Trial of TRC105 and Pazopanib Versus Pazopanib Alone in Patients With Advanced Angiosarcoma

NCT ID: NCT02979899

Last Updated: 2020-05-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 128 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-02-13
• Study Completion Date: 2019-08-31

Brief Summary

This is a study of TRC105 in combination with standard dose pazopanib compared to single agent pazopanib in patients with angiosarcoma not amenable to curative intent surgery (e.g., metastatic or bulky disease, and disease for which surgical resection would carry an unacceptable risk to the patient) who have not received pazopanib or TRC105 previously.

Detailed Description

TRC105 (carotuximab) is a monoclonal antibody to endoglin (CD105), an essential angiogenic target highly expressed on tumor vessels that is distinct from VEGFR. Endoglin is also expressed directly on tumor cells in angiosarcoma and is upregulated following VEGF inhibition. TRC105 inhibits angiogenesis, tumor growth and metastases in preclinical models and complements the activity of bevacizumab and multi-kinase inhibitors that target the VEGFR.

Pazopanib 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.

By targeting a non-VEGF pathway that is upregulated following VEGF inhibition, TRC105 has the potential to complement VEGFR tyrosine kinase inhibitors (TKIs) and could represent a major advance in the treatment of angiosarcoma. Together, the use of TRC105 with pazopanib may result in more effective angiogenesis inhibition and improved clinical efficacy over that seen with pazopanib alone.

Conditions

Advanced Angiosarcoma

Study Design

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

Study Groups

TRC105 plus votrient

weekly TRC105 i.v. in combination with standard dose votrient by mouth, once daily

Group Type: EXPERIMENTAL

TRC105

Intervention Type: BIOLOGICAL

TRC105 antibody

Votrient

Intervention Type: DRUG

pazopanib

votrient

standard dose votrient by mouth, once daily

Group Type: ACTIVE_COMPARATOR

Votrient

Intervention Type: DRUG

pazopanib

Interventions

TRC105

TRC105 antibody

Intervention Type: BIOLOGICAL

Votrient

pazopanib

Intervention Type: DRUG

Other Intervention Names

anti-endoglin antibody; carotuximab; pazopanib

Eligibility Criteria

Inclusion Criteria

1. Histologically-confirmed angiosarcoma that is not amenable to curative intent surgery (e.g., metastatic or bulky disease and disease for which surgical resection would carry an unacceptable risk to the patient). Pathology report will be reviewed by sponsor prior to randomization.

2. Documented progression on or following most recent systemic chemotherapy regimen (not required for chemotherapy-naïve patients), within 4 months prior to screening

3. Measurable disease by RECIST v1.1

4. Age of 18 years or older; in addition, patients age 12 to 17 years may enroll beginning in Cohort 2 if weight ≥ 40 kg

5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

6. Resolution of all acute AEs resulting from prior cancer therapies to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03) grade ≤ 1 or to that patient's pre-study baseline (except alopecia or neuropathy)

7. Adequate organ function

8. Willingness and ability to consent (and assent if under age 18) for self to participate in study

9. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures

10. Angiosarcoma tumor specimen, if available

11. Men who are sterile (including vasectomy confirmed by post vasectomy semen analysis) OR agree to use a condom with spermicide (refer to Section 2.6.1.3) and to not donate sperm during the study and for at least 180 days following last dose of TRC105 or pazopanib

12. Woman of non-child bearing potential due to surgical sterilization (at least 6 weeks following surgical bilateral oophorectomy with or without hysterectomy or tubal ligation) confirmed by medical history or menopause (i.e., no menstrual bleeding for more than 12 months in a women aged 45 years or more), 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 acceptable methods of birth control, one of which must be highly effective, during the study and for at least 180 days after stopping TRC105 or pazopanib

Exclusion Criteria

1. Prior treatment with TRC105

2. Prior treatment with any VEGF inhibitor

3. More than two prior lines (may be combination regimens) of chemotherapy for angiosarcoma (neoadjuvant/adjuvant treatment does not count as a line of treatment)

4. Current treatment or participation on another therapeutic clinical trial

5. Women who are pregnant or breastfeeding

6. Receipt of systemic anticancer therapy, including investigational agents, within 5 times the agent's elimination half-life of starting study treatment

7. Major surgical procedure or significant traumatic injury within 4 weeks prior to randomization and must have fully recovered from any such procedure or injury; planned surgery (if applicable) or the anticipated need for a major surgical procedure within the next six months. Note: the following are not considered to be major procedures and are permitted up to 7 days before randomization: Thoracentesis, paracentesis, port placement, laparoscopy, thoracoscopy, tube thoracostomy, bronchoscopy, endoscopic ultrasonographic procedures, mediastinoscopy, skin biopsies, and imaging-guided biopsy for diagnostic purposes

8. Patients who have received wide field radiotherapy ≤ 28 days (defined as > 50% of volume of pelvic bones or equivalent) or limited field radiation for palliation < 14 days prior to randomization

9. Uncontrolled hypertension defined as systolic > 150 or diastolic > 100 mm Hg on the average of the 3 most recent BP readings. Anti-hypertensives may be started prior to randomization.

