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Clinical Trial Results:
A Phase 1/2 Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including CNS Tumors

Summary
EudraCT number	2022-003736-77
Trial protocol	Outside EU/EEA
Global end of trial date	30 Sep 2022

Results information
Results version number	v1(current)
This version publication date	15 Apr 2023
First version publication date	15 Apr 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

E7080-A001-216

ISRCTN number

US NCT number

NCT03245151

WHO universal trial number (UTN)

Sponsor organisation name

Eisai Inc.

Sponsor organisation address

200 Metro Blvd, Nutley, New Jersey, United States, 07110

Public contact

Eisai Medical Information, Eisai Inc., +1 888-274-2378, esi_medinfo@eisai.com

Scientific contact

Eisai Medical Information, Eisai Inc., +1 888-274-2378, esi_medinfo@eisai.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001119-PIP03-19

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

30 Sep 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

30 Sep 2022

Was the trial ended prematurely?

Main objective of the trial

Phase 1 of this study, utilizing a rolling 6 design, was conducted to determine a maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), and to describe the toxicities of lenvatinib administered in combination with everolimus once daily to pediatric subjects with recurrent/refractory solid tumors. Phase 2, utilizing Simon's optimal 2-stage design, was conducted to estimate the antitumor activity of lenvatinib in combination with everolimus in pediatric subjects with selected recurrent/refractory solid tumors including Ewing sarcoma (EWS), rhabdomyosarcoma (RMS), and high grade glioma (HGG) using objective response rate (ORR) at Week 16 as the endpoint.

Protection of trial subjects

This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.

Background therapy

Evidence for comparator

Actual start date of recruitment

16 Nov 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 62

Country: Number of subjects enrolled

Canada: 2

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects took part in the study at 24 investigative sites in the United States and Canada from 16 November 2017 to 30 September 2022.

Screening details

A total of 86 subjects were screened, out of which 64 were enrolled and 9 subjects completed the study.

Period 1 title

Overall (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2

Arm description

Subjects with recurrent or refractory solid tumors received lenvatinib 8 milligram per square meter (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 disease progression (PD), clinical benefit, development of unacceptable toxicity leading to withdrawal from the study, study termination or for a maximum of 18 cycles (each cycle was 28 days) whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Lenvatinib

Investigational medicinal product code

Other name

E7080

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Subjects with recurrent or refractory solid tumors received lenvatinib 8 mg/m^2, capsules, 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 termination or for a maximum of 18 cycles (each cycle was 28 days) whichever occurred first.

Investigational medicinal product name

Everolimus

Investigational medicinal product code

Other name

Pharmaceutical forms

Dispersible tablet

Routes of administration

Oral use

Dosage and administration details

Subjects with recurrent or refractory solid tumors received 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 termination or for a maximum of 18 cycles (each cycle was 28 days) whichever occurred first.

Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2

Arm description

Subjects 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 termination or for a maximum of 18 cycles (each cycle was 28 days) whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Everolimus

Investigational medicinal product code

Other name

Pharmaceutical forms

Dispersible tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Lenvatinib

Investigational medicinal product code

Other name

E7080

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Subjects with recurrent or refractory solid tumors received lenvatinib 11 mg/m^2, capsules, 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 termination or for a maximum of 18 cycles (each cycle was 28 days) whichever occurred first.

Phase 2: Cohort 1, Ewing sarcoma

Arm description

Subjects 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 subject discontinued early from the study.

Arm type

Experimental

Investigational medicinal product name

Everolimus

Investigational medicinal product code

Other name

Pharmaceutical forms

Dispersible tablet

Routes of administration

Oral use

Dosage and administration details

Subjects with recurrent or refractory ewing sarcoma received everolimus 3 mg/m^2, tablets, orally, once daily for up to 7 cycles (each cycle was 28 days) unless subject discontinued early from the study.

Investigational medicinal product name

Lenvatinib

Investigational medicinal product code

Other name

E7080

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Subjects with recurrent or refractory ewing sarcoma received lenvatinib 11 mg/m^2, capsules, orally, once daily for up to 7 cycles (each cycle was 28 days) unless subject discontinued early from the study.

Phase 2: Cohort 2, Rhabdomyosarcoma

Arm description

Subjects 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 subject discontinued early from the study.

Arm type

Experimental

Investigational medicinal product name

Everolimus

Investigational medicinal product code

Other name

Pharmaceutical forms

Dispersible tablet

Routes of administration

Oral use

Dosage and administration details

Subjects with recurrent or refractory rhabdomyosarcoma received everolimus 3 mg/m^2, tablets, orally, once daily for up to 7 cycles (each cycle was 28 days) unless subject discontinued early from the study.

Investigational medicinal product name

Lenvatinib

Investigational medicinal product code

Other name

E7080

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Subjects with recurrent or refractory rhabdomyosarcoma received lenvatinib 11 mg/m^2, capsules, orally, once daily for up to 7 cycles (each cycle was 28 days) unless subject discontinued early from the study.

Phase 2: Cohort 3, High Grade Glioma

Arm description

Subjects 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 subject discontinued early from the study.

Arm type

Experimental

Investigational medicinal product name

Everolimus

Investigational medicinal product code

Other name

Pharmaceutical forms

Dispersible tablet

Routes of administration

Oral use

Dosage and administration details

Subjects with recurrent or refractory HCG received everolimus 3 mg/m^2, tablets, orally, once daily for up to 7 cycles (each cycle was 28 days) unless subject discontinued early from the study.

Investigational medicinal product name

Lenvatinib

Investigational medicinal product code

Other name

E7080

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Subjects with recurrent or refractory HCG received lenvatinib 11 mg/m^2, capsules, orally, once daily for up to 7 cycles (each cycle was 28 days) unless subject discontinued early from the study.

