Trial of Afatinib in Pediatric Tumours

Phase I/II Open Label, Dose Escalation Trial to Determine the MTD, Safety, PK and Efficacy of Afatinib Monotherapy in Children Aged ≥1 Year to <18 Years With Recurrent/Refractory Neuroectodermal Tumours, Rhabdomyosarcoma and/or Other Solid Tumours With Known ErbB Pathway Deregulation Regardless of Tumour Histology

Open-label, dose escalation, monotherapy, basket trial with biomarker specific MTD expansion cohort/Phase II part.

The trial will consist of 2 parts:

1. Dose finding part to determine the MTD
2. Biomarker specific MTD expansion cohort/Phase II part to assess clinical anti-tumour activity in included tumour types

Study Overview

• Status: Completed
• Conditions: Neuroectodermal Tumors; Rhabdomyosarcoma
• Intervention / Treatment: Drug: afatinib

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • Sydney Childrens Hospital
• Austria
  • Vienna, Austria, 1090
    • AKH - Medical University of Vienna
  • Wien, Austria, 1090
    • St. Anna Children-Hospital, Children's Cancer Research, Wien
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children
• Denmark
  • København Ø, Denmark, 2100
    • Rigshospitalet, København, Børneonkologisk Afsnit 5002
• Faroe Islands
  • Toulouse, Faroe Islands, 31059
    • HOP Toulouse, Pédiat, Toulouse
• France
  • Bordeaux, France, 33076
    • HOP Pellegrin
  • Lille, France, 59020
    • CTR Oscar Lambret
  • Lyon, France, 69008
    • CTR Leon Berard
  • Paris, France, 75248
    • INS Curie
  • Villejuif, France, 94805
    • INS Gustave Roussy
• Germany
  • Berlin, Germany, 13353
    • Charité - Universitätsmedizin Berlin
  • Essen, Germany, 45147
    • Universitätsklinikum Essen AöR
  • Tübingen, Germany, 72076
    • Universitätsklinikum Tübingen
• Italy
  • Genova, Italy, 16147
    • Istituto G. Gaslini
  • Milano, Italy, 20133
    • Fondazione IRCCS Istituto Nazionale dei Tumori
  • Padova, Italy, 35128
    • Azienda Ospedaliera Universitaria di Padova
  • Roma, Italy, 00165
    • Osp. Pediatrico Bambin Gesù
• Netherlands
  • Rotterdam, Netherlands, 3015 CN
    • Erasmus MC - Sophia Kinderziekenhuis
• Spain
  • Barcelona, Spain, 08035
    • Hospital Vall d'Hebron
  • Madrid, Spain, 28009
    • Hospital Infantil Universitario Niño Jesús
• United Kingdom
  • Birmingham, United Kingdom, B4 6NH
    • Birmingham Children's Hospital
  • London, United Kingdom, WC1N 3BN
    • Great Ormond Street Hospital
  • Manchester, United Kingdom, M13 9WL
    • Royal Manchester Children's Hospital
  • Sutton, United Kingdom, SM2 5PT
    • The Royal Marsden Hospital
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas health Science Center at Houston
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Paediatric patients aged 1 year to <18 years at the time of informed consent
• diagnosis of HGG, DIPG, low grade astrocytoma, medulloblastoma/PNET, ependymoma, neuroblastoma, RMS and tumours with ErbB deregulation
• recurrent/refractory disease after they received at least one prior standard treatment regimen
• no effective conventional therapy exists
• Performance status >= 50% (Lansky for =<12ys; Karnofsky for >12ys)
• Further inclusion criteria apply

Exclusion criteria:

