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

Study Overview
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Brief Summary
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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.

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

Conditions
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Central Nervous System Tumors

Intervention / Treatment
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* Drug: Avelumab
* Drug: Lenvatinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Avelumab + Lenvatinib<br> | Drug: Avelumab<br>* 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.<br>Drug: Lenvatinib<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | up to 857 days | 
| Dose Escalation Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) |  | Baseline (Day 1) up to Day 28 | 
| Dose Expansion Part 2: Progression-free Survival (PFS) According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators |  | until progressive disease or death, assessed up to Day 1534 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | up to 876 days | 
| 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 |  | up to 876 days | 
| Dose Escalation Part 1: Number of Participants with Clinically Significant Changes from Baseline in Laboratory Parameters |  | up to 876 days | 
| Dose Escalation Part 1: Objective Response Rate (ORR) According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators |  | up to 876 days | 
| Dose Escalation Part 1: Duration of Response (DOR) According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators |  | up to 876 days | 
| Dose Escalation Part 1: Progression-Free Survival (PFS) According to Response Assessment in Neuro-Oncology (RANO) Criteria |  | until progressive disease or death, assessed up to 876 days | 
| Dose Escalation Part 1: Overall Survival (OS) |  | up to 876 days | 
| Dose Escalation Part 1: Serum Observed Concentration at End of Infusion (CEOI) of Avelumab |  | Pre-dose up to 30 days after last dose, assessed up to approximately 876 days | 
| Dose Escalation Part 1: Area Under the Serum Concentration-Time Curve From the Time of Dosing 336 Hours (AUC0-336 [hr]) of Avelumab |  | Pre-dose up to 336 hours post-dose, assessed up to approximately 876 days | 
| Dose Escalation Part 1: Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of Avelumab |  | Pre-dose up to 30 days after last dose, assessed up to approximately 876 days | 
| Dose Escalation Part 1: Maximum Observed Plasma Concentration (Cmax) of Lenvatinib |  | Pre-dose up to 30 days after last dose, assessed up to approximately 876 days | 
| Dose Escalation Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Lenvatinib |  | Pre-dose up to 30 days after last dose, assessed up to approximately 876 days | 
| Dose Escalation (Part 1): Area Under the Plasma Concentration-Time Curve From the Time of Dosing to 24 Hours (AUC0-24 [hr]) of Lenvatinib: |  | Pre-dose up to 24 hours post-dose, assessed up to approximately 876 days | 
| Dose Escalation Part 1: Immunogenicity of Avelumab as Measured by Antidrug Antibody (ADA) Assay |  | up to 876 days | 
| 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 |  | up to Day 1534 | 
| 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 |  | up to Day 1534 | 
| Dose Expansion Part 2: Number of Participants with Clinically Significant Changes in Laboratory Parameters |  | up to Day 1534 | 
| Dose Expansion Part 2: Objective Response Rate (ORR) Rate According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators |  | up to Day 1534 | 
| Dose Expansion Part 2: Duration of Response (DOR) According to Response Assessment in Neuro-Oncology (RANO) Criteria as Assessed by Investigators |  | up to Day 1534 | 
| Dose Expansion Part 2: Overall Survival (OS) |  | up to Day 1534 | 
| Dose Expansion Part 2: Serum Observed Concentration at End of Infusion (CEOI) of Avelumab |  | Pre-dose up to 30 days after last dose, assessed up to approximately Day 1534 | 
| Dose Expansion Part 2:Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of Avelumab |  | Pre-dose up to 30 days after last dose, assessed up to approximately Day 1534 | 
| Dose Expansion Part 2: Maximum Observed Plasma Concentration (Cmax) of Lenvatinib |  | Pre-dose up to 30 days after last dose, assessed up to approximately Day 1534 | 
| Dose Expansion Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Lenvatinib |  | Pre-dose up to 30 days after last dose, assessed up to approximately Day 1534 | 
| Dose Expansion Part 2: Immunogenicity of avelumab as measured by ADA assay |  | up to Day 1534 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Avelumab, Lenvatinib, Tumors, Pediatric CNS tumors