Open, non-controlled, dose escalating Phase I trial to evaluate the pharmacokinetics, pharmacodynamics, tolerability, and toxicity of volasertib in paediatric patients from 2 years to less than 18 years of age with acute leukaemia or advanced solid tumour, for whom no effective treatment is known

The present trial will be performed in the context of a Paediatric
Investigational Plan (PIP) agreed by the Sponsor with the European Medicines
Agency (EMA).

The present trial is aimed to investigate the safety profile and dosing of
volasertib without interference with other anti-cancer drugs in paediatric
patients with relapsed or refractory leukaemia ineligible to intensive curative
treatment and paediatric patients with advanced solid tumours, for whom no
effective treatment is known. The trial shall provide the basis for further
development of volasertib in paediatric oncology patients.

The objective is to define the maximum tolerable dose (MTD) by evaluation of
dose-limiting toxicity (DLT) of volasertib in paediatric leukaemia and solid
tumours in the age group 2 to less than 12 and 12 to less than 18 years. A
further objective is to collect data on safety, tolerability, toxicity,
efficacy (preliminary activity), pharmacokinetics and pharmacodynamics of
volasertib in paediatric leukaemias and solid tumours.

The present trial will be performed according to an open design. At least three
patients in each age group will be treated with volasertib at a given dose.
Dose escalation will be done according to a 3 plus 3 design, based on the
occurence of side effects.

Approximately 36 patients (at least 12) will be included in this multicentre
trial in approximately 10 centres in Europe.

The patients will be treated in this trial as long as they have benefit from
therapy, do not develop unequivocal progression or relapse, do not meet any of
the treatment withdrawal criteria, and neither parents and/or patient (and/or
legal representative) nor investigator request therapy discontinuation

Patients will be treated with volasertib in treatment courses of two weeks
duration. Volasertib will be administered as a strictly intravenous infusion
during 1 hour through a secure venous access on day 1 of a treatment course.

The starting dose in each age group will be 200 mg/m2 body surface area (BSA)
which is equivalent to 80 % of the MTD as determined in adult AML patients
(with an assumed average BSA of 1.8 m2) treated with volasertib monotherapy.
The dose will be escalated in steps of up to 50 mg/m2. Dose escalation and/or
de-escalation will be recommended by the Data Monitoring Committee (DMC) after
having reviewed the data from previously treated patients.

Treatment may be continued as long as the patient benefits from the treatment.

The most relevant side effect of volasertib administration in adult patients is
a transient inhibition of proliferation of normal dividing cells (e.g. in bone
marrow and mucosal tissue). Cytopenia is a common side effect of conventional
cytotoxic drugs as well in solid tumours and can be monitored and treated
symptomatically. The investigators will provide adequate therapy to treat the
symptoms of cytopenia.

Inhibition of mucosal proliferation by volasertib may lead to gastrointestinal
symptoms such as nausea/vomiting and/or diarrhoea, although these events were
reported only in a limited number of adult patients so far.

Volasertib administration resulted in a transient prolongation of the QTc
interval on the ECG occurring within the first 1 to 2 hours after start of
volasertib infusion. QTc values returned to baseline levels within 24 hours
post-dosing in adults and no clinical events were reported as a consequence of
these prolongations.

The risk benefit ratio is considered positive in the paediatric patient
population in this trial taking into consideration that only paediatric
patients will be enrolled in the trial who are not eligible for further
intensive therapy with curative intent or for whom no therapy is known. The
adverse event profile is considered manageable and there is evidence from adult
patients that monotherapy with volasertib may exert efficacy in this heavily
pretreated patient population with poor prognosis.