Stepwise Medical Treatment of Cushing*s Disease: a prospective open label multi-center trial with SOM230 mono- and combination therapy with dopamine agonists and ketoconazole

Cushing*s disease is caused by an ACTH-producing pituitary adenoma leading to
cortisol overproduction. Currently, there is no medical treatment modality
available which combines optimal clinical efficacy with minimal toxicity.
Cushing's disease is therefore primarily treated by pituitary surgery, with a
success rate of 60-70 %, eventually followed by radiotherapy. The mean period
after which radiotherapy becomes effective is two years. Medical treatment is
temporarily applied as pre-treatment before pituitary surgery and after
radiotherapy, but the clinical utility of available drugs such as ketoconazole
is limited due to lack of efficacy or serious toxicity.
The currently available somatostatin analogs, which suppress hormone
overproduction by various neuroendocrine tumors, have no inhibitory effects on
ACTH production in Cushing's disease. This is explained by the fact that these
somatostatin analogs preferentially bind to somatostatin receptor subtype (sst)
2, whereas corticotroph adenomas predominantly express sst5. SOM230 is a novel
somatostatin analog that binds with high affinity to sst 1, 2, 3 and 5. In
vitro, SOM230 suppresses ACTH secretion and the combination of SOM230 and
ketoconazole has additive effects on ACTH secretion and cell growth of
corticotroph tumor cells. In a pilot study SOM230 decreased cortisol production
in patients with Cushing's disease with complete normalization of cortisoluria
in a minority of patients. Higher SOM230 dosages (1200 mcg daily), however, can
induce a (transient) worsening of glucose tolerance in Cushing's disease.
In addition to sst 5 expression, about 80 % of corticotroph adenomas express
dopamine subtype 2 receptors (DA2). Both in vitro and in vivo dopamine agonists
have inhibitory effects on ACTH production by corticotroph tumor cells.
Dopamine agonist monotherapy normalizes cortisol production in about 40 % of
patients. So the majority of corticotroph adenomas simultaneously express sst5
and DA2 to a variable degree. It is anticipated that these adenomas will
respond beneficially to a combination of SOM230 and DA2-agonists.
Ketoconazole is currently the standard therapy for pre-treatment in high
dosages of 800 to 1200 mg daily. This is, however, frequently accompanied by
gastro-intestinal side effects and hepatotoxicity. In dosages of 400-600 mg
daily, ketoconazole plasma concentrations are reached (between 10-6M and 10-5M)
which combined with SOM230 had additive inhibitory effects on ACTH secretion
by corticotroph tumor cells in vitro. The combination of SOM230 and low-dose
ketoconazole may therefore be more effective and less toxic than high-dose
ketoconazole monotherapy.

The objective of the study is to improve medical treatment of Cushing's disease
by combining partially independent medical therapies which act through
differential mechanisms. Given the high affinity of SOM230 to sst5 and
considering the facts that patients with Cushing*s disease are prone to develop
glucose intolerance and that in the majority of patients ACTH production can
only partially be controlled by SOM230, there seems a rationale to treat
patients with Cushing*s disease with low to moderate dosages of SOM230 and to
combine this, when control of hypercortisolism is not accomplished, with agents
with additive or potentiating effects, i.e. dopamine agonists and ketoconazole.
Therefore, this study uses a stepwise approach of medical treatment of patients
with Cushing*s disease with SOM230 as basic treatment modality, sequentially
extended with cabergoline and low-dose ketoconazole, according to parameters of
hypercortisolism. As such, maximum clinical efficacy will be coupled to minimum
toxicity.

The total study period is estimated at 60 days which compares to the period
which is currently used to treat patients with cortisol lowering drugs before
pituitary surgery. All patients will be treated with the same medication
schedule. Treatment starts with administration of SOM230 s.c. 100 mcg three
times daily. If after 10 days urinary free cortisol excretion (UFC) is
normalized, this SOM230 dosage will be continued. If UFC is not normalized, the
dosage SOM230 will be increased to 250 mcg s.c. three times daily. At day 20,
patients will again be evaluated and if UFC is normalized, patients will
continue to receive SOM230 250 mcg three times daily. In case of persistent
hypercortisolism, cabergoline will be added to SOM230 in a dosage of 0.5 mg
every other day which is increased to 1 respectively 2 mg every other day in 15
days. At day 45, patients will again be evaluated and if hypercortisolism is
not controlled, ketoconazole will be added to SOM230 and cabergoline in a lower
dose (600 mg daily) than the standard dose (800-1200 mg). The last evaluation
will be performed at day 60, after which patients can continue medication or
can undergo transsphenoidal adenomectomy.

Intervention consists of medical therapy (see study design)

The burden for patients includes subcutaneous administration of the study
medication (SOM230), 4 additional admission days during the study period,
filling in of quality of life questionaires and more frequent collection of 24
hour urine.
Higher dosages of SOM230 can induce a transient worsening of glucose tolerance.
Therefore, in this study a lower dose is applied with careful monitoring of
glucose levels. Finally, during cortisol-lowering therapy hypocortisolism can
theoretically develop for which patients are instructed and monitored.