confirmed response (PR or CR) to the date of the first observation of progression based on the investigator's assessment utilizing RECIST 1.1 for non-HGG cohorts and RANO for HGG cohorts, or date of death, whatever the cause. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Time frame: From date of the first observation of CR or PR until the date of first observation of progression or date of death (up to 16.5 months)
Population: SAS included all participants who received at least 1 dose of study drug (lenvatinib or everolimus). Here, 'overall number of participants analyzed' signifies participants who had CR or PR (0 participants hence, none were analyzed for this outcome measure).
Secondary
Phase 1: Maximum Plasma Concentration of Lenvatinib (Cmax)
Cmax of lenvatinib was quantified using validated liquid LC-MS/MS methods.
Time frame: Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days)
Population: Pharmacokinetic analysis set included participants who had at least one measurable postdose plasma concentration with an adequately documented drug administration history. Here, 'number analyzed' signifies participants who were evaluable for given timepoints of this outcome measure. Pharmacokinetic data was planned to be analyzed for Phase 1 only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Maximum Plasma Concentration of Lenvatinib (Cmax) | Cycle 1 Day 1 | 240.20 nanogram per milliliter (ng/mL) | Standard Deviation 130.892 |
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Maximum Plasma Concentration of Lenvatinib (Cmax) | Cycle 1 Day 15 | 314.20 nanogram per milliliter (ng/mL) | Standard Deviation 149.527 |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 1: Maximum Plasma Concentration of Lenvatinib (Cmax) | Cycle 1 Day 1 | 404.13 nanogram per milliliter (ng/mL) | Standard Deviation 121.473 |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 1: Maximum Plasma Concentration of Lenvatinib (Cmax) | Cycle 1 Day 15 | 447.62 nanogram per milliliter (ng/mL) | Standard Deviation 272.79 |
Secondary
Phase 1: Objective Response Rate (ORR)
ORR was defined as the percentage of participants with BOR of CR or PR based on investigator assessment according to RECIST version 1.1 for non-HGG cohorts and RANO for HGG cohort. CR was defined as disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters.
Time frame: From the date of the first dose of study drug to the date of first documentation of disease progression or death, whichever occurred first (up to 16.5 months)
Population: SAS included all participants who received at least 1 dose of study drug (lenvatinib or everolimus). Here, 'overall number of participants analyzed' signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Objective Response Rate (ORR) | 0.0 percentage of participants | 95% Confidence Interval 0 |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 1: Objective Response Rate (ORR) | 0.0 percentage of participants | 95% Confidence Interval 0 |
Secondary
Phase 1: Time to Reach Maximum Plasma Concentration (Cmax) of Lenvatinib (Tmax)
Tmax of lenvatinib was quantified using validated liquid LC-MS/MS methods.
Time frame: Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days)
Population: Pharmacokinetic analysis set included participants who had at least one measurable postdose plasma concentration with an adequately documented drug administration history. Here, 'number analyzed' signifies participants who were evaluable for given timepoints of this outcome measure. Pharmacokinetic data was planned to be analyzed for Phase 1 only.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Time to Reach Maximum Plasma Concentration (Cmax) of Lenvatinib (Tmax) | Cycle 1 Day 1 | 3.000 hours |
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Time to Reach Maximum Plasma Concentration (Cmax) of Lenvatinib (Tmax) | Cycle 1 Day 15 | 3.950 hours |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 1: Time to Reach Maximum Plasma Concentration (Cmax) of Lenvatinib (Tmax) | Cycle 1 Day 1 | 2.890 hours |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 1: Time to Reach Maximum Plasma Concentration (Cmax) of Lenvatinib (Tmax) | Cycle 1 Day 15 | 2.950 hours |
Secondary
Phase 1: Trough Concentrations (Ctrough) of Everolimus When Administered in Combination With Lenvatinib
Trough concentrations of everolimus was quantified using validated liquid LC-MS/MS methods.
