Study of TRC105 With Abiraterone and With Enzalutamide in Prostate Cancer Patients Progressing on Therapy

Study Overview
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Brief Summary
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This research study is being done to measure the clinical benefit of TRC105 in combination with abiraterone or enzalutamide in metastatic, castration-resistant prostate cancer patients who are taking either abiraterone or enzalutamide and showing signs of biochemical progression without radiographic progression. A patient who is progressing on AR-therapy will continue the same AR-therapy on study with the addition of TRC105. The two arms will accrue in parallel and independently.

Detailed Description
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This is a Phase II, open-label study of TRC105 (anti-endoglin antibody) in combination with abiraterone or enzalutamide in metastatic, castration-resistant prostate cancer patients who are taking either abiraterone or enzalutamide and showing signs of biochemical progression without radiographic progression. A patient who is progressing on AR-therapy will continue the same AR-therapy on study with the addition of TRC105. The two arms will accrue in parallel and independently. There will be a 2-week washout of the active AR-targeted therapy prior to initiation of combination therapy. Tumor response should be assessed at a frequency of 8 weeks by CT/MRI chest, abdomen and pelvis as well as bone scan. Patients may continue on therapy until radiographic progression by RECIST 1.1 or PCWG3 criteria.

Official Title
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A Phase 2 Study of TRC105 (Anti-endoglin Antibody) With Abiraterone and With Enzalutamide in Metastatic, Castration Resistant Prostate Cancer Patients Progressing on Therapy

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: TRC105
* Drug: Abiraterone
* Drug: Enzalutamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of metastatic, castration-resistant prostate cancer with rising PSA on either abiraterone or enzalutamide PSA rise will be defined as an increase in PSA of 0.2 ng/mL or higher on at least 2 separate occasions greater than 1 week apart while on either abiraterone or enzalutamide If there is a drop in serum PSA after the first rise, and the patient has another PSA rise which is greater than the first, the patient will still be considered eligible. ECOG 0-2 Resolution of adverse events results as described below. Laboratory abnormalities must meet values specified below in criteria #4 If the patient's most recent line of therapy is treatment with abiraterone or enzalutamide, then all adverse events must be resolved to Grade 2 or better If the most recent line of therapy is any other treatment for mCRPC then all Adverse events must be resolved to grade 1 or better, with the exception of fatigue, alopecia and neuropathy (which must resolve to CTCAE grade 2) Adequate organ function defined by: AST and ALT < 2.5 x ULN Total serum bilirubin < 1.5 x ULN Platelets > 60,000 Hgb > 8.5 g/dL Serum Cr <1.5 x ULN or a creatinine clearance > 30. INR ≤ 1.2 unless the patient is receiving a direct Factor Xa inhibitor or a direct thrombin inhibitor Patients must be surgically sterile or must agree to use effective contraception during the study and for 3 months following last dose of TRC105. The definition of effective contraception will be based on the judgment of the Principal Investigator or a designated associate. Abstinence from intercourse is an acceptable form of contraception. Exclusion Criteria: Non-PSA producing prostate cancers- such as small cell prostate cancers or those prostate cancers which exhibit radiographic progression without PSA rise Inability to tolerate standard doses of abiraterone (1000 mg daily) or enzalutamide (160 mg daily). Other prior malignancy requiring active anticancer therapy Prior exposure to TRC105 or any CD105 targeted antibody Any major surgical procedure within 2 weeks of starting therapy Uncontrolled chronic hypertension defined as sustained by systolic pressure (SBP) >150 mmHg or diastolic pressure (DBP) >90 despite optimal therapy. Active bleeding or pathologic conditions that carries a high bleeding risk Use of thrombolytics within 10 days prior to the first day of TRC105 Known hypersensitivity to Chinese hamster ovary products or other recombinant human, chimeric, or humanized antibodies A known diagnosis of Osler-Weber-Rendu syndrome Ascites or pericardial or pleural effusion requiring external drainage procedures History of untreated brain involvement with cancer, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease. Patients with radiated or resected lesions are permitted, provided the lesions are fully treated and inactive, patients are asymptomatic, and no steroids have been administered for at least 28 days. Imaging for CNS disease will not be required for screening unless there is a history of a neurological finding such as new onset weakness or numbness that cannot be explained by other medical history. Acute cardiovascular event within the past 6 months. An acute cardiovascular event will be defined as a myocardial infraction, NYHA Class II or worse congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, percutaneous transluminal coronary angioplasty (PTCA), or CABG. Deep venous thrombosis within 6 months, unless the patient is anti-coagulated without the use of warfarin for at least 2 weeks. In this situation, low molecular weight heparin is preferred.

