Pasireotide (SOM230) With or Without Everolimus in Treating Patients With Hormone Resistant, Chemotherapy Naive Prostate Cancer

An Open Label Randomized Phase II Study of SOM230 and Everolimus in Castrate-Resistant, Chemotherapy-Naïve Prostate Cancer Patients

This is an open label randomized phase II study for prostate cancer patients who have disease progression after hormonal therapy. SOM230 LAR (Pasireotide) binds to its receptor of prostate cancer cells and can prevent them from growing. Everolimus works by targeting a cell survival factor in prostate cancer. The combination of these drugs may work better for the treatment of prostate cancer without toxic chemotherapy. Patients will receive either SOM230 LAR (group A) or SOM230 LAR in combination with Everolimus (group B).

Prostate cancer cells typically have neuroendocrine (NE) differentiation features after they become resistant to hormonal therapy. Somatostatin (SST - a peptide hormone) receptors (SSTR) are usually expressed in a high level in these advanced prostate cancer cells. When SSTR is activated pharmacologically by drugs similar to SST, prostate cancer cell growth is inhibited. SOM230 is a new agent which can activate SSTR and block other key survival molecules/pathways such as phosphatidylinositol 3-kinases (PI3K), mitogen-activated protein (MAP) kinases (MAPK) signaling pathways. Thus SOM230 itself has anticancer activity for prostate cancer.

It is also well known that hormonal refractory prostate cancer can grow in an environment of very low male hormone level because of the activation of several non-androgen receptor survival pathways. One key survival pathway is mediated by an important molecule called mammalian target of rapamycin (mTOR). Drugs, such as Everolimus, have anticancer activity in prostate cancer pre-clinically, but do not sustain its activity. The reason was that cancer cells can up-regulate other survival pathways such as PI3K, MAPK, thus bypass mTOR.

It is hypothesized that SOM230 not only have anti-tumor effect in prostate cancer directly, but also can block the up-regulated (feed-back loop), alternative PI3K or MAPK survival pathways induced by mTOR inhibitors.

The goal of this study is to develop a new well tolerated therapy that can be offered to prostate cancer patients prior to receiving chemotherapy.

Inclusion Criteria:

• Age minimum: 18 years old
• Histological confirmation of prostatic adenocarcinoma
• PSA > or = to 2 ng/ml
• PSA progression (serially rises on two occasions each at least one week apart) OR disease progression on imaging studies (CT scan or bone scan).
• Minimally symptomatic - no symptoms attributed to prostate cancer greater than Grade I based on NCI CTCAE Version 4.0 grading of toxicities
• Discontinuation of all antiandrogen, ketoconazole and investigational drugs for at least 4 weeks (6 weeks for bicalutamide) prior to study initiation
• Maintain castrate levels of testosterone (<50ng/dL)
• Karnofsky Performance Status > or = to 60%
• Life expectancy > 3 months
• Adequate hematologic, renal, and liver function

Exclusion Criteria:

• Currently active second malignancy other than non-melanoma skin cancers.
• Clinically significant cardiovascular disease: EF < 30%, NHYA Class III or greater congestive heart failure, myocardial infarction/unstable angina within 6 months prior to study enrollment, or significant ECG abnormalities such as QRS/QT prolongation (see Section 5.3).
• Progressive pulmonary disease, such as advanced COPD, pulmonary fibrosis, or supplemental O2 requirement.
• Known CNS disease, except for treated brain metastases.
• Poorly controlled diabetes mellitus (HbA1c > 7 %) or fasting blood glucose level >126 mg/dL in non-diabetic patients or > 189 mg/dL in diabetic patients (can be enrolled after initiation or titration of anti-diabetic agent(s)).
• Poorly controlled hypercholesterolemia (fasting serum cholesterol >300 mg/dL) or hypertriglyceridemia (> 2.5 x ULN). Patients above either threshold can be included after initiation of appropriate lipid lowering medication.
• Current use of chronic steroids (equivalent of 20mg prednisone daily). Inhaled steroids are acceptable.
• Active gallbladder disease or hepatitis (AST or ALT > 2.0, or bilirubin > 1.5x ULN), liver cirrhosis, or severe liver impairment (Child-Pugh class C). It is highly recommended that patients positive for HBV-DNA or HBsAg are treated prophylactically with an antiviral for 1-2 weeks prior to receiving study drug.
• Serum creatinine >1.5 upper limit of normal or on dialysis.
• Prior use of a somatostatin analog or mTOR inhibitor for the treatment of PC.