BrUOG 329 Onivyde & Metronomic Temozolomide in Recurrent Glioblastoma

Inclusion Criteria: * Histologically confirmed glioblastoma multiforme (gliosarcoma also eligible), Pathology report to be sent to BrUOG. * Progression or recurrence after at least one line of therapy. Patient must have received temozolomide and radiation but it is not required that they were given concurrently. * Age \>18 years * Karnofsky performance score \> 60 * Life expectancy \>12 weeks as noted by treating investigator * Laboratory results requirements * Absolute neutrophil count (ANC) ≥ 1500/mm3. * Platelets (Plt) ≥ 100,000/mm3 * Hemoglobin (Hgb) ≥ 9.0 g/dL * Total bilirubin \< 1x ULN * Albumin levels ≥ 3.0 g/dL * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN * Serum creatinine ≤ 1.5 x ULN * Not pregnant and not nursing. Women of child bearing potential must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to Day 1 of treatment. Post-menopausal women (surgical menopause or lack of menses \>12 months) do not need to have a pregnancy test, please document status. * Confirmation of informed consent. * Men and women of childbearing potential enrolled in this study must agree to use adequate barrier birth control measures during the course of the study and for at least 2 months after the last treatment on study. * Recovered (\< grade 1) from clinically significant effects of any prior surgery, radiotherapy or other anti-neoplastic therapy, except alopecia or hematological laboratory values * Stable corticosteroid dose at least 7 days prior to day 1 * Patients must have assessable (measurable) disease at baseline by brain MRI. Must be contrast enhancing. The tumor size will be measured in millimeters and is the largest cross-sectional area using perpendicular measurements of contrast enhancing abnormality. * Patient must be able to tolerate brain MRI with contrast Exclusion Criteria: * Non-GBM primary invasive malignant neoplasm that is considered by treating investigator to likely cause death in the next 5 years. * Radiation therapy or cytotoxic chemotherapy or biologics or immunotherapy within previous three weeks from day 1 of drug (no anticancer treatment of any kind within 3 weeks of day 1 of drug- steroids are acceptable if stable dose per 3.1.11). * Patients not to be receiving any cancer therapy or investigational anti-cancer drug. * Evidence of an active infection requiring intravenous antibiotic therapy * Any medical condition that in the opinion of the Investigator may interfere with a subject's participation in or compliance with the study. Must receive confirmation in writing from treating MD. * Pregnant or breast feeding; females of child-bearing potential must test negative for pregnancy at the time of enrollment based on serum pregnancy test. * Unwillingness or inability to follow the procedures required in the protocol, site to have documentation to confirm at time of registration that this is not the case. * Patient with a history of Gilbert's disease or known UGT1A1\*28 allele. (Assessment for the UGT1A1\*28 allele is not required for protocol entry.) Documentation required at time of study entry by treating MD. * myocardial infarction, unstable angina pectoris, stroke within 6 months of study registration. * NYHA Class III or IV congestive heart failure * Known hypersensitivity to any of the components of nanoliposomal irinotecan , other liposomal products, or temozolomide. Must be documented by treating MD. * Investigational anticancer therapy administered within 4 weeks of day 1, or within a time interval less than at least 5 half lives of the investigational agent, whichever is longer, prior to the first scheduled day of dosing in this study. Site must submit all prior investigational agents with last dose administered and half-life for BrUOG review. * Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed. All recent vaccines (within 30 days) to be listed on conmed log and submitted to BrUOG. * Use of strong CYP3A4 inducers is not allowed and patients must be off any of these exclusionary products for \> 2 weeks from day 1.