Number of subjects in period 1	Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2	Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2	Phase 2: Cohort 1, Ewing sarcoma	Phase 2: Cohort 2, Rhabdomyosarcoma	Phase 2: Cohort 3, High Grade Glioma
Started	5	18	10	20	11
Completed	0	3	1	2	3
Not completed	5	15	9	18	8
Sponsor's decision	-	1	-	-	-
Consent withdrawn by subject	2	-	-	2	1
Death	3	14	9	16	7

Baseline characteristics

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Reporting group title

Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2

Reporting group description

Reporting group title

Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2

Reporting group description

Reporting group title

Phase 2: Cohort 1, Ewing sarcoma

Reporting group description

Reporting group title

Phase 2: Cohort 2, Rhabdomyosarcoma

Reporting group description

Reporting group title

Phase 2: Cohort 3, High Grade Glioma

Reporting group description

Reporting group values	Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2	Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2	Phase 2: Cohort 1, Ewing sarcoma	Phase 2: Cohort 2, Rhabdomyosarcoma	Phase 2: Cohort 3, High Grade Glioma	Total
Number of subjects	5	18	10	20	11	64
Age Categorical
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	16	3	9	3	31
Adolescents (12-17 years)	4	1	3	6	7	21
Adults (18-64 years)	1	1	4	5	1	12
From 65-84 years	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0
Gender Categorical
Units: Subjects
Female	2	10	3	8	8	31
Male	3	8	7	12	3	33
Ethnicity
Units: Subjects
Hispanic or Latino	1	7	2	2	0	12
Not Hispanic or Latino	4	11	8	18	11	52
Race
Units: Subjects
White	3	11	9	16	6	45
Black or African American	1	1	0	1	3	6
Asian	0	1	1	0	0	2
Not Specified	1	4	0	3	2	10
American Indian or Alaskan Native	0	1	0	0	0	1

End points

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Reporting group title

Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2

Reporting group description

Reporting group title

Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2

Reporting group description

Reporting group title

Phase 2: Cohort 1, Ewing sarcoma

Reporting group description

Reporting group title

Phase 2: Cohort 2, Rhabdomyosarcoma

Reporting group description

Reporting group title

Phase 2: Cohort 3, High Grade Glioma

Reporting group description

Subject analysis set title

Phase 1: Lenvatinib + Everolimus (All Subjects)

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects with recurrent or refractory solid tumors received lenvatinib 8 or 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 termination or for a maximum of 18 cycles (each cycle was 28 days) whichever occurred first.

Primary: Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib in Combination with Everolimus

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End point title

Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib in Combination with Everolimus ^[1]

End point description

MTD was defined as the highest dose level at which no more than 1/6 subjects experienced a dose limiting toxicity (DLTs), with the next higher dose having at least 0 of 3 or 1 of 6 subjects experiencing DLTs. DLT was graded according to common terminology criteria for adverse events (CTCAE) v4.03. Safety analysis set (SAS) included all subjects who received at least one dose of study drug (Lenvatinib or Everolimus).

End point type

Primary

End point timeframe

Cycle 1 (28 days)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No inferential statistics was planned for this primary endpoint.

End point values	Phase 1: Lenvatinib + Everolimus (All Subjects)
Number of subjects analysed	23
Units: milligram per square meter (mg/m^2)
number (not applicable)	11

No statistical analyses for this end point

Primary: Phase 1: Number of Subjects with any Treatment-emergent Adverse Event (TEAE)

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End point title

Phase 1: Number of Subjects with any Treatment-emergent Adverse Event (TEAE) ^[2] ^[3]

End point description

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 subject administered an investigational product. SAS included all subjects who received at least one dose of study drug (Lenvatinib or Everolimus).

End point type

Primary

End point timeframe

From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No inferential statistics was planned for this primary endpoint.
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analysed for specified arms only.

End point values	Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2	Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2
Number of subjects analysed	5	18
Units: subjects	5	18

No statistical analyses for this end point

Primary: Phase 1: Number of Subjects with any Treatment-emergent Serious Adverse Event (TESAE)

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End point title

Phase 1: Number of Subjects with any Treatment-emergent Serious Adverse Event (TESAE) ^[4] ^[5]

End point description

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 subject administered an investigational product. SAS included all subjects who received at least one dose of study drug (Lenvatinib or Everolimus).

End point type

Primary

End point timeframe

From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months)

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No inferential statistics was planned for this primary endpoint.
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analysed for specified arms only.

End point values	Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2	Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2
Number of subjects analysed	5	18
Units: subjects	2	12

No statistical analyses for this end point

Primary: Phase 1: Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination with Everolimus

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End point title

Phase 1: Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination with Everolimus ^[6]

End point description

The RP2D of lenvatinib in combination with everolimus was determined by Dose Escalation Committee (DEC) based on safety, pharmacokinetic and clinical data. DLT was graded according to CTCAE v4.03. SAS included all subjects who received at least one dose of study drug (Lenvatinib or Everolimus).

End point type

Primary

End point timeframe

Cycle 1 (28 days)

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No inferential statistics was planned for this primary endpoint.

End point values	Phase 1: Lenvatinib + Everolimus (All Subjects)
Number of subjects analysed	23
Units: mg/m^2
number (not applicable)	11

No statistical analyses for this end point

Primary: Phase 2: Objective Response Rate (ORR) at Week 16

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End point title

Phase 2: Objective Response Rate (ORR) at Week 16 ^[7] ^[8]

End point description

ORR at Week 16 was defined as the percentage of subjects whose best overall response (BOR) was confirmed 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. Evaluable analysis set included all evaluable subjects 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.

End point type

Primary

End point timeframe

Week 16

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No inferential statistics was planned for this primary endpoint.
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analysed for specified arms only.

