A phase 2, single arm, European multi-center trial evaluating the efficacy of afatinib as first-line or later-line treatment in advanced chordoma.

Chordomas are rare bone tumors which are accompanied by great morbidity and
mortality in case of locoregional recurrence and metastases. There is an unmet
need for new systemic treatments for this group of patients. EGFR expression is
present on the majority of chordomas and some activity was shown in a previous
phase 2 study with EGFR inhibitor lapatinib. Therefore this phase 2 study on
the activity of afatinib in chordoma patients in indicated.

Primary objectives
- To evaluate the treatment efficacy by progression free survival (PFS)
according to RECIST 1.1.
- Quality of life assessment

Secondary objectives
- To evaluate the treatment efficacy by growth modulation index
- To evaluate the safety and tolerability of afatinib in chordoma
- To determine the overall survival after start of treatment

Translational research objectives
- To evaluate whether EGFR pathway and genetic alterations of pre-treatment
tumor material correlates with outcome in patients treated with afatinib
- To evaluate circulating predictive and prognostic biomarkers in patients
treated with afatinib

Pharmacokinetic research objectives
- To explore the population pharmacokinetics, pharmacogenetics and dynamics of
afatinib in metastatic or unresectable chordoma.
o To develop a population pharmacokinetics (PK) / pharmacodynamics (PD) /
pharmacogenetic (PG) model using non-linear mixed effects modeling (NONMEM)
o To develop a limited sampling model able to accurately predict afatinib
exposure with a limited amount of blood samples
o To develop a time to event model based on the collected data to be able to
simulate optimal dosing strategies for afatinib in metastatic or unresectable
chordoma patients
o To model tumor imaging data (growth or shrinkage) in relationship to afatinib
exposure and genetic data of the tumor

Phase 2 study with single treatment arm, where patients with advanced chordoma
are treated with afatinib. Two different cohorts will be included: 20 patients
in whom afatinib will be first-line treatment and 20 patients in whom afatinib
will be second or later-line treatment. Afatinib is given in 4-week cycles
until disease progression or discontinuation for other reasons. Median
progression free survival and quality of life will be primarlity evaluated.

Afatinib tablets 40mg once daily continuous in 4-week cycles until disease
progression

Subjects will visit the study clinic every 4 weeks for an appointment with
their doctor, dispensation of study medication, blood checks
chemistry/haematology, physical exam and check of vital signs. Visits will take
approximately 30-45 minutes, with the exeption of two long days on which PK
samples will be taken. Those days patients will be in the clinic for a maximum
of 4-8 hours. Further burden:
- Questionnaires on quality of life and pain (2 questionnaires per visit, once
every 8 weeks, 5 minutes per questionnaire)
- Keeping up a study medication diary daily (time of dosing, dose of afatinib)

Blood withdrawals:
- Every 4 weeks haematology / chemistry 10 mL total
- Translational research: Baseline, at C4D1, C7D1 and at end of treatment (< 30
days of last dose afatinib), 40mL drawn for translational research
- Draws for pharmacokinetic research; 4 days / 12 draws via canulla in total:
cycle 1 day 1 (C1D1) 20mL, C1D15 30 mL, C3D1 5mL, C5D1 5 mL.

Possible risks:
- Biopsy: ultrasound / CT guided tumor biopsy, risk of bleeding / infection
(these will be performed in the minority of subjects, since most patients will
have archival tumor tissue available and do not need a fresh biopsy)
- Venapuncture / cannula: low risk of bleeding / infection / pain
- Study medication: side-effects (skin rash 70%, diarrhea 95%, mucositis 70%,
nail infections 50% etc, see patient information)