Choriocarcinoma, Epithelioid Trophoblastic Tumor, Gestational Trophoblastic Neoplasia, Placental Site Trophoblastic Tumor
Conditions
Keywords
TRC105, CD105, Endoglin, Angiogenesis inhibitor, GTN, Bevacizumab, Avastin
Brief summary
The purpose of the study is to determine the overall response rate of single agent TRC105 and the combination of TRC105 and bevacizumab in patients with refractory GTN (including choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT)). Up to 30 patients will be treated.
Detailed description
TRC105 is a monoclonal antibody that binds to endoglin, an angiogenic target highly expressed on the tumor vessels and tumor cells in gestational trophoblastic neoplasia (GTN). 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 has been well tolerated as a single agent and when combined with bevacizumab. These antibodies may be efficacious in refractory GTN, a tumor type that is highly vascular and has been shown to densely express endoglin.
Interventions
DRUGTRC105
Subjects will begin by receiving TRC105 weekly. Subjects who achieve a complete response on single agent TRC105 may transition to every two week dosing.
DRUGBevacizumab
Bevacizumab will be dosed every two weeks.
Sponsors
Tracon Pharmaceuticals Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
16 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Willingness and ability to consent for self to participate in study 2. Willingness and ability to comply with study procedures 3. Elevated serum hCG (in cases of choriocarcinoma); elevated hCG or measurable disease (in cases of PSTT or ETT) 4. Histologically proven trophoblastic neoplasia, or clinically demonstrated trophoblastic neoplasia that has progressed following treatment with at least one chemotherapy regimen that included 2 or more chemotherapy agents. 5. Age of 16 years or older 6. ECOG performance status ≤ 1 7. Resolution of all acute adverse events resulting from prior cancer therapies to NCI CTCAE grade ≤ 1 or baseline 8. Adequate organ function
Exclusion criteria
1. Male 2. Prior treatment with TRC105 3. . Current treatment on another therapeutic clinical trial 4. Uncontrolled chronic hypertension defined as systolic \> 150 or diastolic \> 90 despite optimal therapy 5. Significant pericardial effusion, pleural effusion, or ascites 6. Active bleeding or pathologic condition that carries a high risk of bleeding 7. Tumors located in the central chest or other location where bleeding is associated with high morbidity 8. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to first day of study therapy 9. Angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG) within the past 6 months. Deep venous thrombosis within 6 months, unless the patient is therapeutically anti-coagulated for at least 2 weeks. In this situation, low molecular weight heparin is preferred 10. Known active viral or nonviral hepatitis 11. Pregnant or actively breastfeeding without intention to discontinue prior to initiation of study 12. Open wounds or unhealed fractures within 28 days of starting study treatment 13. 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 14. History of gastrointestinal perforation or fistula in the past 6 months, or while previously on antiangiogenic therapy, unless underlying risk has been resolved 15. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness 16. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for this study 17. History of brain involvement with cancer, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease. Patients with radiated or resected lesions are permitted, provided the lesions are fully treated and inactive, patients are asymptomatic, and no steroids have been administered for brain edema for at least 28 days 18. Receipt of systemic anticancer therapy, including investigational agents, within 28 days of starting study treatment. If anticancer therapy was given within 28 days of starting study treatment, patients may be included if 5 times the elimination half-life of the drug has passed 19. Patients who have received wide field radiotherapy ≤ 28 days (defined as \> 50% of volume of pelvic bones or equivalent) or limited field radiation for palliation \< 14 days prior to starting study treatment or those patients who have not recovered adequately from side effects of such therapy 20. Major surgical procedure or significant traumatic injury within 6 weeks prior to study registration or not fully recovered from any such procedure