End point values	Phase 2: Cohort 1, Ewing sarcoma	Phase 2: Cohort 2, Rhabdomyosarcoma	Phase 2: Cohort 3, High Grade Glioma
Number of subjects analysed	10	20	10
Units: percentage of subjects
number (confidence interval 95%)	0.0 (0.0 to 30.8)	10.0 (1.2 to 31.7)	0 (0.0 to 30.8)

No statistical analyses for this end point

Secondary: Phase 2: Objective Response Rate (ORR)

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End point title

Phase 2: Objective Response Rate (ORR) ^[9]

End point description

ORR was defined as the percentage of subjects whose BOR was confirmed CR or PR based on investigator assessment according to RECIST version 1.1 for non-HGG cohorts and RANO for HGG cohort. Evaluable analysis set included all evaluable subjects 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.

End point type

Secondary

End point timeframe

From first dose date until PD, clinical benefit, development of unacceptable toxicity leading to withdrawal from the study, study termination (up to 5.6 months)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analysed for specified arms only.

End point values	Phase 2: Cohort 1, Ewing sarcoma	Phase 2: Cohort 2, Rhabdomyosarcoma	Phase 2: Cohort 3, High Grade Glioma
Number of subjects analysed	10	20	10
Units: percentage of subjects
number (confidence interval 95%)	0.0 (0.0 to 30.8)	10.0 (1.2 to 31.7)	0.0 (0.0 to 30.8)

No statistical analyses for this end point

Secondary: Phase 1: Objective Response Rate (ORR)

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End point title

Phase 1: Objective Response Rate (ORR) ^[10]

End point description

ORR was defined as the percentage of subjects whose BOR was confirmed CR or PR based on investigator assessment according to RECIST version 1.1 for non-HGG cohorts and RANO for HGG cohort. SAS included all subjects who received at least 1 dose of study drug (lenvatinib or everolimus). Here, N 'number of subjects analyzed' signifies subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

From first dose date until PD, clinical benefit, development of unacceptable toxicity leading to withdrawal from the study, study termination (up to 17 months)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analysed for specified arms only.

End point values	Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2	Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2
Number of subjects analysed	3	15
Units: percentage of subjects
number (confidence interval 95%)	0.0 (0.0 to 70.8)	0.0 (0.0 to 21.8)

No statistical analyses for this end point

Secondary: Phase 2: Disease Control Rate (DCR)

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End point title

Phase 2: Disease Control Rate (DCR) ^[11]

End point description

DCR: percentage of subjects with confirmed CR, PR, or SD (SD duration >=7 weeks since first dose of study treatment) divided by number of subjects in analysis set. DCR was assessed by investigator based on RECIST v1.1 for non-HGG cohorts or RANO for HGG cohort. Evaluable analysis set: evaluable subjects 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 PD.

End point type

Secondary

End point timeframe

From first dose date until PD, clinical benefit, development of unacceptable toxicity leading to withdrawal from the study, study termination (up to 5.6 months)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analysed for specified arms only.

End point values	Phase 2: Cohort 1, Ewing sarcoma	Phase 2: Cohort 2, Rhabdomyosarcoma	Phase 2: Cohort 3, High Grade Glioma
Number of subjects analysed	10	20	10
Units: percentage of subjects
number (confidence interval 95%)	40.0 (12.2 to 73.8)	40.0 (19.1 to 63.9)	30.0 (6.7 to 65.2)

No statistical analyses for this end point

Secondary: Phase 1: Disease Control Rate (DCR)

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End point title

Phase 1: Disease Control Rate (DCR) ^[12]

End point description

DCR: percentage of subjects with a confirmed CR, PR, or stable disease (SD) (SD duration >=7 weeks since the first dose of study treatment) divided by number of subjects in analysis set. DCR was assessed by an investigator based on RECIST v1.1 for non-HGG subjects or RANO for HGG subjects. SAS included all subjects who received at least 1 dose of study drug (lenvatinib or everolimus).

End point type

Secondary

End point timeframe

From first dose date until PD, clinical benefit, development of unacceptable toxicity leading to withdrawal from the study, study termination (up to 17 months)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analysed for specified arms only.

End point values	Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2	Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2
Number of subjects analysed	5	18
Units: Percentage of subjects
number (confidence interval 95%)	20.0 (0.5 to 71.6)	50.0 (26.0 to 74.0)

No statistical analyses for this end point

Secondary: Phase 1: Clinical Benefit Rate (CBR)

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End point title

Phase 1: Clinical Benefit Rate (CBR) ^[13]

End point description

CBR: percentage of subjects with a confirmed CR, PR, or SD (SD duration >=23 weeks since the first dose of study treatment) divided by number of subjects in analysis set. CBR was assessed by an investigator based on RECIST v1.1 for non-HGG subjects or RANO for HGG subjects. SAS included all subjects who received at least 1 dose of study drug (lenvatinib or everolimus).

End point type

Secondary

End point timeframe

From first dose date until PD, clinical benefit, development of unacceptable toxicity leading to withdrawal from the study, study termination (up to 17 months)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analysed for specified arms only.

End point values	Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2	Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2
Number of subjects analysed	5	18
Units: percentage of subjects
number (confidence interval 95%)	20.0 (0.5 to 71.6)	22.2 (6.4 to 47.6)

No statistical analyses for this end point

Secondary: Phase 1: Duration of Response (DOR)

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End point title

Phase 1: Duration of Response (DOR) ^[14]

End point description

End point type

Secondary

End point timeframe

From date of the first observation of CR or PR until the date of first observation of progression or date of death up to 17 months

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analysed for specified arms only.

End point values	Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2	Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2
Number of subjects analysed	0 ^[15]	0 ^[16]
Units: months
median (full range (min-max))	( to )	( to )

Notes
[15] - No subject was analyzed for this arm.
[16] - No subject was analyzed for this arm.

