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, Ramesk 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 & 5 others Thomas Schluep, Timothy W. Synold, Przemyslaw Twardowski, Mark E. Davis, Yun Yen

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

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/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.

Original languageEnglish (US)
Pages (from-to)986-1000
Number of pages15
JournalInvestigational New Drugs
Volume31
Issue number4
DOIs
StatePublished - Aug 2013
Externally publishedYes

Fingerprint

Camptothecin
Maximum Tolerated Dose
Neoplasms
Polymers
Pharmacokinetics
cyclodextrin polymer
IT-101
Neutropenia
Disease-Free Survival
Area Under Curve
Fatigue
Appointments and Schedules
Safety

Keywords

  • Nanopharmaceutical
  • Phase 1/2a
  • Polymer conjugate camptothecin
  • Solid tumor

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies. / Weiss, Glen J.; Chao, Joseph; Neidhart, Jeffrey D.; Ramanathan, Ramesk K; Bassett, Dawn; Neidhart, James A.; Choi, Chung Hang J; Chow, Warren; Chung, Vincent; Forman, Stephen J.; Garmey, Edward; Hwang, Jungyeon; Kalinoski, D. Lynn; Koczywas, Marianna; Longmate, Jeffrey; Melton, Roger J.; Morgan, Robert; Oliver, Jamie; Peterkin, Joanna J.; Ryan, John L.; Schluep, Thomas; Synold, Timothy W.; Twardowski, Przemyslaw; Davis, Mark E.; Yen, Yun.

In: Investigational New Drugs, Vol. 31, No. 4, 08.2013, p. 986-1000.

Research output: Contribution to journalArticle

Weiss, GJ, Chao, J, Neidhart, JD, Ramanathan, RK, Bassett, D, Neidhart, JA, Choi, CHJ, Chow, W, Chung, V, Forman, SJ, Garmey, E, Hwang, J, Kalinoski, DL, Koczywas, M, Longmate, J, Melton, RJ, Morgan, R, Oliver, J, Peterkin, JJ, Ryan, JL, Schluep, T, Synold, TW, Twardowski, P, Davis, ME & Yen, Y 2013, 'First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies', Investigational New Drugs, vol. 31, no. 4, pp. 986-1000. https://doi.org/10.1007/s10637-012-9921-8
Weiss, Glen J. ; Chao, Joseph ; Neidhart, Jeffrey D. ; Ramanathan, Ramesk K ; Bassett, Dawn ; Neidhart, James A. ; Choi, Chung Hang J ; Chow, Warren ; Chung, Vincent ; Forman, Stephen J. ; Garmey, Edward ; Hwang, Jungyeon ; Kalinoski, D. Lynn ; Koczywas, Marianna ; Longmate, Jeffrey ; Melton, Roger J. ; Morgan, Robert ; Oliver, Jamie ; Peterkin, Joanna J. ; Ryan, John L. ; Schluep, Thomas ; Synold, Timothy W. ; Twardowski, Przemyslaw ; Davis, Mark E. ; Yen, Yun. / First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies. In: Investigational New Drugs. 2013 ; Vol. 31, No. 4. pp. 986-1000.
@article{4bbc97ea5945432287f9b551d656f321,
title = "First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies",
abstract = "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/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.",
keywords = "Nanopharmaceutical, Phase 1/2a, Polymer conjugate camptothecin, Solid tumor",
author = "Weiss, {Glen J.} and Joseph Chao and Neidhart, {Jeffrey D.} and Ramanathan, {Ramesk K} and Dawn Bassett and Neidhart, {James A.} and Choi, {Chung Hang J} and Warren Chow and Vincent Chung and Forman, {Stephen J.} and Edward Garmey and Jungyeon Hwang and Kalinoski, {D. Lynn} and Marianna Koczywas and Jeffrey Longmate and Melton, {Roger J.} and Robert Morgan and Jamie Oliver and Peterkin, {Joanna J.} and Ryan, {John L.} and Thomas Schluep and Synold, {Timothy W.} and Przemyslaw Twardowski and Davis, {Mark E.} and Yun Yen",
year = "2013",
month = "8",
doi = "10.1007/s10637-012-9921-8",
language = "English (US)",
volume = "31",
pages = "986--1000",
journal = "Investigational New Drugs",
issn = "0167-6997",
publisher = "Kluwer Academic Publishers",
number = "4",

}

TY - JOUR

T1 - First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies

AU - Weiss, Glen J.

AU - Chao, Joseph

AU - Neidhart, Jeffrey D.

AU - Ramanathan, Ramesk K

AU - Bassett, Dawn

AU - Neidhart, James A.

AU - Choi, Chung Hang J

AU - Chow, Warren

AU - Chung, Vincent

AU - Forman, Stephen J.

AU - Garmey, Edward

AU - Hwang, Jungyeon

AU - Kalinoski, D. Lynn

AU - Koczywas, Marianna

AU - Longmate, Jeffrey

AU - Melton, Roger J.

AU - Morgan, Robert

AU - Oliver, Jamie

AU - Peterkin, Joanna J.

AU - Ryan, John L.

AU - Schluep, Thomas

AU - Synold, Timothy W.

AU - Twardowski, Przemyslaw

AU - Davis, Mark E.

AU - Yen, Yun

PY - 2013/8

Y1 - 2013/8

N2 - 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/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.

AB - 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/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.

KW - Nanopharmaceutical

KW - Phase 1/2a

KW - Polymer conjugate camptothecin

KW - Solid tumor

UR - http://www.scopus.com/inward/record.url?scp=84880917692&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880917692&partnerID=8YFLogxK

U2 - 10.1007/s10637-012-9921-8

DO - 10.1007/s10637-012-9921-8

M3 - Article

VL - 31

SP - 986

EP - 1000

JO - Investigational New Drugs

JF - Investigational New Drugs

SN - 0167-6997

IS - 4

ER -