TRC105 for Recurrent Glioblastoma
Condition: Glioblastoma Multiforme
MeSH terms: Glioblastoma
Intervention: TRC105
Intervention description: Intravenous infusion.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Glioblastoma; Anti-Angiogenesis; Radiotherapy; Malignant Glioma; Progression

Summary:

      Background:

      - Glioblastoma is an aggressive type of brain cancer that often resists treatment. TRC105 is
      an experimental drug that blocks the growth of new blood vessels. It is being studied for
      possible use in treating different kinds of cancer. Researchers want to see if TRC105 can be
      used to treat glioblastoma that has not responded to standard treatments.

      Objectives:

      - To test the safety and effectiveness of TRC105 in adults who have glioblastoma that has not
      responded to standard treatments.

      Eligibility:

      - Individuals at least 18 years of age who have glioblastoma that has not responded to
      standard treatments.

      Design:

        -  Participants will be screened with a physical exam and medical history. Blood and urine
           samples will be collected. Imaging studies and other tests will be used to study the
           tumor before the start of treatment.

        -  Participants will have 28-day (4-week) cycles of treatment.

        -  Participants will have TRC105 intravenously once a week. The first infusion will take
           about 4 hours. The length of time needed for the infusion may be slowly reduced if it is
           well tolerated.

        -  At the end of the first cycle (the first 4 weeks), the imaging studies will be repeated
           before continuing TRC105.

        -  Participants will take TRC105 for as long as the tumor does not grow and the side
           effects are not too severe. They will have imaging studies at the end of every cycle to
           evaluate the tumor.
    

Eligibility criteria:

        -  INCLUSION CRITERIA

          -  Patients must have histologically confirmed glioblastoma or gliosarcoma.

          -  Patients must have evidence for tumor progression by magnetic resonance imaging (MRI)
             or computed tomography (CT) scan. This scan should be performed within 14 days prior
             to registration and on a fixed dose of steroids for at least 5 days. If the steroid
             dose is increased between the date of imaging and registration a new baseline MR/CT is
             required. The same type of scan, ie, MRI or CT must be used throughout the period of
             protocol treatment for tumor measurement.

          -  Patients must have progressed after radiation therapy and must have an interval of
             greater

          -  Patients must have recovered from the toxic effects of prior therapy: 4 weeks from any
             investigational agent, 4 weeks from prior cytotoxic therapy, two weeks from
             vincristine, 6 weeks from nitrosoureas, 3 weeks from procarbazine administration, and
             1 week for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide,
             cis-retinoic acid, etc. Any questions related to the definition of non-cytotoxic
             agents should be directed to the Study Chair. All toxicities from prior therapies
             should be resolved to National Cancer Institute (NCI) Common Terminology Criteria for
             Adverse Events (CTCAE) less than or equal to grade 1 (except for toxicities such as
             alopecia or vitiligo).

          -  Patients must be > 18 years old. Because no dosing or adverse event data are currently
             available on the use of TRC105 in patients < 18 years of age, children are excluded
             from this study, but will be eligible for future pediatric trials.

          -  Karnofsky performance status > 60%

          -  Life expectancy of greater than 12 weeks.

          -  Patients must have normal organ and marrow function as defined below:

               -  leukocytes > 3,000/microliter

               -  absolute neutrophil count > 1,500/microliter

               -  platelets > 100,000/microliter

               -  total bilirubin < 1.5 times ULN institutional upper limit of normal

               -  Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase
                  (SGOT)/alanine aminotransaminase (ALT) serum glutamic pyruvic transaminase (SGPT)
                  < 2.5 times institutional upper limit of normal

               -  Prothrombin time (PT)/Partial thromboplastin time (PTT) < 1.5 times institutional
                  upper limit of normal

          -  creatinine < 1.5 times ULN within normal institutional limits

        OR

        --creatinine clearance > 60 glomerular filtration rate for patients with creatinine

        levels above institutional normal.

