An open label phase I dose finding study of BI 853520 administered orally in a continuous dosing schedule in patients with various advanced or metastatic non-hematologic malignancies

Cancer is a leading cause of death globally with deaths from cancer projected
to rise. There is a substantial need for novel therapeutic strategies to
improve the outcome for patients with advanced or metastatic malignancies who
have failed conventional treatment, or for whom no therapy of proven efficacy
exists.
In recent years, a number of novel compounds targeting specific cellular
molecules have been developed based on increasing understanding of cancer
biology and cell regulation. Protein tyrosine kinase-2 (PTK2), also known as
focal adhesion kinase (FAK), is a nonreceptor tyrosine kinase. Several
publications over the last two decades have shown that PTK2 may be
over-expressed in a variety of human tumours and its over-expression is
associated with an increased malignant phenotype.
There is pre-clinical evidence from both in vitro and in vivo studies
demonstrating anti-tumour activity with PTK2 blockade. BI 853520 is a highly
potent and exquisitely selective inhibitor of PTK2 kinase activity. The
favourable pre-clinical efficacy and safety profile of BI 853520 is expected to
translate into a benefit for cancer patients. Published results of a phase I
study of another compound targeting PTK2 showed nausea, vomiting, diarrhea and
orthostatic hypotension as dose limiting toxicities (DLTs) with several
patients deriving a clinical benefit.
Biomarker studies have recently indicated that sensitivity of carcinomas to
PTK2 inhibitors may be predicted based on the pattern of E-cadherin expression.
Therefore, expression of E-cadherin in tumour tissue will be analyzed for all
patients in this study.

Primary objective: to determine the safety and tolerability of BI 853520
monotherapy by defining the MTD (maximum tolerated dose) and recommending the
dose for further trials in the development of this compound.
Secondary objectives: A) determination of the pharmacokinetic profile; B)
exploration of biomarkers; and C) collection of preliminary data on anti-tumour
efficacy.

The trial is an open label, dose finding study, followed by an expansion
cohort. The data obtained from this study are expected to allow the definition
of the MTD of BI 853520 monotherapy in patients with advanced solid tumour.
To determine the MTD, patients will be treated at escalating dose levels,
utilizing the 3+3 design. Depending on the observed adverse events, dose
cohorts at escalating dose levels will be enrolled until the MTD has been
defined by the occurrence of drug-related dose limiting toxicity (DLT). The MTD
is defined as the dose level immediately below the dose level at which 2 or
more patients out of a maximum of 6 patients experience DLT.
The observation period for DLT is the duration of the first treatment cycle
only (the first 28 days). However, relevant safety information of all treatment
cycles, including any delays in start of a subsequent cycle due to drug related
adverse events (AEs), will be considered for the recommendation of the dose for
phase II studies.
Once the MTD has been determined, up to 50 additional patients with measurable
disease will be treated in the expansion phase. This expansion phase will
further evaluate the safety, pharmacokinetic and pharmacodynamic profile and
preliminary data on efficacy of BI 853520 in patients..

Once daily oral intake of BI 853520

In this study, patients with advanced or metastatic solid tumours for whom no
other treatment options are available, will be treated with oral BI 853520.
Preclinical studies indicate an acceptable toxicity for BI 853520 with
potential adverse events being nausea, vomiting, diarrhea, and headache.
Furthermore, BI 853520 may be of potential clinical benefit for these patients.
Additional blood and urine samplings will be performed for safety and
pharmacokinetic analyses (6 mL per sampling). Furthermore, patients will
undergo recording of vital signs and repeated scans for tumour imaging. The
patient will receive a financial compensation as this is an additional
procedure and the patient has to stay in the hospital for 24 hours twice during
the first cycle. Repeated biopsies will be taken of either tumour or skin
before and after the first cycle. Blood may be drawn once for an optional
pharmacogenetic test (8,5 mL) during the first cycle. The subject may refuse
participation in this sampling, but can continue to participate in the main
study. These procedures can lead to local pain, irritation, bruising, or an
infection in rare cases.