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Study of Avelumab in Combination With Lenvatinib for Children With Primary CNS Tumors

Primary Purpose

Central Nervous System Tumors

Status

Recruiting

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Avelumab

Lenvatinib

About this trial

This is an interventional treatment trial for Central Nervous System Tumors focused on measuring Avelumab, Lenvatinib, Tumors, Pediatric CNS tumors

Eligibility Criteria

2 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Participants with histologically confirmed diagnosis of primary CNS malignancy as follows: a) Primary CNS tumors: the tumor should be considered high-grade histologically; prior radiotherapy is allowed; participants must have progressed after at least 1 prior systemic therapy, except for those with diffuse midline glioma with or without the H3 K27M mutation. b) Specific for participants with diffuse midline glioma with or without the H3 K27M mutation: prior radiotherapy is allowed; no more than 1 prior systemic therapy is allowed; participants with diffuse midline glioma with or without the H3 K27M mutation who have not received prior systemic therapy but have prior radiotherapy only are allowed to enroll
On screening scans, measurable disease by RANO criteria
Participants must have a Lansky performance status >= 50 for age <= 16 years or Karnofsky performance status >= 50 for age > 16 years at Screening
Other protocol defined inclusion criteria could apply

Exclusion Criteria:

Participants with low-grade gliomas, for example but not limited to, subependymal giant cell astrocytoma, pilocytic astrocytoma and World Health organization (WHO) Grade 1 tumors
Participants demonstrating evidence of worsening of neurologic deficit within 1 week prior to initiation of study interventions
Participants with bulky tumor, defined as: a) Tumor with any evidence of uncal herniation or midline shift; b) Tumor with a diameter of > 4 centimeters (cm) in 1 dimension on T2/ fluid-attenuated inversion recovery (FLAIR) images; c) Tumor that in the opinion of the Investigator shows significant mass effect
Participants are not eligible if they experience uncontrolled seizures, defined as: a) Seizures requiring regular use of rescue medications. b) Seizures requiring increasing doses of antiepileptic medications. c) Seizures that in the opinion of the Investigator compromise the ability of the participant to tolerate study intervention or interfere with study procedures
Participants who have received major surgery (including but not limited to neurosurgical resection, brain biopsy, or radiation to the primary brain tumor) within 28 days prior to the first dose of study interventions
Participants with history of intracranial hemorrhage/spinal cord hemorrhage within 28 days prior to the first dose of study interventions
Other protocol defined exclusion criteria could apply

Sites / Locations

Washington University
CHU Sainte-JustineRecruiting
The Hospital for Sick ChildrenRecruiting
CHU Angers - Hôpital Hôtel Dieu - Service de Cancérologie PédiatriqueRecruiting
Hôpital de la TimoneRecruiting
Institut Curie - Centre de Lutte Contre le Cancer (CLCC) de ParisRecruiting
Universitaetsklinikum Hamburg EppendorfRecruiting
Universitaetsklinikum MuensterRecruiting
Seoul National University HospitalRecruiting
Severance Hospital, Yonsei University Health SystemRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Avelumab + Lenvatinib

Arm Description

Outcomes

Primary Outcome Measures

Dose Escalation Part 1: Number of Participants with Common Terminology Criteria for Adverse Events (CTCAE) Grade Greater Than or Equal to (>=) 3 Treatment-emergent Adverse Event (TEAEs) According to National Cancer Institute-CTCAE Version 5.0

Dose Escalation Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)

Dose Expansion Part 2: Progression-free Survival (PFS) According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators

Secondary Outcome Measures

Dose Escalation Part 1: Number of Participants with Treatment-Emergent Adverse Events (TEAEs), Treatment-related Adverse Events (AEs), Adverse Event of Special Interest (AESIs), AEs Leading to Deaths

Dose Escalation Part 1: Number of Participants with Treatment-Emergent Adverse Events (AEs) Based on Severity According to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0

Dose Escalation Part 1: Number of Participants with Clinically Significant Changes from Baseline in Laboratory Parameters

Dose Escalation Part 1: Objective Response Rate (ORR) According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators

Dose Escalation Part 1: Duration of Response (DOR) According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators

Dose Escalation Part 1: Progression-Free Survival (PFS) According to Response Assessment in Neuro-Oncology (RANO) Criteria

Dose Escalation Part 1: Overall Survival (OS)

Dose Escalation Part 1: Serum Observed Concentration at End of Infusion (CEOI) of Avelumab

Dose Escalation Part 1: Area Under the Serum Concentration-Time Curve From the Time of Dosing 336 Hours (AUC0-336 [hr]) of Avelumab

