Investigational New Drugs

, Volume 31, Issue 4, pp 986–1000

First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies

  • Glen J. Weiss
  • Joseph Chao
  • Jeffrey D. Neidhart
  • Ramesh K. Ramanathan
  • Dawn Bassett
  • James A. Neidhart
  • Chung Hang J. Choi
  • Warren Chow
  • Vincent Chung
  • Stephen J. Forman
  • Edward Garmey
  • Jungyeon Hwang
  • D. Lynn Kalinoski
  • Marianna Koczywas
  • Jeffrey Longmate
  • Roger J. Melton
  • Robert Morgan
  • Jamie Oliver
  • Joanna J. Peterkin
  • John L. Ryan
  • Thomas Schluep
  • Timothy W. Synold
  • Przemyslaw Twardowski
  • Mark E. Davis
  • Yun Yen
PHASE II STUDIES

DOI: 10.1007/s10637-012-9921-8

Cite this article as:
Weiss, G.J., Chao, J., Neidhart, J.D. et al. Invest New Drugs (2013) 31: 986. doi:10.1007/s10637-012-9921-8

Summary

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.

Keywords

NanopharmaceuticalPolymer conjugate camptothecinPhase 1/2aSolid tumor

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Glen J. Weiss
    • 1
  • Joseph Chao
    • 2
  • Jeffrey D. Neidhart
    • 3
  • Ramesh K. Ramanathan
    • 1
  • Dawn Bassett
    • 1
  • James A. Neidhart
    • 3
  • Chung Hang J. Choi
    • 4
  • Warren Chow
    • 2
  • Vincent Chung
    • 2
  • Stephen J. Forman
    • 2
  • Edward Garmey
    • 5
  • Jungyeon Hwang
    • 5
  • D. Lynn Kalinoski
    • 5
    • 8
  • Marianna Koczywas
    • 2
  • Jeffrey Longmate
    • 2
  • Roger J. Melton
    • 6
  • Robert Morgan
    • 2
  • Jamie Oliver
    • 7
  • Joanna J. Peterkin
    • 5
  • John L. Ryan
    • 5
  • Thomas Schluep
    • 8
  • Timothy W. Synold
    • 2
  • Przemyslaw Twardowski
    • 2
  • Mark E. Davis
    • 4
  • Yun Yen
    • 2
    • 9
  1. 1.Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGenScottsdaleUSA
  2. 2.City of Hope Comprehensive Cancer CenterDuarteUSA
  3. 3.San Juan Oncology AssociatesFarmingtonUSA
  4. 4.California Institute of TechnologyPasadenaUSA
  5. 5.Cerulean Pharma Inc.CambridgeUSA
  6. 6.Seventh WaveChesterfieldUSA
  7. 7.Peptagen, Inc.RaleighUSA
  8. 8.Calando PharmaceuticalsPasadenaUSA
  9. 9.Department of Medical Oncology and Therapeutics ResearchCity of Hope Comprehensive Cancer CenterDuarteUSA