Renal Cell Carcinoma
Conditions
Keywords
TRC105, CD105, RCC, Renal Cell Carcinoma, Axitinib, INLYTA, Advanced Renal Cell Carcinoma
Brief summary
Phase 1b: To evaluate safety and tolerability and determine a recommended phase 2 dose for TRC105 when added to standard dose axitinib in patients with advanced renal cell carcinoma. Phase 2: To estimate the PFS of patients with advanced or metastatic RCC by RECIST 1.1 criteria in patients treated with axitinib and TRC105 compared to those treated with axitinib alone, following failure of one prior VEGF TKI
Detailed description
Axitinib is an oral inhibitor of multiple receptor tyrosine kinases including vascular endothelial growth factor receptor VEGFR-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression. Axitinib is approved for the treatment of advanced renal cell carcinoma, following progression on one prior systemic therapy. TRC105 is an antibody to CD105, an important angiogenic target on vascular endothelial cells that is distinct from VEGFR. TRC105 inhibits angiogenesis, tumor growth and metastases in preclinical models and complements the activity of bevacizumab and multi-kinase inhibitors that target VEGFR. In a phase 1 study of advanced solid tumors,TRC105 therapy caused a global reduction in angiogenic biomarkers and reduced tumor burden at doses that were well-tolerated. By targeting a non-VEGF pathway that is upregulated following VEGF inhibition, TRC105 has the potential to complement VEGF inhibitors and could represent a major advance in cancer therapy. TRC105 potentiates bevacizumab and VEGFR tyrosine kinases (VEGFR TKI) in preclinical models. In a phase 1b study, the combination of TRC105 and bevacizumab produced radiographic reductions in tumor volume in bevacizumab refractory patients. Together, the use of TRC105 with axitinib may result in more effective angiogenesis inhibition and improved clinical efficacy over that seen with axitinib alone.
Interventions
DRUGTRC105 and Axitinib
DRUGAxitinib
Sponsors
Tracon Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed advanced or metastatic renal cell carcinoma with a clear cell component that has progressed by investigator assessment following treatment with one and only one multi-targeted tyrosine kinase inhibitor (TKI) other than axitinib that targets the VEGF receptor (VEGFR) (e.g., sunitinib, pazopanib, sorafenib, tivozanib, cabozantinib). One prior immunotherapy (interleukin-2 or interferon-alpha or immune checkpoint inhibitor or tumor vaccine) and one prior mTOR inhibitor treatment are allowed. 2. 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. 3. Measurable disease by RECIST 1.1 criteria 4. Age of 18 years or older 5. ECOG performance status ≤ 1 6. Resolution of all acute adverse events resulting from prior cancer therapies to NCI CTCAE grade ≤ 1 or baseline (except alopecia) 7. Adequate organ function as defined by the following criteria: 8. Willingness and ability to consent for self to participate in study 9. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
Exclusion criteria
1. Prior treatment with TRC105 or axitinib or any agent targeting the endoglin pathway (including a fusion protein that binds bone morphogenic protein) 2. Grade 3 or 4 toxicity related to prior VEGFR TKI that did not resolve to grade 1 3. Current treatment on another therapeutic clinical trial 4. Receipt of a small molecule anticancer agent, including an investigational anticancer small molecule, within 14 days of starting study treatment or receipt of a biologic anticancer agent (e.g., antibody) within 28 days of starting study treatment. 5. Prior radiation therapy within 28 days of starting the study treatment, except radiation therapy for bone metastases or radiosurgery is permitted up to 14 days of starting treatment 6. No major surgical procedure or significant traumatic injury within 6 weeks prior to study registration, and must have fully recovered from any such procedure; date of surgery (if applicable). Note: the following are not considered to be major procedures and are permitted up to 7 days before therapy initiation: Thoracentesis, paracentesis, port placement, laparoscopy, thorascopy, tube thoracostomy, bronchoscopy, endoscopic ultrasonographic procedures, mediastinoscopy, skin biopsies, incisional biopsies, imaging-guided biopsy for diagnostic purposes, and routine dental procedures 7. Uncontrolled chronic hypertension defined as systolic \> 150 or diastolic \> 90 despite optimal therapy (initiation or adjustment of BP medication prior to study entry is allowed provided that the average of 3 BP readings at a visit prior to enrollment is \< 150/90 mm Hg) 8. 