Dose Escalation Part 1: Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of Avelumab

Dose Escalation Part 1: Maximum Observed Plasma Concentration (Cmax) of Lenvatinib

Dose Escalation Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Lenvatinib

Dose Escalation (Part 1): Area Under the Plasma Concentration-Time Curve From the Time of Dosing to 24 Hours (AUC0-24 [hr]) of Lenvatinib:

Dose Escalation Part 1: Immunogenicity of Avelumab as Measured by Antidrug Antibody (ADA) Assay

Dose Expansion Part 2: Number of Participants with Treatment-Emergent Adverse Events (TEAEs), Treatment-related Adverse Events (AEs), Adverse Event of Special Interest (AESIs), AEs Leading to Deaths

Dose Expansion Part 2: Number of Participants with Treatment-Emergent Adverse Events (AEs) Based on Severity According to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0

Dose Expansion Part 2: Number of Participants with Clinically Significant Changes in Laboratory Parameters

Dose Expansion Part 2: Objective Response Rate (ORR) Rate According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators

Dose Expansion Part 2: Duration of Response (DOR) According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators

Dose Expansion Part 2: Overall Survival (OS)

Dose Expansion Part 2: Serum Observed Concentration at End of Infusion (CEOI) of Avelumab

Dose Expansion Part 2:Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of Avelumab

Dose Expansion Part 2: Maximum Observed Plasma Concentration (Cmax) of Lenvatinib

Dose Expansion Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Lenvatinib

Dose Expansion Part 2: Immunogenicity of avelumab as measured by ADA assay

Full Information

NCT ID

NCT05081180

First Posted

October 4, 2021

Last Updated

October 12, 2023

Sponsor

EMD Serono Research & Development Institute, Inc.

Collaborators

Merck KGaA, Darmstadt, Germany

1. Study Identification

Unique Protocol Identification Number

NCT05081180

Brief Title

Study of Avelumab in Combination With Lenvatinib for Children With Primary CNS Tumors

Official Title

Single-arm, Multicenter Phase I/Ib Study of Avelumab + Lenvatinib in Children With Primary CNS Tumors

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

December 3, 2021 (Actual)

Primary Completion Date

December 21, 2025 (Anticipated)

Study Completion Date

December 21, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

EMD Serono Research & Development Institute, Inc.

Collaborators

Merck KGaA, Darmstadt, Germany

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This study consists of 2 parts: Dose Escalation Part 1 and Dose Expansion Part 2. The Dose Escalation Part 1 will evaluate the safety and tolerability of Avelumab in combination with Lenvatinib and determine the recommended Avelumab and Lenvatinib dose for expansion. Dose Expansion Part 2 will assess the efficacy of Avelumab in combination with Lenvatinib by Progression-free Survival in participants with pre-defined primary central nervous system (CNS) tumors.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Central Nervous System Tumors

Keywords

Avelumab, Lenvatinib, Tumors, Pediatric CNS tumors

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Avelumab + Lenvatinib

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

Avelumab

Intervention Description

Participants with primary CNS malignancies who have received at least 1 prior therapy will be enrolled into Dose Escalation Part 1 and will receive intravenous infusion at a flat dose or weight based dose of Avelumab, every 2 weeks (Q2W) until progression, unacceptable toxicity, or withdrawal of consent. Enrollment into part 1 of the study will end when Maximum tolerated dose (MTD) and/or a safe Recommended Dose for Expansion (RDE) for the expansion cohort is determined. Participants with defined CNS tumors will be enrolled into Dose Expansion Part 2 and will receive RDE in Part 2 until progression, unacceptable toxicity, or withdrawal of consent.

Intervention Type

Drug

Intervention Name(s)

Lenvatinib

Intervention Description

Participants with primary CNS malignancies who have received at least 1 prior therapy will be enrolled into Dose Escalation Part 1 and will receive daily oral escalated dose level of Lenvatinib until progression, unacceptable toxicity, or withdrawal of consent. Enrollment into part 1 of the study will end when MTD and/or a safe Recommended Dose for Expansion (RDE) for the expansion cohort is determined. Participants with defined CNS tumors will be enrolled into Dose Expansion Part 2 and will receive RDE of Lenvatinib in Part 2 until progression, unacceptable toxicity, or withdrawal of consent.

