Trial of TRC105 and Pazopanib Versus Pazopanib Alone in Patients With Advanced Angiosarcoma
Condition: Advanced Angiosarcoma
MeSH terms: Hemangiosarcoma
Intervention: TRC105; Votrient
Intervention description: TRC105 antibody; pazopanib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 128.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No
Keywords: angiosarcoma

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.
    

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