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 at least 28 days. 9. Angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, PTCA or CABG within the past 6 months. Deep venous thrombosis within 6 months unless the patient is anticoagulated without the use of warfarin for at least 2 weeks. In this situation, low molecular weight heparin is preferred. 10. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g. hereditary hemorrhagic telangiectasia). 11. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to first day of study therapy 12. Known active viral or nonviral hepatitis or cirrhosis 13. History of hemorrhage or hemoptysis (\> ½ teaspoon bright red blood) within 3 months of starting study treatment 14. History of peptic ulcer disease within 3 months of treatment, unless treated for the condition and complete resolution has been documented by esophagogastroduodenoscopy (EGD) within 28 days of starting study treatment 15. History of gastrointestinal perforation or fistula in the past 6 months, or while previously on antiangiogenic therapy, unless underlying risk has been resolved (e.g., through surgical resection or repair) 16. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness 17. Requirement for concomitant medications that strongly induce or inhibit CYP3A4/5 18. Pregnancy or breastfeeding. Female patients must be surgically sterile (i.e.: hysterectomy) or be postmenopausal, or must agree to use effective contraception during the study and for 3 months following last dose of TRC105. All female patients of reproductive potential must have a negative pregnancy test (serum or urine) within 7 days prior to first dose. Male patients must be surgically sterile or must agree to use effective contraception during the study and for 3 months following last dose of TRC105. The definition of effective contraception will be based on the judgment of the Principal Investigator or a designated associate. 19. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Patients With DLT | 12 Months | Phase 1b: For dose limiting toxicity (DLT) evaluation, severity (grade) was classified according to common terminology criteria for adverse events version 4.0 (CTCAE v4.0). |
| Phase 2: Progression Free Survival (PFS) of Patients With RCC | 15 Months | Median progression free survival (PFS) of patients with advanced or metastatic RCC by RECIST 1.1. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b & 2: Response Rate of Patients With RCC | 15 Months | Number of patients with partial response (PR) or complete response (CR) by RECIST 1.1 criteria. 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. |
| Phase 2: Overall Response Rate of Patients With RCC by Choi | 15 Months | Overall response (OR) rate is the number of patients with partial response (PR) or complete response (CR) by Choi Criteria. Per Choi criteria for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), A decrease in size ≥ 10% or a decrease in tumor attenuation (Houndsfield units) ≥ 15% on CT and no new lesions; Overall Response (OR) = CR + PR. |
| Phase 1b & 2: Trough Concentrations of TRC105 by Dose Level in Phase 1b | 2.5 months (cycle 2 day 15) | Trough Serum TRC105 concentrations at steady state (cycle 2 day 15) were measured using validated ELISA methods. |
| Phase 1b & 2: Number of Patients With Development of Immunogenicity Antibodies. | 12 months | Anti-product antibody concentration were measured using validated ELISA methods. |
Countries
Czechia, Hungary, United Kingdom, United States
Participant flow
Recruitment details
23 patients enrolled in phase 1b portion. 150 patients randomized in the phase 2 portion.