Time frame: Cycle 1 Days 1, 2, 15 and 22: Pre-dose (Cycle length=28 days)
Population: Pharmacokinetic analysis set included participants who had at least one measurable postdose plasma concentration with an adequately documented drug administration history. Here, 'overall number of participants analyzed' signifies participants who were evaluable for this outcome measure and 'number analyzed' signifies participants who were evaluable for given timepoints of this outcome measure. Pharmacokinetic data was planned to be analyzed for Phase 1 only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Trough Concentrations (Ctrough) of Everolimus When Administered in Combination With Lenvatinib | Cycle 1 Day 2: Pre-dose | 2.1 ng/mL | Standard Deviation 1.34 |
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Trough Concentrations (Ctrough) of Everolimus When Administered in Combination With Lenvatinib | Cycle 1 Day 1: Pre-dose | 0.0 ng/mL | Standard Deviation 0 |
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Trough Concentrations (Ctrough) of Everolimus When Administered in Combination With Lenvatinib | Cycle 1 Day 15: Pre-dose | 3.2 ng/mL | Standard Deviation 2.42 |
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 1: Trough Concentrations (Ctrough) of Everolimus When Administered in Combination With Lenvatinib | Cycle 1 Day 22: Pre-dose | 2.8 ng/mL | Standard Deviation 1.96 |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 1: Trough Concentrations (Ctrough) of Everolimus When Administered in Combination With Lenvatinib | Cycle 1 Day 22: Pre-dose | 4.2 ng/mL | Standard Deviation 2.73 |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 1: Trough Concentrations (Ctrough) of Everolimus When Administered in Combination With Lenvatinib | Cycle 1 Day 1: Pre-dose | 0.0 ng/mL | Standard Deviation 0 |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 1: Trough Concentrations (Ctrough) of Everolimus When Administered in Combination With Lenvatinib | Cycle 1 Day 2: Pre-dose | 2.2 ng/mL | Standard Deviation 1.13 |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 1: Trough Concentrations (Ctrough) of Everolimus When Administered in Combination With Lenvatinib | Cycle 1 Day 15: Pre-dose | 5.1 ng/mL | Standard Deviation 2.98 |
Secondary
Phase 2: Clinical Benefit Rate (CBR)
CBR was defined as percentage of participants who had BOR of CR, PR, or durable SD (SD duration \>=23 weeks since the first dose of study treatment) divided by number of participants in analysis set. CBR was assessed by an investigator based on RECIST v1.1 for non-HGG cohorts or RANO for HGG cohort. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Time frame: From first dose of study drug until PD or death, whichever occurred first (up to 6.5 months)
Population: Evaluable analysis set included all evaluable participants who have measurable disease present at baseline, and at least one postbaseline efficacy assessment, unless they have discontinued prior to the first efficacy assessment due to PD.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 2: Clinical Benefit Rate (CBR) | 20.0 percentage of participants | 95% Confidence Interval 2.5 |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 2: Clinical Benefit Rate (CBR) | 10.0 percentage of participants | 95% Confidence Interval 1.2 |
| Phase 2: Cohort 3, HGG | Phase 2: Clinical Benefit Rate (CBR) | 0.0 percentage of participants | 95% Confidence Interval 0 |
Secondary
Phase 2: Disease Control Rate (DCR)
DCR was defined as percentage of participants with confirmed CR, PR, or SD (SD duration greater than or equal to \[\>=\] 7 weeks since first dose of study treatment) divided by number of participants in analysis set. DCR was assessed by investigator based on RECIST v1.1 for non-HGG cohorts or RANO for HGG cohort. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Time frame: From first dose of study drug until PD or death, whichever occurred first (up to 6.5 months)
Population: Evaluable analysis set included all evaluable participants who have measurable disease present at baseline, and at least one postbaseline efficacy assessment, unless they have discontinued prior to the first efficacy assessment due to progressive disease.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 2: Disease Control Rate (DCR) | 40.0 percentage of participants | 95% Confidence Interval 12.2 |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 2: Disease Control Rate (DCR) | 40.0 percentage of participants | 95% Confidence Interval 19.1 |
| Phase 2: Cohort 3, HGG | Phase 2: Disease Control Rate (DCR) | 30.0 percentage of participants | 95% Confidence Interval 6.7 |
Secondary
Phase 2: Duration of Response (DOR)
DOR was defined as the time (in months) from the date of first observation of confirmed response (PR or CR) to the date of the first observation of progression based on the investigator's assessment utilizing RECIST 1.1 for non-HGG cohorts and RANO for HGG cohort, or date of death, whatever the cause. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Time frame: From date of the first observation of CR or PR until the date of first observation of progression or date of death (up to 6.5 months)
Population: Evaluable analysis set included all evaluable participants who have measurable disease present at baseline, and at least one postbaseline efficacy assessment, unless they have discontinued prior to first efficacy assessment due to progressive disease. Here, 'overall number of participants analyzed' signifies participants who had CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 2: Duration of Response (DOR) | 2.4 months |
Secondary
Phase 2: Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
A TEAE was defined as an adverse event that emerged during treatment, having been absent at pretreatment or reemerged during treatment, having been present at pretreatment but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the adverse event is continuous. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product.
Time frame: From date of first dose up to 28 days after the last dose of study treatment (up to 7.5 months)
Population: SAS included all participants who received at least one dose of study drug (Lenvatinib or Everolimus).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 2: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 10 Participants |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 2: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 19 Participants |
| Phase 2: Cohort 3, HGG | Phase 2: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 11 Participants |
Secondary
Phase 2: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE)
A TESAE was any untoward medical occurrence that at any dose: resulted in death; life threatening condition; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically important due to other reasons than the above mentioned criteria. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product.
Time frame: From date of first dose up to 28 days after the last dose of study treatment (up to 7.5 months)
Population: SAS included all participants who received at least one dose of study drug (Lenvatinib or Everolimus).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 2: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE) | 6 Participants |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 2: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE) | 8 Participants |
| Phase 2: Cohort 3, HGG | Phase 2: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE) | 8 Participants |
Secondary
Phase 2: Objective Response Rate (ORR)
ORR was defined as the percentage of participants with BOR of CR or PR based on investigator assessment according to RECIST version 1.1 for non-HGG cohorts and RANO for HGG cohort. CR was defined as disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters.
Time frame: From the date of the first dose of study drug to the date of first documentation of disease progression or death, which ever occurred first (up to 6.5 months)
Population: Evaluable analysis set included all evaluable participants who have measurable disease present at baseline, and at least one postbaseline efficacy assessment, unless they have discontinued prior to the first efficacy assessment due to progressive disease.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Phase 1: Lenvatinib + Everolimus (All Participants) | Phase 2: Objective Response Rate (ORR) | 0.0 percentage of participants | 95% Confidence Interval 0 |
| Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2 | Phase 2: Objective Response Rate (ORR) | 10.0 percentage of participants | 95% Confidence Interval 1.2 |
| Phase 2: Cohort 3, HGG | Phase 2: Objective Response Rate (ORR) | 0.0 percentage of participants | 95% Confidence Interval 0 |