394P - Pharmacokinetics (PK) of CRLX101 administered weekly in patients (pts) with advanced solid tumors

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Drug Development
Pharmacology
Presenter Hongwei Wang
Citation Annals of Oncology (2016) 27 (6): 114-135. 10.1093/annonc/mdw368
Authors H. Wang1, W. Zamboni2, A. Tolcher3, N. Lakhani4, S.A. Piha-Paul5, K. Caliri6, T. Crowell6, A. Senderowicz6
  • 1Research, Cerulean Pharma, Inc., 02451-1215 - Waltham/US
  • 2Unc Lineberger Comprehensive Cancer Center, UNC Eshelman School of Pharmacy, Carolina Center for Cancer Nanotechnology Excellence, Chapel Hill/US
  • 3Clinical Research, START - South Texas Accelerated Research Therapeutics, LLC, 78229 - San Antonio/US
  • 4Clinical Research, START Midwest/Cancer & Hematology Centers of Western Michigan, PC, 49503 - Grand Rapids/US
  • 5Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 77030 - Houston/US
  • 6Clinical Operations, Cerulean Pharma, Inc., 02451-1215 - Waltham/US

Abstract

Background

CRLX101 is a novel investigational nanoparticle-drug conjugate (NDC) containing the payload camptothecin (CPT) covalently conjugated to a cyclodextrin-polyethylene glycol co-polymer that is 10-30 nm in diameter. The PK of NDCs depends on the polymer until the active-drug payload is released. It is important to characterize the PK of the conjugated CPT and the active released CPT. The maximum tolerated dose (MTD) of CRLX101 from the first-in-human study is 15 mg/m2 biweekly (QOW; Weiss, 2013. Invest New Drugs. 31:986), which is being used clinically in several tumor types (Keefe et al., 2015. JCO. 15:4543; Krasner, 2016. AACR. CT090). This study evaluated the PK of a more intensive weekly (QW) dosing schedule of CRLX101.

Methods

CRLX101 was administered QW at 12 and 15 mg/m2 intravenously over 1-2 h, representing an equivalent mg dose of CPT. PK assessment was performed at weeks 1, 3 and 7. Plasma samples were processed to measure total and released CPT by an LC-MS/MS assay. The concentration of conjugated CPT was calculated as total CPT minus released CPT. Area under concentration vs time curves (AUC0-168h) in plasma were estimated.

Results

PK results are included in the Table. In plasma, >90% of the total CPT remains as the conjugated form. The interpatient variability in the exposure of conjugated CPT is lower compared to many other liposomal anticancer agents (Schell et al., 2014. Nanomedicine. 10:109). The variability of the released CPT is greater than for conjugated CPT. The plasma exposure of conjugated and released CPT is consistent from week 1 to 7, suggesting no accumulation after multiple weekly doses.

Summary of conjugated and released CPT exposures on weeks 1, 3 and 7 after weekly administration of CRLX101

AUC0-168h (µg/mL·h) 12 mg/m2 n = 7 Mean ± SD 15 mg/m2 n= 8 Mean ± SD
Week 1 Conjugated CPT 211.2 ± 123.0 (n = 7) 221.8 ± 33.6 (n = 5)
Released CPT 16.2 ± 10.6 (n = 7) 18.1 ± 10.6 (n = 5)
Ratio released CPT to conjugated CPT 0.07 ± 0.02 (n = 7) 0.08 ± 0.04 (n = 5)
Week 3 Conjugated CPT 181.9 ± 28.6 (n = 5) 217.1 ± 46.3 (n = 5)
Released CPT 15.5 ± 5.4 (n = 5) 20.3 ± 11.6 (n = 5)
Ratio released CPT to conjugated CPT 0.08 ± 0.02 (n = 5) 0.09 ± 0.06 (n = 5)
Ratio conjugated CPT week 3 to week 1 1.10 ± 0.14 (n = 5) 1.03 ± 0.14 (n = 4)
Ratio released CPT week 3 to week 1 1.19 ± 0.30 (n = 5) 1.13 ± 0.13 (n = 4)
Week 7 Conjugated CPT 188.3 ± 35.7 (n = 2) 219.5 (n = 1)
Released CPT 19.5 ± 0.3 (n = 2) 14.4 (n = 1)
Ratio released CPT to conjugated CPT 0.11 ± 0.02 (n = 2) 0.06 (n = 1)
Ratio conjugated CPT week 7 to week 1 0.96 ± 0.16 (n = 2) 1.12 (n = 1)
Ratio released CPT week 7 to week 1 1.17 ± 0.16 (n = 2) 2.23 (n = 1)

Conclusions

CRLX101 exhibits high retention of drug in plasma, slow clearance and controlled slow release of CPT from the polymer. The PK data support QW dosing of CRLX101 at 15 mg/m2, which represents a 100% increase in dose intensity when compared to QOW dosing of CRLX101 in other phase 2 trials. This more dose-intensive CRLX101 schedule will be tested in future combination studies.

Clinical trial identification

NCT02648711 (NIH)

Legal entity responsible for the study

Cerulean Pharma, Inc

Funding

Cerulean Pharma, Inc

Disclosure

H. Wang, K. Caliri, T. Crowell, A. Senderowicz: Employee at Cerulean Pharma Inc. W. Zamboni: Personal fees from Cerulean Pharma, during the conduct of the study; personal fees from Cerulean Pharma, outside the submitted work.A. Tolcher: Received fees: Bind Therapeutics, Blend Therapeutics, Celator, Decerna, Janssen, Merus, Nanobiotix, Pharmacyclics, Pierre Fabre Medicament, Symphogen, Valent Tech, Heron, J&J, Asana Biosciences, Akebia, Genmab, Mersana, Endocyte, Proximagan, Upsher-Smith. N. Lakhani: Non-financial support from Cerulean, during the conduct of the study; non-financial support from Cerulean, Merck, Pfizer, Abbvie, ArQule Pharma, Regeneron Pharma, Novartis, BMS, Foundation Medicine, LAM Therapeutics, Pronai outside the submitted work.