Non Small Cell Lung Cancer
Conditions
Brief summary
This is a single center, open-label, nonrandomized, phase 1b, dose-finding study of TRC105 in combination with standard dose bevacizumab and paclitaxel/carboplatin in treatment-naive patients with stage IV non-squamous NSCLC.
Detailed description
Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) that inhibits angiogenesis and extends survival in non-squamous non-small cell lung cancer (NSCLC) patients when given with carboplatin and paclitaxel. TRC105 is an antibody to endoglin, an essential angiogenic target expressed on proliferating endothelial cells that is distinct from the VEGFR and overexpressed in response to VEGF inhibition. TRC105 inhibits angiogenesis, tumor growth and metastases in preclinical models and complements the activity of antibodies and small molecules that target the VEGFR. In a phase 1b study, the combination of TRC105 and bevacizumab produced radiographic reductions in tumor volume in bevacizumab-refractory patients, and was well tolerated. TRC105 was also well tolerated with chemotherapy in a trial with capecitabine in breast cancer patients. The use of TRC105 with bevacizumab and paclitaxel/carboplatin may result in more effective angiogenesis inhibition and improved clinical efficacy over that seen with bevacizumab and paclitaxel/carboplatin alone.
Interventions
DRUGTRC105
Dose-finding study of TRC105 in combination with standard dose bevacizumab and paclitaxel/carboplatin in treatment-naive patients with stage IV non-squamous NSCLC.
Sponsors
University of Alabama at Birmingham
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
Key Inclusion Criteria: * Stage 4 Non-Squamous Cell Lung Cancer that has not been treated previously with systemic chemotherapy or bevacizumab, but may have received prior targeted treatment (e.g., alk1 inhibitor) * ECOG performance status ≤ 1 * Measurable disease by RECIST Key
Exclusion criteria
* Non-small cell lung cancer of squamous histology * Current treatment on another therapeutic clinical trial * 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 study registration or those patients who have not recovered adequately from side effects of such therapy * Active bleeding or pathologic condition that carries a high risk of bleeding (e.g. hereditary hemorrhagic telangiectasia). Patients who have been uneventfully anti-coagulated with low molecular weight heparin are eligible.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-Emergent Adverse Events | from screening until completion of follow-up, on average 6 months | Incidence of treatment-emergent (i.e. TRC105, bevacizumab, paclitaxel and/or carboplatin) adverse events by CTCAE v4.03 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall RECIST 1.1 Response Rate | 6 months | Response rate determined according to RECIST 1.1 criteria |
| Percent of Patients With Progression-free Survival (PFS) at 6 Months | 6 months | Number of patients with progression-free survival at 6 months determined according to RECIST 1.1 criteria |
| Median Progression Free Survival | months | Median duration of progression free survival according to RECIST 1.1 criteria |
| Pharmacokinetic Profile of TRC105 When Given With Bevacizumab and Paclitaxel/Carboplatin | 3 months | Trough serum TRC105 pharmacokinetic concentrations at steady state (cycle 3 day 1) will be measured using validated ELISA methods. |
| Number of Patients Who Have TRC105 Positive Anti-Product Antibodies | 6 months | Anti-product antibody concentrations will be measured using validated ELISA methods. Anti-product antibody concentrations will be evaluated in the context of pharmacokinetic parameters and AE profiles. |
Participant flow
Recruitment details
medical clinic
Participants by arm
| Arm | Count |
|---|---|
| 8 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin Dose Level 1: 8 mg/kg of TRC105 in combination with standard dose bevacizumab and paclitaxel/carboplatin in treatment-naive patients with stage IV non-squamous NSCLC. | 3 |
| 10 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin Dose Level 2: 10 mg/kg of TRC105 in combination with standard dose bevacizumab and paclitaxel/carboplatin in treatment-naive patients with stage IV non-squamous NSCLC. | 12 |
| Total | 15 |
Baseline characteristics
| Characteristic | 10 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | 8 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Total |
|---|---|---|---|
| Age, Continuous | 70 years | 69 years | 69 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 3 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Number of prior regimens | 0 number of prior regimens | 0 number of prior regimens | 0 number of prior regimens |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 3 Participants | 12 Participants |
| Region of Enrollment United States | 12 participants | 3 participants | 15 participants |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 8 Participants |
| Sex: Female, Male Male | 6 Participants | 1 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 15 | 0 / 1 | 0 / 12 | 0 / 5 | 0 / 6 | 0 / 9 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 2 | 0 / 1 |
| other Total, other adverse events | 15 / 15 | 1 / 1 | 12 / 12 | 5 / 5 | 6 / 6 | 7 / 9 | 5 / 5 | 5 / 5 | 5 / 5 | 2 / 2 | 1 / 1 |
| serious Total, serious adverse events | 3 / 15 | 0 / 1 | 1 / 12 | 0 / 5 | 0 / 6 | 1 / 9 | 1 / 5 | 1 / 5 | 2 / 5 | 2 / 2 | 0 / 1 |
Outcome results
Primary
Treatment-Emergent Adverse Events
Incidence of treatment-emergent (i.e. TRC105, bevacizumab, paclitaxel and/or carboplatin) adverse events by CTCAE v4.03
Time frame: from screening until completion of follow-up, on average 6 months
Population: All patients who received at least a portion of a dose of any study drug (TRC105, Bevacizumab or Paclitaxel/Carboplatin)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 8 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Treatment-Emergent Adverse Events | Participants who experienced a TRC105 related AE | 3 Participants |
