Trial Information

A Phase II Study of SOM230 in Patients With Recurrent or Progressive Meningioma Who Have Previously Undergone or Are Not Candidates for Additional Surgery or Radiation

Study rationale/purpose:

Most, though not all (Lamberts 1995; Koper 1992) in vitro studies suggest that the addition
of somatostatin inhibits meningioma growth, and accelerates apoptosis, suggesting a
potential therapeutic role for somatostatin receptor agonists (Arena 2004). SOM230
(pasireotide) is a novel somatostatin analogue with affinity for multiple somatostatin
receptors. Compared to octreotide (Sandostatin®), SOM230 binds to a wider spectrum of
somatostatin receptors, including subtypes 1, 2, 3, and 5, and possesses as a higher
binding affinity for subtypes 1, 3, and 5). In a recent study evaluating the expression of
somatostatin receptor mRNA in human meningiomas (Arena 2004), 88% of the tumors (37/42) were
positive for at least 1 of the 5 SSTR subtypes. SSTR1 and SSTR2 were most commonly detected
in meningiomas (69 % (29/42) and 79% (33/42) respectively). The other subtypes were also
frequently detected (43%, 33%, and 33% for SSTR3, SSTR4, and SSTR5 respectively). In
recently completed studies with SOM230 in patients with Cushing's disease and acromegaly,
clinical responses have been documented in patients who were refractory to Sandostatin. In
summary, SOM230 has broader binding affinity to somatostatin receptors than Sandostatin®,
its toxicity is very modest, and qualitatively identical to that of Sandostatin®, and its
longer half-life (approximately 23 hours) allows a more convenient (twice daily in contrast
to three times a day) dosing schedule compared with Sandostatin®. For all these reasons, we
anticipate that the efficacy and tolerability of SOM230 in patients with recurrent
meningiomas should be better than that observed with Sandostatin. We therefore, propose a
formal phase II trial of SOM230 (pasireotide) in patients with recurrent or progressive
meningiomas who have already undergone or are not candidates for additional surgery or
radiation.

OBJECTIVES:

Primary objective To determine the objective response rate (ORR) (complete response [CR]
plus partial response [PR]) of SOM230 monotherapy in patients with recurrent or progressive
meningiomas who have previously undergone or are not candidates for additional surgery or
radiation.

Secondary objectives

1. To determine the duration of response to SOM230

2. To establish the 6-month progression-free survival rate

3. To establish the median PFS and overall survival (OS)

4. To determine the clinical benefit rate (CR + PR + stable disease) of SOM230

5. To characterize the safety and tolerability of SOM230

Exploratory objectives

1. To determine the pharmacokinetic profile of SOM230

2. To analyze the expression of somatostatin receptor subtypes in tumor specimens (by
immunohistochemistry) and in study participants (by octreotide scan). Please refer to
sections 7.7.2 and 7.5.4.5 of the full protocol.

3. To measure serum IGF levels in patients prior to and after receiving SOM230

4. To determine the ORR for Grade 1 versus Grade 2 /3 meningiomas

SOM230 will be administered to all patients at a dose of 1200 µg given subcutaneously twice
daily (Figure). One treatment cycle will be defined as four weeks of therapy. Complete
blood counts will be obtained, and neurologic examinations and contrast-enhanced cranial MRI
scans will be performed as described below (see Table 7-1). Serum IGF levels will be
measured at the start of treatment, and at each MRI assessment point. Plasma
pharmacokinetic studies will be performed in the subset of patients who consent to this
additional study procedure. Participation in the pharmacokinetic component of this study is
not mandatory.

All patients will continue to receive SOM230 until disease progression or death occurs,
unacceptable toxicity is reported, or the patient declines further therapy.

In patients with stable (clinically unchanged or improved and radiographic disease increase
or decrease in tumor size by less than 25%) or responding disease (clinically unchanged or
improved and radiographic disease decrease in size by 50% or more), three additional cycles
of SOM230 will be adminis¬tered, following which patients will be reassessed.

Post-Treatment Evaluation, Study Completion, and Survival Phase Study evaluation and
determination of response status will be performed every 3 treatment cycles for the first 12
cycles of therapy and every 6 cycles thereafter for the duration of SOM230 treatment. At
the time of the final primary analysis, all patients who are continuing to receive treatment
with SOM230, as well as those who are being followed for post-treatment evaluations, and
those who are being followed for survival only will complete the core phase of the study and
will transition to the extension phase. During the extension phase, data on response
duration, PFS and safety will continue to be collected.

Study completion will be declared following documentation of objective tumor progression by
Macdonald and Levin criteria (either while on-treatment or during post-treatment
evaluations) or at the time of death.

It is critical that objective tumor progression by Macdonald and Levin criteria be
documented for each patient. In the event of treatment discontinuation prior to objective
disease progression, patients will remain eligible for ongoing post-treatment evaluations.
All antineoplastic therapies administered during the post-treatment phase will also be
recorded as part of the post-treatment evaluation phase.