Phase I/II Study of Avelumab in Pediatric Cancer Subjects

Study Overview
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Brief Summary
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This is a multi-center, open-label, international study to evaluate the dose, safety and tolerability, antitumor activity, pharmacokinetic and pharmacodynamics of avelumab in pediatric subjects 0 to less than 18 years of age with refractory or relapsed malignant solid tumors (including central nervous system tumors) and lymphoma for which no standard therapy is available or for which the subject is not eligible for the existing therapy. The study was planned to be conducted in 2 parts: the dose-finding part (Phase I) and the tumor-specified expansion part (Phase II). However, Phase II was cancelled due to limited clinical benefit of PD-L1 monotherapy in pediatric participants.

Official Title
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Open-label, Phase I/II Study to Evaluate Pharmacokinetics, Pharmacodynamics, Safety, and Anticancer Activity of Avelumab in Pediatric Subjects From Birth to Less Than 18 Years of Age With Refractory or Relapsed Solid Tumors and Lymphoma

Conditions
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Refractory or Relapsed Solid Tumors, Lymphoma

Intervention / Treatment
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* Drug: Avelumab
* Drug: Avelumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects 0 to less than 18 years of age at the time of first treatment dose with histologically or cytologically confirmed solid malignant tumors (including CNS tumors) or lymphoma for which no standard therapy is available Confirmed progression on or refractory to standard therapy or no standard therapy available. Availability of archival formalin-fixed, paraffin-embedded block containing tumor tissue, or slides, or a fresh/recent tumor biopsy prior to avelumab treatment for subjects in Phase 2 Adequate bone marrow, kidney, and liver function Other protocol defined inclusion criteria could apply Exclusion Criteria: Prior therapy with any antibody or drug targeting T-cell coregulatory proteins Concurrent anticancer treatment or immunosuppressive agents Prior organ transplantation Significant acute or chronic infections Other significant diseases or conditions that might impair the subject's tolerance of trial treatment Other protocol defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 0 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Avelumab<br> | Drug: Avelumab<br>* Subjects will receive avelumab administered intravenously (IV) once every 2 weeks.<br>|
| Experimental: Phase 2, Cohort 1: Avelumab<br> | Drug: Avelumab<br>* Subjects will receive avelumab at a recommended phase II dose (RP2D) adjudicated by a safety monitoring committee (SMC) from phase I part of the study.<br>|
| Experimental: Phase 2, Cohort 2: Avelumab<br> | Drug: Avelumab<br>* Subjects will receive avelumab at a recommended phase II dose (RP2D) adjudicated by a safety monitoring committee (SMC) from phase I part of the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Occurrence and Severity of Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.03) |  | From first dose of the study drug administration up to 30 days after the last dose (assessed up to maximum of 13 months) | 
| Phase 1: Occurrence of Dose Limiting Toxicity |  | Day 1 up to Day 28 | 
| Phase 2: Confirmed Best Overall Response (BOR) as per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator |  | Time from first dose until confirmed disease progression assessed up to maximum of 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Confirmed Best Overall Response (BOR) as per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator |  | Time from first dose until confirmed disease progression assessed up to maximum of 48 months | 
| Phase 1 and Phase 2: Duration of Response (DOR) as per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator |  | Time from first documented complete response (CR) or partial response (PR) to the date of first documentation of Progressive disease (PD) or death, assessed up to maximum of 48 months | 
| Phase 1 and Phase 2: Time to Response According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator |  | Time from first dose up to first documented CR or PR, assessed up to maximum of 48 months | 
| Phase 1 and Phase 2: Progression-Free Survival According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator |  | Time from first dose up to the date of first documented disease progression or death due to any cause, assessed up to maximum of 48 months | 
| Phase 1 and Phase 2: Overall Survival (OS) Time |  | Time from first dose until death, assessed up to maximum of 48 months | 
| Phase 1 and Phase 2: Occurrence and Severity of Treatment Emergent Adverse Events (TEAEs), AEs of Special Interest, and Treatment-Related AEs, According to the NCI-CTCAE Version 4.03 |  | From first dose of the study drug administration up to 30 days after the last dose (assessed up to maximum of 48 months) | 
| Phase 1 and Phase 2: Incidence of Laboratory Abnormalities as Graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 |  | Baseline up to 48 months | 
| Phase 1 and Phase 2: Maximum Observed Plasma Concentration (Cmax) of Single and Multiple Dose of Avelumab |  | Baseline up to 48 months | 
| Phase 1 and Phase 2: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Avelumab |  | Baseline up to 48 months | 
| Phase 1 and Phase 2: Half life (t1/2) of Single and Multiple Dose of Avelumab |  | Baseline up to 48 months | 
| Phase 1 and Phase 2: Minimum Post-dose Trough Concentration of Single and Multiple Dose of Avelumab |  | Baseline up to 48 months | 
| Phase 1 and Phase 2: Immunogenicity as measured by Incidence of Antidrug Antibody (ADA) and Neutralizing Antibody (Nabs) |  | Baseline up to 30 days after the last dose (assessed maximum up to 48 months) | 
| Phase 1 and Phase 2: Tumor Programmed Death Ligand 1 (PD-L1) Expression Levels |  | Baseline and at disease progression (assessed up to maximum of 48 months) | 
| Phase 1 and Phase 2: Tumor-Infiltrating T-cell Levels |  | Baseline up to 48 months | 
| Phase 1 and Phase 2: T-cell Population in Blood |  | Baseline up to 48 months | 
| Phase 1 and Phase 2: Number of T-cell, B-cell and NK-cell in Blood |  | Baseline up to 48 months | 
| Phase 1 and Phase 2: Vaccination-Related Antibody Concentrations |  | Baseline up to 48 months | 
| Phase 1 and Phase 2: Body Temperature |  | Baseline up to 48 months | 
| Phase 1 and Phase 2: Heart Rate |  | Baseline up to 48 months | 
| Phase 1 and Phase 2: Respiratory Rate |  | Baseline up to 48 months | 
| Phase 1 and Phase 2: Systolic and Diastolic Blood Pressure |  | Baseline up to 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Avelumab, Anti PD-L1, Solid tumors, CNS tumors, Lymphoma, Pediatric subjects