Bevacizumab With or Without Trebananib in Treating Patients With Recurrent Brain Tumor

• Dose-limiting toxicity (DLT) (Cohort 1) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  Defined as a clinically significant adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications and meets any of the criteria below.
• Progression-free survival (Cohort 2) [ Time Frame: At 6 months ] [ Designated as safety issue: No ]

• Dose-limiting toxicity (DLT) (Cohort 1) [ Designated as safety issue: Yes ]
• 6-month progression-free survival (Cohort 2) [ Designated as safety issue: No ]

• Treatment-related toxicity, measured by CTCAE v. 4 [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
• Feasibility of trebananib weekly in combination with bevacizumab every 2 weeks, measured by the percentage of patients requiring dose reduction/interruption or discontinuation in the first 2 and subsequent cycle (Cohort 1) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Radiographic RR as measured by Revised Assessment in Neuro-Oncology (RANO) response criteria (Cohort 2) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• PFS [ Time Frame: From the date of randomization to the date of first progression or death or, otherwise, the last follow-up date on which the patient is reported alive, assessed up to 2 years ] [ Designated as safety issue: No ]
  Will be estimated using the Kaplan-Meier method and differences between treatment arms will be tested in the log rank test.
• Overall survival (OS) (Cohort 2) [ Time Frame: From the date of randomization to the date of death or, otherwise, the last follow-up date on which the patient is reported alive, assessed up to 2 years ] [ Designated as safety issue: No ]
  Estimated using the Kaplan-Meier method and differences between treatment arms will be tested in the log rank test.
• Tumor genotype, expression profile, and circulating angiogenesis biomarkers (Cohort 2) [ Time Frame: Day 1 of course 1, day 1 and 8 of all subsequent courses, and up to 30 days post-treatment ] [ Designated as safety issue: No ]

• Treatment-related toxicity, measured by CTCAE v. 4 [ Designated as safety issue: Yes ]
• Feasibility of AMG 386 weekly in combination with bevacizumab every 2 weeks, measured by the percentage of patients requiring dose reduction/interruption or discontinuation in the first 2 and subsequent cycle (Cohort 1) [ Designated as safety issue: No ]
• Radiographic RR as measured by Revised Assessment in Neuro-Oncology (RANO) response criteria assessed up to 2 years (Cohort 2) [ Designated as safety issue: No ]
• Overall survival (OS) from the time of study entry to death estimated by Kaplan-Meier method, assessed up to 2 years (Cohort 2) [ Designated as safety issue: No ]
• Tumor genotype, expression profile, and circulating angiogenesis biomarkers (Cohort 2) [ Designated as safety issue: No ]

This randomized phase II trial studies how well bevacizumab given with or without trebananib works in treating patients with brain tumor. Monoclonal antibody, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Trebananib may stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether giving bevacizumab together with trebananib is more effective than bevacizumab alone in treating brain tumors.

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of AMG 386 (trebananib) 15 mg/kg weekly in combination with bevacizumab 10 mg/kg every 2 weeks (Cohort 1). (closed to accrual 10/2/12) II. To assess the efficacy of AMG 386 in combination with bevacizumab 10 mg/kg every 2 weeks compared to bevacizumab monotherapy in bevacizumab-naïve patients, as measured by 6-month progression-free survival (PFS6) (Cohort 2).

SECONDARY OBJECTIVES:

I. To further assess the toxicity profile (Cohorts 1 and 2). II. To assess feasibility of AMG 386 15 mg/kg weekly in combination with bevacizumab 10 mg/kg every 2 weeks (Cohort 1 [closed to accrual 10/2/12]), as measured by the percentage of patients requiring dose reduction/interruption or discontinuation in the first 2 and subsequent cycles.

III. To determine the radiographic response rate (RR), median progression-free survival (PFS), and OS in bevacizumab-naïve patients (Cohort 2).

IV. To assess the efficacy of AMG 386 15 mg/kg weekly in combination with bevacizumab 10 mg/kg every 2 weeks in patients who have progressed while on bevacizumab, as measured by overall survival (OS) (cross-over from placebo arm of Cohort 2).

