Saracatinib in Treating Patients With Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
This randomized phase II clinical trial is studying how well saracatinib works in treating patients with prostate cancer. Saracatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Determine if AZD0530 (saracatinib) increases time to radiographic progression in men with CRPC compared to placebo. SECONDARY OBJECTIVES: I. Describe the adverse events related to AZD0530 in this population. II. Explore the role of FYN and other SRC kinase expression as a predictor of response to AZD0530. OUTLINE: This is a multicenter study. LEAD-IN PHASE: Patients receive oral saracatinib once daily during for 8 weeks. Patients who achieve disease regression or a PSA decrease of > 50% continue to receive open-label saracatinib. Patients who do not show radiographic evidence of new metastases on bone scan and CT, disease regression, or a > 50% decrease in PSA continue on to the randomized phase. RANDOMIZED PHASE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive oral saracatinib once daily on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive oral placebo once daily on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Upon progression, patients may crossover to arm I. Tissue samples may be collected for correlative studies. After completion of study treatment, patients are followed up for 12 months.

Official Title
-----------------
A Randomized Discontinuation Phase 2 Study of AZD0530 as a Metastasis Inhibitor in Castrate Resistant Prostate Cancer

Conditions
-----------------
Hormone-resistant Prostate Cancer, Recurrent Prostate Cancer, Stage IV Prostate Cancer

Intervention / Treatment
-----------------
* Drug: saracatinib
* Other: hydrocortisone/placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed prostate cancer with progressive disease; progressive disease may be defined as either New clinical or radiographic metastases Rising PSA: PSA must be greater than 1.0 ng/mL with at least 2 consecutive rises after completion of prior therapy; the PSA values documenting these rises should be separated by no less than 10 days; the baseline PSA value may be taken from the end of prior therapy Previous treatment with docetaxel for disease progression following hormonal therapy (i.e., castrate-resistant disease) required Treatment in the adjuvant or neoadjuvant setting will NOT be grounds for inclusion unless docetaxel has been used again in the setting of progressive CRPC ECOG performance status 0-1 ANC ≥ 1,500/mm³ Hemoglobin > 9.0 g/dL Platelet count > 100,000/mm³ Total bilirubin < 2.0 x institutional ULN AST/ALT < 5 x institutional ULN in the presence of bone/liver metastases Serum creatinine (Cr) within ULN Patients with Cr > ULN must have a Cr clearance of > 60 mL/min Testosterone 50 ng/mL or lower if a patient is receiving an LHRH agonist No testosterone testing is required for men who have undergone surgical orchiectomy Fertile patients must agree to abstinence or some adequate form of contraception No patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs the ability to swallow AZD0530 tablets No history of uncontrolled or unstable cardiac dysrhythmia No resting ECG with measurable QTc interval of > 480 msec at 2 or more time points within a 24-hour period No evidence of interstitial lung disease (bilateral, diffuse, parenchymal lung disease) A high-resolution CT of the chest will be required during screening No evidence of severe or uncontrolled systemic conditions (e.g., severe hepatic impairment) or current unstable or uncompensated respiratory or cardiac conditions which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol No patients with a known immunodeficiency syndrome No patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD0530 No patients receiving any other investigational agents Previous AZD0530 exposure is allowed provided that the patient did not show radiographic progression during treatment Patients receiving non-steroidal anti-androgens (e.g., flutamide) or other hormonal treatment (such as ketoconazole, abiraterone, or TAK-700) must have stopped these drugs at least 28 days prior to enrollment for flutamide or ketoconazole, or at least 42 days prior to enrollment for bicalutamide or nilutamide, and the patients must have demonstrated progression of disease since the agents were suspended Patients should be at least 2 weeks away from previous chemotherapy, surgery, or radiotherapy No unresolved toxicity from previous treatments that are CTCAE grade 2 from previous anti-cancer therapy (except alopecia) Patients who are currently on zoledronic acid (Zometa) or other bisphosphonate therapy are eligible provided that they have been on therapy at least 6 weeks prior to participation Increases in bisphosphonate dosing will not be allowed (i.e., starting within 6 weeks or changing from every 3-month to every 1-month dosing) Use of specifically prohibited CYP3A4-active agents or substances are not permitted during protocol treatment, and patients who must continue treatment with these agents are not eligible Prohibited drugs should be discontinued 7 days prior to the administration of the first dose of AZD0530 and for 7 days following discontinuation of AZD0530 (unless otherwise specified) No concurrent use of non-FDA approved medications
Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (saracatinib)<br>Patients receive oral saracatinib once daily on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. | Drug: saracatinib<br>* Given orally<br>* Other names: AZD0530;|
| Placebo Comparator: Arm II (placebo)<br>Patients receive oral placebo once daily on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Upon progression, patients may crossover to arm I. | Other: hydrocortisone/placebo<br>* Given orally<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Stable Disease. (Time to Disease Progression by CT and/or Bone Scan or Clinical Progression.) | Time to progression will be assessed using the Kaplan-Meier method and compared between groups via Wilcoxon rank-sum test. | Up to 6 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity and Incidence of Adverse Events | Percentage of patients with grade 4 toxicity. | Up to 6 months. | 
| Toxicity and Incidence of Adverse Events. | Percentage of patients who discontinued therapy due to toxicity. | Up to 6 months. | 
| Correlation of Molecular Profile With Clinical Outcomes | Study terminated after randomization of only 8 subjects. Correlative data not analyzed. | Up to 2 years |