TRC105 for Recurrent Glioblastoma

• 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.