Hepatocellular Carcinoma
Conditions
Keywords
TRC105, CD105, Endoglin, Angiogenesis inhibitor, HCC, TKI, Tyrosine Kinase Inhibitor, Sorafenib, Nexavar
Brief summary
The purpose of the phase 1b portion is to evaluate safety and tolerability and determine a recommended phase 2 dose for TRC105 when added to standard dose sorafenib in patients with hepatocellular carcinoma. Up to 18 patients will be treated. The purpose of the phase 2 portion is to estimate the ORR of patients with hepatocellular carcinoma by RECIST 1.1. Up to 21 patients will be treated in phase 2.
Detailed description
Sorafenib is an oral multikinase inhibitor targeting several receptor tyrosine kinases, including the VEGF receptor (VEGFR), implicated in pathologic angiogenesis, tumor growth, and cancer progression. Sorafenib is approved for the treatment of unresectable hepatocellular carcinoma (HCC). TRC105 is an antibody to endoglin, an important angiogenic target on proliferating endothelial cells that is distinct from VEGFR. TRC105 inhibits angiogenesis, tumor growth and metastases and complements the activity of bevacizumab and multi-kinase inhibitors that target the VEGFR in preclinical models. Together, the use of TRC105 with sorafenib may result in more effective angiogenesis inhibition and improved clinical efficacy over that seen with sorafenib alone.
Interventions
Bi-weekly iv TRC105 (15 mg/kg) will be given with 400mg sorafenib twice daily in the phase 1B portion of the study. Weekly iv TRC105 (10 mg/kg) will be given with 400mg sorafenib twice daily in the phase 2 portion of the study.
DRUGSorafenib
400 mg of sorafenib will be given twice daily.
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. Patients must have confirmed hepatocellular carcinoma (HCC) by histopathology or imaging criteria according to AASLD guidelines. 2. Patients must have disease that is not amenable to potentially curative resection or ablative techniques or that has recurred following ablative techniques. In addition, disease must not be amenable to transhepatic arterial chemoembolization (TACE) or must have progressed on TACE. Patients must not be candidates for liver transplantation. 3. If liver cirrhosis is present, patient must have a Child-Pugh A or B (7 points) classification. 4. No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission per investigators' clinical judgment. 5. Measurable disease by RECIST 1.1 (Phase 2 only) 6. Age of 18 years or older 7. ECOG performance status ≤ 1 8. Resolution of all acute adverse events resulting from prior cancer therapies to NCI CTCAE grade ≤ 1 or baseline 9. Adequate organ function 10. Willingness and ability to consent to participate in study 11. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures 12. Men who are sterile OR agree to use at least two forms of a reliable and highly effective method of birth control and to not donate sperm and for at least 180 days following last dose of TRC105 or sorafenib. 13. Woman of non-child bearing potential due to surgical sterilization confirmed by medical history or menopause, OR woman of child bearing potential who test negative for pregnancy at time of enrollment based on serum pregnancy test and agree to use at least 2 forms of a reliable and highly effective method of birth control during the study and for at least 180 days after stopping TRC105 or sorafenib.
Exclusion criteria
1. Prior anticancer systemic therapy 2. Current treatment on another therapeutic clinical trial 3. Prior radiation therapy within 28 days of starting the study treatment 4. No major surgical procedure or significant traumatic injury within 6 weeks prior to study registration, and must have fully recovered from any such procedure. 5. Proteinuria 6. Uncontrolled chronic hypertension defined as systolic \> 150 or diastolic \> 90 despite optimal therapy. 7. History of brain involvement with cancer, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease. 8. Angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, PTCA or CABG within the past 6 months. 9. Active bleeding or pathologic condition that carries a high risk of bleeding. No bleeding diathesis. 10. Thrombolytic use within 10 days prior to first day of study therapy 11. History of hemorrhage or hemoptysis (\> ½ teaspoon bright red blood) within 3 months of starting study treatment 12. Need for anticoagulation 13. History of liver transplant 14. History of bleeding esophageal varices in previous 6 months, which have not been adequately managed with banding or sclerotherapy. 15. History of peptic ulcer disease within 3 months of treatment. 16. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness 17. Patients may not have received a strong CYP3A4 inducer within 12 days prior to registration 18. Patients with known hypersensitivity to Chinese hamster ovary products or other recombinant human, chimeric, or humanized antibodies. 19. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 20. Ascites or pleural effusion requiring intervention or that required intervention within the last month and has recurred 21. Pericardial effusion (except trace effusion identified by echocardiogram)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Experience Dose Limiting Toxicities by Dose Level | 4 months | If 1 of 3 patients experienced a DLT, the dose level was expanded to 6 patients. The maximum tolerated dose (MTD) would have been exceeded if ≥ 33% of patients experience DLT at a given dose level. DLT occurred when a patient had 1 or more toxicities outlined in the protocol that was considered at least possibly related to TRC105 during the first 4 months of participation in the trial. The number of DLTs by dose cohort have been presented. |
