Abstract A97: Final phase 1/2a results evaluating the cyclodextrin-containing nanoparticle CRLX101 in patients with advanced solid tumor malignancies

• Published in: Molecular cancer therapeutics 2011-11, Vol.10 (11_Supplement), p.A97-A97
• Main Authors: Yen, Yun, Coerver, Lori A., Garmey, Edward G., Kalinoski, D. Lynn, Koczywas, Marianna, Neidhart, James A., Neidhart, Jeffrey D., Peterkin, Joanna J., Ramanathan, Ramesh K., Ryan, John, Weiss, Glen J.
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-11-A97

Introduction: Topoisomerase-1-inhibiting camptothecin (CPT) and derivatives such as irinotecan (CPT-11) and topotecan demonstrate clinical utility across multiple cancer types. Use of these agents remains limited by insufficient tumor exposure and high systemic toxicity. A novel cyclodextrin-containing polymer conjugate of CPT that self-assembles into nanoparticles, CRLX101 delivers sustained levels of active CPT into cancer cells while substantially reducing systemic exposure. In vitro and in vivo data suggest superior activity of CRLX101 in multiple tumor models. Efforts are made now to demonstrate the safety and efficacy of CRLX101 in human patients with advanced solid tumor malignancies. Experimental Procedures: CRLX101 was administered intravenously over 1 hour every other week (EOW) to patients (pts.) with advanced and multiply pre-treated solid tumor malignancies. In phase 1, 24 pts. received CRLX101 at 5 escalating dose levels. Following identification of a maximum tolerated dose (MTD), a 38 patient phase 2a MTD-expansion cohort was enrolled at 3 clinical sites. Summary of Data: As of a data cut-off of 6/1/11, 62 total pts. (31 F; 31 M) received CRLX101 at doses ranging from 6 mg/m2 to 18 mg/m2 of CPT equivalent per dose. In phase 1, 2 pts. (18 mg/m2) experienced dose limiting toxicity of CTCAE v3.0 grade (G)4 thrombocytopenia with one of these pts. additionally experiencing G4 neutropenia. An MTD/recommended phase 2 dose (RP2D) of CRLX101 was established at 15 mg/m2 EOW. Among 44 phase 1 or 2a pts. receiving the MTD/RP2D, most common grade 3/4 adverse events considered by investigators to be at least possibly related to study drug included neutropenia (9 events observed among 6 pts.) and lymphopenia (3 events observed among 2 pts.). Phase 2a pts. received CRLX101 for periods of time ranging from 1 day to approximately 13 months (mos.) with an average duration of 3.3 mos. Among 36 evaluable phase 2a pts. receiving the MTD, mean plasma Cmax and AUCall were 306 μg./L. and 27.1 mg./L.*hr. (polymer-unconjugated) and 8260 μg./L. and 300 mg./L.*hr. (polymer-conjugated), respectively. Mean urinary clearance of polymer-conjugated and free CPT over the 0–8 hr., 8–24 hr., and 24–48 hr. collection intervals post CRLX101 dosing were 0.0299, 0.0074, and 0.0062 L./hr. (polymer-conjugated) and 0.0888, 0.0898, and 0.1010 L./hr. (free CPT), respectively. Among all phase 2a pts., overall median progression-free survival (mPFS) was 3.7 mos., with mPFS of 4.4 mos. obs