Phase II NKTR-102 In Bevacizumab-Resistant High Grade Glioma

Inclusion criteria

• Pathologically proven high-grade glioma (WHO III or IV) with astrocytic component and must be in recurrence after treatment with bevacizumab
• Patients must have received conventional radiation therapy of total radiation dosage (ranging from 5400 to 6000 cGy administered in daily fractions of 150 to 200 cGy over 6 weeks) with concurrent temozolomide.

Patients must have received bevacizumab and be in recurrence after bevacizumab treatment.

• Patients must be at least 28 days from last administration of cytotoxic chemotherapy and at least 14 days from the last administration of bevacizumab.

• Patients must be >18 years of age.
• Patients must have a life expectancy > 6 weeks
• Patients must have a Karnofsky Performance Score (KPS) >=50
• If female, patients of childbearing potential must have a negative serum beta-hCG pregnancy test and must agree to use hormonal or barrier birth control with spermicidal gel to avoid pregnancy during the study
• Adequate organ function (obtained within 14 days prior to randomization and analyzed by the central laboratory) as evidenced by:

• Absolute neutrophil count (ANC) >=1.5 X 10^9/L without myeloid growth factor support for 7 days preceding the lab assessment;
• Hemoglobin (Hgb) >= 9 g/dL (90 g/L); < 9 g/dL (< 90 g/L) is acceptable if hemoglobin is corrected to >= 9 g/dL (90 g/L) as by growth factor or transfusion prior to randomization;
• Platelet count >=100 X 10^9/L without blood transfusions for 7 days preceding the lab assessment;
• Bilirubin <= 1.5 X upper limit of normal (ULN), except for patients with documented history of Gilbert's disease;
• Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <= 2.5 X ULN
• Alkaline phosphatase (AP) <= 3 X ULN
• Serum creatinine <= 1.5 mg/dL (133 µmol/L) or calculated creatinine clearance >= 50 mL/min (using Cockcroft-Gault formula);
• Women of childbearing potential (WCBP): negative serum pregnancy test (this test is required of all women unless post-menopausal, defined as 12 consecutive months since last regular menses, or surgically sterile).
• Patients must be willing and able to comply with the protocol and provide written informed consent prior to study-specific screening procedures.

Exclusion criteria

Patients who meet any of the following criteria must not be permitted entry to the study.

• Patients who have had chemotherapy within 28 days, radiotherapy within 28 days, biological therapy within 14 days, and investigational therapy within 21 days prior to first dose of experimental drug.
• Patients who have received prior treatment for cancer with a camptothecin derivative (eg, irinotecan, topotecan, and investigational agents including but not limited to exatecan, rubitecan, gimatecan, karenitecan, SN38 investigational agents, EZN-2208, SN-2310, and AR-67).
• Patients with the following co-morbid disease or incurrent illness:

• Patients with chronic or acute GI disorders resulting in diarrhea of any severity grade; patients who are using chronic anti-diarrheal supportive care (more than 3 days/week) to control diarrhea in the 28 days prior to first dose of investigational drug.
• Patients with known cirrhosis diagnosed with Child-Pugh Class A or higher liver disease.
• Prior malignancy except for non-melanoma skin cancer and carcinoma in situ (of the cervix or bladder), unless diagnosed and definitively treated more than 3 years prior to first dose of investigational drug.
• Severe/uncontrolled inter-current illness within the previous 28 days prior to first dose of investigational drug.
• Significant known cardiovascular impairment (NYHA CHF > grade 2, unstable angina, myocardial infarction within the previous 6 months prior to first dose of investigational drug, or existing serious cardiac arrhythmia).
• Patients who require daily use of oxygen supplementation in the 28 days prior to first dose of investigational drug.
• Any other significant co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation.
• Patients with a known allergy or hypersensitivity to any of the components of the investigational therapy, including PEG or topoisomerase inhibitors.
• Patients receiving the following medications at the time of first dose of investigational drug:

• Pharmacotherapy for hepatitis B or C, tuberculosis, or HIV.
• enzyme inducing anti-epileptic medications (EIAEDs)
• other chemotherapy, other investigational agents , or biologic agents for
• the treatment of cancer including antibodies(eg, bevacizumab,
• trastuzumab, or pertuzumab) or any investigational agent(s).
• Pregnant or nursing patients will be excluded from the study.
• Patients receiving active treatment for HIV will be excluded from this study because non-nucleoside reverse transcriptase inhibitors, protease inhibitors and maraviroc (a CCR5-antagonist) are extensively metabolized by the cytochrome P450 system. Interactions with these drugs may induce or inhibit irinotecan or SN38 metabolism, leading to over or under-dosing.