Abstract 2047: Pharmacokinetics (PK) of CRLX301, a novel nanoparticle-drug conjugate (NDC) containing the payload docetaxel, in patients with refractory solid tumors
Authors: Zamboni William C. , Markman Ben , de Souza Paul , Dees E. Claire , Gangadhar Tara , Eliasof Scott , Murphy Curran , Senderowicz Adrian , Wang Hongwei 
Published: July 2016

Abstract
Introduction. Nanoparticles (NPs) provide many advantages over small molecule drugs, such as greater solubility, increased duration of exposure, and enhanced tumor delivery, which may lead to improved antitumor activity and reduced toxicity. PK of NPs is complex as the PK is dependent upon the carrier and not the therapeutic entity until the active-drug payload is released. It is important to evaluate the PK of the inactive carrier-associated drug and active released drug. CRLX301 is an investigational NDC containing the payload docetaxel covalently conjugated to a cyclodextrin-polyethylene glycol (CD-PEG) co-polymer that is 10-30 nm in diameter. This study evaluated CRLX301 PK in a phase 1 study in patients with refractory solid tumors.
Methods. CRLX301 was administered at 7.5, 15, 30, 60 and 75 mg/m2 IV over 1 h every 21 days. The doses of CRLX301 represent mg of docetaxel. PK studies were performed on days 1-21 of cycles 1, 3 and 6. Plasma samples were processed to measure total (conjugated + released) and released docetaxel. PK parameters area under conc-time curve (AUC0-inf) and volume of distribution (Vd) were estimated. Results were compared to a prior PK study of Taxotere® at 75 mg/m2 IV x 1 every 21 days (Zamboni, et al. CCP 2011).
Results. Plasma PK of total and released docetaxel were linear after CRLX301 from 7.5 to 75 mg/m2. CRLX301 plasma PK was similar on cycles 1, 3 and 6 suggesting no accumulation after multiple doses. For CRLX301 at 75 mg/m2 on cycle 1, mean ± SD plasma AUC0-inf of total and released docetaxel were 321,355 ± 9,831 and 3,015 ± 904 ng/mL•h, respectively. Mean ± SD% of docetaxel released from CRLX301 into the plasma was 1.0 ± 0.2%.
Exposures of total and released docetaxel in plasma after administration of CRLX301 (7 days) were prolonged compared with Taxotere (24 h). Total docetaxel plasma AUC after CRLX301 at 75 mg/m2 was ∼63-fold greater than for Taxotere. The Vd of CRLX301 total docetaxel and Taxotere were 2.1 ± 0.1 and 74-99 L/m2, respectively. The overall plasma AUC of released docetaxel after CRLX301 (3,015 ± 904 ng/mL•h) was similar to Taxotere (2,000-10,000 ng/mL•h); however, most of the released docetaxel AUC after CRLX301 is associated with exposures at 24-168 h. Early exposures of released docetaxel in plasma after CRLX301 (Cmax = 242 ± 44 ng/mL) were ∼25-fold lower than Taxotere (Cmax = 5,000-8,000 ng/mL).
Conclusions. CRLX301 exhibits PK advantages over Taxotere such as higher retention of drug in plasma, slower clearance and controlled slow release of docetaxel from the carrier. CRLX301 exhibits low inter- and intra-patient PK variability. It is anticipated that this unique PK profile of CRLX301 may improve efficacy as well as the tolerability profile when compared to Taxotere. The study continues with dose escalation to further explore the safety, efficacy and PK of CRLX301.
Citation Format: William C. Zamboni, Ben Markman, Paul de Souza, E. Claire Dees, Tara Gangadhar, Scott Eliasof, Curran Murphy, Adrian Senderowicz, Hongwei Wang. Pharmacokinetics (PK) of CRLX301, a novel nanoparticle-drug conjugate (NDC) containing the payload docetaxel, in patients with refractory solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2047.