Randomized Phase 2 Trial of Axitinib and TRC105 Versus Axitinib Alone in Patients Renal Cell Carcinoma

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized Phase 2 Trial of Axitinib and TRC105 Versus Axitinib Alone (Including a lead-in Phase 1B Dose Escalation Portion) in Patients With Advanced or Metastatic Renal Cell Carcinoma

Conditions
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Renal Cell Carcinoma

Intervention / Treatment
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* Drug: TRC105 and Axitinib
* Drug: Axitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. Measurable disease by RECIST 1.1 criteria Age of 18 years or older ECOG performance status ≤ 1 Resolution of all acute adverse events resulting from prior cancer therapies to NCI CTCAE grade ≤ 1 or baseline (except alopecia) Adequate organ function as defined by the following criteria: Willingness and ability to consent for self to participate in study Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures Exclusion Criteria: Prior treatment with TRC105 or axitinib or any agent targeting the endoglin pathway (including a fusion protein that binds bone morphogenic protein) Grade 3 or 4 toxicity related to prior VEGFR TKI that did not resolve to grade 1 Current treatment on another therapeutic clinical trial 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. 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 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 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) 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. 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. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g. hereditary hemorrhagic telangiectasia). Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to first day of study therapy Known active viral or nonviral hepatitis or cirrhosis History of hemorrhage or hemoptysis (> ½ teaspoon bright red blood) within 3 months of starting study treatment 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 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) Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness Requirement for concomitant medications that strongly induce or inhibit CYP3A4/5 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. 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TRC105 and Axitinib<br>Patients randomized to receive TRC105 at 3 mg/kg on day 1, 7 mg/kg on day 4, and 10 mg/kg on day 8 and weekly thereafter in combination with axitinib 5 mg twice daily | Drug: TRC105 and Axitinib<br> <br> * Other names: Inlyta;|
| Active Comparator: Axitinib<br>Patients randomized to receive axitinib 5 mg twice daily | Drug: Axitinib<br> <br> * Other names: Inlyta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 12 Months | 
| 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. | 15 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 15 Months | 
| 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. | 15 Months | 
| 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. | 2.5 months (cycle 2 day 15) | 
| Phase 1b & 2: Number of Patients With Development of Immunogenicity Antibodies. | Anti-product antibody concentration were measured using validated ELISA methods. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RCC, TRC105, CD105, Renal Cell Carcinoma, Axitinib, INLYTA, Advanced Renal Cell Carcinoma