10. Ascites or pleural effusion requiring intervention or that required intervention or recurred within three months prior to randomization

11. Pericardial effusion (except trace effusion identified by echocardiogram) within three months prior to randomization

12. 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 prior to randomization

13. Angina, myocardial infarction, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism , pulmonary embolism, percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG) within 6 months prior to randomization. Deep venous thrombosis within 3 months prior to randomization unrelated to a central venous catheter, unless the patient is anti-coagulated without the use of warfarin for at least 2 weeks prior to randomization. In this situation, low molecular weight heparin is preferred

14. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g., hereditary hemorrhagic telangiectasia). Patients with bleeding cutaneous lesions not actively requiring transfusions are eligible. Patients who have been uneventfully anti-coagulated with low molecular weight heparin are eligible

15. Hemoptysis (> ½ teaspoon [2.5 mL] of bright red blood) within 6 months prior to randomization

16. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to randomization

17. Known active viral or nonviral hepatitis or cirrhosis

18. Peptic ulcer within the past 3 months prior to randomization, unless treated for the condition and complete resolution has been documented by esophagogastroduodenoscopy (EGD)

19. Presence of tumor(s) invading into the heart or great vessels (including carotid artery) or another location where bleeding is associated with high morbidity including patients with primary cardiac or great vessel angiosarcoma

20. Gastrointestinal perforation or fistula in the 6 months prior to randomization unless underlying risk has been resolved (e.g., through surgical resection or repair)

21. Presence of a malabsorption syndrome, gastrointestinal disorder, or gastrointestinal surgery that could affect the absorption of pazopanib

22. History of prior malignancy except adequately treated basal cell or squamous cell skin cancer or adequately treated, with curative intent, cancer from which the patient is currently in complete remission per Investigator's judgment; patients with history of breast cancer and no evidence of disease on hormonal therapy to prevent recurrence and patients with prostate cancer on adjuvant hormonal therapy with undetectable PSA are eligible

23. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness

24. Active infection that requires systemic treatment

25. Concurrent use or receipt of a strong CYP3A4 inducer within 12 days prior to randomization or a strong CYP3A4 inhibitor within 7 days prior to randomization (see Table 10)

26. History of severe hypersensitivity reaction to any monoclonal antibody

27. Other severe acute or chronic medical (including bone marrow suppressive diseases) or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation, impede the ability of the patient to complete all protocol-specified activities, 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: 12 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

Role: STUDY_DIRECTOR

TRACON Pharmaceuticals

Locations

University of Arizona Cancer Center

Tucson, Arizona, United States

Stanford University

Palo Alto, California, United States

Sarcoma Oncology Center

Santa Monica, California, United States

University of Colorado Denver

Aurora, Colorado, United States

Mayo Clinic Jacksonville

Jacksonville, Florida, United States

Moffitt Cancer Center

Tampa, Florida, United States

Northside Hospital

Sandy Springs, Georgia, United States

University of Iowa

Iowa City, Iowa, United States

Johns Hopkins

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Mayo Clinic Rochester

Rochester, Minnesota, United States

Washington University St. Louis

St Louis, Missouri, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

Northwell Health

Lake Success, New York, United States

MSKCC

New York, New York, United States

Duke University

Durham, North Carolina, United States

Cleveland Clinic

Cleveland, Ohio, United States

Ohio State University

Columbus, Ohio, United States

Thomas Jefferson University

Philadelphia, Pennsylvania, United States

UPMC

Pittsburgh, Pennsylvania, United States

Vanderbilt University

Nashville, Tennessee, United States

MD Anderson

Houston, Texas, United States

University of Utah, Huntsman Cancer Institute

Salt Lake City, Utah, United States

University of Washinton

Seattle, Washington, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Medical University,Vienna

Vienna, , Austria

Institut Bergonié

Bordeaux, , France

Centre Oscar Lambret

Lille, , France

Centre Léon Bérard

Lyon, , France

Institut Gustave Roussy

Villejuif, , France

Helios Klinikum

Bad Saarow, , Germany

Mannheim University Medical Center

Mannheim, , Germany

Klinikum derUniversitat Munchen

Munich, , Germany

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, , Italy

Memorial Cancer Center and Institute of Oncology

Warsaw, , Poland

Institut Català d'Oncologia (ICO)

Barcelona, , Spain

12 de Octubre University Hospital

Madrid, , Spain

Royal Marsden NHS

Chelsea, , United Kingdom

Countries

United States; Austria; France; Germany; Italy; Poland; Spain; United Kingdom

References

Jones RL, Ravi V, Brohl AS, Chawla S, Ganjoo KN, Italiano A, Attia S, Burgess MA, Thornton K, Cranmer LD, Cheang MCU, Liu L, Robertson L, Adams B, Theuer C, Maki RG. Efficacy and Safety of TRC105 Plus Pazopanib vs Pazopanib Alone for Treatment of Patients With Advanced Angiosarcoma: A Randomized Clinical Trial. JAMA Oncol. 2022 May 1;8(5):740-747. doi: 10.1001/jamaoncol.2021.3547.

Reference Type: DERIVED

PMID: 35357396 (View on PubMed)

Mehta CR, Liu L, Theuer C. An adaptive population enrichment phase III trial of TRC105 and pazopanib versus pazopanib alone in patients with advanced angiosarcoma (TAPPAS trial). Ann Oncol. 2019 Jan 1;30(1):103-108. doi: 10.1093/annonc/mdy464.

Reference Type: DERIVED

PMID: 30357394 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

105SAR301

Identifier Type: -

Identifier Source: org_study_id