Glioblastoma, Glioblastoma Multiforme
Conditions
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.
Interventions
DRUGTRC105
10 mg/kg weekly by intravenous administration on Days 1, 8, 15 and 22 of each 28-day cycle
DRUGBevacizumab
IV
Sponsors
The Cleveland Clinic
Case Comprehensive Cancer Center
Tracon Pharmaceuticals Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with histologically confirmed glioblastoma, recurrent after prior external-beam fractionated radiotherapy and temozolomide chemotherapy. 2. Patients with documented radiographic progression following bevacizumab therapy for treatment of glioblastoma. 3. Patients with up to 3 prior recurrences are allowed. 4. Karnofsky performance status ≥ 70%. 5. Age ≥ 18 years old. 6. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Overall Survival (OS) | 6 Months | Overall survival assessed by determination from time of informed consent on trial to the date of death of each patient enrolled in the trial |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Duration That Patients Remained Progression Free on Study | Patients are scanned every 8 weeks for approximately 6 months | 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. |
| Number of Participants With Adverse Events | Patients were followed for at least 28 days after the last dose of TRC105 study drug for adverse events, an average of 4 months | Adverse event frequency per patient according to CTCAE version 4.0. |
| Number of Patients Who Respond to Study Treatment According to Modified RANO Criteria (Objective Response Rate (ORR)). | Patients are scanned every 8 weeks | 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. |
Countries
United States
Participant flow
Recruitment details
Patients were screened and enrolled at 4 sites
Participants by arm
| Arm | Count |
|---|---|
| TRC105, Bevacizumab Single arm study
TRC105: 10 mg/kg weekly by intravenous administration on Days 1, 8, 15 and 22 of each 28-day cycle
Bevacizumab: IV 10 mg/kg every 2 weeks | 16 |
| TRC105 Single arm
TRC105: 10 mg/kg weekly by intravenous administration on Days 1, 8, 15 and 22 of each 28-day cycle | 6 |
| Total | 22 |
Baseline characteristics
| Characteristic | TRC105 | Total | TRC105, Bevacizumab |
|---|---|---|---|
| Age, Customized Age | 56.5 years | 62 years | 64.5 years |
| Cancer Histology Astrocytoma | 1 Participants | 1 Participants | 0 Participants |
| Cancer Histology Giant Cell Glioblastoma | 0 Participants | 1 Participants | 1 Participants |
| Cancer Histology Glioblastoma | 5 Participants | 20 Participants | 15 Participants |
| Number of Prior Regimens | 3 prior regimens | 3 prior regimens | 2.5 prior regimens |
| Screening Karnofsky Score Score = 60: requires occasional assistance | 3 participants | 4 participants | 1 participants |
| Screening Karnofsky Score Score = 70: Can care for self; not normal activity | 0 participants | 4 participants | 4 participants |
| Screening Karnofsky Score Score = 80: Normal activity with effort | 2 participants | 10 participants | 8 participants |
| Screening Karnofsky Score Score = 90: Normal activities, minor symptoms. | 1 participants | 4 participants | 3 participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 16 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 16 | 1 / 6 |
| other Total, other adverse events | 16 / 16 | 6 / 6 |
| serious Total, serious adverse events | 6 / 16 | 3 / 6 |
Outcome results
Primary
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
Time frame: 6 Months
Population: Patients treated with TRC105 and bevacizumab who expired. Overall survival was not captured in the monotherapy portion of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carotuximab (TRC105), Bevacizumab | Median Overall Survival (OS) | 5.75 months |
Secondary
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.
Time frame: Patients are scanned every 8 weeks for approximately 6 months
Population: Patients with at least 1 on study scan were included in the efficacy population. The number of months that patients remained progression free was calculated for 5 evaluable monotherapy patients and 14 evaluable combination therapy patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carotuximab (TRC105), Bevacizumab | Median Duration That Patients Remained Progression Free on Study | 1.81 months |
| Carotuximab (TRC105) | Median Duration That Patients Remained Progression Free on Study | 1.38 months |
Secondary
Number of Participants With Adverse Events
Adverse event frequency per patient according to CTCAE version 4.0.
Time frame: Patients were followed for at least 28 days after the last dose of TRC105 study drug for adverse events, an average of 4 months
Population: Patients who received at least a portion of a dose of TRC105 and/or Bevacizumab
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Carotuximab (TRC105), Bevacizumab | Number of Participants With Adverse Events | Total SAEs | 6 Participants |
| Carotuximab (TRC105), Bevacizumab | Number of Participants With Adverse Events | TRC105 Related SAEs | 2 Participants |
| Carotuximab (TRC105) | Number of Participants With Adverse Events | Total SAEs | 3 Participants |
| Carotuximab (TRC105) | Number of Participants With Adverse Events | TRC105 Related SAEs | 0 Participants |
Secondary
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.
Time frame: Patients are scanned every 8 weeks
Population: Nineteen patients had measurable disease at baseline and received at least one follow up scan and were evaluable for the secondary efficacy outcome measure of PFS by modified RANO criteria. None of the patients treated on this study had a reduction in tumor burden compared to baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carotuximab (TRC105), Bevacizumab | Number of Patients Who Respond to Study Treatment According to Modified RANO Criteria (Objective Response Rate (ORR)). | 0 Participants |
| Carotuximab (TRC105) | Number of Patients Who Respond to Study Treatment According to Modified RANO Criteria (Objective Response Rate (ORR)). | 0 Participants |