Abstract CT315: IG-002 Phase 3 data: Absence of correlation between unbound paclitaxel and response in MBC
Authors: Choi Monica , Hsu Jeff , Trieu Vuong 
Published: May 2015

Abstract
Study Purpose: Nab-paclitaxel is a Cremophor-free formulation of paclitaxel with increased systemic level of unbound paclitaxel. It has been suggested that increased exposure to unbound paclitaxel accounted for the increased response rate observed for nab-paclitaxel. This hypothesis was challenged by examining the phase 3 data of IG-002 Paclitaxel (formerly Tocosol-Paclitaxel), where unbound paclitaxel levels were 4X higher than Cremophor-EL Paclitaxel (Taxol®) at Cmax.
Methods: PK Clinical Study: The primary objective of this clinical pharmacology study was to compare the pharmacokinetics of unbound (“free”) paclitaxel in plasma ultrafiltrates of patients receiving equivalent paclitaxel doses administered as IG-002 Paclitaxeland as Cremophor-EL Paclitaxel. Eligible patients were required to have an advanced non-hematological malignancy for which there was no curative therapy and for which treatment with a single agent taxane was appropriate. Efficacy Clinical Study: One thousand fifty MBC patients were screened for the study and a total of 821 were randomized to receive either IG-002 (100 mg/m2 weekly, IV) or Cremophor-EL Paclitaxel (80 mg/m2 weekly, IV) until disease progression.
Results: A single 175 mg/m² dose of IG-002 Paclitaxel produces a mean 67% higher exposure to unbound paclitaxel, and a mean 108% higher exposure to total paclitaxel, than an equivalent single dose of Cremophor-EL Paclitaxel. A single 175 mg/m² dose of IG-002 Paclitaxel results in greater myelosuppression than an equivalent single dose of Cremophor-EL Paclitaxel, assessed by duration of ANC &lt;1500, &lt;1000 or &lt;500 cells/mm³. Similar neutropenia was observed in the phase 3 trial, where free paclitaxel was expected to be 84% higher. There was significantly more neutropenia (p&lt;0.001) and shift towards higher grades of neutropenia (p&lt;0.001) for IG-002 Paclitaxel compared to Cremophor-EL Paclitaxel. These differences were also seen with leucopenia (p &lt;0.002). However, the primary endpoint of adjudicated overall response rate (ORR) demonstrated an ORR of 44.7% for Cremophor-EL Paclitaxel and 37.4 % for IG-002 Paclitaxel. The hypothesis of non-inferiority of IG-002 Paclitaxel compared to Cremophor-EL Paclitaxel was not statistically significant (1-sided p-value of 0.085).
Conclusions: Reexamination of phase 3 data of IG-002 Paclitaxel versus Cremophor-EL Paclitaxel revealed that higher systemic exposure to free paclitaxel resulted in greater bone marrow suppression manifested as neutropenia without concomitant increase in tumor response. The deeper tissue penetration required for tumor response involving albumin-mediated transport of paclitaxel would explain why free paclitaxel was not a predictor of tumor response.
Citation Format: Monica Choi, Jeff Hsu, Vuong Trieu. IG-002 Phase 3 data: Absence of correlation between unbound paclitaxel and response in MBC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT315. doi:10.1158/1538-7445.AM2014-CT315