Phase II 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.
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase II, Single Arm, Open Label Study Of NKTR-102 In Bevacizumab-Resistant High Grade Glioma|
- Progression free survival, assessed by Revised Assessment in Neuro-oncology (RANO) criteria [ Time Frame: 6 weeks from first administration of NKTR-102 ] [ Designated as safety issue: No ]Will be described using Kaplan-Meier estimates. The PFS probability at 6 weeks (PFS-6week) will be estimated with an 80% power and 95% confidence intervals (80% in accord with the planned alpha level, 95% for comparability with other studies, confidence intervals based on the Greenwood formula for the variance of a survival probability).
- Survival from the time of first NKTR-102 dose for patients with BEV-resistant glioma receiving NKTR-102 to date of death [ Time Frame: From date of first dose of NKTR-102 to date of death, assessed up to 2 years ] [ Designated as safety issue: No ]Will be described using Kaplan-Meier estimates.
- Overall survival from time of diagnosis [ Time Frame: From date of pathologic diagnosis/confirmation of high grade glioma to date of death, assessed up to 2 years. ] [ Designated as safety issue: No ]Will be described using Kaplan-Meier estimates.
- Safety profile of NKTR-102 in patients with high-grade glioma assessed using the Common Terminology Criteria for Adverse Events version 4 (CTCAE v4.0) [ Time Frame: From date of first dose of NKTR-102 to date of death, assessed up to 2 years ] [ Designated as safety issue: Yes ]Toxicity will be tabulated by organ system and grade.
|Study Start Date:||July 2012|
|Estimated Study Completion Date:||July 2014|
|Estimated Primary Completion Date:||July 2014 (Final data collection date for primary outcome measure)|
Experimental: Drug: NKTR-102
145 mg/m2 dose
Other Name: Etirinotecan pegol
|United States, California|
|Stanford University School of Medicine|
|Palo Alto, California, United States, 94305|
|Principal Investigator:||Lawrence Recht, MD||Stanford University|