Docetaxel, Prednisone, and Pasireotide in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose (MTD) level of SOM 230 (pasireotide) in
combination with docetaxel and prednisone.

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability of the combination in metastatic
castration-resistant prostate cancer (CRPC).

II. To evaluate preliminary efficacy of the combination of SOM 230 and docetaxel and
prednisone as defined by response rates (measurable and prostate-specific antigen [PSA]),
time to progression (TTP) and overall survival (OS).

III. To evaluate the pharmacokinetics (PK) of the combination. IV. To assess the
pharmacodynamic (PD) effects of the combination as seen by baseline levels of and changes in
insulin-like growth factor (IGF)-1, serum chromogranin A (SCA), and neuron specific enolase
(NSE), and to associate them with TTP and OS.

V. To assess the pretherapy circulating tumor cell (CTC) counts and change in CTC after
therapy, and to associate them with TTP and OS.

OUTLINE: This is a phase I dose-escalation study of pasireotide followed by a phase II
study.

Patients receive pasireotide intramuscularly (IM) on day 1, docetaxel intravenously (IV)
over 1 hour, and prednisone orally (PO) twice daily (BID) continuously. Courses with
docetaxel repeat every 21 days and courses with pasireotide repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 28 days and then every 3
months thereafter.

Inclusion Criteria:

- Histologically confirmed prostate adenocarcinoma with metastasis, and objective
progression or rising PSA despite androgen deprivation therapy and antiandrogen
withdrawal when applicable; patients with rising PSA must demonstrate a rising trend
with 2 successive elevations at a minimum interval of 1 week; a minimum PSA of 5
ng/ml or new areas of bony metastases on bone scan are required for patients with no
measurable disease; no minimum PSA requirement for patients with measurable disease

- Patient must not have received any prior chemotherapy for metastatic disease; all
patients must be documented to be castrate with a testosterone level < 0.5 ng/ml;
luteinizing hormone-releasing hormone (LHRH) agonist therapy must be continued, if
required to maintain castrate levels of testosterone; patients must be off
antiandrogens for a minimum of 4 weeks for flutamide and 6 weeks for bicalutamide or
nilutamide

- Minimum of four weeks since any major surgery, completion of radiation, or completion
of all prior systemic anticancer therapy (adequately recovered from the acute
toxicities of any prior therapy)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Life expectancy 12 weeks or more

- Absolute neutrophil (ANC) >= 1.5 x 10^9/L

- Platelets >= 100 x 10^9/L

- Hemoglobin (Hgb) > 9 g/dL

- Serum bilirubin =< 2 x upper limit of normal (ULN)

- Serum transaminases activity =< 3 x ULN, with the exception of serum transaminases (<
5 x ULN) if the patient has liver metastases

- Serum creatinine =< 1.5 x ULN

- Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =<
2.5 x ULN; NOTE: in case one or both of these thresholds are exceeded, the patient
can only be included after initiation of appropriate lipid lowering medication

- Patients must be advised of the importance of using effective birth control measures
during the course of the study

- Signed informed consent to participate in the study must be obtained from patients
after they have been fully informed of the nature and potential risks by the
investigator (or his/her designee) with the aid of written information

Exclusion Criteria:

- Prior treatment with any cytotoxic chemotherapy, radiation, immunotherapy, or any
investigational drug within the preceding 4 weeks

- Patients who have undergone major surgery within 4 weeks prior to study enrollment

- Chronic treatment with immunosuppressive agents except steroids

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

- Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases

- Patients with prior or concurrent malignancy except for the following: adequately
treated basal cell or squamous cell skin cancer, or other adequately treated in situ
cancer, or any other cancer from which the patient has been disease free for five
years

- Patients with uncontrolled diabetes mellitus, which is defined as a hemoglobin A1C >
8% on therapy or > 7% without therapy, or a fasting plasma glucose > 1.5 ULN; Note:
at the principle investigator's discretion, non-eligible patients can be re-screened
after adequate medical therapy has been instituted

- Patients with symptomatic cholelithiasis

- Patients who have congestive heart failure (New York Heart Association [NYHA] Class
III or IV), unstable angina, sustained ventricular tachycardia, ventricular
fibrillation, clinically significant bradycardia, advanced heart block or a history
of acute myocardial infarction within the six months preceding enrollment

- QT-related exclusion criteria:

- Patients with baseline QTc > or = 470 msec

- History of syncope or family history of idiopathic sudden death

- Sustained or clinically significant cardiac arrhythmias

- Patients with risk factors for Torsades de Pointes such as hypokalemia,
hypomagnesemia, cardiac failure, clinically significant/symptomatic bradycardia, or
high-grade AV block

- Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by
diabetes or Parkinson's disease), human immunodeficiency virus (HIV), cirrhosis,
uncontrolled hypothyroidism or cardiac failure

- Concomitant medication(s) known to prolong the QT interval

- Patients with the presence of active or suspected acute or chronic uncontrolled
infection or with a history of immunocompromise, including a positive HIV test result
(enzyme-linked immunosorbent assay [ELISA] and Western blot)

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

- Severely impaired lung function

- Any active (acute or chronic) or uncontrolled infection/ disorders

- Nonmalignant medical illnesses that are uncontrolled or whose control may be
jeopardized by the treatment with the study therapy

- Known hypersensitivity to somatostatin analogues or any component of the pasireotide
or octreotide long-acting release (LAR) formulations

- History of noncompliance to medical regimens

- Patients unwilling to or unable to comply with the protocol

- Men and any female partners of child-bearing potential must agree to use adequate
contraception (hormonal or barrier method of birth control) prior to study entry and
for the duration of study participation and for additional 2 months after finishing
therapy; should a patient's sexual partner become pregnant or suspect she is pregnant
while patient is participating in this study, he should inform the treating physician
immediately