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
Interventional Model Description: Bayesian design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: TRC105 + Abiraterone<br>Patients progressing on Abiraterone will undergo a washout period and then continue treatment with TRC105 + Abiraterone | Drug: TRC105<br>* Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks<br>* Other names: Carotuximab;Drug: Abiraterone<br>* Patients who are progressing on Abiraterone will undergo a washout period and then continue treatment with standard dosing of Abiraterone plus TRC105.<br>* Other names: Zytiga;|
| Experimental: Arm E: TRC105 + Enzalutamide<br>Patients progressing on Enzalutamide will undergo a washout period and then continue treatment with TRC105 + Enzalutamide | Drug: TRC105<br>* Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks<br>* Other names: Carotuximab;Drug: Enzalutamide<br>* Patients who are progressing on Enzalutamide will undergo a washout period and then continue standard treatment with Enzalutamide plus TRC105.<br>* Other names: Xtandi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Clinical Benefit | Number of participants with stabilization of disease for at least 2 months or disease improvement at any time from start of combination therapy by radiographic and/or biochemical criteria through treatment completion up to an estimated period of 24 months radiographic improvement defined as a PR (At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum. There can be no appearance of new lesions) or CR (Disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions) by RECIST 1.1 or improvement by PCWG3 criteria Biochemical response will be defined by PCWG3 criteria Stabilization will be defined as the absence of progression by BOTH radiographic and biochemical criteria | Through study completion, average 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events From TRC105 and Abiraterone or Enzalutamide | Number of participants with grade 3/4 Adverse Events Related to investigational therapy as assessed Using CTCAE (v.4) up to 4 months from treatment initiation. | 4 months | 
| Progression Free Survival | Time (in Months) from treatment initiation to radiographic and clinical progression over study duration (estimated 24 months) - radiographic criteria measured by RECIST 1.1 [Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions plus an absolute increase of at least 5 mm, taking as reference the smallest sum recorded since the start of study] | 24 months | 
| Clinical Benefit at Two Months | Proportion of participants with stabilization of disease for two months or disease improvement at anytime from start of combination therapy to two months by radiographic and/or biochemical criteria radiographic improvement defined as a PR (At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum. There can be no appearance of new lesions) or CR (Disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions) by RECIST 1.1 or improvement by PCWG3 criteria Biochemical response will be defined by PCWG3 criteria Stabilization will be defined as the absence of progression by BOTH radiographic and biochemical criteria | 2 months | 
| Clinical Benefit at Four Months | Proportion of participants with stabilization of disease for at least 4 months or disease improvement at anytime from start of combination therapy to four months by radiographic and/or biochemical criteria radiographic improvement defined as a PR (At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum. There can be no appearance of new lesions) or CR (Disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions) by RECIST 1.1 or improvement by PCWG3 criteria Biochemical response will be defined by PCWG3 criteria Stabilization will be defined as the absence of progression by BOTH radiographic and biochemical criteria | 4 months | 
| Clinical Benefit From PSA Serum Concentration (2 Months) | Proportion of participants with stabilization of disease based on PSA serum concentration levels. Stabilization of disease refers to PSA values that do not meet criteria for progression where progression will be defined as a rise in serum PSA that is ≥ 25% and 2 ng/mL above nadir which is confirmed by a second value ≥ 3 weeks later. | 2 months | 
| Clinical Benefit From PSA Serum Concentration (4 Months) | Proportion of participants with stabilization of disease based on PSA serum concentration levels. Stabilization of disease refers to PSA values that do not meet criteria for progression where progression will be defined as a rise in serum PSA that is ≥ 25% and 2 ng/mL above nadir which is confirmed by a second value ≥ 3 weeks later. | 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate Cancer, Metastatic Prostate Cancer, Castration Resistant Prostate Cancer, Metastatic Castration Resistant