Participants by arm
| Arm | Count |
|---|---|
| P1b: 8 mg/kg TRC105 Wkly + 5 mg Axitinib BID Phase 1b Dose Level 1: 8 mg/kg TRC105 weekly in combination with 5 mg Axitinib twice daily | 3 |
| P1b: 10 mg/kg TRC105 Wkly + 5 mg Axitinib BID Phase 1b Dose Level 2: 10 mg/kg TRC105 weekly in combination with 5 mg Axitinib twice daily | 15 |
| P1b: 10 mg/kg Wkly/15 mg/kg q2wks TRC105 + 5 mg Axitinib BID Phase 1b Dose Level 3: 10 mg/kg TRC105 weekly during cycle 1 then 15 mg/kg TRC105 every two weeks beginning in cycle 2 in combination with 5 mg Axitinib twice daily | 5 |
| P2 Arm A: 5 mg Axitinib BID Phase 2 Arm A: 5 mg Axitinib twice daily | 75 |
| P2 Arm B: 10 mg/kg TRC105 Wkly + 5 mg Axitinib BID Phase 2 Arm B: 10 mg/kg TRC105 weekly + 5 mg Axitinib twice daily | 75 |
| Total | 173 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Randomized Not Enrolled | 0 | 0 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | P1b: 8 mg/kg TRC105 Wkly + 5 mg Axitinib BID | P1b: 10 mg/kg TRC105 Wkly + 5 mg Axitinib BID | P1b: 10 mg/kg Wkly/15 mg/kg q2wks TRC105 + 5 mg Axitinib BID | P2 Arm A: 5 mg Axitinib BID | P2 Arm B: 10 mg/kg TRC105 Wkly + 5 mg Axitinib BID | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 2 Participants | 3 Participants | 40 Participants | 32 Participants | 80 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 13 Participants | 2 Participants | 35 Participants | 43 Participants | 93 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Caucasian | 3 Participants | 12 Participants | 5 Participants | 70 Participants | 71 Participants | 161 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 3 Participants | 0 Participants | 5 Participants | 1 Participants | 9 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Czechia | 0 participants | 0 participants | 0 participants | 8 participants | 5 participants | 13 participants |
| Region of Enrollment Hungary | 0 participants | 0 participants | 0 participants | 11 participants | 10 participants | 21 participants |
| Region of Enrollment United Kingdom | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United States | 3 participants | 15 participants | 5 participants | 56 participants | 59 participants | 138 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants | 18 Participants | 26 Participants | 48 Participants |
| Sex: Female, Male Male | 3 Participants | 13 Participants | 3 Participants | 57 Participants | 49 Participants | 125 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 15 | 0 / 5 | 3 / 74 | 6 / 73 |
| other Total, other adverse events | 3 / 3 | 15 / 15 | 5 / 5 | 71 / 74 | 72 / 73 |
| serious Total, serious adverse events | 1 / 3 | 4 / 15 | 3 / 5 | 27 / 74 | 28 / 73 |
Outcome results
Primary
Phase 1b: Number of Patients With DLT
Phase 1b: For dose limiting toxicity (DLT) evaluation, severity (grade) was classified according to common terminology criteria for adverse events version 4.0 (CTCAE v4.0).
Time frame: 12 Months
Population: Patients who discontinued the study prior to completing the DLT evaluation period were not evaluable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| P1b: 8 mg/kg TRC105 Wkly + 5 mg Axitinib BID | Phase 1b: Number of Patients With DLT | 0 Participants |
| P1b: 10 mg/kg TRC105 Wkly + 5 mg Axitinib BID | Phase 1b: Number of Patients With DLT | 0 Participants |
| P1b: 10 mg/kg Wkly/15 mg/kg q2wks TRC105 + 5 mg Axitinib BID | Phase 1b: Number of Patients With DLT | 0 Participants |
Primary
Phase 2: Progression Free Survival (PFS) of Patients With RCC
Median progression free survival (PFS) of patients with advanced or metastatic RCC by RECIST 1.1. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: 15 Months
Population: 95% confidence interval was applied. NA is listed for the confidence interval if there were not enough events to estimate a standard error. For Phase 2 all randomized patients were included in the efficacy population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| P1b: 8 mg/kg TRC105 Wkly + 5 mg Axitinib BID | Phase 2: Progression Free Survival (PFS) of Patients With RCC | 11.4 Months |
| P1b: 10 mg/kg TRC105 Wkly + 5 mg Axitinib BID | Phase 2: Progression Free Survival (PFS) of Patients With RCC | 6.7 Months |
Secondary
Phase 1b & 2: Number of Patients With Development of Immunogenicity Antibodies.
Anti-product antibody concentration were measured using validated ELISA methods.