No statistical analyses for this end point

Secondary: Phase 2: Clinical Benefit Rate (CBR)

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End point title

Phase 2: Clinical Benefit Rate (CBR) ^[17]

End point description

CBR: percentage of subjects with a confirmed CR, PR, or SD (SD duration >=23 weeks since the first dose of study treatment) divided by number of subjects in analysis set. CBR was assessed by an investigator based on RECIST v1.1 for non-HGG cohorts or RANO for HGG cohort. Evaluable analysis set included all evaluable subjects 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.

End point type

Secondary

End point timeframe

From first dose date until PD, clinical benefit, development of unacceptable toxicity leading to withdrawal from the study, study termination (up to 5.6 months)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analysed for specified arms only.

End point values	Phase 2: Cohort 1, Ewing sarcoma	Phase 2: Cohort 2, Rhabdomyosarcoma	Phase 2: Cohort 3, High Grade Glioma
Number of subjects analysed	10	20	10
Units: percentage of subjects
number (confidence interval 95%)	20.0 (2.5 to 55.6)	10.0 (1.2 to 31.7)	0.0 (0.0 to 30.8)

No statistical analyses for this end point

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)

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End point title

Phase 1: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration of Lenvatinib AUC(0-t Hours) ^[18]

End point description

Pharmacokinetic analysis set included subjects who had at least one measurable postdose plasma concentration with an adequately documented drug administration history. Here, n 'number of subjects analyzed' signifies subjects who were evaluable for this endpoint at given categories. Pharmacokinetic data was planned to be analyzed for Phase 1 only.

End point type

Secondary

End point timeframe

Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analysed for specified arms only.

End point values	Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2	Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2
Number of subjects analysed	5	18
Units: nanogramhour per milliliter (nghr/mL)
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n=5, 18)	2338.0 ( 1633.41 )	3281.1 ( 1064.72 )
Cycle 1 Day 15 (n=5, 17)	1328.0 ( 520.69 )	2139.8 ( 1156.48 )

No statistical analyses for this end point

Secondary: Phase 2: Duration of Response (DOR)

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End point title

Phase 2: Duration of Response (DOR) ^[19]

End point description

DOR: 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. Evaluable analysis set included all evaluable subjects 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 99999 refers to 95% CI was not estimated.

End point type

Secondary

End point timeframe

From date of the first observation of CR or PR until the date of first observation of progression or date of death up to 5.6 months

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analysed for specified arms only.

End point values	Phase 2: Cohort 1, Ewing sarcoma	Phase 2: Cohort 2, Rhabdomyosarcoma	Phase 2: Cohort 3, High Grade Glioma
Number of subjects analysed	0 ^[20]	2	0 ^[21]
Units: months
median (confidence interval 95%)	( to )	2.4 (2.1 to 99999)	( to )

Notes
[20] - No subject was analyzed for this arm.
[21] - No subject was analyzed for this arm.

No statistical analyses for this end point

Secondary: Phase 1: Maximum Plasma Concentration of Lenvatinib (Cmax)

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End point title

Phase 1: Maximum Plasma Concentration of Lenvatinib (Cmax) ^[22]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days)

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analysed for specified arms only.

End point values	Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2	Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2
Number of subjects analysed	5	18
Units: nanogram per milliliter (ng/mL)
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n=5, 18)	240.20 ( 130.892 )	404.13 ( 121.473 )
Cycle 1 Day 15 (n=5, 17)	314.20 ( 149.527 )	447.62 ( 272.790 )

No statistical analyses for this end point

Secondary: Phase 1: Time to Reach Maximum Plasma Concentration (Cmax) of Lenvatinib (Tmax)

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End point title

Phase 1: Time to Reach Maximum Plasma Concentration (Cmax) of Lenvatinib (Tmax) ^[23]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days)

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analysed for specified arms only.

End point values	Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2	Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2
Number of subjects analysed	5	18
Units: hours
median (full range (min-max))
Cycle 1 Day 1 (n=5, 18)	3.000 (2.000 to 4.000)	2.890 (1.000 to 7.78)
Cycle 1 Day 15 (n=5, 17)	3.950 (2.000 to 8.05)	2.950 (0 to 8.02)

No statistical analyses for this end point

Secondary: Phase 2: Number of Subjects with any Treatment-emergent Adverse Event (TEAE)

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End point title

Phase 2: Number of Subjects with any Treatment-emergent Adverse Event (TEAE) ^[24]

End point description

End point type

Secondary

End point timeframe

From date of first dose up to 28 days after the last dose of study treatment (Up to 6.5 months)

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analysed for specified arms only.

End point values	Phase 2: Cohort 1, Ewing sarcoma	Phase 2: Cohort 2, Rhabdomyosarcoma	Phase 2: Cohort 3, High Grade Glioma
Number of subjects analysed	10	20	11
Units: subjects	10	19	11

No statistical analyses for this end point

Secondary: Phase 2: Number of Subjects with any Treatment-emergent Serious Adverse Event (TESAE)

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End point title

Phase 2: Number of Subjects with any Treatment-emergent Serious Adverse Event (TESAE) ^[25]

End point description

End point type

Secondary

End point timeframe

From date of first dose up to 28 days after the last dose of study treatment (Up to 6.5 months)

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analysed for specified arms only.

End point values	Phase 2: Cohort 1, Ewing sarcoma	Phase 2: Cohort 2, Rhabdomyosarcoma	Phase 2: Cohort 3, High Grade Glioma
Number of subjects analysed	10	20	11
Units: subjects	6	8	8

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From date of first dose up to 28 days after the last dose of study treatment (Phase 1: Up to 17.5 months; Phase 2: Up to 6.5 months)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2

Reporting group description

Subjects 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 termination or for a maximum of 18 cycles (each cycle was 28 days) whichever occurred first.

Reporting group title

Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2

Reporting group description

Reporting group title

Phase 2: Cohort 3, High Grade Glioma (HGG)

Reporting group description

Subjects with recurrent or refractory HCG 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 subject discontinued early from the study.

