A Phase I/II Study of TRC105 in Metastatic Castrate Resistant Prostate Cancer (CRPC)

Study Overview
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Brief Summary
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Background: Currently, there is no curative therapy for metastatic castrate-resistant prostate cancer (CRPC), a leading cause of death in men. However, researchers are exploring new treatments that involve drugs that prevent angiogenesis (the process by which new blood vessels are formed) and can slow or prevent tumor growth. TRC105 is an experimental drug that blocks angiogenesis, and has been studied for possible use in treating different kinds of cancer. However, it has not been validated to treat prostate cancer in general or CRPC in particular. Objectives: To determine the effects of TRC105 as a treatment for CRPC To determine the safety and effectiveness of TRC105 in treating CRPC Eligibility: - Men at least 18 years of age who have been diagnosed with castrate-resistant prostate cancer for which existing treatments have not been effective. Design: Eligible individuals will have a series of blood and other tests to determine their suitability for participating in the study. Participants will receive intravenous infusions of TRC105 in a 28-day treatment cycle. Participants will receive i.v. (intravenous) infusions of TRC105 every two weeks on days 1 and 15 of each 28-day cycle (cohorts 1, 2, 3, 5, and 6) and every week on days 1, 8, 15, and 22 of each 28 day cycle (cohort 4). Participants will receive different doses of TRC105 depending on when they enter the study, up to a maximum tolerated dose or optimum treatment dose. Frequent blood and urine tests will be performed during treatment, as well as other tests of cancer progression as directed by the study doctors. Participants will receive medicines to help prevent possible adverse side effects of TRC105, such as allergic reaction to the drug. Participants will continue treatment with TRC105 until they or the study team decides that the medication is not beneficial. No additional testing will be required unless participants discontinue the treatment because of side effects (which the study doctors will follow until the side effects are resolved).

Detailed Description
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Background: - Inhibition of angiogenesis has demonstrable antitumor efficacy against castrate-resistant prostate cancer (CRPC). TRC105 is a human/murine chimeric immunoglobulin heavy constant gamma 1 (IgG1) kappa monoclonal antibody that binds to human CD105 (endoglin), thus inhibiting angiogenesis and tumor growth. Data from an ongoing phase I clinical trial suggest that TRC105 is well tolerated with evidence of clinical efficacy in patients with metastatic CRPC. Primary Objectives: - Define the maximum tolerable dose (MTD) of TRC105 given every one to two weeks. Secondary Objectives: Define the dose-limiting toxicities and toxicity profile of TRC105 given every one to two weeks Evaluate time to disease progression, overall response rate and overall survival. Describe the prostate specific antigen (PSA) response rate to therapy with TRC105 Characterize the pharmacokinetics of TRC105 Demonstrate a biologic effect of TRC105 in the patient and, when possible, on the tumor via laboratory evaluation of the molecular markers of angiogenesis before and after drug administration respectively Eligibility: Progressive, castrate-resistant, metastatic adenocarcinoma of the prostate Eastern Cooperative Oncology Group (ECOG) less than or equal to 2 Design: - An initial single-arm, phase I dose escalation study open to all patients with progressive metastatic CRPC. The study will evaluate patients in five cohorts of escalating dose levels. A maximum of 30 patients will be needed to complete the phase I evaluation.

Official Title
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A Phase I/II Study of TRC105 in Metastatic Castrate Resistant Prostate Cancer (CRPC)

Conditions
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Prostate Cancer, Metastatic Castrate Resistant Prostate Cancer

Intervention / Treatment
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* Drug: TRC105


