Clinical trial NCT03451825: Phase I/II Study of Avelumab in Pediatric Cancer Participants
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Refractory or Relapsed Solid Tumors
Lymphoma
Keywords: Avelumab
Anti PD-L1
Solid tumors
CNS tumors
Lymphoma
Pediatric subjects
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2018-03-02
Enrollment: 21
Sex: ALL
Minimum age (years): 0
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: 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)
timeFrame: Baseline up to 1182 days
measure: Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
timeFrame: Baseline up to 28 days
Secondary outcomes:
measure: 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
timeFrame: Baseline up to 1182 days
measure: Duration of Response (DOR) as Per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator
timeFrame: Time from first documentation of objective response up to 1182 days
measure: Time to Response According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator
timeFrame: Time from start of study treatment up to 1182 days
measure: Progression-Free Survival According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator
timeFrame: Time from first administration of study drug until the first documentation of PD or death, assessed up to 1182 days
measure: Overall Survival (OS)
timeFrame: Time from first administration of study drug up to 1182 days
measure: 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
timeFrame: Baseline up to 1182 days
measure: 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
timeFrame: Baseline up to 1182 days
measure: Maximum Observed Serum Concentration (Cmax) of Avelumab
timeFrame: Pre-dose, end of infusion (1 hour), 3 hours post-dose on Day 1, cycle 1 (each cycle is for 14 days)
measure: Area Under the Serum Concentration-Time Curve From Time Zero to the 336 Hours Post-Dose (AUC 0-336 Hours) of Avelumab
timeFrame: Pre-dose, end of infusion (1 hour), 3 hours to 336 hours post-dose
measure: Apparent Terminal Half Life (t1/2) of Avelumab
timeFrame: Pre-dose, end of infusion (1 hour), 3 hours post-dose on Day 1, cycle 1 (each cycle is for 14 days)
measure: Minimum Serum Post-dose Trough (Ctrough) Concentration of Avelumab
timeFrame: Pre-dose at Day 15
measure: Number of Participants With Positive Treatment Emergent Anti-drug Antibodies (ADA) and Neutralizing Antibodies (Nabs)
timeFrame: Baseline up to 1182 days
measure: Number of Participants With Positive Tumor Programmed Death Ligand 1 (PD-L1) Expression
timeFrame: Baseline up to end of treatment visit (27.5 weeks)
measure: Number of Participants With Substantial, Sustained, or Significant Changes From Baseline for Tumor-Infiltrating T-cell Levels
timeFrame: Baseline up to end of treatment visit (27.5 weeks)
measure: Number of Participants With Substantial, Sustained, or Significant Changes From Baseline for T-cell Population in Blood
timeFrame: Baseline up to end of treatment visit (27.5 weeks)
measure: Number of Participants With Substantial, Sustained, or Significant Changes From Baseline for B-cell and Natural Killer Cell (NK-Cell) in Blood
timeFrame: Baseline up to end of treatment visit (27.5 weeks)
measure: Number of Participants With Substantial, Sustained, or Significant Changes From Baseline for Vaccination-Related Antibody Concentrations
timeFrame: Baseline up to end of treatment visit (27.5 weeks)
measure: Number of Participants With TEAEs Related to Vital Signs That Resulted in Treatment Discontinuation
timeFrame: Baseline up to 1182 days
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Bronx
country: United States
facility: The Children's Hospital at Montefiore (CHAM)
state: New York
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Leuven
country: Belgium
facility: UZ Leuven
city: London
country: Canada
facility: Children's Hospital - London Health Sciences Centre
city: Montréal
country: Canada
facility: CHU Sainte-Justine
city: Toronto
country: Canada
facility: The Hospital for Sick Children
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.