| Overall Response Rate (ORR) | 4 months | Number of patients with a response (PR or CR) are included by dose level. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Patients must have had a screening scan and at least 1 on study scan to be eligible for RECIST 1.1 evaluation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Profile of TRC105 When Given With Sorafenib | 5 weeks | Steady state mean trough serum concentrations by dose level of TRC105 after 5 weeks of dosing were measured using validated methods after 5 weeks of dosing. |
| TRC105 Immunogenicity as Assessed by Anti-Product Antibody (APA) | 19 months | Number of patients who tested positive for antibodies to TRC105 by dose level. Anti-Product Antibody (APA) concentrations were measured using validated ELISA methods. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Carotuximab (10 mg/kg wk to 15 mg/kg Bi-wk) Plus Sorafenib Carotuximab (TRC105) given weekly (10 mg/kg) for 2 cycles then bi-weekly iv TRC105 (15 mg/kg) with 400mg sorafenib twice daily | 14 |
| Carotuximab (10 mg/kg Weekly) Plus Sorafenib Carotuximab (TRC105) given weekly iv (10 mg/kg) with 400mg sorafenib twice daily | 13 |
| Total | 27 |
Baseline characteristics
| Characteristic | Carotuximab (10 mg/kg wk to 15 mg/kg Bi-wk) Plus Sorafenib | Carotuximab (10 mg/kg Weekly) Plus Sorafenib | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 7 Participants | 15 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 12 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 5 Participants | 7 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 9 Participants | 7 Participants | 16 Participants |
| Region of Enrollment United States | 14 participants | 13 participants | 27 participants |
| Sex: Female, Male Female | 0 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 14 Participants | 9 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 13 |
| other Total, other adverse events | 14 / 14 | 13 / 13 |
| serious Total, serious adverse events | 5 / 14 | 9 / 13 |
Outcome results
Primary
Number of Patients Who Experience Dose Limiting Toxicities by Dose Level
If 1 of 3 patients experienced a DLT, the dose level was expanded to 6 patients. The maximum tolerated dose (MTD) would have been exceeded if ≥ 33% of patients experience DLT at a given dose level. DLT occurred when a patient had 1 or more toxicities outlined in the protocol that was considered at least possibly related to TRC105 during the first 4 months of participation in the trial. The number of DLTs by dose cohort have been presented.
Time frame: 4 months
Population: Patients must have received at least a portion of a dose of TRC105 or sorafenib to be evaluable for assessment of DLT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carotuximab (10 mg/kg wk to 15 mg/kg Bi-wk) Plus Sorafenib | Number of Patients Who Experience Dose Limiting Toxicities by Dose Level | 1 Participants |
| Carotuximab (10 mg/kg Weekly) Plus Sorafenib | Number of Patients Who Experience Dose Limiting Toxicities by Dose Level | 0 Participants |
Primary
Overall Response Rate (ORR)
Number of patients with a response (PR or CR) are included by dose level. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Patients must have had a screening scan and at least 1 on study scan to be eligible for RECIST 1.1 evaluation.
Time frame: 4 months
Population: Patients must have had a screening scan and at least 1 on study scan to be eligible for RECIST 1.1 evaluation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carotuximab (10 mg/kg wk to 15 mg/kg Bi-wk) Plus Sorafenib | Overall Response Rate (ORR) | 2 Participants |
| Carotuximab (10 mg/kg Weekly) Plus Sorafenib | Overall Response Rate (ORR) | 1 Participants |
Secondary
Pharmacokinetic Profile of TRC105 When Given With Sorafenib
Steady state mean trough serum concentrations by dose level of TRC105 after 5 weeks of dosing were measured using validated methods after 5 weeks of dosing.
Time frame: 5 weeks
Population: Steady state mean trough serum concentration by dose level after 5 weeks of dosing. Patients must have received all protocol required TRC105 doses to be included in the analysis. Additional analysis were not performed as TRC105 development overall was canceled due to lack of efficacy.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Carotuximab (10 mg/kg wk to 15 mg/kg Bi-wk) Plus Sorafenib | Pharmacokinetic Profile of TRC105 When Given With Sorafenib | 14.2 ug/ML | Standard Deviation 12.1 |
| Carotuximab (10 mg/kg Weekly) Plus Sorafenib | Pharmacokinetic Profile of TRC105 When Given With Sorafenib | 44.7 ug/ML | Standard Deviation 9 |
Secondary
TRC105 Immunogenicity as Assessed by Anti-Product Antibody (APA)
Number of patients who tested positive for antibodies to TRC105 by dose level. Anti-Product Antibody (APA) concentrations were measured using validated ELISA methods.
Time frame: 19 months
Population: Number of patients who tested positive for antibodies to TRC105. Patients must have tested negative for TRC105 antibodies at baseline and have had an on study test performed to be included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carotuximab (10 mg/kg wk to 15 mg/kg Bi-wk) Plus Sorafenib | TRC105 Immunogenicity as Assessed by Anti-Product Antibody (APA) | 9 Participants |
| Carotuximab (10 mg/kg Weekly) Plus Sorafenib | TRC105 Immunogenicity as Assessed by Anti-Product Antibody (APA) | 5 Participants |