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients must have histopathological confirmation of prostate cancer by the Laboratory of Pathology of the National Cancer Institute (NCI), Pathology Department of the National Naval Medical Center or Pathology Department of Walter Reed Army Medical Center prior to entering this study. Patients whose pathology specimens are no longer available may be enrolled in the trial if the patient has a clinical course consistent with prostate cancer and available documentation from an outside pathology laboratory of the diagnosis. In cases where original tissue blocks or archival biopsy material is available, efforts will be made to contact referring physicians and outside pathology departments to have the material forwarded to the research team for use in correlative studies. Patients must have metastatic progressive castrate-resistant prostate cancer defined as progressive disease (see below) despite surgical castration or ongoing use of gonadotropin-releasing hormone agonists with confirmed castrate levels of testosterone. Criteria of progression for trial eligibility are defined from the Prostate Cancer Clinical Trials Working Group-2. Clinically progressive prostate cancer must be evidenced and documented by any of the following parameters: Two consecutively rising prostate specific antigen (PSA) values at a minimum of 1-week intervals (2.0 ng/mL is the minimum starting value for PSA) Appearance of one or more new lesion on bone scans Progressive measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Patients on flutamide for at least 6 months must have disease progression at least 4 weeks after withdrawal. Patients on bicalutamide or nilutamide for at least 6 months must have progression at least 6 weeks after withdrawal. All patients enrolled will be required to have measurable or non-measurable disease on imaging studies. 4. Age greater than or equal to 18 years. 5. Life expectancy of greater than 3 months. 6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. 7. Patients must have normal organ and marrow function as defined below: Absolute neutrophil count greater than or equal to 1,500/mcL Platelets greater than or equal to 100,000/mcL Total bilirubin less than or equal to 1.5 times upper normal limits or less than 3 mg/dl in subjects with Gilbert's Syndrome Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) less than or equal to 2.5 times upper limit of normal Creatinine less than or equal to 1.5 times upper normal limits OR creatinine clearance greater than or equal to 40 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal, as calculated by the Cockcroft Gault formula. 8. Patients must have recovered from any acute toxicity related to prior therapy, including surgery. Toxicity should be less than or equal to grade 1 or returned to baseline. 9. All patients who have not undergone bilateral surgical castration must continue suppression of testosterone production by appropriate usage of gonadotropin releasing hormone (GnRH) agonists or antagonists. 10. Patients must not have other invasive malignancies (within the past 2 years with the exception of non-melanoma skin cancers or non-invasive bladder cancer). 11. Enrolled patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, the duration of study participation and 3 months after the end of the treatment. 12. Patient must be able to understand and willing to sign a written informed consent document. 13. Patients on a stable dose of steroids of 10 mg/day or less can continue on steroids if they are on peptic ulcer disease prophylaxis with an H2-blocker or proton pump inhibitor. EXCLUSION CRITERIA: Patients who have had chemotherapy, large field radiotherapy, or major surgery must wait 3 weeks prior to entering the study. Patients may not be receiving any agents not approved by the Food and Drug Administration (FDA) within the past 4 weeks. Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Proteinuria, as demonstrated by a 24 hour protein of (Bullet) 2000 mg. Urine protein will be screened by urine protein-creatinine ratio (UPC). For UPC ratio > 1.0, a 24-hour urine protein will need to be obtained and the level should be < 2000 mg for patient enrollment. Uncontrolled intercurrent illness including, but not limited to, hypertension (systolic blood pressure (BP) > 160, diastolic BP > 100), ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements. Thrombolytic or treatment-dose anticoagulant use within 10 days prior to first dose with TRC105. Hemorrhage within 30 days of dosing. History of peptic ulcer disease or gastritis within 6 months of TRC105 administration, unless patient has received adequate treatment for peptic ulcer disease and has evidence of complete resolution documented by esophagogastroduodenoscopy (EGD). Corrected QT interval (QTc) > 500 msec. Known human immunodeficiency virus (HIV)-positive patients are excluded. History of hypersensitivity reaction to human or mouse antibody products. Patients with a history of familial bleeding disorders. Patients with a history of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome). Use of non-steroidal anti-inflammatory drugs (NSAIDs) beginning 14 days prior to the first TRC105 dose, with the exception of aspirin when clinically indicated.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TRC105 1 mg/kg every 2 weeks<br>Intravenous infusion at 1 mg/kg every 2 weeks | Drug: TRC105<br> <br> |
| Experimental: TRC105 3 mg/kg every 2 weeks<br>Intravenous infusion at 3 mg/kg every 2 weeks | Drug: TRC105<br> <br> |
| Experimental: TRC105 10 mg/kg every 2 weeks<br>Intravenous infusion at 10 mg/kg every 2 weeks | Drug: TRC105<br> <br> |
| Experimental: TRC105 10 mg/kg weekly<br>Intravenous infusion at 10 mg/kg weekly | Drug: TRC105<br> <br> |
| Experimental: TRC105 15 mg/kg every 2 weeks<br>Intravenous infusion at 15 mg/kg every 2 weeks | Drug: TRC105<br> <br> |
| Experimental: TRC105 20 mg/kg every 2 weeks<br>Intravenous infusion at 20 mg/kg every 2 weeks | Drug: TRC105<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Maximum Tolerated Dose (MTD) of TRC105 Given Every Two Weeks. | The MTD, to be administered in the phase II portion, is defined as the highest dose studied for which the incidence of dose limiting toxicity (DLT) was less than 33%. TRC105 was administered at 20 mg/kg intravenous every two weeks until MTD was achieved. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module. | Date treatment consent signed to date off study, approximately 43 months, 5 days | 
| Dose Limiting Toxicity (DLT) | Dose limiting toxicity is defined as any grade 3 or higher hematologic (excluding anemia) or non-hematologic toxicity considered to be possibly related to TRC105. | First 28 days on study | 
| Prostatic-Specific Antigen (PSA) Decline | PSA decline (i.e., PSA greater than 4.0 ng/mL) is defined as two consecutively rising PSA values at a minimum of 1-week intervals (2.0 ng/mL is the minimum starting values for PSA). Normal PSA is 4.0 ng/mL or lower. | 1- week intervals up to 6 months | 
| Clinical Response | Clinical response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% decrease in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | 56 days (one cycle = 28 days, restaging post cycle 2) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate, Tumor, Cancer, Hormone, Androgen, Prostate Cancer