First International Randomized Study in MAlignant Progressive Pheochromocytoma and Paraganglioma

Pheochromocytomas and paragangliomas (PPGLs) arise respectively from the
chromaffin cells of the adrenal medulla (80 to 90%) and paraganglia of the
sympathetic or parasympathetic nervous system. These tumors belong within the
larger family of neuroendocrine tumors. Malignant PPGLs are defined by the
presence of metastases at sites where chromaffin cells are normally absent
(i.e., liver, lungs, bones, lymph nodes). Surgery currently remains the single
option for cure in patients with malignant PPGLs. Systemic therapy in most
patients with progressive disease is usually considered. Data on targeted
molecular therapy are largely lacking in malignant PPGLs. Sunitinib is an oral
multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and
antitumor activity with proven efficacy in the treatment of progressive
gastrointestinal stromal tumors and metastatic renal cell carcinoma. The safety
and efficacy of sunitinib for the treatment of pheochromocytoma and
paragangliomas has not yet been determined.

Primary objective:
To determine the efficacy of Sunitinib on the progression-free survival at 12
months in subjects with progressive malignant pheochromocytoma and
paraganglioma treated with sunitinib at a starting dose of 37.5 mg daily
(continuous dosing).

Secondary objectives:
- To determine overall survival and progression free survival.
- To determine time to progression.
- To determine objective response rate at one year.
- To determine time to and duration of tumor response.
- To assess safety profile including a dedicated cardiovascular management
(home-blood pressure monitoring, ECG and echocardiography).

Exploratory objectives:
- Identification of predictors of response as well as surrogate markers of
overall survival is anticipated.

Randomized, double-blind, phase II, international, multicenter study

Patients are randomized for sunitinib 37.5 mg per day versus Placebo. For the
patients randomized in the Placebo, cross over is allowed if progression.
Treatment duration: 24 months.

In case of participation the patient has to visit the study center at least 18
times;
- twice during screening phase
- 1,2 and 3 weeks after start treatment
- 1 and 2 months after start treatment
- every 3 months during the treatment phase (2 years)
- every 3 months during follow up (1 year)
NB: Most visits are part of regulatory controls by the physican.

Participation will comprise the following examinations and procedures:
- Medical history, current and/or previous treatments, physical examination
including dental examination, measurement of vital signs: every visit
- Blood and urinary samples: every visit
- Pregnancy test: once, before start of treatment
- Computerized tomography (CT) scan and/or Magnetic Resonance Imaging (MRI)
(with intravenous injection of contrast fluid): before start of treatment and
every 3 months from the 3rd month during treatment and follow up
- FDG-PET and/or MIBG-scan (with intravenous injection of radioactive
isotopes): both before start of treatment, an FDG-PET or MIBG-scan every 3
months from the 3rd month during treatment and follow up
- Electrocardiogram (ECG): before start of treatment, 1 month after the
beginning of treatment every 3 months and during follow-up
- Echocardiography: before start of treatment, every 3 months from the 3rd
month during treatment and follow up

Furthermore, the patient is asked to:
- Estiminate pain on a visual scale (VAS score): every 3 months
- Answer a questionnaire of thirty questions about quality of life: after 3, 6
and 24 months of the beginning of treatment as well after ending the study
- Measure their blood pressure at home (6 times/day during 7 days): every week
during a month, one week a month during 3 months, and then every 3 months.

The investigated drug Sunitinib may cause side effects. As with all blood
drawing for the purpose of obtaining samples, there is a risk of bruising,
pain, infection or bleeding at the site of the blood draw. The scans which
involve exposure to radiation. The amount of radiation exposure is considered
small, and will not adversely affect the patients health.