Improving the tolerability of the oral targeted anti-cancer drug pazopanib by food intake (DIET).

Pazopanib (Votrient) is a multi targeted tyrosine kinase inhibitor of vascular
endothelial growth factor receptor, (VEGFR-1, -2 en -3), platelet-derived
growth factor receptor (PDGFR-* and **), and stem cell factor receptor (c-KIT).
Pazopanib is registered for the treatment of patients with advanced renal cell
carcinoma and patients with soft tissue sarcoma who have received prior
chemotherapy. Pazopanib is administered at a fixed oral dose of 800 mg OD
regardless of size, age and clinical condition. Pazopanib is absorbed from the
gastrointestinal tract with an absolute oral bioavailability of ~21%.
Pazopanib is practically insoluble and highly permeable. When ingested with
high fat food the pazopanib exposure (area under the concentration time curve
(AUC)) is doubled. Common adverse effects are diarrhea and nausea. This might
be caused by the non-absorbed proportion of pazopanib. A dose reduction when
ingested with food could be a logical approach to reduce these side effects;
however this is not tested in patients yet. Therefore we want to perform a
bioequivalent study to investigate what dose with a continental breakfast
equals the dose of 800 mg in fasted conditions (study part A). In part B of the
study we want to investigate whether the intake with food reduces the
frequently reported side effects.

Part A
Primary objective:
To determine the equivalent dose of pazopanib when taken with a continental
breakfast compared to 800 mg in fasted state.
Secondary objective:
To monitor the occurrence of adverse events of pazopanib with and without food
according to the CTC-AE criteria v 4.03

Part B
Primary objective:
To evaluate whether a reduced pazopanib dose ingested with food can reduce the
side effects diarrhea and nausea.
Secondary objective:
To evaluate the preference of the patients: intake of pazopanib with or without
food.
To evaluate the progression free survival time in all patients.

Part A
Patients who use pazopanib are included.
A total of 16 - 19 patients will be included, pharmacokinetic (PK) and safety
evaluation will initially be performed in three patients treated with 800 mg
OD (100%) pazopanib in a fasted state for two weeks followed by two weeks of
600 mg OD (75%) pazopanib together with a standardized continental breakfast.
PK assessment will be performed after 2 (800mg OD without food) and 4 weeks
(600mg OD with food) of pazopanib therapy. The results of these three patients
will be analysed and discussed to determine a safe and feasible dose for the
next patients in the study. The dose for the next 13 * 16 patients will either
be 600mg OD (75%) or 400mg OD (50%) partly based on the safety profile observed
in the initial three patients, PK assessment and literature data.
After the second PK assessment all patients go back to the standard dose of
800mg OD taken without food.

Part B
Patients who use pazopanib within label are eligible for inclusion.
A total of 60 patients are included and randomized over two groups. Group 1
starts with 800 mg pazopanib in a fasted state. After one month of therapy they
will switch to a reduced though equivalent dose (established in part A of the
study) taken together with a continental breakfast during the next month. Group
2 starts with the reduced equivalent dose of pazopanib ingested with food and
will switch after one month to 800 mg pazopanib in a fasted state. During both
treatment periods diarrhea and nausea will be monitored and scored according to
the CTC AEv4.03 criteria.
After each treatment period patients will be asked to complete a questionnaire
regarding their pazopanib intake comfort. At the end of the study period of two
months, all patients will be asked for their preference.
After the two months of observed and controlled intake of pazopanib patients
will continue pazopanib therapy at the standard dose taken in fasted state
until they do no longer have clinical benefit from the therapy.

In general the risk for participation in this study is regarded low. If no bio*
equivalent exposure is reached when ingested with food, patients get a
sub-optimal treatment for only two weeks The risk of suboptimal dosing is
minimized by the run in of three patients at 600 mg OD with food. Heath et al
showed that pazopanib ingestion with food increases bioavailability with 200%.
The continental breakfast in this study contains half the amount of fat
compared to the FDA meals Heath et al used (4). Therefore, we will start to
test a dose reduction of 25 % instead of 50% in a small number of three
patients to prevent under dosing. After a short period of two weeks, PK
assessments will be preformed to monitor the potential risk of under or over
dosing. . However if this occurs this is for only a short period of time in
part A (2 weeks). This short period of potential suboptimal dosing will not
affect the treatment outcome .

Benefits for patient participating in part A will be regarded low.
Participants in part B will probably experience less side effects and the
intake of pazopanib will be more easily incorporated in their normal life
style.