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

NCT ID: NCT01806064

Last Updated: 2020-10-19

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 173 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-03-08
• Study Completion Date: 2019-06-12

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.

Conditions

Renal Cell Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

TRC105 and Axitinib

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

Group Type: EXPERIMENTAL

TRC105 and Axitinib

Intervention Type: DRUG

Axitinib

Patients randomized to receive axitinib 5 mg twice daily

Group Type: ACTIVE_COMPARATOR

Axitinib

Intervention Type: DRUG

Interventions

TRC105 and Axitinib

Intervention Type: DRUG

Axitinib

Intervention Type: DRUG

Other Intervention Names

Chimeric Antibody (TRC105) to CD105; Inlyta; Inlyta

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tracon Pharmaceuticals Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Charles Theuer, MD PhD

Role: STUDY_DIRECTOR

ctheuer@traconpharma.com

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Mayo Clinic Arizona

Scottsdale, Arizona, United States

City of Hope

Duarte, California, United States

St. Joseph Heritage Healthcare

Fullerton, California, United States

University of California, Irvine

Irvine, California, United States

Cedars-Sinai Medical Center

Los Angeles, California, United States

University of California, Davis

Sacramento, California, United States

University of Florida

Gainesville, Florida, United States

University of Miami

Miami, Florida, United States

Moffitt Cancer Center

Tampa, Florida, United States

Illinois CancerCare

Peoria, Illinois, United States

Indiana Univeristy

Indianapolis, Indiana, United States

University of Iowa

Iowa City, Iowa, United States

University of Kentucky

Lexington, Kentucky, United States

Johns Hopkins University

Baltimore, Maryland, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

University of Michigan

Ann Arbor, Michigan, United States

Washington University in St. Louis

St Louis, Missouri, United States

Nebraska Cancer Specialists

Omaha, Nebraska, United States

Atlantic Health System

Morristown, New Jersey, United States

Gabrail Cancer Center Research

Canton, Ohio, United States

Ohio State University

Columbus, Ohio, United States

Oregon Health & Science University

Portland, Oregon, United States

Vanderbilt University

Nashville, Tennessee, United States

Joe Arrington Cancer Research & Treatment Center

Lubbock, Texas, United States

University of Utah

Salt Lake City, Utah, United States

Masaryk Institute

Brno, , Czechia

St. Anne's

Brno, , Czechia

University Hospital Brno

Brno, , Czechia

Na Bulovce Hospital

Prague, , Czechia

Thomayer Hospital

Prague, , Czechia

Integrated Szent Istvan and Szent Laszlo Hospital

Budapest, , Hungary

National Institute of Oncology

Budapest, , Hungary

University of Debrecen Medical Center Institute of Oncology

Debrecen, , Hungary

Kaposi Mor Teaching Hospital

Kaposvár, , Hungary

Medical Center of the University of Pecs

Pécs, , Hungary

Sussex Cancer Center, Royal Sussex County Hospital

Brighton, East Sussex, United Kingdom

Countries

United States; Czechia; Hungary; United Kingdom

References

Choueiri TK, Michaelson MD, Posadas EM, Sonpavde GP, McDermott DF, Nixon AB, Liu Y, Yuan Z, Seon BK, Walsh M, Jivani MA, Adams BJ, Theuer CP. An Open Label Phase Ib Dose Escalation Study of TRC105 (Anti-Endoglin Antibody) with Axitinib in Patients with Metastatic Renal Cell Carcinoma. Oncologist. 2019 Feb;24(2):202-210. doi: 10.1634/theoncologist.2018-0299. Epub 2018 Sep 6.

Reference Type: DERIVED

PMID: 30190302 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

105RC101

Identifier Type: -

Identifier Source: org_study_id