Reporting group title

Phase 2: Cohort 2, Rhabdomyosarcoma

Reporting group description

Reporting group title

Phase 2: Cohort 1, Ewing sarcoma

Reporting group description

Serious adverse events	Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2	Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2	Phase 2: Cohort 3, High Grade Glioma (HGG)	Phase 2: Cohort 2, Rhabdomyosarcoma	Phase 2: Cohort 1, Ewing sarcoma
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 5 (40.00%)	12 / 18 (66.67%)	8 / 11 (72.73%)	8 / 20 (40.00%)	6 / 10 (60.00%)
number of deaths (all causes)	4	14	8	17	9
number of deaths resulting from adverse events	0	1	0	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant pleural effusion
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cancer pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pain
subjects affected / exposed	1 / 5 (20.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	3 / 10 (30.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Face oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Hypoxia
subjects affected / exposed	0 / 5 (0.00%)	3 / 18 (16.67%)	0 / 11 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemothorax
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	2 / 10 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Mental status changes
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Tendon rupture
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	1 / 5 (20.00%)	1 / 18 (5.56%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 5 (0.00%)	3 / 18 (16.67%)	2 / 11 (18.18%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nystagmus
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Depressed level of consciousness
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrospinal fluid leakage
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Optic neuritis
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Eyelid oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oral cavity fistula
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumatosis intestinalis
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia aspiration
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infections
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2	Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2	Phase 2: Cohort 3, High Grade Glioma (HGG)	Phase 2: Cohort 2, Rhabdomyosarcoma	Phase 2: Cohort 1, Ewing sarcoma
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 5 (100.00%)	18 / 18 (100.00%)	11 / 11 (100.00%)	19 / 20 (95.00%)	10 / 10 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Fibrous cortical defect
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Tumour haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Tumour pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Cancer pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	3	3
Malignant pleural effusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	0	2
Vascular disorders
Hypertension
subjects affected / exposed	4 / 5 (80.00%)	13 / 18 (72.22%)	4 / 11 (36.36%)	10 / 20 (50.00%)	3 / 10 (30.00%)
occurrences all number	14	19	5	18	4
Hot flush
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Hypotension
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	1
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 5 (20.00%)	5 / 18 (27.78%)	0 / 11 (0.00%)	3 / 20 (15.00%)	4 / 10 (40.00%)
occurrences all number	1	7	0	4	8
Localised oedema
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	0	0	1
Influenza like illness
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0
Fatigue
subjects affected / exposed	3 / 5 (60.00%)	6 / 18 (33.33%)	3 / 11 (27.27%)	11 / 20 (55.00%)	6 / 10 (60.00%)
occurrences all number	4	9	5	16	7
Pain
subjects affected / exposed	3 / 5 (60.00%)	2 / 18 (11.11%)	1 / 11 (9.09%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	7	2	1	1	2
Oedema peripheral
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	1	0	1	2	1
Gait disturbances
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1	0	1
Face oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	1
Asthenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Peripheral swelling
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Non-cardiac chest pain
subjects affected / exposed	0 / 5 (0.00%)	3 / 18 (16.67%)	1 / 11 (9.09%)	5 / 20 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	7	1	8	1
Malaise
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0	0	0
Immune system disorders
Contrast media allergy
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	1 / 11 (9.09%)	6 / 20 (30.00%)	1 / 10 (10.00%)
occurrences all number	0	1	1	9	1
Dyspnoea
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	4 / 20 (20.00%)	2 / 10 (20.00%)
occurrences all number	0	4	0	5	2
Dysphonia
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0
Cough
subjects affected / exposed	1 / 5 (20.00%)	4 / 18 (22.22%)	1 / 11 (9.09%)	4 / 20 (20.00%)	1 / 10 (10.00%)
occurrences all number	1	7	1	5	1
Atelectasis
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	0	1
Tachypnoea
subjects affected / exposed	0 / 5 (0.00%)	3 / 18 (16.67%)	0 / 11 (0.00%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	4	0	4	1
Productive cough
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Rhinitis allergic
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0
Rhinorrhoea
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	0	0	1
Pneumothorax
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Pleural effusion
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	1 / 20 (5.00%)	2 / 10 (20.00%)
occurrences all number	0	3	0	1	5
Oropharyngeal pain
subjects affected / exposed	1 / 5 (20.00%)	4 / 18 (22.22%)	1 / 11 (9.09%)	7 / 20 (35.00%)	2 / 10 (20.00%)
occurrences all number	1	4	1	12	3
Nasal congestion
subjects affected / exposed	2 / 5 (40.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	5 / 20 (25.00%)	1 / 10 (10.00%)
occurrences all number	2	3	0	5	1
Hypoxia
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	1 / 20 (5.00%)	2 / 10 (20.00%)
occurrences all number	0	2	0	1	3
Hiccups
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0
Respiratory distress
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Pulmonary oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Psychiatric disorders
Depression
subjects affected / exposed	2 / 5 (40.00%)	1 / 18 (5.56%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	3	1	1	0	0
Anxiety
subjects affected / exposed	1 / 5 (20.00%)	2 / 18 (11.11%)	1 / 11 (9.09%)	4 / 20 (20.00%)	2 / 10 (20.00%)
occurrences all number	2	3	1	4	2
Irritability
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Restlessness
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Agitation
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	2 / 20 (10.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	2	3
Insomnia
subjects affected / exposed	2 / 5 (40.00%)	2 / 18 (11.11%)	1 / 11 (9.09%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	3	4	1	2	1
Product issues
Device dislocation
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	5 / 18 (27.78%)	3 / 11 (27.27%)	7 / 20 (35.00%)	3 / 10 (30.00%)
occurrences all number	0	10	4	7	7
Amylase increased
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0
Blood fibrinogen decreased
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Blood thyroid stimulating hormone increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	3	2
International normalised ratio increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	1
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Haemoglobin increased
