A Randomized Phase 2 Trial of Axitinib and TRC105 Versus Axitinib Alone in Patients With Advanced or Metastatic Renal Cell Carcinoma

Study Description

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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

Condition or disease	Intervention/treatment	Phase
Renal Cell Carcinoma	Drug: TRC105 and Axitinib	Phase 1; Phase 2

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	168 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Study Start Date :	March 2013
Estimated Primary Completion Date :	December 2017
Estimated Study Completion Date :	June 2018

Arms and Interventions

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Arm	Intervention/treatment
Experimental: TRC105 and Axitinib	Drug: TRC105 and Axitinib; Other Names: Chimeric Antibody (TRC105) to CD105; INLYTA

Outcome Measures

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Primary Outcome Measures :

1. Phase 1b [ Time Frame: 1 Year ]
   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
2. Phase 2 [ Time Frame: 15 Months ]
   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.

Secondary Outcome Measures :

1. Phase 1b: [ Time Frame: 1 Year ]

   To look for preliminary evidence of antitumor activity when TRC105 is added to axitinib, by assessing overall response rate and progression-free survival

   To characterize the pharmacokinetic profile of TRC105 when given with axitinib

   To evaluate TRC105 immunogenicity by measuring human antimurine antibody (HAMA) and human antichimeric antibody (HACA) formation

   To explore the pharmacodynamic changes in circulating angiogenic biomarkers following treatment with TRC105 and axitinib

2. Phase 2 [ Time Frame: 15 Months ]
   To estimate overall response rate by RECIST 1.1 and Choi criteria, including duration of response by RECIST 1.1 To estimate the disease control rate (CR + PR + SD) at 12 weeks by RECIST 1.1 and Choi criteria, and to estimate the time to next metastasis To determine the frequency and severity of adverse events as assessed by NCI CTCAE (Version 4.0) To evaluate TRC105 immunogenicity as measured by human anti-murine antibody (HAMA) and human anti-chimeric antibody (HACA) concentrations To explore the effects of TRC105 on circulating angiogenic protein biomarkers

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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Sponsors and Collaborators

Tracon Pharmaceuticals Inc.

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Tracon Pharmaceuticals Inc.
ClinicalTrials.gov Identifier:	NCT01806064 History of Changes
Other Study ID Numbers:	105RC101
First Posted:	March 7, 2013
Last Update Posted:	October 6, 2017
Last Verified:	October 2017

Keywords provided by Tracon Pharmaceuticals Inc.:

TRC105; CD105; RCC; Renal Cell Carcinoma	Axitinib; INLYTA; Advanced Renal Cell Carcinoma

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Renal Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site	Kidney Diseases; Urologic Diseases; Axitinib; Antibodies, Monoclonal; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunologic Factors; Physiological Effects of Drugs