Amgen 386 for Recurrent Glioblastoma

Inclusion Criteria

• Signed informed consent approved by the Institutional Review Board prior toparticipant entry

• Age ≥ 18 years.

• Karnofsky ≥ 70%

• Participant must be able and willing to comply with study and/or follow‐up proceduresParticipants must have histologically confirmed diagnosis of GBM patients with eithergrade III or IV malignant glioma are eligible to the Phase I portion of the study) andradiographic evidence of recurrence or disease progression (defined as either agreater than 25% increase in the largest bidimensional product of enhancement, a newenhancing lesion, or significant increase in T2 FLAIR) following prior therapy (i.e.chemotherapy, XRT, other investigational therapies).

• No more than 2 prior episodes of progressive disease (patients with more than 2 priorepisodes of progressive disease are eligible for the Cohort B, Phase I portion of thisstudy)

• An interval of at least 4 weeks (to start of study agent) between prior surgicalresection or one week from stereotactic biopsy

• An interval of at least 12 weeks (to start of study agent) from the end of priorradiotherapy unless there is a new area of enhancement consistent with recurrent tumoroutside of the radiation field, or there is histological confirmation of unequivocaltumor progression

• From the projected start of scheduled study treatment, the following time periods musthave relapsed: 4 weeks (or 5 half lives, whichever is shorter) from anyinvestigational agent, 4 weeks (or 5 half lives, whichever is shorter) from cytotoxictherapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks fromantibodies (or 5 half lives, whichever is shorter), or 4 weeks (or 5 half lives,whichever is shorter) from other anti‐tumor therapies.

• Participants must have recovered to a grade 0 or 1 from the toxic effects of priortherapy (with the exception of lymphopenia, which is common after therapy withtemozolomide, and alopecia).

• No evidence of hemorrhage on the baseline MRI or CT scan other than those that are ≤grade 1 and either post‐operative or stable on at least two consecutive scans.Clinical Labs - performed within 14 days prior to enrollment

• Hematocrit ≥ 29%, ANC ≥ 1,000 cells/μl, platelets ≥ 100,000 cells/μl ;

• Serum creatinine ≤ 1.5 mg/dl, serum SGOT and bilirubin ≤ 1.5 times upper limit ofnormal;

• PTT or aPTT ≤ 1.5 times upper limit of normal and INR ≤ 1.5

• Calculated creatinine clearance ≥ 40 mL/min according to the Cockcroft‐Gault formulaOR per 24 hour urine collection

• Urinary protein quantitative value of < 30 mg/dL in urinalysis or <1+ on dipstick,unless quantitative protein is < 1000 mg in a 24 hour urine sample;

• Participants of child‐bearing potential who have not undergone a bilateralsalpingo‐oophorectomy and are sexually active must consent to use an accepted andhighly effective non‐hormonal method of contraception (i.e. double barrier method [e.g., condom plus diaphragm]) from signing the informed consent through 6 monthsafter last dose of study drug.

Exclusion Criteria:

• Prior anti‐angiogenic therapy targeting VEGF or VEGF receptor including priorbevacizumab.

• Prior AMG 386 therapy or other molecules that inhibit the angiopoietins or Tie2receptor.

• Co-medication that may interfere with study results; e.g. immunosuppressive agentsother than corticosteroids.

• Active infection requiring intravenous antibiotics

• Current or within 30 days prior to enrollment treatment with immune modulators such assystemic cyclosporine and tacrolimus.

• Current us of warfarin sodium or any other Coumadin‐derivative anticoagulant.Participant must be off Coumadin‐derivative anticoagulants for at least seven daysprior to starting study drug. ow molecular weight heparin is allowed.

• Current, recent (within 4 weeks of the first infusion of this study), or plannedparticipation in an experimental drug study other than supportive care orepidemiologic studies.

• Herbal preparations/medications are not allowed throughout the study. These herbalmedications include, but are not limited to: St. John's wort, Kava, ephedra (mahuang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng.Participants should stop using any herbal medications 7 days prior to first dose ofstudy drug.

• History of clinically significant bleeding within 6 months of enrollment

• History of allergic reactions to bacterially produced proteins

• Known hypersensitivity to any component of bevacizumab (cohort B only)

• Known sensitivity to any of the products to be administered during dosing

• History of venous or arterial thromboembolism within 12 months prior to enrollment.

• Severe hepatic insufficiency (ongoing grade 3 or greater hepatic adverse events) orknown active chronic hepatitis.

• Inadequately controlled hypertension (defined as systolic blood pressure >140 and/ordiastolic blood pressure > 90 mmHg). The use of anti‐hypertensive medications tocontrol hypertension is permitted.

• Any prior history of hypertensive crisis or hypertensive encephalopathy

• Clinically significant cardiovascular disease within 12 months prior to enrollment,including myocardial infarction, unstable angina, grade 2 or greater peripheralvascular disease, cerebrovascular accident, transient ischemic attack, congestiveheart failure, or arrhythmias not controlled by outpatient medication, percutaneoustransluminal coronary angioplasty/stent.

• Evidence of bleeding diathesis or coagulopathy

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 daysprior to study enrollment or anticipation of need for major surgical procedure duringthe course of the study

• Core biopsy or other minor surgical procedure, excluding placement of a vascularaccess device, within 7 days prior to study enrollment.

• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscesswithin 6 months prior to study enrollment.

• Serious, non‐healing wound, ulcer (including gastrointestinal), or bone fracture.

• Any condition which in the investigator's opinion makes the subject unsuitable forstudy participation.

• Pregnant (positive pregnancy test) or lactating. Refusal or inability to use highlyeffective means of contraception (men and women) in participants of child‐bearingpotential.