A phase II study of paclitaxel poliglumex (PPX), temozolamide (TMZ), and radiation (RT) for newly diagnosed high-grade gliomas.

Abstract

2036 Background: PPX is a drug conjugate that links paclitaxel to a polyglutamic acid polymer yielding a radiosensitization index of 4-8 as compared to 1.5-2 for paclitaxel. Phase I/II studies of PPX in esophageal cancer established that 50 mg/m2/week of PPX can be safely administered with concurrent chemo/RT. The primary objective of this study is to determine the safety of PPX with standard TMZ and RT for high-grade gliomas. Methods: Patients received weekly PPX 50 mg/ m2 and daily TMZ 75 mg/m2 for 6 weeks with concomitant RT (60 Gy). Adjuvant chemotherapy with TMZ (200 mg/m2/d x 5 d), every 28 days, was started 1 month after completion of chemoradiation. Results: This study completed planned accrual of 25 patients (median age, 60 years; 48% male; 60% GBMs). Grade 4 hematologic toxicity occurred in 6 of 25 patients, starting 4-6 weeks after initiating PPX/TMZ/RT and lasting up to 5 months. Median follow-up is 13 months (range, 1-24). 6- and 12- month PFS were 76% (19/25 patients) and 52% (13/25). The 6-month PFS of GBM patients was 66.7% (10/15). Median PFS is 12.5 months. Pseudoprogression (PsdP) was prominent. 16 patients had post-PPX enhancement, 5 were classified with progressive disease (mean time to progression = 4.6 months; rCBV at progression ranged from 2.66 to 6.25, mean = 4.1) and 11 remain on trial. For cases of PsdP, rCBV at time of initial progressive enhancement ranged from 0.63 to 5.28 (mean 2.55), but subsequently stabilized or monotonically decreased, with no statistically significant increased rCBV compared with initial post-PPX baseline. rCBV in progressive disease was not found to be significantly larger than rCBV at initial progressive enhancement in PsdP (p=0.16, unpaired t-test). 5 patients with apparent progression by MRI had resection (2) or biopsy (3). Pathologic specimens showed gliotic edematous brain and all had Ki-67 < 5%. Conclusions: PPX is a promising radiation enhancer in high grade gliomas. Stable or decreasing rCBV on longitudinal follow-up exams may be a better indicator of PsdP than individual absolute rCBV values. Hematologic toxicity may be due to interaction between PPX and TMZ. A randomized study of PPX/RT versus TMZ/RT for with non-methylated MGMTpatients is planned.