A phase I, open-label, multicenter study to evaluate the pharmacokinetics and safety of oral panobinostat in patients with advanced solid tumors and various degrees of hepatic function

Panobinostat (LBH589) is a deacetylase inhibitor (DACi) which belongs to a
structurally novel cinnamic hydroxamic acid class of compounds. It is a potent
class I/II pan-DAC inhibitor (pan-DACi) that has shown anti-tumor activity in
pre-clinical models and patients with solid tumors and hematological
malignancies.
As results from a recently completed radio-labeled human ADME study in patients
indicated that both kidney and liver are involved in the elimination and
metabolism of panobinostat, understanding the impact of altered organ function
status on panobinostat PK
has become important and thus provides a rationale for this study.
Panobinostat is likely to be utilized in cancer patients with co-existing
morbidities such as impaired hepatic function. Patients with liver impairment
may be at risk with decreased ability to eliminate panobinostat. Decreased
elimination of the drug as a result of impaired organ
function may lead to an increased systemic exposure and possible toxicity.
Although, a number of patients with mild or moderate hepatic dysfunction have
been included in prior clinical studies of single agent panobinostat,
currently, there has been no formal evaluation of the disposition of
panobinostat in patients with cancer and impaired hepatic function.

Primary:
To assess the effect of various degrees of impairment in hepatic function as
measured by NCICTEPcriteria, on the pharmacokinetics of panobinostat.

Secondary:
To assess the effect of various degrees of hepatic functions on the safety of
panobinostat and to evaluate whether there is a relationship between PK and
safety parameters in patient with various degrees of hepatic functions.

This is a phase I, open-label, multi-center study to evaluate the PK and safety
of oral panobinostat in patients with advanced solid tumors with varyious
degrees of hepatic function. Initially, patients with normal hepatic function
and mild or moderate hepatic dysfunction will be enrolled in the study.
A decision to enroll patients with severe liver impairment will be made
following review of the preliminary safety data of all patients dosed and
completed the core phase and cycle 1 of treatment (extension) phase, of which
at least three (3) patients must be from the moderate group. In an unlikely
scenario, the first 3 patients enrolled in the study may all belong to the
moderate hepatic dysfunction group and may not, exhibit major toxicities. Such
a case, historical data from prior studies of oral panobinostat, where patients
with normal hepatic function and mild hepatic dysfunction have been enrolled,
will be taken into account prior to making a decision to open enrollment for
the severe hepatic dysfunction patients.

The study will have 2 phases.
The core phase, in which on day 1 the patient will be administered one dose of
panobinostat followed by pharmacokinetic assessments and ECG monitoring. on
days 1 to 5 (post-dose).
Treatment will be continued on day 8, which is day 1 of the extension phase.
The extension phase will excists of 28-days cycles. Panobinostat will be
administered 3 times weekly until progression or unacceptable toxicity.

Studiedrug: panobinostat 30mg, oral

Corephase (pharmacokinetics) (dag 1-7): a single dose panobinostat 30 mg on day
1

Extensionphase: 30 mg panobinostat 3 x weekly.

Side effects from panobinostat seen in animals that might happen in human. Most
frequently reported adverse events seen in patients treated with oral
panobinostat are:
* Decrease in the platelets
* Mild to moderate nausea, vomiting, and diarrhea
* Decreased appetite
* Fatigue, feeling weak or tired.
Taking blood may cause pain, bleeding, and/or bruising.