V. To correlate outcome to treatment with tumor genotype, expression profile, and circulating angiogenesis biomarkers in tumor specimens (Cohort 2).

VI. To determine the RR, PFS6, and PFS in patients who have progressed while on bevacizumab therapy and receive AMG 386 in combination with bevacizumab (cross-over from placebo arm of Cohort 2).

VII. To determine the serum pharmacokinetics of AMG 386.

OUTLINE: This is a safety study (cohort 1 [closed to accrual 10/2/12]) followed by a randomized study (cohort 2). Patients are stratified according to age in years (< 50 vs >= 50), Karnofsky performance status (70-80% vs 90-100%), and recent resection (yes vs no).

Cohort 1: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and trebananib IV over 30-60 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/2/12)

Cohort 2: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive bevacizumab and trebananib as in cohort 1.

ARM II: Patients receive bevacizumab as in arm I and placebo IV over 30-60 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may cross over to arm I.

After completion of study treatment, patients are followed up every 2 months for 1 year, every 6 months for 1 year, and then annually thereafter.

• Adult Anaplastic Oligodendroglioma
• Adult Giant Cell Glioblastoma
• Adult Glioblastoma
• Adult Gliosarcoma
• Adult Oligodendroglioma
• Recurrent Adult Brain Tumor

• Biological: trebananib
  Given IV
  Other Names:

  • AMG 386
  • AMG386
• Drug: placebo administration
  Given IV
• Biological: bevacizumab
  Given IV
  Other Names:

  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
• Other: pharmacological study
  Correlative studies
  Other Name: pharmacological studies
• Other: laboratory biomarker analysis
  Correlative studies

• Experimental: Arm I (trebananib and bevacizumab)
  Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and trebananib IV over 30-60 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Biological: trebananib
  • Biological: bevacizumab
  • Other: pharmacological study
  • Other: laboratory biomarker analysis
• Placebo Comparator: Arm II (bevacizumab and placebo)
  Patients receive bevacizumab as in arm I and placebo IV over 30-60 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may cross over to arm I.
  Interventions:

  • Drug: placebo administration
  • Biological: bevacizumab
  • Other: pharmacological study
  • Other: laboratory biomarker analysis

Inclusion Criteria:

• Histologically proven diagnosis of glioblastoma or variants (gliosarcoma, glioblastoma with oligodendroglial features, giant cell glioblastoma); patients will be eligible if the original histology was a lower-grade glioma and a subsequent histological diagnosis of glioblastoma or variants is made

• Patients must have shown unequivocal evidence for tumor progression on the previous treatment regimen (prior to enrollment on this study) by magnetic resonance imaging (MRI) scan of the brain with and without contrast within 14 days prior to registration; the dose of steroids must be stable or decreasing for at least 5 days prior to the scan

  • Patients unable to undergo MRI because of non-compatible devices can be enrolled, provided computed tomography (CT) scans are obtained and are of sufficient quality; patients without non-compatible devices may not have CT scans performed to meet this requirement
• Patients who have received prior treatment with interstitial brachytherapy, stereotactic radiosurgery, or implanted chemotherapy sources, such as wafers of polifeprosan 20 with carmustine, must have confirmation of progressive disease within 14 days prior to registration based upon nuclear imaging, MR spectroscopy, perfusion imaging, or histopathology
• No more than 2 relapses
• No intratumoral hemorrhage or peritumoral hemorrhage, demonstrated by MRI or CT scan, Common Terminology Criteria for Adverse Events (CTCAE) v. 4 grade 2 or greater, or evidence of significant hemorrhage (regardless of CTCAE, v. 4 grade) defined as > 1 cm diameter of blood (including postoperative hemorrhage)
• Karnofsky performance scale >= 70%
• Leukocytes > 3,000/mm^3
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Hemoglobin (Hgb) >= 10.0 g/dL (Note: The use of transfusion or other intervention to achieve Hgb >= 10.0 g/dL is acceptable)
• Platelets >= 100,000/mm^3
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) < 2.5 times institutional upper limit of normal
• Bilirubin =< 2.0 mg/dL
• Creatinine within normal institutional limits OR creatinine clearance > 60 mL/min (per 24-hour urine collection or calculated according to the Cockcroft-Gault formula)
• Prothrombin time (PT)/international normalized ratio (INR) =< 1.5
• Urinary protein =< 30 mg/dL in urinalysis or =< 1+ on dipstick
• Generally well-controlled blood pressure with systolic blood pressure =< 140 mm Hg AND diastolic blood pressure =< 90 mm Hg within 5 days prior to registration; the use of anti-hypertensive medications to control hypertension is permitted
• Women of childbearing potential must have a negative serum beta (β)-human chorionic gonadotropin (HCG) pregnancy test within 14 days prior to registration
• Women of childbearing potential and male patients who are sexually active must practice adequate contraception during therapy and for 180 days (6 months) afterwards
• No prior invasive malignancy (except non-melanomatous skin cancer) unless disease-free for a minimum of 1095 days (3 years); (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
• No gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE, v. 4 grade 3 or greater within 30 days prior to study entry

