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A RANDOMIZED PHASE 3 TRIAL OF TRC105 AND PAZOPANIB VERSUS PAZOPANIB ALONE IN PATIENTS WITH ADVANCED ANGIOSARCOMA (TAPPAS)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2017 by Tracon Pharmaceuticals Inc.
Sponsor:
Information provided by (Responsible Party):
Tracon Pharmaceuticals Inc.
ClinicalTrials.gov Identifier:
NCT02979899
First received: November 29, 2016
Last updated: February 16, 2017
Last verified: February 2017
  Purpose
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.

Condition Intervention Phase
Advanced Angiosarcoma
Biological: TRC105
Drug: Votrient
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A RANDOMIZED PHASE 3 TRIAL OF TRC105 AND PAZOPANIB VERSUS PAZOPANIB ALONE IN PATIENTS WITH ADVANCED ANGIOSARCOMA (TAPPAS)

Resource links provided by NLM:


Further study details as provided by Tracon Pharmaceuticals Inc.:

Primary Outcome Measures:
  • To compare PFS of TRC105 and pazopanib vs single agent pazopanib in patients with unresectable angiosarcoma [ Time Frame: 24 months ]
    PFS is defined as time from randomization to either first disease progression (per independent radiology review of images by RECIST 1.1) or death from any cause.


Secondary Outcome Measures:
  • To compare the objective response rate (ORR) of TRC105 and pazopanib vs single agent pazopanib in patients with unresectable angiosarcoma [ Time Frame: 24 months ]
    Objective response rate (ORR) is defined as the number of patients with a best response of complete response (CR) or partial response (PR) divided by the number of randomized patients. ORR is defined as the best response designation recorded between the date of randomization and the date of documented progression, as determined by Central Radiographic Review according to RECIST 1.1, or date of subsequent therapy, whichever occurs first.

  • To compare overall survival (OS) of TRC105 and pazopanib vs single agent pazopanib in patients with unresectable angiosarcoma [ Time Frame: 24 months ]
    Overall Survival (OS) is defined as the time between the date of randomization and the date of death from any cause. Overall survival will be calculated in days as: Date of Death - Date of Randomization +1.

  • To assess the overall safety and tolerability of TRC105 and pazopanib vs single agent pazopanib in patients with unresectable angiosarcoma [ Time Frame: 24 months ]
    Type, incidence, severity (graded by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] Version 4.03), timing, seriousness, and relatedness of AEs and laboratory abnormalities.

  • To characterize patient reported outcomes between the two arms of the study [ Time Frame: 24 months ]
    Patient reported outcomes as measured by the EuroQol five dimensions questionnaire (EQ-5D-5L) and the EORTC QLQ-C30 questionnaire.

  • To characterize the pharmacokinetic (PK) profile of TRC105 and pazopanib between the two arms of the study [ Time Frame: 24 months ]
    TRC105 and pazopanib pharmacokinetic (PK) concentrations will be measured using validated methods from peak and trough samples.

  • To characterize the immunogenicity of TRC105 [ Time Frame: 24 months ]
    Anti-TRC105 antibodies will be measured using validated methods and anti-drug antibody (ADA) titers will be correlated with PK parameters and AEs.


Estimated Enrollment: 124
Actual Study Start Date: February 13, 2017
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: September 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: TRC105 plus votrient
weekly TRC105 i.v. in combination with standard dose votrient by mouth, once daily
Biological: TRC105
Other Names:
  • anti-endoglin antibody
  • carotuximab
Drug: Votrient
Other Name: pazopanib
Active Comparator: votrient
standard dose votrient by mouth, once daily
Drug: Votrient
Other Name: pazopanib

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.

  Eligibility

Ages Eligible for Study:   12 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02979899

Contacts
Contact: TRACON Clinical Trials 858-550-0780 clinicaltrials@traconpharma.com

  Show 39 Study Locations
Sponsors and Collaborators
Tracon Pharmaceuticals Inc.
Investigators
Study Director: Richard Yocum, MD TRACON Pharmaceuticals
  More Information

Responsible Party: Tracon Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT02979899     History of Changes
Other Study ID Numbers: 105SAR301
Study First Received: November 29, 2016
Last Updated: February 16, 2017
Individual Participant Data  
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Tracon Pharmaceuticals Inc.:
angiosarcoma

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

ClinicalTrials.gov processed this record on April 27, 2017