Orteronel in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well orteronel works in treating patients with metastatic hormone-resistant prostate cancer. Orteronel may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the relationship between circulating tumor cell (CTC)-based androgen receptor (AR) expression level and >=-50% prostate-specific antigen (PSA) decline following 12 weeks of therapy with TAK-700 (orteronel). SECONDARY OBJECTIVES: I. To assess changes in PSA and CTC levels and time to PSA progression (best response, decline at 12 weeks as continuous variable, etc.) with or without prior docetaxel-based treatment. II. To assess measurable disease response and time to radiographic disease progression for castration-resistant prostate cancer (CRPC) with or without prior docetaxel-based treatment. III. To explore relationships between endocrine and clinical responses. IV. To confirm the safety of TAK-700 administered without prednisone in patients with metastatic CRPC. OUTLINE: Patients receive orteronel orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Official Title
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Phase 2 Trial of TAK-700 (Also Known as Orteronel) Without Prednisone for Metastatic Castration-Resistant Prostate Cancer

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: orteronel
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed adenocarcinoma of the prostate Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care Patients, even if surgically sterilized (i.e., status post vasectomy), who agree to practice effective barrier contraception during the entire study treatment period and for 4 months after the last dose of study drug, or Agree to completely abstain from intercourse Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be =< 2.5 x the upper limit of normal (ULN) Total bilirubin =< 1.5 x ULN Estimated creatinine clearance using the Cockcroft-Gault formula must be > 40 mL/minute Absolute neutrophil count (ANC) >= 1500 cells/microliter Platelet count >= 100,000 cells/microliter Testosterone < 50 ng/dL Screening calculated ejection fraction of >= 50% by multiple gated acquisition (MUGA) scan or echocardiogram; metastatic progression on primary androgen-deprivation therapy (medical or surgical castration) Progression requiring a change in oncologic therapy defined by any of the following: Radiographic progression: appearance or increase in measurable lesions on cross-sectional imaging or appearance of one or more new lesions on bone scan * Rising PSA (>= 2 ng/ml) which has risen on two occasions >= 1 week apart Clinical progression evidenced by increased pain or other cancer-related symptoms Patients should have recovered from prior oncologic therapies to a Common Terminology Criteria (CTC) grade =< 1 except stable neuropathy or alopecia at National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade =< 2; if rapid clinical progression is documented by imaging, changes in PSA, or symptoms, then study treatment can begin >= 2 weeks from prior therapy; otherwise, the following time periods between prior anti-cancer therapies and study treatment day 1 will apply: >= 3 weeks for prior cytotoxic therapies >= 4 weeks for flutamide or nilutamide >= 6 weeks for bicalutamide >= 6 weeks since bone targeted radiopharmaceutical (e.g. samarium-153, radium-223) Gonadotropin-releasing hormone (GnRH) agonists (leuprolide acetate, goserelin, etc.) or antagonists (degarelix, etc.) should be continued in patients without surgically-induced castrate androgen levels For chemotherapy naïve castration-resistant prostate cancer who are moderately symptomatic or who have hepatic metastasis: subjects must not be a candidate for docetaxel-based chemotherapy. Exclusion Criteria: History of myocardial infarction, unstable symptomatic ischemic heart disease, ongoing arrhythmias of grade > 2 (NCI CTCAE, version 4), thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (e.g. pericardial effusion, restrictive cardiomyopathy) within 6 months prior to first dose of study drug; chronic stable atrial fibrillation on stable anticoagulant therapy is allowed New York Heart Association class III or IV heart failure Electrocardiogram (ECG) abnormalities of: Q-wave infarction, unless identified 6 or more months prior to screening Corrected QT (QTc) interval > 460 msec Patient has received other investigational drugs within 28 days before enrollment Diagnosed or treated for another malignancy within 2 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy Known hypersensitivity to compounds related to TAK-700 or to TAK-700 excipients Uncontrolled hypertension despite appropriate medical therapy (blood pressure [BP] of greater than 160 mmHg systolic and 90 mmHg diastolic at 2 separate measurements no more than 60 minutes apart during the screening visit); Note: patients may be rescreened after adjustment of antihypertensive medications Known active chronic hepatitis B or C, life-threatening illness unrelated to cancer, or any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with participation in this study Likely inability to comply with the protocol or cooperate fully with the investigator and site personnel Known gastrointestinal (GI) disease or GI procedure that could interfere with the GI absorption or tolerance of TAK-700, including difficulty swallowing tablets Prior treatment with >= 3 lines of cytotoxic chemotherapy for metastatic prostate cancer Prior treatment with TAK-700

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 (orteronel)<br>Patients receive orteronel 300 mg PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: orteronel<br>* Given PO<br>* Other names: TAK-700;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Androgen Receptor (AR) Protein Expression Levels in CTCs | The two-sample t-test will be used. Once association between AR protein expression levels and response is established, graphical methods such as receiver-operator curves (ROC) or more quantitative methods such as the maximal chi-square method to determine whether there might be a cut-point with either great sensitivity or great specificity (or both) for identifying a cohort with either a high or low likelihood of prostate-specific antigen (PSA) response. | Up to 4 weeks | 
| PSA Response, Defined as Occurrence of PSA Decline to Greater Than or Equal to 50% From Baseline | Standard descriptive methods will be used to summarize PSA. Values will be tabulated as outlined in the Prostate Cancer Working Group 2 (PCWG2) criteria and presented as Kaplan-Meier survival curves, as appropriate. | At 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best PSA Response | Values will be tabulated as outlined in the PCWG2 criteria and presented as Kaplan-Meier survival curves, as appropriate. | Up to 24 weeks | 
| Absolute Change in PSA | Values will be tabulated as outlined in the PCWG2 criteria and presented as Kaplan-Meier survival curves, as appropriate. | Baseline to 24 weeks | 
| Overall Response Rate Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and PCWG2 Criteria | Response will be tabulated descriptively with 95% confidence intervals (CIs) and Kaplan-Meier survival curves, as appropriate. | Up to 3 years | 
| Duration of Response Using RECIST Version 1.1 and PCWG2 Criteria | Response will be tabulated descriptively with 95% CIs and Kaplan-Meier survival curves, as appropriate. | Up to 3 years | 
| Number of Participants With Grade 3 or Higher Toxicity | Summary of grade 3 (per Common Terminology Criteria for Adverse Events (CTCAE v4.0) or higher toxicities which generally is described as a severe reaction or symptom. | 30 days |