Study Combining Imatinib Mesylate (Gleevec) With Sorafenib in Patients With Androgen-independent Prostate Cancer (AIPC)

Study Overview
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Brief Summary
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Eligible patients will be enrolled in one of 4 cohorts where each cohort will allow 3 patients to be on study. Patients will receive both study drugs on escalated dosing schedule until the maximum of 400 mg PO BID is reached for both drugs or toxicity is established. Once the pre-specified 400 mg by mouth two times a day (PO BID) dosing for both drugs is reached without toxicity, the study will close for accrual. If toxicity is noted prior to reaching the 400 mg PO BID dosing, then the dosing schedule that is deemed safest as per study design will be the one used for any future phase II study.

Detailed Description
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Gleevec and Sorafenib have modest efficacy in androgen-independent prostate cancer (AIPC) and the fact that both agents can be given orally with what appears to be tolerable side effects, we hypothesize that combining both agents may provide patients with another effective regimen in a disease where therapeutic options are limited. This study is designed to investigate the safety of combining Gleevec and Sorafenib as well as feasibility in AIPC patients who have failed one or more lines of systemic chemotherapy. Once safety is established, a follow-up phase II study will commence to investigate efficacy.

Official Title
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Phase I Study Investigating the Safety and Feasibility of Combining Imatinib Mesylate (Gleevec) With Sorafenib in Patients With Androgen-Independent Chemotherapy-Failure Prostate Cancer.

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Gleevec + Sorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 18 years of age or older. Histologically documented diagnosis of Prostate Cancer regardless of Gleason score. Androgen-Independent Prostate Cancer At least one measurable site of disease Patients must have failed one or more lines of systemic chemotherapy, regardless of the chemotherapeutic agent used. There is NO limit to how many lines of chemotherapy a patient can receive Patients receiving anti-coagulation treatment with an agent such as heparin may be allowed to participate. Patients on Warfarin are NOT allowed to participate. Last chemotherapy exposure 4 weeks prior to study entry Prior exposure to Sorafenib is allowed as long as last Sorafenib dose was 3 weeks or more from study entry Prior exposure to Gleevec is an EXCLUSION Progression after chemotherapy can be demonstrated radiographically (as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria) or biochemically with prostate-specific antigen (PSA) being elevated more than 25% than previous value as long as a repeat PSA confirms progression. (repeat PSA should be done within 3 weeks from the last one). Patients with bone-only disease are considered progressing if there are two more lesions on a new bone scan. Performance status 0,1, 2 (ECOG) Adequate end organ function, defined as the following: total bilirubin < 1.5 x Upper Limit of Normal (ULN), serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) < 2.5 x Upper Limit of Normal (UNL), creatinine < 1.5 x Upper Limit of Normal (ULN), absolute neutrophil count (ANC) > 1.0 x 109/L, platelets > 75 x 109/L. Men of childbearing potential must agree to employ an effective barrier method of birth control prior to the study entry, throughout the duration of the study and for up to 3 months following discontinuation of study drug. Written, voluntary informed consent. Patients are allowed the following concurrent therapies: Intravenous bisphosphonates if administered for bone metastases luteinizing hormone releasing hormone (LHRH) analogues Narcotic-type medical interventions to control malignancy-related pain Exclusion Criteria: Patient has received any other investigational agents within 21 days of first day of study drug dosing, unless the disease is rapidly progressing. Patient is < 3 years free of another primary malignancy except: if the other primary malignancy is not currently clinically significant nor requiring active intervention, or if other primary malignancy is a basal or squamous cell skin cancer. Existence of any other malignant disease is not allowed. Patient with Grade III/IV cardiac problems Patient has a severe and/or uncontrolled medical disease Patient has a known brain metastasis. Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management. Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months. Pulmonary hemorrhage/bleeding event > Common Toxicity Criteria for Adverse Effects (CTCAE) Grade 2 within 4 weeks of first dose of study drug. Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of study drug. Serious non-healing wound, ulcer, or bone fracture. Use of St. John's Wort or rifampin (rifampicin). Any condition that impairs patient's ability to swallow whole pills. Patient has known chronic liver disease (i.e., chronic active hepatitis, and cirrhosis). Patient has a known diagnosis of human immunodeficiency virus (HIV) infection. Patient previously received radiotherapy to ³ 25 % of the bone marrow Patient had a major surgery within 2 weeks prior to study entry. Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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: Arm 1<br>Only 1 arm for the study - this arm gets both drugs, gleevec and sorafenib | Drug: Gleevec + Sorafenib<br>* 400 mg Sorafenib every day (QD) 300mg Gleevec QD<br>* Other names: Imatinib mesylate; Nexavar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Experiencing Dose Limiting Toxicities (DLT's) | Eligible patients were enrolled in one of 4 cohorts, where each cohort allowed 3 evaluable patients to be on study, patients withdrawn from treatment for reasons other than toxicity were not considered evaluable. If one of the three evaluable patients experienced a dose limiting toxicity (DLT) the cohort was expanded to 6 evaluable patients. Patients will receive both study drugs on escalated dosing schedule until the maximum of 400 mg PO BID is reached for both drugs or toxicity is established. If 2 out of six evaluable patients experience a dose limiting toxicity this would show that the Maximum Tolerated Dose (MTD) was the dose from the prior cohort. | up to 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Clinical Benefit | Overall Clinical Benefit was measured as the sum of complete response (CR), partial response (PR), and stable disease (SD). | up to 20 weeks | 
| Time to Disease Progression (TTP) | Medium TTP is 2 months (range 1-5). 10 patients were evaluable for disease progression for these patients occurred between 1-5 months after starting the study. The TTP was calculated per protocol. For radiographic assessment Response Evaluation Criteria in Solid Tumors (RECIST) was used. Complete response = disappearance of all lesions. Partial response (PR)=30% or greater decrease in sum of longest diameter of measureable lesions SD. Lesions have no sufficient decrease for progressive disease and no sufficient increase to meet Progressive Disease (PD). PD more than 20% increase in sum of longest diameter of measurable lesions or 2 or more new bone mets. prostate-specific antigen (PSA) assessment for patients with measurable disease, PSA progression in the absence of measurable disease progression will not be considered progressive disease. | up to 5 cycles, an average of 20 weeks, from the day of first treatment until the date of the last dose of study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AIPC, Prostate cancer, prostate