Primary Outcome Measure Information:

Title

Time Frame

up to 857 days

Title

Dose Escalation Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)

Time Frame

Baseline (Day 1) up to Day 28

Title

Dose Expansion Part 2: Progression-free Survival (PFS) According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators

Time Frame

until progressive disease or death, assessed up to Day 1534

Secondary Outcome Measure Information:

Title

Dose Escalation Part 1: Number of Participants with Treatment-Emergent Adverse Events (TEAEs), Treatment-related Adverse Events (AEs), Adverse Event of Special Interest (AESIs), AEs Leading to Deaths

Time Frame

up to 876 days

Title

Time Frame

up to 876 days

Title

Dose Escalation Part 1: Number of Participants with Clinically Significant Changes from Baseline in Laboratory Parameters

Time Frame

up to 876 days

Title

Dose Escalation Part 1: Objective Response Rate (ORR) According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators

Time Frame

up to 876 days

Title

Dose Escalation Part 1: Duration of Response (DOR) According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators

Time Frame

up to 876 days

Title

Dose Escalation Part 1: Progression-Free Survival (PFS) According to Response Assessment in Neuro-Oncology (RANO) Criteria

Time Frame

until progressive disease or death, assessed up to 876 days

Title

Dose Escalation Part 1: Overall Survival (OS)

Time Frame

up to 876 days

Title

Dose Escalation Part 1: Serum Observed Concentration at End of Infusion (CEOI) of Avelumab

Time Frame

Pre-dose up to 30 days after last dose, assessed up to approximately 876 days

Title

Dose Escalation Part 1: Area Under the Serum Concentration-Time Curve From the Time of Dosing 336 Hours (AUC0-336 [hr]) of Avelumab

Time Frame

Pre-dose up to 336 hours post-dose, assessed up to approximately 876 days

Title

Dose Escalation Part 1: Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of Avelumab

Time Frame

Pre-dose up to 30 days after last dose, assessed up to approximately 876 days

Title

Dose Escalation Part 1: Maximum Observed Plasma Concentration (Cmax) of Lenvatinib

Time Frame

Pre-dose up to 30 days after last dose, assessed up to approximately 876 days

Title

Dose Escalation Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Lenvatinib

Time Frame

Pre-dose up to 30 days after last dose, assessed up to approximately 876 days

Title

Dose Escalation (Part 1): Area Under the Plasma Concentration-Time Curve From the Time of Dosing to 24 Hours (AUC0-24 [hr]) of Lenvatinib:

Time Frame

Pre-dose up to 24 hours post-dose, assessed up to approximately 876 days

Title

Dose Escalation Part 1: Immunogenicity of Avelumab as Measured by Antidrug Antibody (ADA) Assay

Time Frame

up to 876 days

Title

Dose Expansion Part 2: Number of Participants with Treatment-Emergent Adverse Events (TEAEs), Treatment-related Adverse Events (AEs), Adverse Event of Special Interest (AESIs), AEs Leading to Deaths

Time Frame

up to Day 1534

Title

Time Frame

up to Day 1534

Title

Dose Expansion Part 2: Number of Participants with Clinically Significant Changes in Laboratory Parameters

Time Frame

up to Day 1534

Title

Dose Expansion Part 2: Objective Response Rate (ORR) Rate According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators

Time Frame

up to Day 1534

Title

Dose Expansion Part 2: Duration of Response (DOR) According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators

Time Frame

up to Day 1534

Title

Dose Expansion Part 2: Overall Survival (OS)

Time Frame

up to Day 1534

Title

Dose Expansion Part 2: Serum Observed Concentration at End of Infusion (CEOI) of Avelumab

Time Frame

Pre-dose up to 30 days after last dose, assessed up to approximately Day 1534

Title

Dose Expansion Part 2:Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of Avelumab

Time Frame

Pre-dose up to 30 days after last dose, assessed up to approximately Day 1534

Title

Dose Expansion Part 2: Maximum Observed Plasma Concentration (Cmax) of Lenvatinib

