Adult Solid Tumor
Conditions
Keywords
TRC105, CD105, Endoglin, Solid Tumors, Avastin, Bevacizumab
Brief summary
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
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.
Interventions
DRUGTRC105 and Bevacizumab
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.
Sponsors
Tracon Pharmaceuticals Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically proven advanced or metastatic solid cancer 2. Measurable disease, evaluable disease or elevation of a relevant soluble tumor marker (e.g., CEA, PSA, CA125) 3. Age of 18 years or older 4. ECOG performance status of 0 or 1 5. Resolution of all acute AEs resulting from prior cancer therapies to NCI CTCAE Grade ≤ 1 or baseline (except alopecia) 6. Adequate organ function 7. Willing and able to consent for self to participate in study
Exclusion criteria
1. Prior treatment with TRC105 2. Serious dose-limiting toxicity related to prior bevacizumab 3. Current treatment on another therapeutic clinical trial 4. Receipt of an investigational agent within 28 days of starting study treatment 5. Prior surgery (including open biopsy) within 28 days of starting the study treatment 6. Prior radiation therapy or systemic therapy within 21 days of starting the study treatment 7. Minor surgical procedures such as fine needle aspirations, Mediport placement or core biopsies within 7 days of study treatment 8. 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) 9. Symptomatic pericardial or pleural effusions 10. Uncontrolled peritoneal effusions requiring paracentesis more frequently than every 2 weeks 11. 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) 12. Angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, DVT, PTCA or CABG within the past 6 months 13. Active bleeding or pathologic condition that carries a high risk of bleeding 14. Thrombolytic or anticoagulant use (except to maintain i.v. catheters) within 10 days prior to first day of study therapy 15. Cardiac dysrhythmias of NCI CTCAE Grade ≥ 2 within the last 28 days 16. Known active viral or nonviral hepatitis 17. Centrally located non-small cell lung cancer (regardless of histologic sub-type), or non-small cell lung cancer of squamous histology. 18. History of hemorrhage or hemoptysis (\>½ teaspoon bright red blood) within 6 months of starting study treatment 19. Open wounds or unhealed fractures within 28 days of starting study treatment 20. 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 21. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness 22. Pregnancy or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determine Maximum Tolerated Dose of TRC105 in Combination With Bevacizumab | 1.5 years | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| TRC105 Pharmacokinetic Concentrations | 1.5 years | Plasma TRC105 concentrations will be measured at specified timepoints. |
| Immune Response to TRC105 | 1.5 years | HAMA and HACA titers will be measured at specified time-points. |
| Objective Response According to RECIST 1.1 | 1.5 years | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TRC105 and Bevacizumab Escalating doses of TRC105 were studied in combination with standard dose bevacizumab. In accordance with the original protocol, patients in cohorts 1 and 2 received TRC105 on day 1, day 8, and day 15 and bevacizumab on day 1 of each 3 week cycle. Cohort 3 and 4 patients received TRC105 on days 8, 15, and 22 and bevacizumab on days 1 and 15 of cycle 1 (4 week cycle), and cohort 4a and 5 patients received TRC105 on days 8, 11, 15, and 22 and bevacizumab on days 1 and 15 of cycle 1 (4 week cycle). Beyond cycle 1, patients in cohorts 3, 4, 4a, and 5 received TRC105 on days 1, 8, 15 and 22 and bevacizumab on days 1 and 15 of each 4 week cycle. | 38 |
| Total | 38 |
Baseline characteristics
| Characteristic | TRC105 and Bevacizumab |
|---|---|
| Age, Continuous | 63 Years |
| Prior VEGF inhibitor treatment No prior VEGF inhibitor treatment | 8 participants |
| Prior VEGF inhibitor treatment Prior VEGF inhibitor treatment | 30 participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 38 / 38 |
| serious Total, serious adverse events | 9 / 38 |
Outcome results
Primary
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).
Time frame: 1.5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TRC105 and Bevacizumab | Determine Maximum Tolerated Dose of TRC105 in Combination With Bevacizumab | 10 mg/kg |
Secondary
Immune Response to TRC105
HAMA and HACA titers will be measured at specified time-points.
Time frame: 1.5 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TRC105 and Bevacizumab | Immune Response to TRC105 | HAMA POSITIVE | 3 participants |
| TRC105 and Bevacizumab | Immune Response to TRC105 | HAMA NEGATIVE | 23 participants |
| TRC105 and Bevacizumab | Immune Response to TRC105 | HACA POSITIVE | 4 participants |
| TRC105 and Bevacizumab | Immune Response to TRC105 | HACA NEGATIVE | 22 participants |
Secondary
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
Time frame: 1.5 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TRC105 and Bevacizumab | Objective Response According to RECIST 1.1 | RECIST 1.1 defined response | 2 participants |
| TRC105 and Bevacizumab | Objective Response According to RECIST 1.1 | Tumor burden decreases | 14 participants |
Secondary
TRC105 Pharmacokinetic Concentrations
Plasma TRC105 concentrations will be measured at specified timepoints.
Time frame: 1.5 years