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

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of pasireotide and to see how well it works when given together with docetaxel and prednisone in treating patients with metastatic hormone-resistant prostate cancer. Drugs used in chemotherapy, such as docetaxel and prednisone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pasireotide may inhibit the secretion of hormones. Giving pasireotide together with docetaxel and prednisone may kill more tumor cells.

Detailed Description
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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.

Official Title
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Phase I/II Trial to Establish the Safety and Preliminary Efficacy of the Combination of Docetaxel, Prednisone, and SOM 230 (Pasireotide) in Metastatic Castrate Resistant Prostate Cancer (CRPC).

Conditions
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Adenocarcinoma of the Prostate, Hormone-resistant Prostate Cancer, Recurrent Prostate Cancer, Stage IV Prostate Cancer

Intervention / Treatment
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* Drug: docetaxel
* Drug: pasireotide
* Drug: prednisone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy, receptor agonist)<br>Patients receive pasireotide IM, 40 mg on day 1, docetaxel 75mg/m2 IV over 1 hour, and prednisone 5mg PO 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. | Drug: docetaxel<br>* Given IV<br>* Other names: TXT;Drug: pasireotide<br>* Given IM<br>* Other names: SOM230;Drug: prednisone<br>* Given PO<br>* Other names: Deltra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Pasireotide in Combination With Docetaxel and Prednisone by the Occurrence of Adverse Events and the Associated Grade Per NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | To identify the maximum tolerated dose (MTD) of pasireotide, The occurrence rate of binary endpoints (eg, specific types of toxicity at a certain dose level and severity grade, response, etc) will be described by point estimates and exact 90% confidence intervals (CIs) for proportions using Wilson's method. | Up to day 57 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Patients With Toxicity as Assessed Via NCI CTCAE Version 4.0 | The count of patients who experience a given type and grade of toxicity as assessed via NCI CTCAE version 4.0 | On days 1, 8, 15, 22, 29, 36 43, 50 and 57 | 
| Measurements of Tumor Using Response Evaluation Criteria In Solid Tumors (RECIST) Criteria Before and After Treatment With the Combination of Pasireotide in Combination With Docetaxel | Percentage of participants responding to treatment by measurements of tumor using Response Evaluation Criteria In Solid Tumors (RECISTv1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR, before and after treatment with the combination of pasireotide in combination with docetaxel | Every 12 weeks for the first 36 weeks and then every 16 weeks thereafter up to 100 weeks | 
| Percentage Prostate-specific Antigen (PSA) Change Noted | Percentage change of prostate-specific antigen (PSA) decline or increase noted | On days 1, 22, 43 | 
| Time to Progression (TTP) | Time from Treatment start date to Progression (TTP) Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | Every 3 months for the first 9 months on study then every 4 months after the first 9 months on study, up to 2 years | 
| Overall Survival (OS) | Time from Treatment start date to date of death or last follow-up. | Every 3 months for the first 9 months on study then every 4 months after the first 9 months on study | 
| Pharmacokinetics (PK) of SOM230 | Pharmacokinetics (PK) of SOM230 measured in the bloodstream (in ng/ml) at days 29, 57, and 85. | Predosing/end of infusion/2, 3, 4 ,7, 24 and 48 hours after start of docetaxel; Day 43; predosing for docetaxel and pasireotide/end of infusion/2, 3, 4, 7, 24 hours day 44/48 hours day 45 after start of infusion; days 29, 57, and 85 prior to pasireotide | 
| Measurement of Levels of IGF-1, Serum Chromogranin A (SCA), and Neuron Specific Enolase (NSE), the Change Between Time Points Pre-therapy, Post-therapy | Measurement of levels of IGF-1, serum chromogranin A (SCA), and neuron specific enolase (NSE), the change between time points (day 22 and day 43) from day 1 as measured in percent change. | Baseline and days 22 and 43 | 
| Measurements of CTC Counts, the Change Between Time-points Pre-therapy, Post-therapy | Measurements of CTC counts, the change between time-points (day 22 and day 43) from day 1 as measured in percent change. | Baseline and days 22 and 43 |