Phase I/II Study of Avelumab in Pediatric Cancer Participants

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

• Study Type: Interventional
• Enrollment (Actual): 21
• 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 (Child, Adult)
• Accepts Healthy Volunteers: No

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 Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Avelumab: 10 miligram per kilogram (mg/kg)	Drug: Avelumab; Participants received an intravenous infusion of avelumab 10mg/kg intervention (IV) once every 2 weeks until confirmed progression, death, unacceptable toxicity, or any criterion for withdrawal occurred.; Drug: Avelumab; Participants received an intravenous infusion of avelumab 20mg/kg intervention (IV) once every 2 weeks until confirmed progression, death, unacceptable toxicity, or any criterion for withdrawal occurred.
Experimental: Avelumab 20mg/kg	Drug: Avelumab; Participants received an intravenous infusion of avelumab 10mg/kg intervention (IV) once every 2 weeks until confirmed progression, death, unacceptable toxicity, or any criterion for withdrawal occurred.; Drug: Avelumab; Participants received an intravenous infusion of avelumab 20mg/kg intervention (IV) once every 2 weeks until confirmed progression, death, unacceptable toxicity, or any criterion for withdrawal occurred.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) as Per Severity With Grade 3 or Higher According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	Adverse event (AE) was defined as any untoward medical occurrence in a participant, which does not necessarily have causal relationship with treatment. A serious AE was defined as an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged in participant hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event was during the on-treatment period. TEAEs included both serious TEAEs and non-serious TEAEs. Severity of grade 3 or higher TEAEs were graded using NCI-CTCAE v4.03 toxicity grades, as follows: Grade 1 = Mild, Grade 2= Moderate, Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. Number of participants with TEAEs as per severity with Grade 3 and higher were reported.	Baseline up to 1182 days
Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)	For the purpose of dose finding, any of the following AEs occurring during the primary DLT observation period. Hematologic: Grade 4 neutropenia for more than 7 days in duration; Grade greater than or equal to (>=) 3 neutropenic infection; Grade >= 3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia > 7 days and Grade 4 anemia. Nonhematologic: Any Grade >= 3 toxicity, except for any of the following: Transient (less than or equal to (<=) 72 hours; Grade 3 flu-like symptoms or fever, which was controlled with medical management; Transient (<= 72 hours) Grade 3 fatigue, local reactions, headache, nausea, or emesis that resolved to Grade <= 1 or to Baseline. Grade 3 diarrhea or Grade 3 skin toxicity that resolved to Grade <= 1 in less than 7 days after medical management (immunosuppressant treatment) had been initiated. Grade >= 3 amylase or lipase abnormality that was not associated with clinical manifestations of pancreatitis.	Baseline up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator	Confirmed BOR was evaluated based on RECIST v1.1 and Investigator's assessments and defined as best response of any of confirmed complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of study treatment until disease progression. CR: Disappearance of all evidence of target/non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD: at least a 20% increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1or more new lesions and unequivocal progression of non-target lesions.	Baseline up to 1182 days
Duration of Response (DOR) as Per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator	Duration of response was defined for participants with confirmed objective response (OR), as the time from first documentation of objective response (Complete Response or Partial Response) to the date of first documentation of objective PD or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. DOR was determined according to RECIST v1.1 and assessed by Investigator.	Time from first documentation of objective response up to 1182 days
Time to Response According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator	Time to response (TTR) was defined, for participants with an objective response, as the time from the start date of study treatment to the first documentation of OR (CR or PR) which was subsequently confirmed.	Time from start of study treatment up to 1182 days
Progression-Free Survival According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator	Progression-Free survival was defined as the time from first administration of study treatment until the first documentation of disease progression (PD) or death due to any cause, whichever occurred first. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates.	Time from first administration of study drug until the first documentation of PD or death, assessed up to 1182 days
Overall Survival (OS)	Overall Survival was defined as the time from date of first dose of study drug to the date of death due to any cause. For participants who were still alive at the time of data analysis or who were lost to follow-up, OS time was censored at the date of last contact. OS was measured using Kaplan-Meier (KM) estimates.	Time from first administration of study drug up to 1182 days
Number of Participants With Treatment-Emergent Adverse Events, Adverse Events of Special Interest (AESI) and Treatment-related Adverse Events According to NCI-CTCAE v4.03	Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily had a causal relationship with this treatment. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs: TEAEs was defined as events with onset date or worsening during the on-treatment period. TEAEs included serious AEs and non-serious AEs. Treatment-related TEAEs: reasonably related to the study intervention. AESIs included Infusion-related reactions (IRRs) and Immune-related AE (irAEs).	Baseline up to 1182 days