subjects affected / exposed	0 / 5 (0.00%)	3 / 18 (16.67%)	3 / 11 (27.27%)	3 / 20 (15.00%)	1 / 10 (10.00%)
occurrences all number	0	4	5	9	1
Electrocardiogram QT prolonged
subjects affected / exposed	2 / 5 (40.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	2	0	0	0
Ejection fraction decreased
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	1	0	1	1	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	2 / 20 (10.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	2	3
Aspartate aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	5 / 18 (27.78%)	4 / 11 (36.36%)	8 / 20 (40.00%)	4 / 10 (40.00%)
occurrences all number	0	13	5	13	6
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 5 (20.00%)	1 / 18 (5.56%)	1 / 11 (9.09%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	1	1	3	1	1
Blood cholesterol increased
subjects affected / exposed	1 / 5 (20.00%)	6 / 18 (33.33%)	4 / 11 (36.36%)	11 / 20 (55.00%)	2 / 10 (20.00%)
occurrences all number	1	23	12	14	2
Blood creatinine increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	4	2
Weight increased
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	3	0	0
Weight decreased
subjects affected / exposed	2 / 5 (40.00%)	6 / 18 (33.33%)	0 / 11 (0.00%)	6 / 20 (30.00%)	1 / 10 (10.00%)
occurrences all number	3	12	0	10	2
SARS-CoV-2 test positive
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Platelet count increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Neutrophil count decreased
subjects affected / exposed	3 / 5 (60.00%)	4 / 18 (22.22%)	2 / 11 (18.18%)	7 / 20 (35.00%)	3 / 10 (30.00%)
occurrences all number	6	12	9	14	7
Lymphocyte count decreased
subjects affected / exposed	3 / 5 (60.00%)	6 / 18 (33.33%)	2 / 11 (18.18%)	11 / 20 (55.00%)	8 / 10 (80.00%)
occurrences all number	14	13	10	32	27
Lipase increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	1 / 11 (9.09%)	4 / 20 (20.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	6	0
White blood cell count decreased
subjects affected / exposed	2 / 5 (40.00%)	6 / 18 (33.33%)	2 / 11 (18.18%)	8 / 20 (40.00%)	6 / 10 (60.00%)
occurrences all number	7	16	8	24	17
Platelet count decreased
subjects affected / exposed	2 / 5 (40.00%)	7 / 18 (38.89%)	3 / 11 (27.27%)	10 / 20 (50.00%)	5 / 10 (50.00%)
occurrences all number	6	22	4	21	9
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	1 / 11 (9.09%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	3	1	1	0
Fall
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	2	0	0
Stoma site pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Tendon rupture
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Wrist fracture
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Procedural pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	2	0
Wound complication
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Wound dehiscence
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Allergic transfusion reaction
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0
Cardiac disorders
Sinus bradycardia
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	3 / 20 (15.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	3	0
Wolff-Parkinson-White syndrome
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Tachycardia
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	1	1
Sinus tachycardia
subjects affected / exposed	2 / 5 (40.00%)	4 / 18 (22.22%)	0 / 11 (0.00%)	3 / 20 (15.00%)	1 / 10 (10.00%)
occurrences all number	6	5	0	5	2
Bradycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Nervous system disorders
Ataxia
subjects affected / exposed	1 / 5 (20.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	0	0	0
Dizziness
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	1 / 11 (9.09%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	2	1	2	1
Dysarthria
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0
Dysgeusia
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	3	0
Headache
subjects affected / exposed	3 / 5 (60.00%)	8 / 18 (44.44%)	5 / 11 (45.45%)	5 / 20 (25.00%)	1 / 10 (10.00%)
occurrences all number	14	10	7	5	1
Hydrocephalus
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0
Hypersomnia
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0
Lethargy
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0
Seizure
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0
Somnolence
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	1	0	0
Tremor
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	2	0	0	1
Intracranial haematoma
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Haemorrhage intracranial
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Blood and lymphatic system disorders
Lymphopenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Neutropenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Anaemia
subjects affected / exposed	2 / 5 (40.00%)	6 / 18 (33.33%)	1 / 11 (9.09%)	7 / 20 (35.00%)	5 / 10 (50.00%)
occurrences all number	6	16	5	10	17
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Eye disorders
Dry eye
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0
Miosis
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Eye pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Vision blurred
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 5 (20.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	3	1	0	0	1
Abdominal pain
subjects affected / exposed	3 / 5 (60.00%)	9 / 18 (50.00%)	4 / 11 (36.36%)	7 / 20 (35.00%)	1 / 10 (10.00%)
occurrences all number	4	16	5	10	1
Abdominal pain upper
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	1 / 11 (9.09%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	1	1	1	2
Anal incontinence
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0
Gingival pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Cheilitis
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	0	0	1
Constipation
subjects affected / exposed	2 / 5 (40.00%)	3 / 18 (16.67%)	3 / 11 (27.27%)	6 / 20 (30.00%)	4 / 10 (40.00%)
occurrences all number	4	4	3	8	5
Diarrhoea
subjects affected / exposed	3 / 5 (60.00%)	10 / 18 (55.56%)	7 / 11 (63.64%)	8 / 20 (40.00%)	5 / 10 (50.00%)
occurrences all number	10	23	9	11	10
Dry mouth
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	2	0
Dysphagia
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	1 / 11 (9.09%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	2	1	2	0
Aphthous ulcer
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Oral pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	3	0
Nausea
subjects affected / exposed	4 / 5 (80.00%)	5 / 18 (27.78%)	4 / 11 (36.36%)	9 / 20 (45.00%)	3 / 10 (30.00%)
occurrences all number	9	8	5	14	4
Mouth haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Stomatitis
subjects affected / exposed	4 / 5 (80.00%)	5 / 18 (27.78%)	2 / 11 (18.18%)	9 / 20 (45.00%)	2 / 10 (20.00%)
occurrences all number	10	8	3	21	2
Flatulence
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Pancreatitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	3
Vomiting
subjects affected / exposed	3 / 5 (60.00%)	11 / 18 (61.11%)	7 / 11 (63.64%)	7 / 20 (35.00%)	3 / 10 (30.00%)
occurrences all number	10	20	10	11	7
Toothache
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	3	0	0	1
Hepatobiliary disorders
Steatohepatitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Hypertransaminasaemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Skin and subcutaneous tissue disorders
Skin ulcer
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	4	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	1 / 5 (20.00%)	1 / 18 (5.56%)	2 / 11 (18.18%)	1 / 20 (5.00%)	2 / 10 (20.00%)
occurrences all number	1	1	5	5	2
Pruritus
