IGF-1 Inhibitor Pasireotide Lar in Combination With the m-TOR Inhibitor Everolimus

Multiple myeloma (MM) is a B-cell malignancy of plasma cells. It represents the second most
common hematological malignancy, with non-Hodgkin's lymphoma being the most common.In this
protocol, we propose a regimen consisting of a novel combination of two agents with a
promising preclinical activity, i.e., pasireotide (IGF-1 inhibitor) and everolimus (mTOR
inhibitor), exploring the efficacy of this therapy in patients with MM. We propose
enrollment after failure to the first two lines of FDA-approved agents, even in patients who
did not have high-dose chemotherapy and SCT. In fact, overall survival after SCT has been
shown to be identical when "early" SCT is compared to "late" SCT, i.e., administered at the
time of relapse. This provides an important opportunity to test our novel therapeutic
approach, reserving SCT for relapse. The advantage of the this strategy is that similar
overall survival outcomes can be achieved with fewer patients undergoing SCT. Both
everolimus and pasireotide have the potential of being clinically effective against myeloma.
A phase II trial of the mTOR inhibitor temsirolimus, an analogue of everolimus, produced a
response rate of 38% in relapsed/refractory multiple myeloma. The IGF-1 inhibitor
pasireotide is a promising agent, because IGF has been recently found to be one of the most
important growth signal molecule in myeloma cells. The combination of everolimus and
pasireotide should have a synergistic antimyeloma effect because preclinical data invitro
have shown that combined inhibition of mTOR inhibition and IGF-1 led to a synergistic
increase of cell growth inhibition in multiple myeloma cells and might represent a potential
new treatment strategy.

Inclusion Criteria:

- Histologically documented multiple myeloma

- Multiple myeloma relapsing or refractory to at least 2 of the currently accepted
therapies for multiple myeloma

- Age > 18 years

- Minimum of 4 weeks since any major surgery, radiation or 5 half life since prior
systemic anticancer therapy

- ECOG performance status ≤ 2

- Anticipated life expectancy of 12 weeks or more

- Adequate bone marrow function

- Adequate liver function

- Calculated creatinine

- INR ≤ 1.5

- Fasting serum cholesterol ≤ 300 mg/dL or ≤ 7.75 mmol/L and fasting triglycerides ≤
2.5 x ULN

- Women of childbearing potential must have a negative serum pregnancy test. Women must
not be lactating. Both men and women of childbearing potential must be advised of
the importance of using effective birth control during the course of the study.

Exclusion Criteria:

- Patients should not receive immunization with attenuated live vaccines within one
week of study entry or during study period.

- Patients should not receive immunization with attenuated live vaccines during study
period or within 1 week of study entry.

- Patients with prior or concurrent malignancy

- Patients with uncontrolled diabetes mellitus

- Patients who have congestive heart failure, unstable angina, sustained ventricular
tachycardia, ventricular fibrillation, clinically significant bradycardia, advanced
heart block or history of acute myocardial infarction within the 6 months preceding
enrollment.

- Liver disease

- Patients who have any severe and/or uncontrolled medical condition or other
conditions that could affect their participation in the study.

- Female patients who are pregnant or breast feeding, adults of reproductive potential
who are not using effective birth control methods.

- Male patients whose sexual partner(s) are women of child bering potential and who are
not willing to use adequate contraception during the study and for 8 weeks after the
end of treatment.

- Patients with a known hypersensitivity to everolimus or other rapamycin or to its
excipients.

- Known hypersensitivity to somatostatin analogues or any component of the pasireotide
or octreotide LAR formulations

- History of noncompliance to medical regimens

- Patients unwilling to or unable to comply with the protocol

- Patients taking medication know to inhibit, induce or be a substrate to isoenzyme
CYP3A

- QTcF at screening > 450 msec, history of syncope or family history of idiopathic
sudden death, sustained or clinically significant cardiac arrhythmias, risk factors
for Torsades de pointes, concomitant disease that could prolong QT intervals, use of
concomitant medications know to prolong the QT interval.