Study of TRC105 Combined With Standard-Dose Bevacizumab for Advanced Solid Tumors for Which Bevacizumab is Indicated
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: TRC105 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. |
Drug: TRC105 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.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Alabama at Birmingham | Birmingham | Alabama | United States | 35249 |
| 2 | Pinnacle Oncology Hematology | Scottsdale | Arizona | United States | 85258 |
| 3 | UCLA Hematology and Oncology | Santa Monica | California | United States | 90404 |
| 4 | Indiana University Simon Cancer Center | Indianapolis | Indiana | United States | 46202 |
Sponsors and Collaborators
- Tracon Pharmaceuticals Inc.
Investigators
- Study Director: Charles P Theuer, MD, Tracon Pharmaceuticals Inc.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 105ST102
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | TRC105 and Bevacizumab |
|---|---|
| Arm/Group Description | 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. |
| Period Title: Overall Study | |
| STARTED | 38 |
| COMPLETED | 38 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | TRC105 and Bevacizumab |
|---|---|
| Arm/Group Description | 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. |
| Overall Participants | 38 |
| Age (Years) [Median (Full Range) ] | |
| Median (Full Range) [Years] |
63
|
| Sex: Female, Male (Count of Participants) | |
| Female |
23
60.5%
|
| Male |
15
39.5%
|
| Prior VEGF inhibitor treatment (participants) [Number] | |
| Prior VEGF inhibitor treatment |
30
78.9%
|
| No prior VEGF inhibitor treatment |
8
21.1%
|
Outcome Measures
| Title | Determine Maximum Tolerated Dose of TRC105 in Combination With Bevacizumab |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | TRC105 and Bevacizumab |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 38 |
| Number [mg/kg] |
10
|
| Title | TRC105 Pharmacokinetic Concentrations |
|---|---|
| Description | Plasma TRC105 concentrations will be measured at specified timepoints. |
| Time Frame | 1.5 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Immune Response to TRC105 |
|---|---|
| Description | HAMA and HACA titers will be measured at specified time-points. |
| Time Frame | 1.5 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | TRC105 and Bevacizumab |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 26 |
| HAMA POSITIVE |
3
7.9%
|
| HAMA NEGATIVE |
23
60.5%
|
| HACA POSITIVE |
4
10.5%
|
| HACA NEGATIVE |
22
57.9%
|
| Title | Objective Response According to RECIST 1.1 |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | TRC105 and Bevacizumab |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 31 |
| RECIST 1.1 defined response |
2
5.3%
|
| Tumor burden decreases |
14
36.8%
|
Adverse Events
| Time Frame | The adverse event reporting period for this trial started when a given patient had the first dose of bevacizumab and/or TRC105 study drug and ended 28 days after the last dose of bevacizumab and/or TRC105 study drug was administered whichever was later. In addition, any known untoward event that occurred beyond the adverse event reporting period that the Investigator assessed as possibly related to TRC105 and/or bevacizumab was reported as an adverse event. | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | TRC105 and Bevacizumab | |
| Arm/Group Description | 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. | |
All Cause Mortality |
||
| TRC105 and Bevacizumab | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| TRC105 and Bevacizumab | ||
| Affected / at Risk (%) | # Events | |
| Total | 9/38 (23.7%) | |
| Gastrointestinal disorders | ||
| Ileus | 1/38 (2.6%) | 1 |
| Small Bowel Obstruction | 1/38 (2.6%) | 1 |
| General disorders | ||
| disease progression | 1/38 (2.6%) | 1 |
| Infections and infestations | ||
| Cellulitis of Left Foot | 1/38 (2.6%) | 1 |
| Pneumonia | 1/38 (2.6%) | 1 |
| MRSA Sepsis | 1/38 (2.6%) | 1 |
| Sepsis | 1/38 (2.6%) | 1 |
| Brain Absces | 1/38 (2.6%) | 1 |
| Nervous system disorders | ||
| Headache | 1/38 (2.6%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||
| Recurrent pneumothorax | 1/38 (2.6%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| TRC105 and Bevacizumab | ||
| Affected / at Risk (%) | # Events | |
| Total | 38/38 (100%) | |
| Blood and lymphatic system disorders | ||
| Anaemia | 11/38 (28.9%) | |
| Endocrine disorders | ||
| Hypothyroidism | 2/38 (5.3%) | |
| Eye disorders | ||
| Periorbital oedema | 2/38 (5.3%) | |
| Gastrointestinal disorders | ||
| Gingival pain | 4/38 (10.5%) | |
| Nausea | 3/38 (7.9%) | |
| Oral pain | 3/38 (7.9%) | |
| Vomiting | 2/38 (5.3%) | |
| General disorders | ||
| Face oedema | 4/38 (10.5%) | |
| Fatigue | 10/38 (26.3%) | |
| Injury, poisoning and procedural complications | ||
| Infusion related reaction | 11/38 (28.9%) | |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 4/38 (10.5%) | |
| Nervous system disorders | ||
| Headache | 31/38 (81.6%) | |
| Migraine | 3/38 (7.9%) | |
| Sinus headache | 2/38 (5.3%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnoea | 2/38 (5.3%) | |
| Nasal congestion | 3/38 (7.9%) | |
| Skin and subcutaneous tissue disorders | ||
| Rash | 3/38 (7.9%) | |
| Vascular disorders | ||
| Epistaxis | 25/38 (65.8%) | |
| Flushing | 8/38 (21.1%) | |
| Gingival bleeding | 12/38 (31.6%) | |
| Telangiectasia | 19/38 (50%) | |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Dr Charles Theuer |
|---|---|
| Organization | TRACON Pharmaceuticals |
| Phone | 8585500780 ext 233 |
| ctheuer@traconpharma.com |
- 105ST102