A Phase II Study of Cabozantinib (XL184) Therapy in Castrate Resistant Prostate Cancer (CRPC) With Visceral Metastases

Study Overview
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Brief Summary
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This research study is being done to measure the clinical benefit associated with cabozantinib (XL184) in men who have prostate cancer that has spread to visceral organs (organs other than bone or lymph nodes) and no longer responds to initial hormonal (castration) therapy. This type of prostate cancer is called metastatic, castrate-resistant prostate cancer.

Detailed Description
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Cabozantinib (XL184), a multi-targeted tyrosine kinase inhibitor, has demonstrated a powerful clinical phenotype in men with metastatic castrate resistant prostate cancer (mCRPC) both before and after chemotherapy. This phenotype consists of rapid reduction in pain (when present) and improvement in bone scans that may or may not be accompanied by decrease in serum prostate specific antigen (PSA) concentrations. In previous studies of cabozantinib in advanced prostate cancer, patients with visceral disease have been excluded. Hence, this protocol creates a unique opportunity to define the activity of this disease in the population of men with visceral disease - a marker for poorer prognosis in mCRPC. Primary Objectives: - To assess the clinical benefit (complete response + partial response + stable disease) of cabozantinib in patients with mCRPC with visceral metastases. Secondary Objectives: To assess the impact of cabozantinib on numbers live circulating tumor cells (CTCs) using NanoVelcro Chips To test the feasibility of measuring variation in gene expression in circulating tumor cells (CTCs) in response to therapy. To determine if there is an impact of cabozantinib on live circulating tumor cell (CTC) number and patterns of gene expression. To measure the impact of cabozantinib on serum HGF (hepatocyte growth factor) and VEGF (vascular endothelial growth factor) levels in men with metastatic, castration-resistant prostate cancer (mCRPC). To assess the safety and tolerability of lower doses (i.e. doses below 100 mg daily) of cabozantinib in mCRPC with visceral involvement. To collect blood, urine, tissue, and plasma which may be used determine if there are germline genetic variations that correlate with toxicity. To pilot correlations between molecular content between circulating tumor cells (CTCs), large oncosomes, and tumor tissue.

Official Title
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A Phase II Study of Cabozantinib (XL184) Therapy in Castrate Resistant Prostate Cancer (CRPC) With Visceral Metastases

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Cabozantinib


Participation Criteria
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Eligibility Criteria
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KEY INCLUSION CRITERIA - mCRPC that includes visceral disease. Visceral metastatic disease is defined as solid organ infiltration that is not bone or lymph node metastases. KEY EXCLUSION CRITERIA Recent history (<6 months) of gastrointestinal hemorrhage requiring blood transfusion. Tumor involvement in the intestinal lining which the treating physician deems at risk for perforation with rapid tumor response.

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 (cabozantinib)<br>Cabozantinib 60mg orally daily until disease progression | Drug: Cabozantinib<br>* Cabozantinib 60 mg daily (oral). Subjects may continue to receive study treatment until they experience unacceptable drug-related toxicity or disease progression.<br>* Other names: XL184;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate From Cabozantinib (XL184) | Clinical benefit rate is defined as the combination of complete response, partial response, and stable disease as defined by modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by CT imaging and Prostate Cancer Working Group 2 (PCWG2) criteria. Complete response (CR) defined as disappearance of all target lesions; Partial response (PR) >=30% decrease in som of diameters of target lesions (taking as reference the baseline), and stable disease, neither sufficient shrinkage to qualify for PR nor increase to qualify for progressive disease. | Baseline to 12 weeks after starting therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Number of Circulating Tumor Cells (CTC) in Response to Cabozantinib | Change in number of CTC from baseline at 12 weeks | Baseline and 12 weeks | 
| Number of Patients With NanoVelcro Appropriate for RNA in Circulating Tumor Cells | This is to provide a measure of feasibility using NanoVelcro to measure RNA in circulating tumor cells (CTC) | 12 weeks | 
| Change in Levels of Serum Hepatocyte Growth Factor (HGF) and Vascular Endothelial Growth Factor (VEGF) Concentration | Mean change from baseline in levels of HGF and VEGF | 12 weeks | 
| Number of Participants With Grade 3/4 Adverse Events Related to Cabozantinib as Assessed Using CTCAE (v.4) | Each cycle is 28 days. Safety and tolerability was defined as related grade 3-4 AEs of doses of cabozantinib below 100 mg daily using common terminology criteria for adverse events (CTCAE) | Every 2 weeks for first 3 Cycles and every 4 weeks thereafter for an expected average of 28 weeks. | 
| Number of Patients With Evaluable Protein Content of Large Oncosomes From Baseline to First Documented Progression or Date of Death | This is a feasibility outcome to assess ability to measure protein content in large oncosomes in this population. | From baseline until the date of first documented progression or date of death from any cause, whichever comes first, assessed for an expected average of 28 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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liver metastasis, lung metastasis, metastatic castrate-resistant, prostate cancer