Plerixafor (AMD3100) and Bevacizumab for Recurrent High-Grade Glioma

Inclusion Criteria:

• Histologic diagnosis of glioblastoma (GBM), gliosarcoma, anaplastic astrocytoma (AA),anaplastic oligodendroglioma (AO), or anaplastic mixed oligoastrocytoma (AOA).Patients are eligible if the original histology was lower-grade glioma.

• Unequivocal progression by MRI or CT

• Patients with recurrence who undergo resection and are left without measurable orevaluable disease are eligible.

• Patients must have recurrent disease and may have had any number of prior relapses (including no prior relapses) on NON-anti-VEGF(R) containing regimens. Relapse isdefined as progression following initial therapy. For patients who progressed on aprior anti-VEGF(R) containing regimen including bevacizumab, only one prior relapse onan anti-VEGF(R) containing regimen is allowed.

• 18 years of age or older

• Karnofsky performance status of 60 or greater

• Normal organ and marrow function as outlined in the protocol

• Ability to understand and willingness to sign a written informed consent document.

• Protocol treatment must begin within 5 consecutive days after registration

• Patients enrolled in Part 2 must be willing to undergo surgical resection and havesufficient pre-treatment archival tumor tissue available for molecular analysis

• Women of child-bearing potential must have a negative serum or urine pregnancy testwithin 72 hours before the start of the investigational product. In addition, femalesubjects of child-bearing potential and male subjects with partners of child-bearingpotential must agree to use an effective means of birth control while on study therapyand for a minimum of 4 months following last plerixafor dose and 6 months followinglast bevacizumab dose. Effective birth control includes:

• birth control pills, depot progesterone, or an intrauterine device plus one barriermethod;

• or 2 barrier methods. Effective barrier methods are male and female condoms,diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm).Hormonal contraceptive methods are not sufficient, as information about anyinteraction of plerixafor with hormonal contraceptives is not known.

Exclusion Criteria:

• Patients who have had prior chemotherapy within the past 4 weeks (6 weeks fornitrosoureas or mitomycin C). Patients must be off treatment with Temozolomide for atleast 23 days. Patients who received non-cytotoxic drug therapy must be off treatmentfor at least 2 weeks. For patients enrolling in Part 1 or Part 3 AND who haveprogressed on a prior bevacizumab-containing regimen, patients may continue treatmentwith bevacizumab 10 mg/kg monotherapy, with last dose of bevacizumab administered nofewer than 14 days from start of Plerixafor and bevacizumab. For participantsenrolling in Part 1 or Part 3 AND who have progressed on a prior anti-VEGF(R) (otherthan bevacizumab) containing regimen, patients must be off anti-VEGF(R) treatment forat least 28 days before receiving Plerixafor and bevacizumab. For patients enrolled inPart 2 (surgical substudy) AND who have progressed on a prior bevacizumab or otheranti-VEGF(R) containing regimen, patients must be off anti-VEGF(R) treatment for atleast 28 days prior to surgery. NOTE: Participants must have recovered to a grade 0 or 1 from any clinically significanttoxicity related to prior therapy (with the exception of lymphopenia, which is common aftertherapy with temozolomide). For any patient who received prior bevacizumab or ananti-VEGF(R) therapy, patient must NOT have discontinued that treatment regimen due to atreatment-related toxicity.

• In order to prevent registering patients with pseudoprogression rather than truedisease progression, patients must not have received any form of cranial radiationwithin 12 weeks of study entry. NOTE: Patients who have received cranial radiation within 12 weeks of study entry will beallowed to register to trial only if progressive disease is confirmed via biopsy.

• Major surgical procedure (including craniotomy) or significant traumatic injury lessthan 28 days or those who receive minor surgical procedures (e.g. core biopsy or fineneedle aspiration) within 7 days.

• Patients may not be receiving any other investigational agents within the past 28days. NOTE: If agent's half-life x 5 is < 28 days, patient may have taken it within the last 28days, provided at least 5 half-lives have passed since having last taken it.

• Patients who have had prior therapy with CXCR4 inhibitors.

• Patients with one prior relapse on a bevacizumab or an anti-VEGF(R) (i.e. VEGF-trap,vandetanib, cediranib, sunitinib, sorafenib, XL184, etc.) containing regimen areallowed to participate.

• Prior therapy with thalidomide and lenalidomide is allowed.

• Patients who have received prior treatment with implanted radiotherapy or chemotherapysources such as wafers of polifeprosan 20 with carmustine (e.g. Gliadel wafers).

• History of allergic reactions attributed to compounds of similar chemical or biologiccomposition to plerixafor or bevacizumab.

• For the first 20 patients to register, no anti-coagulation is allowed; for allsubsequent patients screened, patients requiring therapeutic anticoagulation withwarfarin at baseline are excluded (however, therapeutic or prophylactic therapy with alow-molecular weight heparin is acceptable).

• Patients must not have a known coagulopathy that increases risk of bleeding or ahistory of clinically significant hemorrhages in the past.

• Patients whose MRI scan demonstrates intratumoral hemorrhage or peritumoral hemorrhageare not eligible for treatment if deemed significant by the treating physician.

• Patients with gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAEGrade >/= 3 within 30 days prior to study entry.

• Uncontrolled intercurrent illness including but not limited to uncontrolledhypertension, ongoing or active infection, symptomatic congestive heart failure,unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situationsthat would limit compliance with study requirements.

• Patients with greater than 1+ proteinuria on a urine dipstick or equivalent routinelaboratory analysis will require further testing with a urine protein to creatinineratio.

• History of myocardial infarction, unstable angina, stroke, or TIA within 6 monthsprior to planned Day 1 of dosing

• History of non-healing wounds or ulcers, or bone refractures within 3 months offracture

• History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscesswithin 6 months prior to planned Day 1 of dosing

• HIV-positive patients on combination antiretroviral therapy

• Participants with a history of a different malignancy are ineligible except for thefollowing circumstances: Individuals with a history of other malignancies are eligibleif they have been disease-free for at least 3 years AND are deemed by the investigatorto be at low risk for recurrence of that malignancy. Individuals with the followingcancers are eligible if diagnosed and treated within the past 3 years: cervical cancerin situ, and basal cell or squamous cell carcinoma of the skin.

• Pregnant and breastfeeding women

• Men or women of childbearing potential who are unwilling or unable to use anacceptable method to avoid pregnancy for the entire study period and for up a minimumof 4 months following last Plerixafor dose and 6 months following last bevacizumabdose.