Clinical trial NCT05081180: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Central Nervous System Tumors
Keywords: Avelumab
Lenvatinib
Tumors
Pediatric CNS tumors
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2021-10-18
Enrollment: 17
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: 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
timeFrame: up to 857 days
measure: Dose Escalation Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Baseline (Day 1) up to Day 28
measure: Dose Expansion Part 2: Progression-free Survival (PFS) According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators
timeFrame: until progressive disease or death, assessed up to Day 1534
Secondary outcomes:
measure: 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
timeFrame: up to 876 days
measure: 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
timeFrame: up to 876 days
measure: Dose Escalation Part 1: Number of Participants with Clinically Significant Changes from Baseline in Laboratory Parameters
timeFrame: up to 876 days
measure: Dose Escalation Part 1: Objective Response Rate (ORR) According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators
timeFrame: up to 876 days
measure: Dose Escalation Part 1: Duration of Response (DOR) According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators
timeFrame: up to 876 days
measure: Dose Escalation Part 1: Progression-Free Survival (PFS) According to Response Assessment in Neuro-Oncology (RANO) Criteria
timeFrame: until progressive disease or death, assessed up to 876 days
measure: Dose Escalation Part 1: Overall Survival (OS)
timeFrame: up to 876 days
measure: Dose Escalation Part 1: Serum Observed Concentration at End of Infusion (CEOI) of Avelumab
timeFrame: Pre-dose up to 30 days after last dose, assessed up to approximately 876 days
measure: Dose Escalation Part 1: Area Under the Serum Concentration-Time Curve From the Time of Dosing 336 Hours (AUC0-336 [hr]) of Avelumab
timeFrame: Pre-dose up to 336 hours post-dose, assessed up to approximately 876 days
measure: Dose Escalation Part 1: Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of Avelumab
timeFrame: Pre-dose up to 30 days after last dose, assessed up to approximately 876 days
measure: Dose Escalation Part 1: Maximum Observed Plasma Concentration (Cmax) of Lenvatinib
timeFrame: Pre-dose up to 30 days after last dose, assessed up to approximately 876 days
measure: Dose Escalation Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Lenvatinib
timeFrame: Pre-dose up to 30 days after last dose, assessed up to approximately 876 days
measure: Dose Escalation (Part 1): Area Under the Plasma Concentration-Time Curve From the Time of Dosing to 24 Hours (AUC0-24 [hr]) of Lenvatinib:
timeFrame: Pre-dose up to 24 hours post-dose, assessed up to approximately 876 days
measure: Dose Escalation Part 1: Immunogenicity of Avelumab as Measured by Antidrug Antibody (ADA) Assay
timeFrame: up to 876 days
measure: 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
timeFrame: up to Day 1534
measure: 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
timeFrame: up to Day 1534
measure: Dose Expansion Part 2: Number of Participants with Clinically Significant Changes in Laboratory Parameters
timeFrame: up to Day 1534
measure: Dose Expansion Part 2: Objective Response Rate (ORR) Rate According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators
timeFrame: up to Day 1534
measure: Dose Expansion Part 2: Duration of Response (DOR) According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators
timeFrame: up to Day 1534
measure: Dose Expansion Part 2: Overall Survival (OS)
timeFrame: up to Day 1534
measure: Dose Expansion Part 2: Serum Observed Concentration at End of Infusion (CEOI) of Avelumab
timeFrame: Pre-dose up to 30 days after last dose, assessed up to approximately Day 1534
measure: Dose Expansion Part 2:Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of Avelumab
timeFrame: Pre-dose up to 30 days after last dose, assessed up to approximately Day 1534
measure: Dose Expansion Part 2: Maximum Observed Plasma Concentration (Cmax) of Lenvatinib
timeFrame: Pre-dose up to 30 days after last dose, assessed up to approximately Day 1534
measure: Dose Expansion Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Lenvatinib
timeFrame: Pre-dose up to 30 days after last dose, assessed up to approximately Day 1534
measure: Dose Expansion Part 2: Immunogenicity of avelumab as measured by ADA assay
timeFrame: up to Day 1534
Other outcomes:
Locations:
city: Montréal
country: Canada
facility: CHU Sainte-Justine
city: Toronto
country: Canada
facility: The Hospital for Sick Children
city: Angers Cedex 9
country: France
facility: CHU Angers - Hôpital Hôtel Dieu - Service de Cancérologie Pédiatrique
city: Marseille Cedex 05
country: France
facility: Hôpital de la Timone
city: Paris cedex 05
country: France
facility: Institut Curie - Centre de Lutte Contre le Cancer (CLCC) de Paris
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg Eppendorf
city: Muenster
country: Germany
facility: Universitaetsklinikum Muenster
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
Study officials:
affiliation: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: