title: First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies.
abstract: 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/m(2) and later bi-weekly at 12, 15, and 18 mg/m(2). The maximum tolerated dose (MTD) was determined at 15 mg/m(2) 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.
authors: Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, Scottsdale, AZ, USA.
authors: Glen J
authors: GJ
authors: Weiss
authors: City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors: Joseph
authors: J
authors: Chao
authors: San Juan Oncology Associates, Farmington, NM, USA.
authors: Jeffrey D
authors: JD
authors: Neidhart
authors: Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, Scottsdale, AZ, USA.
authors: Ramesh K
authors: RK
authors: Ramanathan
authors: Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, Scottsdale, AZ, USA.
authors: Dawn
authors: D
authors: Bassett
authors: San Juan Oncology Associates, Farmington, NM, USA.
authors: James A
authors: JA
authors: Neidhart
authors: California Institute of Technology, Pasadena, CA, USA.
authors: Chung Hang J
authors: CHJ
authors: Choi
authors: City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors: Warren
authors: W
authors: Chow
authors: City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors: Vincent
authors: V
authors: Chung
authors: City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors: Stephen J
authors: SJ
authors: Forman
authors: Cerulean Pharma Inc., Cambridge, MA, USA.
authors: Edward
authors: E
authors: Garmey
authors: Cerulean Pharma Inc., Cambridge, MA, USA.
authors: Jungyeon
authors: J
authors: Hwang
authors: Cerulean Pharma Inc., Cambridge, MA, USA; Calando Pharmaceuticals, Pasadena, CA, USA.
authors: D Lynn
authors: DL
authors: Kalinoski
authors: City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors: Marianna
authors: M
authors: Koczywas
authors: City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors: Jeffrey
authors: J
authors: Longmate
authors: Seventh Wave, Chesterfield, MO, USA.
authors: Roger J
authors: RJ
authors: Melton
authors: City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors: Robert
authors: R
authors: Morgan
authors: Peptagen, Inc., Raleigh, NC, USA.
authors: Jamie
authors: J
authors: Oliver
authors: Cerulean Pharma Inc., Cambridge, MA, USA.
authors: Joanna J
authors: JJ
authors: Peterkin
authors: Cerulean Pharma Inc., Cambridge, MA, USA.
authors: John L
authors: JL
authors: Ryan
authors: Calando Pharmaceuticals, Pasadena, CA, USA.
authors: Thomas
authors: T
authors: Schluep
authors: City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors: Timothy W
authors: TW
authors: Synold
authors: City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors: Przemyslaw
authors: P
authors: Twardowski
authors: California Institute of Technology, Pasadena, CA, USA.
authors: Mark E
authors: ME
authors: Davis
authors: City of Hope Comprehensive Cancer Center, Duarte, CA, USA; Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Rd., Duarte, CA 91010, USA.
authors: Yun
authors: Y
authors: Yen
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001706:Biopsy; D002166:Camptothecin / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002482:Cellulose / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003505:Cyclodextrins / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003710:Demography; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D053758:Nanoparticles / Q000009:adverse effects / Q000627:therapeutic use*; D009367:Neoplasm Staging; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D003505:Cyclodextrins; C542292:IT-101; C041953:cyclodextrin polymer; D002482:Cellulose; D002166:Camptothecin
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