Anaplastic Astrocytomas Clinical Trial
Official title:
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.
n/a
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT01475006 -
AMG 595 First-in-Human in Recurrent Gliomas
|
Phase 1 | |
| Withdrawn |
NCT00243490 -
Photodynamic Therapy in the Treatment of Malignant Intracranial Tumors
|
Phase 2 |