ClinicalTrials.gov
ClinicalTrials.gov Menu

A Phase 1B Dose-escalation and Phase 2a Study of Carotuximab (TRC105) in Combination With Pazopanib in Patients With Advanced Soft Tissue Sarcoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01975519
Recruitment Status : Active, not recruiting
First Posted : November 4, 2013
Last Update Posted : December 4, 2018
Sponsor:
Information provided by (Responsible Party):
Tracon Pharmaceuticals Inc.

Brief Summary:

The purpose of the phase 1b portion is to evaluate safety and tolerability and determine a recommended phase 2 dose for TRC105 when added to standard dose pazopanib in patients with advanced soft tissue sarcoma. Up to 30 patients will be treated.

The purpose of the phase 2 portion is to estimate the PFS of patients with advanced soft tissue sarcoma by RECIST 1.1 and estimate ORR in a separate cohort of patients with angiosarcoma by RECIST 1.1. Up to 89 patients will be treated in phase 2, including two cohorts of up to 13 patients with angiosarcoma.


Condition or disease Intervention/treatment Phase
Advanced Soft Tissue Sarcoma Drug: TRC105 and Pazopanib Phase 1 Phase 2

Detailed Description:
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. Pazopanib is approved for the treatment of advanced soft tissue sarcoma, following progression on one prior systemic therapy, based on improved progression free survival. 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 the 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. In a phase 1b study, the combination of TRC105 and bevacizumab produced radiographic reductions in tumor volume in bevacizumab-refractory patients, and was well tolerated. TRC105 potentiates bevacizumab and VEGFR tyrosine kinases (VEGFR TKI) in preclinical models. By targeting a non-VEGF pathway that is upregulated following VEGF inhibition, TRC105 has the potential to complement VEGFR TKIs and could represent a major advance in cancer therapy. Together, the use of TRC105 with pazopanib may result in more effective angiogenesis inhibition and improved clinical efficacy over that seen with pazopanib alone.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 111 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1B Dose-escalation and Phase 2a Study of Carotuximab (TRC105) in Combination With Pazopanib in Patients With Advanced Soft Tissue Sarcoma
Study Start Date : December 2013
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : March 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Pazopanib

Arm Intervention/treatment
Experimental: TRC105 and Pazopanib
Weekly TRC105 in combination with standard dose pazopanib or every two week administration during cycle 1, and starting on cycle 2 day 1 and beyond, TRC105 may be administered every two weeks. This is also in combination with standard dose pazopanib.
Drug: TRC105 and Pazopanib
Weekly TRC105 in combination with standard dose Pazopanib.
Other Names:
  • Chimeric Antibody (TRC105) to CD105
  • Votrient




Primary Outcome Measures :
  1. Maximum Tolerated Dose of TRC105 in Combination with Pazopanib (Phase 1b) [ Time Frame: 28 days ]
    Safety and dose limiting toxicity will be assessed by dose cohort.

  2. Progression free survival of patients with advanced soft tissue sarcoma (Phase 2) [ Time Frame: 12 months ]
    By RECIST 1.1

  3. Objective response rate in a cohort of patients with angiosarcoma (Phase 2) [ Time Frame: 12 months ]
    By RECIST 1.1


Secondary Outcome Measures :
  1. Response rate (phase 1) [ Time Frame: 12 months ]
    By RECIST 1.1

  2. Peak and trough concentrations of TRC105 (phase 1 and 2) [ Time Frame: 8 months ]
    Peak and trough serum TRC105 concentrations will be measured using validated ELISA methods.

  3. Development of immunogenicity antibodies (phase 1 and 2) [ Time Frame: 8 months ]
    Anti-Product Antibody (APA) concentrations will be measured using validated ELISA methods.

  4. Expression of endoglin on sarcoma tissue (phase 1 and 2) [ Time Frame: 12 months ]
    Expression will be determined by immunohistochemistry for each patient who received at least one dose of TRC105

  5. Concentrations of a panel of angiogenic protein biomarkers in plasma (phase 1 and 2) [ Time Frame: 24 months ]
    Plasma will be analyzed for biomarkers such as VEGF, VEGF-R2, PIGF, and sCD105

  6. Objective response rate in patients with advanced soft tissue sarcoma by RECIST 1.1 (phase 2) [ Time Frame: 12 months ]
    The best response (CR, PR, SD or PD according to RECIST 1.1) for each patient with measurable disease who received at least one dose of TRC105 study drug

  7. Progression free survival in a cohort of patients with angiosarcoma (phase 2) [ Time Frame: 12 months ]
    By RECIST 1.1

