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N.K.A. van Eijkelenburg et al.
RP2D at DL4, both 1-year pEFS and pOS were 60.0±15.5%, while 2-year pEFS was 50.0±15.8% and 2- year pOS 60.0±15.5% (Figure 2D and E).
Pharmacokinetic analysis
Blood samples were available from the first 19 patients, after which collection of PK data was halted after interim analysis. Comparison of normalized plasma concentra- tions at day 5 pre-dose and 24 hours (h) after the last infu- sion of clofarabine showed similar results with a median concentration of 0.12 and 0.10 ng/mL/mg, indicating a steady state plasma concentration. The median AUC at day 1 was 28.0 ng/mL/mg/h (range 6.0 to 401.2) and 44.0 ng/mL/mg/h (range 19.4 to 135.9) at day 5. Clofarabine t1/2 was identical at day 1 and day 5 (average value of 1.5 h) (Online Supplementary Figure S3A).
Clofarabine levels in CSF (n=11) ranged from 0.3 ng/mL to 3.2ng/mL [median CSF penetration (CSF conc/plasma conc) was 32.9% (range 8.0-66.5%)]. These data are in contrast with the previously reported low clofarabine median penetration of 5% (range 3-26%) into the CSF in non-human primates.30
Bonate et al.31 have fit clofarabine single-agent PK data derived from 3 clinical trials (i.e. the ID99-383 study
A
recruiting pediatric hematologic malignancies, the CLO- 212 study in pediatric ALL, and the CLO-222 study in pediatric refractory AML) using a non-parametric LOESS fit to the observed dose normalized concentration-time plot. Our clofarabine PK data fitted well with the Bonate et al. 2004 PK model (Figure 3B), confirming that the cur- rent combination did not alter clofarabine PK. Furthermore, our PK data in combination were not signif- icantly different from our data with single-agent clofara- bine in relapsed ALL patients,32 suggesting that clofarabine has no major drug-drug interaction with either cytarabine or daunorubicin which can affect clofarabine PK.
Discussion
In this phase IB study, the RP2D of clofarabine in com- bination with cytarabine and DNX was established at 40 mg/m2/day for five consecutive days in combination with 60 mg/m2 DNX at days 1, 3 and 5 and cytarabine 2 gram/m2 for five days in patients with no clinical evidence of subclinical fungal infections at time of treatment. This regimen resulted in a high ORR of 68% in 31 response evaluable patients, and 80% at the RP2D (n=10).
In general, the combination of clofarabine, liposomal
B
Figure 3. Clofarabine phar- macokinetics and Ppasma concentrations. (A) Clofarabine plasma concen- trations normalized to infused dose (ng/mL/mg of infused dose) as measured by liquid chromatography mass spec- trometry (LC-MS)/MS. Each line represents plasma con- centrations for a single patient before receiving clo- farabine infusion (Pre-dose), 2 (T2), 5 (T5) and 24 (T24) hours (h) after starting of clo- farabine infusion at day (d)1 and d5 of the first treatment
cycle. Samples from patients (ns. 0708 and 0717) were available from two differ- ent treatment cycles. (B) A scatter plot for clofarabine plasma concentrations as measured by LC-MS/MS (in color) overlaid on the pharma- cokinetic model developed by Bonate et al.31 (in gray) for sin- gle agent clofarabine in 3 pre- vious clinical studies (ID99- 383, CLO-212 and CLO-222) fitted using non-parametric LOESS fit.
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haematologica | 2018; 103(9)