| 8 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Treatment-Emergent Adverse Events | Participants who experienced a Carbo related AE | 3 Participants |
| 8 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Treatment-Emergent Adverse Events | Participants who experienced a Bev related AE | 3 Participants |
| 8 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Treatment-Emergent Adverse Events | Participants who experienced a Pac related AE | 3 Participants |
| 8 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Treatment-Emergent Adverse Events | Participants who experienced an AE | 3 Participants |
| 10 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Treatment-Emergent Adverse Events | Participants who experienced a Pac related AE | 12 Participants |
| 10 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Treatment-Emergent Adverse Events | Participants who experienced an AE | 12 Participants |
| 10 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Treatment-Emergent Adverse Events | Participants who experienced a TRC105 related AE | 11 Participants |
| 10 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Treatment-Emergent Adverse Events | Participants who experienced a Bev related AE | 10 Participants |
| 10 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Treatment-Emergent Adverse Events | Participants who experienced a Carbo related AE | 12 Participants |
Secondary
Median Progression Free Survival
Median duration of progression free survival according to RECIST 1.1 criteria
Time frame: months
Population: Number of patients progression free according to RECIST 1.1 after 6 months of treatment
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| 8 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Median Progression Free Survival | 3 Months | Standard Deviation 1.73 |
| 10 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Median Progression Free Survival | 6.5 Months | Standard Deviation 3.35 |
Secondary
Number of Patients Who Have TRC105 Positive Anti-Product Antibodies
Anti-product antibody concentrations will be measured using validated ELISA methods. Anti-product antibody concentrations will be evaluated in the context of pharmacokinetic parameters and AE profiles.
Time frame: 6 months
Population: All patients who received at least a portion of a dose of TRC105 with immunogenicity samples collected at baseline and at least 1 time point on study
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 8 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Number of Patients Who Have TRC105 Positive Anti-Product Antibodies | Ptn with low titer treatment emergent ADA | 0 Participants |
| 8 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Number of Patients Who Have TRC105 Positive Anti-Product Antibodies | Ptn without treatment emergent ADA | 3 Participants |
| 10 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Number of Patients Who Have TRC105 Positive Anti-Product Antibodies | Ptn with low titer treatment emergent ADA | 1 Participants |
| 10 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Number of Patients Who Have TRC105 Positive Anti-Product Antibodies | Ptn without treatment emergent ADA | 10 Participants |
Secondary
Overall RECIST 1.1 Response Rate
Response rate determined according to RECIST 1.1 criteria
Time frame: 6 months
Population: Number of patients with a baseline scan and at least 1 on study scan were evaluable for response rate determination
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 8 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Overall RECIST 1.1 Response Rate | Stable Disease Best Response | 2 Participants |
| 8 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Overall RECIST 1.1 Response Rate | Partial Response Best Response | 1 Participants |
| 8 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Overall RECIST 1.1 Response Rate | Progressive Disease Best Response | 0 Participants |
| 8 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Overall RECIST 1.1 Response Rate | Complete Response Best Response | 0 Participants |
| 10 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Overall RECIST 1.1 Response Rate | Complete Response Best Response | 0 Participants |
| 10 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Overall RECIST 1.1 Response Rate | Stable Disease Best Response | 9 Participants |
| 10 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Overall RECIST 1.1 Response Rate | Progressive Disease Best Response | 0 Participants |
| 10 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Overall RECIST 1.1 Response Rate | Partial Response Best Response | 3 Participants |
Secondary
Percent of Patients With Progression-free Survival (PFS) at 6 Months
Number of patients with progression-free survival at 6 months determined according to RECIST 1.1 criteria
Time frame: 6 months
Population: Number of patients progression free according to RECIST 1.1 after 6 months of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 8 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Percent of Patients With Progression-free Survival (PFS) at 6 Months | 1 Participants |
| 10 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Percent of Patients With Progression-free Survival (PFS) at 6 Months | 7 Participants |
Secondary
Pharmacokinetic Profile of TRC105 When Given With Bevacizumab and Paclitaxel/Carboplatin
Trough serum TRC105 pharmacokinetic concentrations at steady state (cycle 3 day 1) will be measured using validated ELISA methods.
Time frame: 3 months
Population: All patients who received at least a portion of a dose of TRC105 with PK samples collected at baseline and at least 1 time point on study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 8 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Pharmacokinetic Profile of TRC105 When Given With Bevacizumab and Paclitaxel/Carboplatin | 56600 ng/mL |
| 10 mg/kg TRC105 + Bevacizumab + Paclitaxel/Carboplatin | Pharmacokinetic Profile of TRC105 When Given With Bevacizumab and Paclitaxel/Carboplatin | 103228 ng/mL |