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First-in-human Phase 1/2a Trial Of CRLX101, A Cyclodextrin-containing Polymer-camptothecin Nanopharmaceutical In Patients With Advanced Solid Tumor Malignancies

G. Weiss, J. Chao, J. Neidhart, R. Ramanathan, D. Bassett, J. Neidhart, C. Choi, W. Chow, V. Chung, S. Forman, E. Garmey, Jungyeon Hwang, D. L. Kalinoski, M. Koczywas, J. Longmate, R. J. Melton, R. Morgan, J. Oliver, J. Peterkin, J. Ryan, T. Schluep, T. Synold, P. Twardowski, M. E. Davis, Y. Yen
Published 2012 · Medicine

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SummaryPatients 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.
This paper references
10.1158/1078-0432.CCR-05-1566
Preclinical Efficacy of the Camptothecin-Polymer Conjugate IT-101 in Multiple Cancer Models
Thomas Schluep (2006)
10.1021/MP049966Y
Antitumor Activity of β-Cyclodextrin Polymer−Camptothecin Conjugates
Jianjun Cheng (2004)
10.1073/pnas.0905487106
Pharmacokinetics and tumor dynamics of the nanoparticle IT-101 from PET imaging and tumor histological measurements
Thomas Schluep (2009)
10.1002/ijc.10565
Cellular effects of CPT‐11 on colon carcinoma cells: Dependence on p53 and hMLH1 status
R. Magrini (2002)
Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea.
T. Ikegami (2002)
New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.
P. Therasse (2000)
10.1016/j.nano.2011.09.007
Preclinical study of the cyclodextrin-polymer conjugate of camptothecin CRLX101 for the treatment of gastric cancer.
Shikha Gaur (2012)
Phase I clinical trial of weekly and daily treatment with camptothecin (NSC-100880): correlation with preclinical studies.
F. Muggia (1972)
10.1200/JCO.1999.17.8.2553
Activity and pharmacodynamics of 21-Day topotecan infusion in patients with ovarian cancer previously treated with platinum-based chemotherapy. New York Gynecologic Oncology Group.
H. Hochster (1999)
Plasma camptothecin (NSC-100880) levels during a 5-day course of treatment: relation to dose and toxicity.
P. Creaven (1972)
Antitumor activity of IT101, a cyclodextrin-containing polymer-camptothecin nanoparticle, in combination with various anticancer agents in human ovarian cancer xenografts
G Jensen (2008)
10.1093/jnci/92.3.205
New Guidelines to Evaluate the Response to Treatment in Solid Tumors.
P. Therasse (2000)
10.1007/s00432-009-0543-2
HIF-1α modulation by topoisomerase inhibitors in non-small cell lung cancer cell lines
Yun Jung Choi (2009)
10.1158/1078-0432.CCR-11-0682
Multihistology, Target-Driven Pilot Trial of Oral Topotecan as an Inhibitor of Hypoxia-Inducible Factor-1α in Advanced Solid Tumors
S. Kummar (2011)
10.1016/j.jconrel.2011.03.007
Preclinical to clinical development of the novel camptothecin nanopharmaceutical CRLX101.
Sonke Svenson (2011)
10.1158/0008-5472.CAN-07-5516
Sixteen-kinase gene expression identifies luminal breast cancers with poor prognosis.
P. Finetti (2008)
10.1093/JNCI/89.15.1138
Accelerated titration designs for phase I clinical trials in oncology.
R. Simon (1997)
10.1007/s00280-005-0091-7
Pharmacokinetics and biodistribution of the camptothecin–polymer conjugate IT-101 in rats and tumor-bearing mice
Thomas Schluep (2005)
10.2174/1568011043352777
Camptothecins and topoisomerase I: a foot in the door. Targeting the genome beyond topoisomerase I with camptothecins and novel anticancer drugs: importance of DNA replication, repair and cell cycle checkpoints.
Y. Pommier (2004)
10.1634/THEONCOLOGIST.7-SUPPL_5-29
Alternate dosing schedules for topotecan in the treatment of recurrent ovarian cancer.
R. Morris (2002)
10.1200/JCO.2012.42.8375
American Society of Clinical Oncology identifies five key opportunities to improve care and reduce costs: the top five list for oncology.
L. Schnipper (2012)
Plasma camptothecin (NSC-100880) levels during a 5-day course of treatment: relation to dose and toxicity.
Creaven Pj (1972)
10.1021/BC0340924
Synthesis of linear, beta-cyclodextrin-based polymers and their camptothecin conjugates.
J. Cheng (2003)
10.1111/j.1349-7006.1997.tb00352.x
Enhanced Topoisomerase I Activity and Increased Topoisomerase IIα Content in Cisplatin‐resistant Cancer Cell Lines
Y. Minagawa (1997)
A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.
Y. Matsumura (1986)
10.1158/1078-0432.CCR-08-2619
Preclinical Results of Camptothecin-Polymer Conjugate (IT-101) in Multiple Human Lymphoma Xenograft Models
T. Numbenjapon (2009)
10.1074/jbc.M112401200
Role of p21 in Apoptosis and Senescence of Human Colon Cancer Cells Treated with Camptothecin*
Z. Han (2002)
10.1016/j.addr.2009.05.005
Design and development of IT-101, a cyclodextrin-containing polymer conjugate of camptothecin.
M. Davis (2009)
10.1038/nrc1977
Topoisomerase I inhibitors: camptothecins and beyond
Y. Pommier (2006)
10.1371/journal.pone.0010522
Inhibition of Hypoxia-Inducible Factor-1α (HIF-1α) Protein Synthesis by DNA Damage Inducing Agents
Jessica Jie Wei Lou (2010)



