Phase I/II trial of afatinib in pediatric tumours

Phase 1

Conditions: Paediatric patients with recurrent/refractory high grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), low grade astrocytoma, neuroblastoma, ependymoma, medulloblastoma/primitive neuroectodermal tumours (PNET), rhabdomyosarcoma (RMS) and/or other solid tumours with known ErbB pathway deregulation regardless of tumour histology
MedDRA version: 20.0Level: LLTClassification code 10029091Term: Neoplasm of unspecified nature of endocrine glands and other parts of nervous systemSystem Organ Class: 100000004864
MedDRA version: 20.0Level: LLTClassification code 10029006Term: Neoplasm of uncertain behavior of brain and spinal cordSystem Organ Class: 100000004864
MedDRA version: 20.0Level: LLTClassification code 10029050Term: Neoplasm of uncertain behaviour of connective and other soft tissueSystem Organ Class: 100000004864
MedDRA version: 20.0Level: LLTClassification code 10028992Term: Neoplasm CNSSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2014-002123-10-DK

Lead Sponsor: SCS Boehringer Ingelheim Comm. V

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 55

Inclusion Criteria

- Paediatric patients
- aged =1 year - <18 years at the time of informed consent
- who present with recurrent/refractory disease after they received at least one prior standard treatment regimen and for whom no effective conventional therapy exists
- Dose finding part: patients with a diagnosis of HGG, DIPG, low grade astrocytoma, neuroblastoma, ependymoma, medulloblastoma/PNET, RMS, and/or solid tumours with known ErbB pathway deregulation regardless of tumour histology.
- MTD expansion cohorts/Phase II part: Patients with HGG, DIPG, EM and other solid tumours than aforementioned which fulfil at least two of the below criteria:
o EGFR gene amplification (FISH): Either EGFR/Cen7 = 2.0 or =10% of cells with =15 copies or =40% of cells with = 4 copies or gene cluster in =10% of cells and/or
o HER2 gene amplification (DDISH): Her2/CEP17 = 2.0 and/or
o EGFR protein expression: H-score > 150 (membrane staining) and/or
o HER2 protein expression: H-score > 0 (membrane staining)
Inclusion will be based on biomarker assessment prior to inclusion, as detected by central laboratory analysis of tumour biopsy materia
- Patients with proven genomic, transcriptomic or proteomic ErbB alterations which are not defined in the above regardless of tumour histology
-Performance status >= 50% (Lansky for =<12ys; Karnofsky for >12ys)

Are the trial subjects under 18? yes
Number of subjects for this age range: 55
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

-relevant toxicity from previous treatment
-known pre-existing relevant cardiac , hepatic, renal, bone marrow dysfunction, ILD, keratitis

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: -Establish MTD of afatinib in pediatric patients<br>-describe pharmacokinetics of afatinib<br>-investigate objective response (OR) to treatment ;Secondary Objective: -Safety<br>-pharmacokinetics<br>-efficacy by objective reponse, duration of response and Progression free survival;Primary end point(s): In dose finding part<br>1) DLT measured during the first course of treatment<br>2) Pharmacokinetics (AUC(T,SS), Cmax(ss))<br><br>In MTD expansion cohort<br>3)Objective Response by investigator assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression of disease.<br>;Timepoint(s) of evaluation of this end point: 1: up to 1 year<br><br>2: up to 1 year<br><br>3: up to 2 years<br><br>

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): In dose finding part <br>1) Objective Response by investigator assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression of disease. <br>2)Pharmacokinetics (AUC0-24, Cmax, tmax(,ss) and accumulation (or effective) half-life)<br><br>In MTD expansion cohort<br>3) Progression free survival (PFS) <br>4) Duration of response<br>5) Pharmacokinetics (AUC,AUCt(,ss), Cmax,(,ss), tmax(,ss) and accumulation (or effective) half-life)<br>;Timepoint(s) of evaluation of this end point: 1: up to 2 years<br><br>2: up to 1 year<br><br>3: up to 2 years<br><br>4: up to 2 years<br><br>5: up to 1 year

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