Time frame: 12 months
Population: Patients must have had a baseline and on study assessment of immunogenicity and their baseline must have been negative.~Samples collected in the phase 2 portion of the study were not analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| P1b: 8 mg/kg TRC105 Wkly + 5 mg Axitinib BID | Phase 1b & 2: Number of Patients With Development of Immunogenicity Antibodies. | 1 Participants |
| P1b: 10 mg/kg TRC105 Wkly + 5 mg Axitinib BID | Phase 1b & 2: Number of Patients With Development of Immunogenicity Antibodies. | 0 Participants |
| P1b: 10 mg/kg Wkly/15 mg/kg q2wks TRC105 + 5 mg Axitinib BID | Phase 1b & 2: Number of Patients With Development of Immunogenicity Antibodies. | 0 Participants |
Secondary
Phase 1b & 2: Response Rate of Patients With RCC
Number of patients with partial response (PR) or complete response (CR) by RECIST 1.1 criteria. 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.
Time frame: 15 Months
Population: For Phase 1b patients with screening and at least one on study scan were included in the efficacy population. For Phase 2 all randomized patients were included in the efficacy population. Patients without a baseline scan and at least 1 on study scan were excluded from analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| P1b: 8 mg/kg TRC105 Wkly + 5 mg Axitinib BID | Phase 1b & 2: Response Rate of Patients With RCC | 0 Participants |
| P1b: 10 mg/kg TRC105 Wkly + 5 mg Axitinib BID | Phase 1b & 2: Response Rate of Patients With RCC | 22 Participants |
| P1b: 10 mg/kg Wkly/15 mg/kg q2wks TRC105 + 5 mg Axitinib BID | Phase 1b & 2: Response Rate of Patients With RCC | 23 Participants |
| P1b: 10 mg/kg TRC105 Wkly + 5 mg Axitinib BID | Phase 1b & 2: Response Rate of Patients With RCC | 5 Participants |
| P1b: 10 mg/kg Wkly/15 mg/kg q2wks TRC105 + 5 mg Axitinib BID | Phase 1b & 2: Response Rate of Patients With RCC | 0 Participants |
Secondary
Phase 1b & 2: Trough Concentrations of TRC105 by Dose Level in Phase 1b
Trough Serum TRC105 concentrations at steady state (cycle 2 day 15) were measured using validated ELISA methods.
Time frame: 2.5 months (cycle 2 day 15)
Population: In 1b patients with a predose sample collected at cycle 2 day 15 were averaged. Patients who missed a dose of TRC105 prior to cycle 2 day 15 were excluded from the analysis. Additional Phase 1b PK analysis beyond steady state concentration at cycle 2 day 15 were not performed. Samples collected in the phase 2 portion of the study were not analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| P1b: 8 mg/kg TRC105 Wkly + 5 mg Axitinib BID | Phase 1b & 2: Trough Concentrations of TRC105 by Dose Level in Phase 1b | 27650 ng/mL | Standard Deviation 39103 |
| P1b: 10 mg/kg TRC105 Wkly + 5 mg Axitinib BID | Phase 1b & 2: Trough Concentrations of TRC105 by Dose Level in Phase 1b | 140022 ng/mL | Standard Deviation 45403.01 |
| P1b: 10 mg/kg Wkly/15 mg/kg q2wks TRC105 + 5 mg Axitinib BID | Phase 1b & 2: Trough Concentrations of TRC105 by Dose Level in Phase 1b | 54375 ng/mL | Standard Deviation 23546.5 |
Secondary
Phase 2: Overall Response Rate of Patients With RCC by Choi
Overall response (OR) rate is the number of patients with partial response (PR) or complete response (CR) by Choi Criteria. Per Choi criteria for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), A decrease in size ≥ 10% or a decrease in tumor attenuation (Houndsfield units) ≥ 15% on CT and no new lesions; Overall Response (OR) = CR + PR.
Time frame: 15 Months
Population: For Phase 2 all randomized patients were included in the efficacy population. Patients without a baseline scan and at least 1 on study scan were excluded from analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| P1b: 8 mg/kg TRC105 Wkly + 5 mg Axitinib BID | Phase 2: Overall Response Rate of Patients With RCC by Choi | 50 Participants |
| P1b: 10 mg/kg TRC105 Wkly + 5 mg Axitinib BID | Phase 2: Overall Response Rate of Patients With RCC by Choi | 50 Participants |