• relevant toxicity from previous treatment
• known pre-existing relevant cardiac , hepatic, renal, bone marrow dysfunction, ILD, keratitis
• Further exclusion criteria apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: afatinib; dose escalation	Drug: afatinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Objective Response - Maximum Tolerated Dose Expansion (MTD) Cohort	Number of participants with objective response for maximum tolerated dose expansion (MTD) cohort was reported. The objective response was defined as a best overall response of complete response or partial response based on investigator's assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression.	Assessed every 8 weeks until progression of disease, up to 336 days.
Area Under the Curve Over Dosing Interval τ at Steady State (AUCτ,ss) - Dose Finding Part	Area under the curve over dosing interval τ at steady state (AUCτ,ss) for Dose finding part was reported.	Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
Maximum Measured Concentration of the Analyte in Plasma at Steady State (Cmax,ss) - Dose Finding Part	Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss) for Dose finding part was reported.	Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
Number of Participants With Dose Limiting Toxicity Adverse Events - Dose Finding Part	Number of participants with Dose Limiting Toxicity adverse events for Dose finding part was reported.	During the first course (28 days) of treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Objective Response - Dose Finding Part	Number of participants with objective response for Dose finding part was reported. The objective response was defined as a best overall response of complete response or partial response based on investigator's assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression.	Assessed every 8 weeks until progression of disease, up to 336 days.
Progression Free Survival - Maximum Tolerated Dose (MTD) Expansion Cohort	Progression free survival for the MTD expansion cohorts was reported. Progression free survival (PFS) was defined as the duration from the date of first treatment until the date of the first documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of last adequate tumour assessment.	From the first treatment until date of first progression or death, up to 336 days.
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 24 Hours (AUC0-24) - Dose Finding Part	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 hours (AUC0-24) for Dose finding part was reported.	Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration on Day 1.
Maximum Measured Concentration (Cmax) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort	Maximum measured concentration (Cmax) for Dose finding part/maximum tolerated dose (MTD) expansion cohort was reported.	Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration on Day 1.
Time From (Last) Dosing to the Maximum Measured Concentration (Tmax) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort	Time from (last) dosing to the maximum measured concentration (tmax) for Dose finding part/maximum tolerated dose (MTD) expansion cohort was reported.	Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration on Day 1.
Time From (Last) Dosing to the Maximum Measured Concentration at Steady State (Tmax,ss) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort	Time from (last) dosing to the maximum measured concentration at steady state (tmax,ss) for Dose finding part/maximum tolerated dose (MTD) expansion cohort was reported.	Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
Accumulation (or Effective) Half-life - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort	Accumulation (or effective) half-life for Dose finding part/maximum tolerated dose (MTD) expansion cohort was reported.	Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
Duration of Objective Response - Maximum Tolerated Dose (MTD) Expansion Cohort	Duration of objective response in maximum tolerated dose expansion (MTD) cohort was reported. The objective response was defined as a best overall response of complete response or partial response based on investigator's assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression.	From first documented response until the earliest of disease progression or death, up to 336 days.
Area Under the Curve Over Dosing Interval τ at Steady State (AUCτ,ss) - Maximum Tolerated Dose (MTD) Expansion Cohort	Area under the curve over dosing interval τ at steady state (AUCτ,ss) in maximum tolerated dose (MTD) expansion cohort was reported.	Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
Maximum Measured Concentration of the Analyte in Plasma at Steady State (Cmax,ss) - Maximum Tolerated Dose (MTD) Expansion Cohort	Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss) in maximum tolerated dose (MTD) expansion cohort was reported.	Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Andrade RC, Boroni M, Amazonas MK, Vargas FR. New drug candidates for osteosarcoma: Drug repurposing based on gene expression signature. Comput Biol Med. 2021 Jul;134:104470. doi: 10.1016/j.compbiomed.2021.104470. Epub 2021 May 7.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): April 29, 2015
• Primary Completion (Actual): August 5, 2020
• Study Completion (Actual): August 5, 2020

Study Registration Dates

• First Submitted: February 24, 2015
• First Submitted That Met QC Criteria: February 24, 2015
• First Posted (Estimate): February 26, 2015

Study Record Updates

• Last Update Posted (Actual): March 4, 2021
• Last Update Submitted That Met QC Criteria: March 3, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Sarcoma; Neoplasms, Muscle Tissue; Myosarcoma; Rhabdomyosarcoma; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Afatinib
• Other Study ID Numbers: 1200.120; 2014-002123-10 (EudraCT Number)