Phase I/II Study of Avelumab in Pediatric Cancer Subjects

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

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Refractory or Relapsed Solid Tumors
• Intervention / Treatment: Drug: Avelumab; Drug: Avelumab

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium
    • Cliniques Universitaires Saint-Luc
  • Leuven, Belgium
    • UZ Leuven
• Canada
  • London, Canada
    • Children's Hospital - London Health Sciences Centre
  • Montréal, Canada
    • CHU Sainte-Justine
  • Toronto, Canada
    • The Hospital for Sick Children
• Denmark
  • Copenhagen, Denmark
    • Rigshospitalet
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
  • Seoul, Korea, Republic of
    • Samsung Medical Center
  • Seoul, Korea, Republic of
    • Severance Hospital, Yonsei University
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • New York
    • Bronx, New York, United States, 10467
      • The Children's Hospital at Montefiore (CHAM)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 18 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Phase 1: Avelumab	Drug: Avelumab; Subjects will receive avelumab administered intravenously (IV) once every 2 weeks.; Drug: Avelumab; 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.
EXPERIMENTAL: Phase 2, Cohort 1: Avelumab	Drug: Avelumab; Subjects will receive avelumab administered intravenously (IV) once every 2 weeks.; Drug: Avelumab; 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.
EXPERIMENTAL: Phase 2, Cohort 2: Avelumab	Drug: Avelumab; Subjects will receive avelumab administered intravenously (IV) once every 2 weeks.; Drug: Avelumab; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborators: Merck KGaA, Darmstadt, Germany

Publications and helpful links

General Publications

• Vugmeyster Y, Grisic AM, Brockhaus B, Rueckert P, Ruisi M, Dai H, Khandelwal A. Avelumab Dose Selection for Clinical Studies in Pediatric Patients with Solid Tumors. Clin Pharmacokinet. 2022 Jul;61(7):985-995. doi: 10.1007/s40262-022-01111-8. Epub 2022 Apr 29.
• Loeb DM, Lee JW, Morgenstern DA, Samson Y, Uyttebroeck A, Lyu CJ, Van Damme A, Nysom K, Macy ME, Zorzi AP, Xiong J, Pollert P, Joerg I, Vugmeyster Y, Ruisi M, Kang HJ. Avelumab in paediatric patients with refractory or relapsed solid tumours: dose-escalation results from an open-label, single-arm, phase 1/2 trial. Cancer Immunol Immunother. 2022 Oct;71(10):2485-2495. doi: 10.1007/s00262-022-03159-8. Epub 2022 Mar 9.

Helpful Links

• US Medical Information website, Medical Resources
• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 7, 2018
• Primary Completion (ACTUAL): July 27, 2021
• Study Completion (ACTUAL): July 27, 2021

Study Registration Dates

• First Submitted: February 26, 2018
• First Submitted That Met QC Criteria: February 26, 2018
• First Posted (ACTUAL): March 2, 2018

Study Record Updates

• Last Update Posted (ACTUAL): December 6, 2021
• Last Update Submitted That Met QC Criteria: December 3, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Solid tumors; Avelumab; Lymphoma; CNS tumors; Anti PD-L1; Pediatric subjects
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Avelumab; Antibodies, Monoclonal
• Other Study ID Numbers: MS100070-0306; 2017-002985-28 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany, will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients 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 https://www.merckgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No