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate on TRC105 Alone and on the Combination of TRC105 and Bevacizumab | 8 weeks | Antitumor Activity of Single Agent TRC105 and the Combination of TRC105 and Bevacizumab will be assessed via RECIST 1.1 and by measuring circulating bHCG. Disease progression is defined as \>20% increase (the absolute increase must be ≥10 IU/L) above the nadir on consecutive measurements separated by at least two weeks; Partial response is defined as a hCG decrease of 50% or more from starting value on consecutive measurements; Complete response will be defined as normalization of hCG on consecutive measurements separated by at least two weeks; Stable disease will be defined as the absence of response or progression on 3 consecutive measurements separated by at least two weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency and Severity of Adverse Events | 20 months | Determine frequency and severity of adverse events as assessed by NCI CTCAE (Version 4.03) |
| Progression-Free Survival (PFS) | 8 weeks | Median Progression-Free Survival (PFS) via Serum hCG levels and response evaluation according to RECIST version 1.1 as a preliminary measure of the antitumor activity of TRC105. Disease progression is defined as \>20% increase (the absolute increase must be ≥10 IU/L) above the nadir on consecutive measurements separated by at least two weeks; Partial response is defined as a hCG decrease of 50% or more from starting value on consecutive measurements; Complete response will be defined as normalization of hCG on consecutive measurements separated by at least two weeks; Stable disease will be defined as the absence of response or progression on 3 consecutive measurements separated by at least two weeks. Patients must have screening (baseline) and at least one on study CT scan to be considered evaluable. |
| Overall Response Rate on Bevacizumab Alone | 8 weeks | Overall Response Rate on bevacizumab alone according to RECIST 1.1 in combination with serum hCG levels. Disease progression is defined as \>20% increase (the absolute increase must be ≥10 IU/L) above the nadir on consecutive measurements separated by at least two weeks; Partial response is defined as a hCG decrease of 50% or more from starting value on consecutive measurements; Complete response will be defined as normalization of hCG on consecutive measurements separated by at least two weeks; Stable disease will be defined as the absence of response or progression on 3 consecutive measurements separated by at least two weeks. |
| Maximum Plasma Concentration (Cmax) of TRC105. | cycle 2 day 1 (28 days after initiation of dosing) | Mean serum TRC105 concentrations were assessed at cycle 1 and cycle 2 on day 1, 8, 15, and 22 and on day 1 of every subsequent cycle using validated methods in order to determine the Cmax of TRC105 |
| TRC105 Immunogenicity as Assessed by Anti-Product Antibody (APA). | 8 weeks | Anti-Product Antibody (APA) concentrations will be measured using validated ELISA methods at the time points specified in the protocol. APA concentrations will be evaluated in the context of pharmacokinetic parameters and AE profiles. Number of patients with positive APA titers on study will be reported. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TRC105 and/or Bevacizumab All subjects will begin by receiving single agent TRC105 weekly. In the case of a complete response to single agent TRC105, subjects will continue to receive single agent TRC105 for at least 3 months following complete response. In the case of a partial response (without a complete response) to single agent TRC105, bevacizumab every two weeks will be added. In the absence of a partial or complete response to single agent TRC105, subjects will receive single agent bevacizumab every two weeks. In the absence of a complete response to single agent bevacizumab, or for subjects who have documented disease progression on a prior bevacizumab containing regimen, subjects will receive TRC105 weekly and bevacizumab every two weeks.
TRC105: Subjects will begin by receiving TRC105 weekly. Subjects who achieve a complete response on single agent TRC105 may transition to every two week dosing.
Bevacizumab: Bevacizumab will be dosed every two weeks. | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | TRC105 and/or Bevacizumab |
|---|---|
| Age, Continuous | 48 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Number of Prior Regimens | 6 prior regimens |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment United States | 3 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 3 |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 1 / 3 |
Outcome results
Primary
Overall Response Rate on TRC105 Alone and on the Combination of TRC105 and Bevacizumab
Antitumor Activity of Single Agent TRC105 and the Combination of TRC105 and Bevacizumab will be assessed via RECIST 1.1 and by measuring circulating bHCG. Disease progression is defined as \>20% increase (the absolute increase must be ≥10 IU/L) above the nadir on consecutive measurements separated by at least two weeks; Partial response is defined as a hCG decrease of 50% or more from starting value on consecutive measurements; Complete response will be defined as normalization of hCG on consecutive measurements separated by at least two weeks; Stable disease will be defined as the absence of response or progression on 3 consecutive measurements separated by at least two weeks.
