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.
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.
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)|
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
Legal entity responsible for the study
Cerulean Pharma, Inc
Cerulean Pharma, Inc
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.