          -  hemoglobin of > 9grams/deciliter without transfusion support in the past 28 days

               -  Patients must not have any significant medical illnesses that, in the
                  investigators opinion, cannot be adequately controlled with appropriate therapy
                  or would compromise the patients ability to tolerate this therapy

               -  Patients having undergone recent resection of recurrent or progressive tumor will
                  be eligible as long as all of the following conditions apply:

          -  They have recovered from the effects of surgery.

          -  They should have residual disease following resection of recurrent tumor.

        To best assess the extent of residual disease post-operatively, a computed tomography (CT)/
        magnetic resonance imaging (MRI) should be done:

        no later than 96 hours in the immediate post-operative period and

          -  at least 4 weeks post-operatively, and

          -  within 14 days of registration, and

          -  on a steroid dosage that has been stable for at least 5 days.

        If the steroid dose is increased between the date of imaging and registration, a new
        baseline MRI/CT is required on a stable steroid dosage for at least 5 days.

          -  The effects of TRC105 on the developing human fetus are unknown. For this reason and
             because antiangiogenic agents are known to be teratogenic, women of child-bearing
             potential and men must agree to use adequate contraception (hormonal or barrier method
             of birth control; abstinence) prior to study entry and for the duration of study
             participation. Should a woman become pregnant or suspect she is pregnant while she or
             her partner is participating in this study, she should inform her treating physician
             immediately. Men treated or enrolled on this protocol must also agree to use adequate
             contraception prior to the study, for the duration of study participation, and 4
             months after completion of TRC105 administration.

          -  Patients must have the ability to understand and the willingness to sign a written
             informed consent document.

          -  A baseline 12 lead electrocardiogram (ECG) to be performed within 2 weeks of trial

        EXCLUSION CRITERIA

          -  Patients who are receiving any other investigational agents and/or who have received
             an investigational agent in the prior 28 days.

          -  Patients may not have had prior therapy with vascular endothelial growth factor (VEGF)
             receptor inhibitors.

          -  Patients with a history of peptic ulcer disease or erosive gastritis within the past 6
             months, unless treated for the condition and complete resolution has been documented
             by esophagogastroduodenoscopy (EGD).

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to TRC105.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

               -  Exclude patients who have had angina, MI, symptomatic congestive heart failure
                  (CHF), cerebral vascular accident (CVA), transient ischemic attack (TIA),
                  arterial embolism, pulmonary embolism, deep vein thrombosis (DVT), percutaneous
                  transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG)
                  within the last 6 months.

               -  Exclude patients with cardiac arrhythmias > grade 2 in the last 28 days.

               -  Exclude patients with chronic hypertension, systolic BP > 140 and/or diastolic BP
                  > 90 despite optimal treatment.

               -  Exclude human immunodeficiency virus (HIV)+ patients who have CD4 counts which
                  are below the lower limit of normal for the institution

          -  Patients known to have a malignancy (other than their glioblastoma) that has required
             treatment in the last 12 months and/or is expected to require treatment in the next 12
             months (except non-melanoma skin cancer or carcinoma in-situ in the cervix)

          -  Patients are not allowed to receive concurrent anti-coagulation, and may not have
             received thrombolytic or anticoagulant agents (except heparin or alteplase to maintain
             intravenous (IV) catheters) within 10 days prior to drug administration

          -  Serious or non-healing wound, ulcer or bone fracture

          -  History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
             within 6 months

          -  Evidence of bleeding diathesis or coagulopathy

          -  Patients with a history of hereditary hemorrhagic telangiectasia (HHT)

          -  Pregnant women are excluded from this study because TRC105 and antiangiogenic agents
             with the potential for teratogenic or abortifacient effects. Because there is an
             unknown but potential risk for adverse events in nursing infants secondary to
             treatment of the mother with TRC105, breastfeeding should be discontinued if the
             mother is treated with TRC105.