A Phase II, Single Arm, Open Label Study Of NKTR-102 In Bevacizumab-Resistant High Grade Glioma

High Grade Gliomas, including anaplastic astrocytomas, anaplastic oligodendrogliomas and glioblastomas (GBM), are the most common and most aggressive primary brain tumors. Prognosis for patients with high-grade gliomas remains poor. The estimated median survival for patients with GBM is between 12 to 18 months. Recurrence after initial therapy with temozolomide and radiation is nearly universal. Since May 2009, the majority of patients in the US with an initial recurrence of high-grade glioma receive bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), which is thought to prevent angiogenesis in these highly vascular tumors. BEV has response rates from 32-62% and has improved overall median survival in patients with recurrent high-grade gliomas1. However, the response is short lived, and nearly 100% of patients eventually progress despite bevacizumab. No chemotherapeutic agent administered following progression through bevacizumab has made a significant impact on survival. Patients progress to death within 1-5 months after resistance develops. Therefore, patients with high-grade gliomas who have progressed through bevacizumab represent a population in dire need of a feasible and tolerable treatment. NKTR-102 is a topoisomerase I inhibitor polymer conjugate that was engineered by attaching irinotecan molecules to a polyethylene glycol (PEG) polymer using a biodegradable linker. Irinotecan released from NKTR-102 following administration is further metabolized to the active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN38), that causes DNA damage through inhibition of topoisomerase. The goal in designing NKTR-102 was to attenuate or eliminate some of the limiting side effects of irinotecan while improving efficacy by modifying the distribution of the agent within the body. The size and structure of NKTR-102 results in marked alteration in pharmacokinetic (PK) profile for the SN38 derived from NKTR-102 compared to that following irinotecan: the maximal plasma concentration (Cmax) is reduced 5- to 10-fold and the half-life (t1/2 ) of SN38 is increased from 2 days to approximately 50 days. This altered profile leads to constant exposure of the tumor to the active drug. In addition, the large NKTR-102 molecule does not freely pass out of intact vasculature, which may account for relatively higher concentrations of the compound and the active metabolites in tumor tissues in in vivo models, where the local vasculature may be relatively more permeable. A 145 mg/m2 dose of NKTR-102, the dose intended for use in this phase II clinical trial (and being used in the phase III clinical program), results in approximately the same plasma exposure to SN38 as a 350 mg/m2 dose of irinotecan, but exposure is protracted, resulting in continuous exposure between dosing cycles and lower Cmax. NKTR-102 was therefore developed as a new chemotherapeutic agent that may improve the clinical outcomes of patients.

Stanford is not currently accepting new patients for this trial. You may want to check clinicaltrials.gov to see if other locations are recruiting.

Investigator(s):

Intervention(s):

  • drug : Etirinotecan pegol

Phase: Phase 2

Eligibility

Ages Eligible For Study:

18 Years - N/A

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: 1. Absolute neutrophil count (ANC) >=1.5 X 10^9/L without myeloid growth factor support for 7 days preceding the lab assessment; 2. 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; 3. Platelet count >=100 X 10^9/L without blood transfusions for 7 days preceding the lab assessment; 4. Bilirubin <= 1.5 X upper limit of normal (ULN), except for patients with documented history of Gilbert's disease; 5. Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <= 2.5 X ULN 6. Alkaline phosphatase (AP) <= 3 X ULN 7. Serum creatinine <= 1.5 mg/dL (133 Ámol/L) or calculated creatinine clearance >= 50 mL/min (using Cockcroft-Gault formula); 8. 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.

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