• No severe, active co-morbidity, defined as follows:

  • Unstable angina and/or congestive heart failure requiring hospitalization within 180 days (6 months) prior to registration
  • Transmural myocardial infarction within 180 days (6 months) prior to registration
  • History of stroke, cerebral vascular accident (CVA), or transient ischemic attack within 180 days (6 months) prior to registration
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
  • Chronic obstructive pulmonary disease (COPD) exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
  • Known acquired immune-deficiency syndrome (AIDS) based upon current CDC definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol
  • Known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhages in the past
  • History of non-healing wounds or ulcers, or bone fractures within 90 days (3 months) prior to registration
• No prior allergic reaction to the study drugs involved in this study
• No prior systemic cytotoxic chemotherapy within 28 days (42 days for nitrosoureas or mitomycin C) prior to registration, or patients who have not returned to baseline or =< CTCAE v. 4 grade 2 from adverse events (excluding alopecia) due to agents administered more than 28 days prior to registration

• Patients who received non-cytotoxic drug therapy must be off treatment for at least 14 days prior to registration

  • Prior treatment with anti-vascular endothelial growth factor(VEGF)-targeted agents, AMG 386 therapy, or other molecules that inhibit angiopoietins or Tie2 receptor including, but not limited to, XL-820, XL-184, and CVX-060/PF-4856884 is not allowed regardless of time frame
• No patients who have not yet completed at least 21 days (30 days for prior monoclonal antibody therapy) since ending other investigational device or drug trials, or who are currently receiving other investigational treatments
• No treatment within 30 days prior to enrollment with strong immune modulators including, but not limited to, systemic cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, methotrexate, azathioprine, rapamycin, thalidomide, lenalidomide, and targeted immune modulators such as abatacept (CTLA-4-Ig), adalimumab, alefacept, anakinra, belatacept (LEA29Y), efalizumab, etanercept, infliximab, or rituximab
• No prior radiotherapy within 90 days (3 months) prior to registration unless there is either: a) histopathologic confirmation of recurrent tumor; or b) new enhancement on MRI outside of the radiation treatment field
• No major surgical procedure (including craniotomy) or significant traumatic injury within 28 days prior to registration or those patients who receive a non-central nervous system (CNS) minor surgical procedures (e.g., core biopsy or fine-needle aspiration) within 3 days prior to registration; there is no waiting period for central line placement
• Prior therapy with anti-VEGF targeted agents (e.g. bevacizumab, cediranib, vandetanib, aflibercept, sunitinib, sorafenib, etc.); prior therapy with thalidomide and lenalidomide is allowed as long as treatment has not occurred within 30 days prior to enrollment
• Prior therapy with thalidomide and lenalidomide is allowed as long as treatment has not occurred within 30 days prior to enrollment

• No therapeutic anticoagulation with warfarin < 7 days prior to registration

  • Therapeutic or prophylactic therapy with aspirin, a low-molecular weight heparin, or a Factor Xa inhibitor is acceptable
• No history of venous or arterial thromboembolism within 12 months prior to registration