Study of TRC105 Combined With Standard-Dose Bevacizumab for Advanced Solid Tumors for Which Bevacizumab is Indicated

Study Overview
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Brief Summary
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The purpose of the study is to evaluate safety and tolerability and determine a recommended Phase 2 dose for TRC105 when added to standard dose bevacizumab in patients with advanced solid tumors for which bevacizumab is indicated.

Detailed Description
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Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) that inhibits angiogenesis and extends survival in patients with a wide variety of solid tumor types. TRC105, a monoclonal antibody to CD105, is a novel angiogenesis inhibitor that complements bevacizumab in preclinical models. Together, these antibodies may result in more effective angiogenesis inhibition and improved clinical efficacy over that seen with bevacizumab alone. The purpose of the study is to evaluate safety and tolerability and determine a recommended Phase 2 dose for TRC105 when added to standard dose bevacizumab in patients with advanced solid tumors for which bevacizumab is indicated.

Official Title
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An Open Label Phase 1B Dose-Escalation Study of TRC105 Combined With Standard-Dose Bevacizumab for Advanced Solid Tumors

Conditions
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Adult Solid Tumor

Intervention / Treatment
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* Drug: TRC105 and Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven advanced or metastatic solid cancer Measurable disease, evaluable disease or elevation of a relevant soluble tumor marker (e.g., CEA, PSA, CA125) Age of 18 years or older ECOG performance status of 0 or 1 Resolution of all acute AEs resulting from prior cancer therapies to NCI CTCAE Grade ≤ 1 or baseline (except alopecia) Adequate organ function Willing and able to consent for self to participate in study Exclusion Criteria: Prior treatment with TRC105 Serious dose-limiting toxicity related to prior bevacizumab Current treatment on another therapeutic clinical trial Receipt of an investigational agent within 28 days of starting study treatment Prior surgery (including open biopsy) within 28 days of starting the study treatment Prior radiation therapy or systemic therapy within 21 days of starting the study treatment Minor surgical procedures such as fine needle aspirations, Mediport placement or core biopsies within 7 days of study treatment Uncontrolled chronic hypertension defined as systolic > 140 or diastolic > 90 despite optimal therapy (initiation or adjustment of BP medication prior to study entry allowed provided that the average of 3 BP readings at a visit prior to enrollment is < 140/90 mm Hg) Symptomatic pericardial or pleural effusions Uncontrolled peritoneal effusions requiring paracentesis more frequently than every 2 weeks History of brain involvement with cancer, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease (except in the expansion cohort at the MTD where brain metastases or primary brain tumors are eligible) Angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, DVT, PTCA or CABG within the past 6 months Active bleeding or pathologic condition that carries a high risk of bleeding Thrombolytic or anticoagulant use (except to maintain i.v. catheters) within 10 days prior to first day of study therapy Cardiac dysrhythmias of NCI CTCAE Grade ≥ 2 within the last 28 days Known active viral or nonviral hepatitis Centrally located non-small cell lung cancer (regardless of histologic sub-type), or non-small cell lung cancer of squamous histology. History of hemorrhage or hemoptysis (>½ teaspoon bright red blood) within 6 months of starting study treatment Open wounds or unhealed fractures within 28 days of starting study treatment History of peptic ulcer disease or erosive gastritis within the past 6 months, unless treated for the condition and complete resolution has been documented by esophagogastroduodenoscopy (EGD) within 28 days of starting study treatment Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness Pregnancy or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: TRC105 and Bevacizumab<br>Escalating doses of i.v. TRC105 will be administered weekly beginning with 3 mg/kg in combination with 15 mg/kg bevacizumab given every 3 weeks. Patients will receive TRC105 treatment on Days 1, 8, and 15 and bevacizumab treatment on Day 1 of each 21-day cycle. | Drug: TRC105 and Bevacizumab<br>* Escalating doses of i.v. TRC105 will be administered weekly beginning with 3 mg/kg in combination with 15 mg/kg bevacizumab given every 3 weeks. Patients will receive TRC105 treatment on Days 1, 8, and 15 and bevacizumab treatment on Day 1 of each 21-day cycle.<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Maximum Tolerated Dose of TRC105 in Combination With Bevacizumab | Three patients will be initially enrolled and treated at each dose level. If none of these 3 patients experiences a dose-limiting toxicity (DLT) during the 28-day evaluation period, dose escalation will proceed following review of safety data with appropriate site staff including the principal investigators at all sites. If 1 of 3 patients experiences DLT, the cohort will be expanded to 6 patients. The maximum tolerated dose (MTD) will have been exceeded if ≥ 33% of patients experience DLT in a given cohort. DLT will have occurred when a patient has 1 or more toxicity listed in the table below that is at least possibly related to the combination of bevacizumab and TRC105 during the first 28 days (cycle 1). | 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TRC105 Pharmacokinetic Concentrations | Plasma TRC105 concentrations will be measured at specified timepoints. | 1.5 years | 
| Immune Response to TRC105 | HAMA and HACA titers will be measured at specified time-points. | 1.5 years | 
| Objective Response According to RECIST 1.1 | The best response according to RECIST 1.1 for each patient with measurable disease and who received at least one dose of study drug will be listed by cohort and tumor type | 1.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TRC105, CD105, Endoglin, Solid Tumors, Avastin, Bevacizumab