A Phase 2 Evaluation of TRC105 In Combination With Bevacizumab in Patients With Glioblastoma

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety and efficacy of TRC105 in patients with recurrent or progressive glioblastoma after prior antiangiogenic therapy (including anti-VEGF therapy)

Detailed Description
-----------------
Angiogenesis plays a central role in the progression of solid cancer. TRC105 is an antibody to CD105, an important non-VEGF angiogenic target on proliferating endothelial cells. TRC105 inhibits angiogenesis, tumor growth and metastases in preclinical models. TRC105 has been well tolerated in patients with glioblastoma (GBM) as a single agent. The combination of TRC105 in combination with bevacizumab has demonstrated activity in bevacizumab refractory cancer patients. We hypothesize that TRC105 when administered with bevacizumab will have activity in GBM patients who progress on bevacizumab. By targeting a non-VEGF pathway, TRC105 has the potential to complement VEGF inhibition by bevacizumab, which could represent a major advance in GBM therapy.

Official Title
-----------------
A Phase 2 Evaluation of TRC105 In Combination With Bevacizumab for the Treatment Of Recurrent or Progressive Glioblastoma That Has Progressed on Bevacizumab

Conditions
-----------------
Glioblastoma, Glioblastoma Multiforme

Intervention / Treatment
-----------------
* Drug: TRC105
* Drug: Bevacizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with histologically confirmed glioblastoma, recurrent after prior external-beam fractionated radiotherapy and temozolomide chemotherapy. Patients with documented radiographic progression following bevacizumab therapy for treatment of glioblastoma. Patients with up to 3 prior recurrences are allowed. Karnofsky performance status ≥ 70%. Age ≥ 18 years old. Normal organ function Exclusion Criteria: Patients who have had previous treatment with TRC105. Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, or patients who have had minor procedures, percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury Patients with cirrhosis, or active viral or nonviral hepatitis. Patients with active bleeding or pathologic conditions that carry a high risk of bleeding,(i.e. hereditary hemorrhagic telangiectasia). Patients who are currently receiving anticoagulation treatment Patients unwilling or unable to comply with the protocol

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: A total of 6 initial patients were treated with 10 mg/kg of TRC105 monotherapy. All patients progressed within 2 months of initiating treatment, reflecting the rapid progression. Due to the lack of activity in this disease setting with TRC105 alone, the study was amended to treat patients with 10 mg/kg TRC105 weekly in combination with 10 mg/kg bevacizumab every two weeks.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TRC105, Bevacizumab<br>Single arm study | Drug: TRC105<br>* 10 mg/kg weekly by intravenous administration on Days 1, 8, 15 and 22 of each 28-day cycle<br>* Other names: carotuximab;Drug: Bevacizumab<br>* IV<br>* Other names: Avastin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Overall Survival (OS) | Overall survival assessed by determination from time of informed consent on trial to the date of death of each patient enrolled in the trial | 6 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Duration That Patients Remained Progression Free on Study | The median number of months that patients remained progression free was calculated using modified RANO criteria to determine progression. Modified RANO criteria is defined as follows: The largest cross-sectional area on the T1-weighted contrast-enhanced images was selected and measured in 2 dimensions with linear measures on the baseline MRI axial sequence. In addition, the largest cross-sectional area of a contiguous hyperintense lesion on FLAIR sequences was measured on the baseline MRI axial sequence. All subsequent scans were compared against these baseline measures (for both CE and FLAIR). New foci of FLAIR signal abnormality were recorded on each subsequent evaluation. Response was scored. | Patients are scanned every 8 weeks for approximately 6 months | 
| Number of Participants With Adverse Events | Adverse event frequency per patient according to CTCAE version 4.0. | Patients were followed for at least 28 days after the last dose of TRC105 study drug for adverse events, an average of 4 months | 
| Number of Patients Who Respond to Study Treatment According to Modified RANO Criteria (Objective Response Rate (ORR)). | Number of patients who respond to study treatment according to modified RANO criteria was calculated (Objective Response Rate (ORR)). Modified RANO criteria is defined as follows: The largest cross-sectional area on the T1-weighted contrast-enhanced images was selected and measured in 2 dimensions with linear measures on the baseline MRI axial sequence. In addition, the largest cross-sectional area of a contiguous hyperintense lesion on FLAIR sequences was measured on the baseline MRI axial sequence. All subsequent scans were compared against these baseline measures (for both CE and FLAIR). New foci of FLAIR signal abnormality were recorded on each subsequent evaluation. Response was scored. | Patients are scanned every 8 weeks |