Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-escalation study, in which CRLX101 was administered intravenously over 60 min among two dosing schedules, initially weekly at 6, 12, and 18 mg/m2 and later bi-weekly at 12, 15, and 18 mg/m2. The maximum tolerated dose (MTD) was determined at 15 mg/m2 bi-weekly, and an expansion phase 2a study was completed. Patient samples were obtained for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Response was evaluated per RECIST criteria v1.0 every 8 weeks. Sixty-two patients (31 male; median age 63 years, range 39–79) received treatment. Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting toxicity. Among all phase 1/2a patients receiving the MTD (n = 44), most common grade 3/4 adverse events were neutropenia and fatigue. Evidence of systemic plasma exposure to both the polymer-conjugated and unconjugated CPT was observed in all treated patients. Mean elimination unconjugated CPT Tmax values ranged from 17.7 to 24.5 h, and maximum plasma concentrations and areas under the curve were generally proportional to dose for both polymer-conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 %) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC patients was 4.4 months. These combined phase 1/2a data demonstrate encouraging safety, pharmacokinetic, and efficacy results. Multinational phase 2 clinical development of CRLX101 across multiple tumor types is ongoing.
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The authors would like to thank all participating patients and their families, as well as the investigators, study coordinators, and operations staff. The authors also want to thank Dr. Marcia M. Miller and Dr. Mariana Tihova, Electron Microscopy Core; Dr. Shu Mi, Clinical Immunobiology Correlative Studies Laboratory (CICSL); and Yafan Wang, Translational Research Laboratory, City of Hope Comprehensive Cancer Center.
Acknowledgement of Research Support for the Study
Financial support for this study was provided by Cerulean Pharma, Inc., and by a grant from the National Cancer Institute (CA U54119347). Financial support for medical editorial assistance was provided by Cerulean Pharma, Inc.
DLK, EG, JH, JLR, and JJP are/were employees at Cerulean Pharma, Inc.
MED has stock in and is a paid consultant to Cerulean Pharma, Inc.
TS is a paid consultant for Cerulean Pharma, Inc. and employee at Calando Pharmaceuticals.
Glen J. Weiss and Joseph Chao contributed equally to this work.
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Weiss, G.J., Chao, J., Neidhart, J.D. et al. First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies. Invest New Drugs 31, 986–1000 (2013). https://doi.org/10.1007/s10637-012-9921-8
- Polymer conjugate camptothecin
- Phase 1/2a
- Solid tumor