  8. Frequency and severity of adverse events (phase 2) [ Time Frame: 1 week ]
    By NCI CTCAE (Version 4.0)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   12 Years to 120 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically confirmed unresectable soft tissue sarcoma that has progressed following treatment with chemotherapy. Prior pazopanib is allowed if the drug was not discontinued for toxicity ( Phase 1b only)
  2. Histologically confirmed metastatic soft tissue sarcoma that has progressed by RECIST following treatment with anthracycline chemotherapy. Patients may have received up to four lines of systemic therapy for metastatic disease and no more than two lines of combination treatment ( Phase 2 only)
  3. Histologically confirmed locally advanced (e.g. unresectable) or metastatic angiosarcoma that has progressed following treatment with prior systemic therapy. Progression must be documented on or following the most recent systemic therapy. Prior pazopanib is allowed if the drug was not discontinued for toxicity (Phase 2 angiosarcoma cohorts only)
  4. Measurable disease by RECIST
  5. Age of 12 years or older (patient must weigh ≥ 40 kg)
  6. ECOG performance status ≤ 1
  7. Resolution of all acute adverse events resulting from prior cancer therapies to NCI CTCAE grade ≤ 1 or baseline (except alopecia or neuropathy)
  8. Adequate organ function.
  9. Willingness and ability to consent for self to participate in study
  10. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
  11. Available archival tumor specimen of the soft tissue sarcoma that meets inclusion criterion #1, #2 or #3

Exclusion Criteria:

  1. Prior treatment with TRC105
  2. Prior treatment with a VEGFR TKI (including pazopanib) (Phase 2 only)
  3. Current treatment on another therapeutic clinical trial
  4. Receipt of systemic anticancer therapy, including investigational agents, within 28 days of starting study treatment.
  5. 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) or the anticipated need for a major surgical procedure within the next six months.
  6. Patients who have received wide field radiotherapy ≤ 28 days or limited field radiation for palliation < 14 days prior to cycle 1 day 1 or those patients who have not recovered adequately from side effects of such therapy
  7. Uncontrolled chronic hypertension
  8. Significant ascites or pericardial or pleural effusion
  9. History of brain involvement with cancer, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease.
  10. 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 anti-coagulated without the use of warfarin for at least 2 weeks. In this situation, low molecular weight heparin is preferred.
  11. Active bleeding or pathologic condition that carries a high risk of bleeding. Patients who have been uneventfully anti-coagulated with low molecular weight heparin are eligible.
  12. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to first day of study therapy
  13. Known active viral or nonviral hepatitis or cirrhosis
  14. History of hemorrhage or hemoptysis within 3 months of starting study treatment
  15. History of peptic ulcer within the past 3 months of treatment
  16. History of gastrointestinal perforation or fistula in the past 6 months, or while previously on antiangiogenic therapy, unless underlying risk has been resolved
  17. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness
  18. Receipt of a strong CYP3A4 inducer within 12 days prior to cycle 1 day 1 or a strong CYP3A4 inhibitor within 7 days prior to cycle 1 day 1.
  19. 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.
  20. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01975519


Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35243
United States, California
Sarcoma Oncology Center
Santa Monica, California, United States, 90403
United States, Florida
Mayo Clinic Jacksonville
Jacksonville, Florida, United States, 32224
United States, Minnesota
Mayo Clinic Rochester
Rochester, Minnesota, United States, 55905
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 92122
Mount Sinai School of Medicine-Tisch Cancer Institute
New York, New York, United States, 10029
United States, North Carolina
Duke University
Durham, North Carolina, United States, 27710
United States, Texas
Mary Crowley Cancer Research Center
Dallas, Texas, United States, 75230
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84112
Sponsors and Collaborators
Tracon Pharmaceuticals Inc.
Investigators
Study Director: Charles Theuer, MD Tracon Pharmaceuticals Inc.

Responsible Party: Tracon Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT01975519     History of Changes
Other Study ID Numbers: 105SAR101
First Posted: November 4, 2013    Key Record Dates
Last Update Posted: December 4, 2018
Last Verified: November 2018

Keywords provided by Tracon Pharmaceuticals Inc.:
TRC105
CD105
Endoglin
Angiogenesis Inhibitor
STS
Soft Tissue Sarcoma
TKI
Tyrosine Kinase Inhibitor
Pazopanib
Votrient
Advanced Soft Tissue Sarcoma
Angiosarcoma

Additional relevant MeSH terms:
Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs