Phase II NKTR-102 In Bevacizumab-Resistant High Grade Glioma
Status:
Completed
Trial end date:
2015-02-01
Target enrollment:
Participant gender:
Summary
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.