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	3 / 20 (15.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	4	0
Rash maculo-papular
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	3 / 20 (15.00%)	0 / 10 (0.00%)
occurrences all number	0	6	0	4	0
Dermatitis contact
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Dry skin
subjects affected / exposed	1 / 5 (20.00%)	4 / 18 (22.22%)	1 / 11 (9.09%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	1	6	1	2	0
Alopecia
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0
Scab
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0
Skin atrophy
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Hyperhidrosis
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Dermatitis acneiform
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	2	0
Urticaria
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	1
Pain of skin
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	1
Erythemas
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Petechiae
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	3	0
Renal and urinary disorders
Urinary incontinence
subjects affected / exposed	1 / 5 (20.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	0	0	0
Pollakiuria
subjects affected / exposed	2 / 5 (40.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0	0	0
Dysuria
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Haematuria
subjects affected / exposed	1 / 5 (20.00%)	2 / 18 (11.11%)	3 / 11 (27.27%)	6 / 20 (30.00%)	4 / 10 (40.00%)
occurrences all number	1	2	3	6	5
Proteinuria
subjects affected / exposed	1 / 5 (20.00%)	8 / 18 (44.44%)	4 / 11 (36.36%)	10 / 20 (50.00%)	8 / 10 (80.00%)
occurrences all number	4	37	4	23	15
Micturition urgency
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0
Renal tubular dysfunction
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Glycosuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	2
Urinary tract pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0
Urinary retention
subjects affected / exposed	1 / 5 (20.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	3	0	0	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	1 / 11 (9.09%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	2	1	1	0
Hypothyroidism
subjects affected / exposed	2 / 5 (40.00%)	10 / 18 (55.56%)	6 / 11 (54.55%)	8 / 20 (40.00%)	2 / 10 (20.00%)
occurrences all number	3	13	7	14	3
Hyperparathyroidism
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Bone pain
subjects affected / exposed	1 / 5 (20.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	0	0	0
Pain in extremity
subjects affected / exposed	1 / 5 (20.00%)	4 / 18 (22.22%)	2 / 11 (18.18%)	5 / 20 (25.00%)	2 / 10 (20.00%)
occurrences all number	1	9	3	7	2
Neck pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	3 / 20 (15.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	5	0
Myalgia
subjects affected / exposed	3 / 5 (60.00%)	2 / 18 (11.11%)	2 / 11 (18.18%)	4 / 20 (20.00%)	1 / 10 (10.00%)
occurrences all number	4	5	2	6	5
Muscular weakness
subjects affected / exposed	1 / 5 (20.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	1	2	0	2	2
Back pain
subjects affected / exposed	4 / 5 (80.00%)	1 / 18 (5.56%)	2 / 11 (18.18%)	4 / 20 (20.00%)	1 / 10 (10.00%)
occurrences all number	4	1	2	6	1
Arthralgia
subjects affected / exposed	1 / 5 (20.00%)	2 / 18 (11.11%)	3 / 11 (27.27%)	6 / 20 (30.00%)	3 / 10 (30.00%)
occurrences all number	3	3	5	11	5
Joint range of motion decreased
subjects affected / exposed	1 / 5 (20.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	3	0	0	0
Spinal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0
Pain in jaw
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	2	0
Periostitis
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Myositis
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	4	0	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0
Muscle spasms
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0
Infections and infestations
Conjunctivitis
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Otitis media
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Pharyngitis
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	3	0	0	0	0
Sinusitis
subjects affected / exposed	1 / 5 (20.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0
Skin infection
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0
Upper respiratory tract infections
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	2	0	0	1
Rash pustular
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	2	0	1
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Otitis media acute
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Oral candidiasis
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Device related infection
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Urinary tract infection
subjects affected / exposed	2 / 5 (40.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	3 / 20 (15.00%)	0 / 10 (0.00%)
occurrences all number	2	1	0	3	0
Respiratory tract infection viral
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Pneumonia
subjects affected / exposed	0 / 5 (0.00%)	3 / 18 (16.67%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	3	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	4 / 5 (80.00%)	4 / 18 (22.22%)	2 / 11 (18.18%)	6 / 20 (30.00%)	2 / 10 (20.00%)
occurrences all number	7	5	2	9	3
Hypermagnesaemia
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	3 / 20 (15.00%)	2 / 10 (20.00%)
occurrences all number	0	2	0	6	4
Hyperkalaemia
subjects affected / exposed	1 / 5 (20.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	4 / 20 (20.00%)	0 / 10 (0.00%)
occurrences all number	1	2	0	4	0
Hypercholesterolaemia
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0
Hypercalcaemia
subjects affected / exposed	0 / 5 (0.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0
Hyperglycaemia
subjects affected / exposed	0 / 5 (0.00%)	4 / 18 (22.22%)	3 / 11 (27.27%)	4 / 20 (20.00%)	2 / 10 (20.00%)
occurrences all number	0	5	7	6	2
Dehydration
subjects affected / exposed	2 / 5 (40.00%)	2 / 18 (11.11%)	0 / 11 (0.00%)	4 / 20 (20.00%)	1 / 10 (10.00%)
occurrences all number	2	5	0	5	2
Hypertriglyceridaemia
subjects affected / exposed	2 / 5 (40.00%)	11 / 18 (61.11%)	6 / 11 (54.55%)	12 / 20 (60.00%)	5 / 10 (50.00%)
occurrences all number	3	51	22	26	18
Hypomagnesaemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	3	2
Hypokalaemia
subjects affected / exposed	1 / 5 (20.00%)	2 / 18 (11.11%)	1 / 11 (9.09%)	2 / 20 (10.00%)	4 / 10 (40.00%)
occurrences all number	1	2	2	2	6
Hypocholesterolaemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 18 (5.56%)	0 / 11 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0
Hypocalcaemia
subjects affected / exposed	0 / 5 (0.00%)	4 / 18 (22.22%)	0 / 11 (0.00%)	4 / 20 (20.00%)	5 / 10 (50.00%)
occurrences all number	0	4	0	6	7
Hypoalbuminaemia
subjects affected / exposed	0 / 5 (0.00%)	4 / 18 (22.22%)	0 / 11 (0.00%)	4 / 20 (20.00%)	5 / 10 (50.00%)
occurrences all number	0	9	0	14	13
Hyponatraemia
subjects affected / exposed	1 / 5 (20.00%)	6 / 18 (33.33%)	1 / 11 (9.09%)	2 / 20 (10.00%)	7 / 10 (70.00%)
occurrences all number	1	7	1	3	15
Hypophosphataemia
subjects affected / exposed	1 / 5 (20.00%)	3 / 18 (16.67%)	1 / 11 (9.09%)	6 / 20 (30.00%)	8 / 10 (80.00%)
occurrences all number	1	6	1	10	14
Hypoglycaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	3	1
Hyperphosphataemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	0 / 11 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1
Hypernatraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 18 (0.00%)	1 / 11 (9.09%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