This paper is referenced by
10.1016/BS.IRCMB.2019.03.001
Molecular platforms for targeted drug delivery.
Katia Maso (2019)
10.3322/caac.21199
Nanooncology: The future of cancer diagnosis and therapy
A. Thakor (2013)
10.1016/j.apsb.2018.07.008
Recent developments in topoisomerase-targeted cancer chemotherapy
KirkE. Hevener (2018)
10.14694/EdBook_AM.2014.34.e381
Novel formulations and new mechanisms of delivering chemotherapy.
Thomas E. Stinchcombe (2014)
10.1016/j.drup.2017.05.002
Targeted nanomedicine for cancer therapeutics: Towards precision medicine overcoming drug resistance.
Maya Bar-Zeev (2017)
10.1016/j.ctrv.2014.02.002
Bridging cancer biology and the patients' needs with nanotechnology-based approaches.
Nuno A. Fonseca (2014)
10.18632/oncotarget.9878
Preclinical effects of CRLX101, an investigational camptothecin-containing nanoparticle drug conjugate, on treating glioblastoma multiforme via apoptosis and antiangiogenesis
C. Lin (2016)
10.1002/wnan.1416
Investigational nanomedicines in 2016: a review of nanotherapeutics currently undergoing clinical trials.
J. Caster (2017)
10.1098/rsfs.2016.0054
Antibody–drug conjugates and other nanomedicines: the frontier of gynaecological cancer treatment
D. Howard (2016)
10.1016/j.ajpath.2020.04.003
Understanding the Oxygen Sensing Pathway and Its Therapeutic Implications in Diseases.
Chengheng Liao (2020)
10.1016/j.molmed.2015.01.001
Cancer Nanomedicine: From Targeted Delivery to Combination Therapy
Xiaoyang Xu (2015)
10.7150/ntno.20564
Prediction of Anti-cancer Nanotherapy Efficacy by Imaging
Miles A. Miller (2017)
10.21037/jgo.2017.08.10
Pilot trial of CRLX101 in patients with advanced, chemotherapy-refractory gastroesophageal cancer.
J. Chao (2017)
10.1007/s00280-020-04134-9
Population pharmacokinetic analysis of nanoparticle-bound and free camptothecin after administration of NLG207 in adults with advanced solid tumors
Keith T. Schmidt (2020)
10.1007/978-94-017-9421-3_14
Targeting Hypoxic Adaptations of Cancer Cells: Molecular Mechanisms and Therapeutic Opportunities
Ceen-Ming Tang (2015)
10.1002/anie.201403036
Engineered nanoparticles for drug delivery in cancer therapy.
T. Sun (2014)
Bioengineering targeted nanodrugs for hematologic malignancies: An innovation in pediatric oncology
V. Krishnan (2015)
10.1158/1535-7163.MCT-14-0475
Tissue Penetration and Activity of Camptothecins in Solid Tumor Xenografts
Alastair Hugh Kyle (2014)
10.1038/mt.2014.137
Efficient drug delivery and induction of apoptosis in colorectal tumors using a death receptor 5-targeted nanomedicine.
D. Schmid (2014)
10.7907/Z9WH2MZ6.
Delivery of Targeted Nanoparticles Across the Blood-Brain Barrier Using a Detachable Targeting Ligand
Andrew J Clark (2016)
10.1016/J.COLSURFA.2018.05.070
Encapsulation of camptothecin into pegylated polyelectrolyte nanocarriers
M. Bzowska (2018)
10.1002/adtp.201800010
Surface‐Functionalized Carrier‐Free Drug Nanorods for Leukemia
V. Krishnan (2018)
10.1016/j.jconrel.2014.12.030
Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications.
A. Wicki (2015)
10.3390/POLYM6082186
Impact of the Enhanced Permeability and Retention (EPR) Effect and Cathepsins Levels on the Activity of Polymer-Drug Conjugates
Amit Kumar Rajora (2014)
10.1021/acs.chemrev.5b00116
Clinical Translation of Nanomedicine.
Y. Min (2015)
10.1159/000443404
Natural Products as a Vital Source for the Discovery of Cancer Chemotherapeutic and Chemopreventive Agents
G. Cragg (2015)
10.1002/btm2.10003
Nanoparticles in the clinic
Aaron C. Anselmo (2016)
10.1073/pnas.1603018113
CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing
Andrew J Clark (2016)
10.1126/scitranslmed.3010722
Postsurgical adjuvant or metastatic renal cell carcinoma therapy models reveal potent antitumor activity of metronomic oral topotecan with pazopanib
C. Jedeszko (2015)
10.1016/j.canlet.2016.01.050
Development of highly efficient nanocarrier-mediated delivery approaches for cancer therapy.
Keunsoo Jeong (2016)
10.7150/thno.34509
Research tools for extrapolating the disposition and pharmacokinetics of nanomaterials from preclinical animals to humans
Michael S. Valic (2019)
10.1016/j.ijpharm.2017.06.010
Amphiphilic cyclodextrin nanoparticles.
Gamze Varan (2017)
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