Castrate Resistant Prostate Cancer, Chemotherapy Naive Prostate Cancer, Prostate Cancer
Conditions
Keywords
Castrate Resistant, Chemotherapy Naive, Prostate Cancer, SOM230, Everolimus
Brief summary
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).
Detailed description
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.
Interventions
DRUGPasireotide
Given IM
DRUGEverolimus
Given PO
OTHERLaboratory biomarker analysis
Correlative studies
Sponsors
Novartis Pharmaceuticals
Sidney Kimmel Cancer Center at Thomas Jefferson University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Alive and Progression Free After 12 Weeks of Treatment | 12 weeks after treatment | Progression of disease is defined as disease progression by RECIST 1.1 criteria on CT scan (X-ray computed tomography), or appearance of \> 2 new bone lesions on bone scan, or prostate-specific antigen (PSA) progression by Prostate Cancer Clinical Trials Working Group (PCWG2) criteria or death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With > 50% Decline From Baseline PSA Level | After 12 weeks of treatment | — |
| Number of Participants Without New Bone Lesions After 12 Weeks of Treatment | After 12 weeks of treatment | — |
| Number of Participants With Progression Free Survival (PFS) Based on RECIST 1.1 Criteria | Assessed up to 30 days after completion of study treatment | Progression free survival (PFS) based on primary outcome criteria for disease progression. Patients without radiographic disease progression who permanently discontinue the study drugs will be censored |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort A (Pasireotide) Patients receive pasireotide IM once every 4 weeks
Pasireotide: Given IM
Laboratory biomarker analysis: Correlative studies | 4 |
| Cohort B (Pasireotide and Everolimus) Patients receive pasireotide as in cohort A and everolimus PO QD
Pasireotide: Given IM
Everolimus: Given PO
Laboratory biomarker analysis: Correlative studies | 2 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Disease progression | 1 | 0 |
| Overall Study | Rising PSA | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Cohort A (Pasireotide) | Cohort B (Pasireotide and Everolimus) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 1 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Continuous | 78.0 years STANDARD_DEVIATION 4.6 | 69.4 years STANDARD_DEVIATION 8.4 | 75.2 years STANDARD_DEVIATION 6.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 2 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 2 Participants | 4 Participants |
| Region of Enrollment United States | 4 participants | 2 participants | 6 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 2 / 2 |
| serious Total, serious adverse events | 1 / 4 | 0 / 2 |
Outcome results
Primary
Number of Participants Alive and Progression Free After 12 Weeks of Treatment
Progression of disease is defined as disease progression by RECIST 1.1 criteria on CT scan (X-ray computed tomography), or appearance of \> 2 new bone lesions on bone scan, or prostate-specific antigen (PSA) progression by Prostate Cancer Clinical Trials Working Group (PCWG2) criteria or death from any cause.
Time frame: 12 weeks after treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A (Pasireotide) | Number of Participants Alive and Progression Free After 12 Weeks of Treatment | 0 participants |
| Cohort B (Pasireotide and Everolimus) | Number of Participants Alive and Progression Free After 12 Weeks of Treatment | 0 participants |
Secondary
Number of Participants With > 50% Decline From Baseline PSA Level
Time frame: After 12 weeks of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A (Pasireotide) | Number of Participants With > 50% Decline From Baseline PSA Level | 2 participants |
| Cohort B (Pasireotide and Everolimus) | Number of Participants With > 50% Decline From Baseline PSA Level | 0 participants |
Secondary
Number of Participants Without New Bone Lesions After 12 Weeks of Treatment
Time frame: After 12 weeks of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A (Pasireotide) | Number of Participants Without New Bone Lesions After 12 Weeks of Treatment | 0 participants |
| Cohort B (Pasireotide and Everolimus) | Number of Participants Without New Bone Lesions After 12 Weeks of Treatment | 0 participants |
Secondary
Number of Participants With Progression Free Survival (PFS) Based on RECIST 1.1 Criteria
Progression free survival (PFS) based on primary outcome criteria for disease progression. Patients without radiographic disease progression who permanently discontinue the study drugs will be censored
Time frame: Assessed up to 30 days after completion of study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A (Pasireotide) | Number of Participants With Progression Free Survival (PFS) Based on RECIST 1.1 Criteria | 0 participants |
| Cohort B (Pasireotide and Everolimus) | Number of Participants With Progression Free Survival (PFS) Based on RECIST 1.1 Criteria | 0 participants |