24 Sep 2018

Protocol amendment 01: Figure 1 study design updated; Reduced maximum number of subjects in the dose levels -1, 1, 2 and 3 to 54 subjects in Phase 1 and 120 subjects in Phase 1 and 2. The projected maximum number of evaluable subjects required in Phase 1 was recalculated to 48 subjects; Study treatment should be discontinued in any subject who develops gastrointestinal perforation or life threatening fistula.

28 Apr 2020

Protocol amendment 02: It was clarified that sponsor will closely monitor enrollment to ensure that at least 50% of subjects enrolled in each cohort are <18 years of age at the time of informed consent; Clarified that lenvatinib should be discontinued in any subject who develops gastrointestinal perforation of any grade or >=grade 4 fistula; Clarified that for CTCAE, version 4.03 will be used and not current version.

16 Aug 2021

Protocol amendment 03: Evaluable analysis set, defined as all subjects who have measurable disease present at baseline and at least one post-baseline efficacy assessment, unless they have discontinued prior to first efficacy assessment due to progressive disease. This will be analysis set for efficacy in Phase 2.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 1/2 Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including CNS Tumors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib in Combination with Everolimus

Primary: Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib in Combination with Everolimus

Primary: Phase 1: Number of Subjects with any Treatment-emergent Adverse Event (TEAE)

Primary: Phase 1: Number of Subjects with any Treatment-emergent Adverse Event (TEAE)

Primary: Phase 1: Number of Subjects with any Treatment-emergent Serious Adverse Event (TESAE)

Primary: Phase 1: Number of Subjects with any Treatment-emergent Serious Adverse Event (TESAE)

Primary: Phase 1: Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination with Everolimus

Primary: Phase 1: Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination with Everolimus

Primary: Phase 2: Objective Response Rate (ORR) at Week 16

Primary: Phase 2: Objective Response Rate (ORR) at Week 16

Secondary: Phase 2: Objective Response Rate (ORR)

Secondary: Phase 2: Objective Response Rate (ORR)

Secondary: Phase 1: Objective Response Rate (ORR)

Secondary: Phase 1: Objective Response Rate (ORR)

Secondary: Phase 2: Disease Control Rate (DCR)

Secondary: Phase 2: Disease Control Rate (DCR)

Secondary: Phase 1: Disease Control Rate (DCR)

Secondary: Phase 1: Disease Control Rate (DCR)

Secondary: Phase 1: Clinical Benefit Rate (CBR)

Secondary: Phase 1: Clinical Benefit Rate (CBR)

Secondary: Phase 1: Duration of Response (DOR)

Secondary: Phase 1: Duration of Response (DOR)

Secondary: Phase 2: Clinical Benefit Rate (CBR)

Secondary: Phase 2: Clinical Benefit Rate (CBR)

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)

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)

Secondary: Phase 2: Duration of Response (DOR)

Secondary: Phase 2: Duration of Response (DOR)

Secondary: Phase 1: Maximum Plasma Concentration of Lenvatinib (Cmax)

Secondary: Phase 1: Maximum Plasma Concentration of Lenvatinib (Cmax)

Secondary: Phase 1: Time to Reach Maximum Plasma Concentration (Cmax) of Lenvatinib (Tmax)

Secondary: Phase 1: Time to Reach Maximum Plasma Concentration (Cmax) of Lenvatinib (Tmax)

Secondary: Phase 2: Number of Subjects with any Treatment-emergent Adverse Event (TEAE)

Secondary: Phase 2: Number of Subjects with any Treatment-emergent Adverse Event (TEAE)

Secondary: Phase 2: Number of Subjects with any Treatment-emergent Serious Adverse Event (TESAE)

Secondary: Phase 2: Number of Subjects with any Treatment-emergent Serious Adverse Event (TESAE)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1/2 Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including CNS Tumors