Time Frame

Pre-dose up to 30 days after last dose, assessed up to approximately Day 1534

Title

Dose Expansion Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Lenvatinib

Time Frame

Pre-dose up to 30 days after last dose, assessed up to approximately Day 1534

Title

Dose Expansion Part 2: Immunogenicity of avelumab as measured by ADA assay

Time Frame

up to Day 1534

10. Eligibility

Sex

All

Minimum Age & Unit of Time

2 Years

Maximum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Participants with histologically confirmed diagnosis of primary CNS malignancy as follows: a) Primary CNS tumors: the tumor should be considered high-grade histologically; prior radiotherapy is allowed; participants must have progressed after at least 1 prior systemic therapy, except for those with diffuse midline glioma with or without the H3 K27M mutation. b) Specific for participants with diffuse midline glioma with or without the H3 K27M mutation: prior radiotherapy is allowed; no more than 1 prior systemic therapy is allowed; participants with diffuse midline glioma with or without the H3 K27M mutation who have not received prior systemic therapy but have prior radiotherapy only are allowed to enroll On screening scans, measurable disease by RANO criteria Participants must have a Lansky performance status >= 50 for age <= 16 years or Karnofsky performance status >= 50 for age > 16 years at Screening Other protocol defined inclusion criteria could apply Exclusion Criteria: Participants with low-grade gliomas, for example but not limited to, subependymal giant cell astrocytoma, pilocytic astrocytoma and World Health organization (WHO) Grade 1 tumors Participants demonstrating evidence of worsening of neurologic deficit within 1 week prior to initiation of study interventions Participants with bulky tumor, defined as: a) Tumor with any evidence of uncal herniation or midline shift; b) Tumor with a diameter of > 4 centimeters (cm) in 1 dimension on T2/ fluid-attenuated inversion recovery (FLAIR) images; c) Tumor that in the opinion of the Investigator shows significant mass effect Participants are not eligible if they experience uncontrolled seizures, defined as: a) Seizures requiring regular use of rescue medications. b) Seizures requiring increasing doses of antiepileptic medications. c) Seizures that in the opinion of the Investigator compromise the ability of the participant to tolerate study intervention or interfere with study procedures Participants who have received major surgery (including but not limited to neurosurgical resection, brain biopsy, or radiation to the primary brain tumor) within 28 days prior to the first dose of study interventions Participants with history of intracranial hemorrhage/spinal cord hemorrhage within 28 days prior to the first dose of study interventions Other protocol defined exclusion criteria could apply

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

US Medical Information

Phone

888-275-7376

eMediUSA@emdserono.com

First Name & Middle Initial & Last Name or Official Title & Degree

Communication Center

Phone

+49 6151 72 5200

service@emdgroup.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Responsible

Organizational Affiliation

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Official's Role

Study Director

Facility Information:

Facility Name

Washington University

City

Saint Louis

State/Province

Missouri

ZIP/Postal Code

63110

Country

United States

Individual Site Status

Withdrawn

Facility Name

CHU Sainte-Justine

City

Montréal

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

s.perreault@umontreal.ca

First Name & Middle Initial & Last Name & Degree

Sebastien Perreault

Facility Name

The Hospital for Sick Children

City

Toronto

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

eric.bouffet@sickkids.ca

First Name & Middle Initial & Last Name & Degree

Eric Bouffet

Facility Name

CHU Angers - Hôpital Hôtel Dieu - Service de Cancérologie Pédiatrique

City

Angers Cedex 9

Country

France

Individual Site Status

Recruiting

Facility Contact:

emdecarli@chu-angers.fr

First Name & Middle Initial & Last Name & Degree

Emilie De Carli

Facility Name

Hôpital de la Timone

City

Marseille Cedex 05

Country

France

Individual Site Status

Recruiting

Facility Contact:

nicolas.andre@mail.ap-hm.fr

First Name & Middle Initial & Last Name & Degree

Nicolas André

Facility Name

Institut Curie - Centre de Lutte Contre le Cancer (CLCC) de Paris

City

Paris cedex 05

Country

France

Individual Site Status

Recruiting

Facility Contact:

francois.doz@curie.fr

First Name & Middle Initial & Last Name & Degree

François Doz

Facility Name

Universitaetsklinikum Hamburg Eppendorf

City

Hamburg

Country

Germany

Individual Site Status

Recruiting

Facility Contact:

kordes@uke.de

First Name & Middle Initial & Last Name & Degree

Uwe Kordes

Facility Name

Universitaetsklinikum Muenster

City

Muenster

Country

Germany

Individual Site Status

Recruiting

Facility Contact:

kornelius.kerl@ukmuenster.de

First Name & Middle Initial & Last Name & Degree

Kornelius Kerl

Facility Name

Seoul National University Hospital

City

Seoul

Country

Korea, Republic of

Individual Site Status

Recruiting

Facility Contact:

kanghj@snu.ac.kr

First Name & Middle Initial & Last Name & Degree

Hyoung Jin Kang

Facility Name

Severance Hospital, Yonsei University Health System

City

Seoul

Country

Korea, Republic of

Individual Site Status

Recruiting

Facility Contact:

jwhan@yuhs.ac

First Name & Middle Initial & Last Name & Degree

Jung Woo Han

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21

Links:

URL

https://clinicaltrials.emdgroup.com/en/trial-details/?id=MS100070_0087

Description

Trial Awareness and Transparency website

URL

https://medical.emdserono.com/en_US/home.html

Description

US Medical Information website, Medical Resources

Learn more about this trial

Study of Avelumab in Combination With Lenvatinib for Children With Primary CNS Tumors

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