Number of Participants With Grade 3 or Higher Laboratory Abnormalities According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03	The total number of participants with laboratory test abnormalities were assessed. Clinical laboratory tests included hematology and biochemistry abnormalities. The hematology and biochemistry abnormalities (by worst on-treatment NCI-CTCAE Grade 3 and Grade 4) were reported. Laboratory abnormalities were graded using NCI-CTCAE v4.03 toxicity grades, as follows: Grade 1 = Mild, Grade 2= Moderate, Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death.	Baseline up to 1182 days
Maximum Observed Serum Concentration (Cmax) of Avelumab	Cmax is the maximum observed serum concentration obtained directly from the concentration versus time curve.	Pre-dose, end of infusion (1 hour), 3 hours post-dose on Day 1, cycle 1 (each cycle is for 14 days)
Area Under the Serum Concentration-Time Curve From Time Zero to the 336 Hours Post-Dose (AUC 0-336 Hours) of Avelumab	Area under the serum concentration-time curve from time zero to the 336 Hours Post-Dose (AUC 0-336 hours) of Avelumab were calculated. Calculated using the mixed loglinear trapezoidal rule (linear up, log down).	Pre-dose, end of infusion (1 hour), 3 hours to 336 hours post-dose
Apparent Terminal Half Life (t1/2) of Avelumab	Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination. Apparent terminal half-life. t1/2 = log (ln) 2/lambdaz (λz).	Pre-dose, end of infusion (1 hour), 3 hours post-dose on Day 1, cycle 1 (each cycle is for 14 days)
Minimum Serum Post-dose Trough (Ctrough) Concentration of Avelumab	The concentration observed immediately before next dosing (corresponding to predose or trough concentration for multiple dosing) was calculated.	Pre-dose at Day 15
Number of Participants With Positive Treatment Emergent Anti-drug Antibodies (ADA) and Neutralizing Antibodies (Nabs)	Serum samples were analyzed by a validated electrochemiluminesce immunoassay to detect the presence of anti-drug antibodies and neutralizing antibodies. Samples that screened positive were subsequently tested in a confirmatory assay. Those confirmed positive were tittered for a quasi-quantitative result. Number of participants with positive treatment emergent anti-drug antibodies and neutralizing antibodies were reported. Participants not positive prior to treatment with avelumab and with at least one positive result in the human-Antihuman Antibodies assay were characterized as treatment-emergent.	Baseline up to 1182 days
Number of Participants With Positive Tumor Programmed Death Ligand 1 (PD-L1) Expression	Number of participants with positive tumor programmed death ligand 1 (PDL-1) with cut off >=1%, >= 5%, >=25%, >=50% and >=80% expression were reported.	Baseline up to end of treatment visit (27.5 weeks)
Number of Participants With Substantial, Sustained, or Significant Changes From Baseline for Tumor-Infiltrating T-cell Levels	Number of participants with substantial, sustained, or significant changes from baseline for Tumor-Infiltrating T-cell Levels were reported. Significant clinical deterioration (clinical progression), defined as new symptoms that are deemed by the Investigator to be clinically significant or significant worsening of existing symptoms.	Baseline up to end of treatment visit (27.5 weeks)
Number of Participants With Substantial, Sustained, or Significant Changes From Baseline for T-cell Population in Blood	Number of participants with substantial, sustained, or significant changes from baseline for T-cell population in blood were reported. Significant clinical deterioration (clinical progression), defined as new symptoms that are deemed by the Investigator to be clinically significant or significant worsening of existing symptoms.	Baseline up to end of treatment visit (27.5 weeks)
Number of Participants With Substantial, Sustained, or Significant Changes From Baseline for B-cell and Natural Killer Cell (NK-Cell) in Blood	Number of participants with substantial, sustained, or significant changes from baseline for B-cell and NK-cell in blood were reported. Significant clinical deterioration (clinical progression), defined as new symptoms that are deemed by the Investigator to be clinically significant or significant worsening of existing symptoms.	Baseline up to end of treatment visit (27.5 weeks)
Number of Participants With Substantial, Sustained, or Significant Changes From Baseline for Vaccination-Related Antibody Concentrations	Samples for the testing of vaccination-related antibody concentrations for diphtheria, tetanus, and pneumococcal conjugate (PCV-7) were collected. Significant clinical deterioration (clinical progression), defined as new symptoms that are deemed by the Investigator to be clinically significant or significant worsening of existing symptoms.	Baseline up to end of treatment visit (27.5 weeks)
Number of Participants With TEAEs Related to Vital Signs That Resulted in Treatment Discontinuation	Vital signs included: Body temperature, Heart Rate, Blood pressure and respiratory rate. Vital signs were measured in semi-supine position after 5 minutes rest for the participants.	Baseline up to 1182 days

Collaborators and Investigators

• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborators: Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Medical Responsible, 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

• 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): June 24, 2024
• Last Update Submitted That Met QC Criteria: January 15, 2024
• Last Verified: January 1, 2024

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)

• 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