Time frame: 8 weeks
Population: All patients who had a baseline scan and at least 1 on study assessment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TRC105 and/or Bevacizumab | Overall Response Rate on TRC105 Alone and on the Combination of TRC105 and Bevacizumab | Number of patients with best response of PR | 0 Participants |
| TRC105 and/or Bevacizumab | Overall Response Rate on TRC105 Alone and on the Combination of TRC105 and Bevacizumab | Number of patients with best response of SD | 0 Participants |
| TRC105 and/or Bevacizumab | Overall Response Rate on TRC105 Alone and on the Combination of TRC105 and Bevacizumab | Number of patients with best response of PD | 3 Participants |
| TRC105 and/or Bevacizumab | Overall Response Rate on TRC105 Alone and on the Combination of TRC105 and Bevacizumab | Number of patients with best response of CR | 0 Participants |
Secondary
Frequency and Severity of Adverse Events
Determine frequency and severity of adverse events as assessed by NCI CTCAE (Version 4.03)
Time frame: 20 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TRC105 and/or Bevacizumab | Frequency and Severity of Adverse Events | Participants who experienced an SAE | 1 Participants |
| TRC105 and/or Bevacizumab | Frequency and Severity of Adverse Events | Participants who experienced a TRC105 related SAE | 0 Participants |
Secondary
Maximum Plasma Concentration (Cmax) of TRC105.
Mean serum TRC105 concentrations were assessed at cycle 1 and cycle 2 on day 1, 8, 15, and 22 and on day 1 of every subsequent cycle using validated methods in order to determine the Cmax of TRC105
Time frame: cycle 2 day 1 (28 days after initiation of dosing)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| TRC105 and/or Bevacizumab | Maximum Plasma Concentration (Cmax) of TRC105. | 232500 ng/mL |
Secondary
Overall Response Rate on Bevacizumab Alone
Overall Response Rate on bevacizumab alone according to RECIST 1.1 in combination with serum hCG levels. Disease progression is defined as \>20% increase (the absolute increase must be ≥10 IU/L) above the nadir on consecutive measurements separated by at least two weeks; Partial response is defined as a hCG decrease of 50% or more from starting value on consecutive measurements; Complete response will be defined as normalization of hCG on consecutive measurements separated by at least two weeks; Stable disease will be defined as the absence of response or progression on 3 consecutive measurements separated by at least two weeks.
Time frame: 8 weeks
Population: No patients received bevacizumab alone.
Secondary
Progression-Free Survival (PFS)
Median Progression-Free Survival (PFS) via Serum hCG levels and response evaluation according to RECIST version 1.1 as a preliminary measure of the antitumor activity of TRC105. Disease progression is defined as \>20% increase (the absolute increase must be ≥10 IU/L) above the nadir on consecutive measurements separated by at least two weeks; Partial response is defined as a hCG decrease of 50% or more from starting value on consecutive measurements; Complete response will be defined as normalization of hCG on consecutive measurements separated by at least two weeks; Stable disease will be defined as the absence of response or progression on 3 consecutive measurements separated by at least two weeks. Patients must have screening (baseline) and at least one on study CT scan to be considered evaluable.
Time frame: 8 weeks
Population: Progression Free Survival
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TRC105 and/or Bevacizumab | Progression-Free Survival (PFS) | 6 weeks |
Secondary
TRC105 Immunogenicity as Assessed by Anti-Product Antibody (APA).
Anti-Product Antibody (APA) concentrations will be measured using validated ELISA methods at the time points specified in the protocol. APA concentrations will be evaluated in the context of pharmacokinetic parameters and AE profiles. Number of patients with positive APA titers on study will be reported.
Time frame: 8 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TRC105 and/or Bevacizumab | TRC105 Immunogenicity as Assessed by Anti-Product Antibody (APA). | Number of patients with negative APA | 1 Participants |
| TRC105 and/or Bevacizumab | TRC105 Immunogenicity as Assessed by Anti-Product Antibody (APA). | Number of patients with positive APA | 2 Participants |