405P - Hepatic functional imaging and genomics to predict irinotecan pharmacokinetics and pharmacodynamics: The PREDICT IR study:

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Pharmacology
Translational Research
Presenter MICHAEL MICHAEL
Citation Annals of Oncology (2017) 28 (suppl_5): v122-v141. 10.1093/annonc/mdx367
Authors M. MICHAEL1, W. Liauw2, S. McLachlan3, E. Link4, A. Matera4, M. Thompson5, M. Jefford1, R.J. Hicks5, C. Cullinane6, I. Campbell6, P.J. Beale7, C.S. Karapetis8, T.J. Price9, M.E. Burge10
  • 1Division Of Cancer Medicine, Peter MacCallum Cancer Centre, 3000 - Melbourne/AU
  • 2Medical Onclogy, St Geroges Hospital, Sydney/AU
  • 3Medcial Oncology, St Vincents Hospital, Melbourne/AU
  • 4Biostatistics And Clinical Trials Centre, Peter MacCallum Cancer Centre, 3000 - Melbourne/AU
  • 5Dept Cancer Imaging, Peter MacCallum Cancer Centre, 3000 - Melbourne/AU
  • 6Division Of Cancer Researchcine, Peter MacCallum Cancer Centre, 3000 - Melbourne/AU
  • 7Medical Oncology, Royal Prince Alfred Hospital, Sydney/AU
  • 8Medical Oncology, Flinders Medical Centre and Flinders Centre for Innovation in Cancer, Adelaide/AU
  • 9Medical Oncology, Queen Elizabeth Hospital, 5011 - Woodville/AU
  • 10Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane/AU

Abstract

Background

Body surface area-based dosing of Irinotecan (IR), has not accounted for its significant pharmacokinetic (PK) and pharmacodynamic (PD) variability. Given IR’s unique metabolism, hepatic functional nuclear imaging (HNI) with probes for hepatic transporters correlated with its PK. This study further evaluated the utility of HNI combined with extensive excretory/metabolic/PD pharmacogenomics (PG) to predict IR PK and PD in patients (pts) treated with FOLFIRI to enable dose individualization.

Methods

Eligible pts had advanced colorectal cancer, suitable for 1st/2nd-line FOLFIRI± Bevacizumab. Pts had blood analyzed by Affymetrix DMET™ Plus Array and additional SNPs were genotyped. For HNI, pts were given IV 250MBq 99mTc-IDA and imaging data analyzed for hepatic extraction/excretion parameters (clearance [CL], 1hour retention [1hRET], deconvulutional CL [DeCL], hepatic extraction fraction [HEF]). Pts treated with chemotherapy, q2-weekly, and restaged after 4 cycles. Blood taken for IR and metabolite (SN38, SN38G) analysis on day 1 cycle 1, PK parameters derived by non-compartmental analysis. Statistical correlations were evaluated between (i) IDA HNI and (2) PGs, with IR PK, toxicity, objective response (ORR) and progression-free survival (PFS).

Results

32 pts analysed, 31 pts completed 4 cycles. (1) PK correlates: (a) HNI CL and 1hRET with SN38 Metabolic CL, (P = 0.04) and (b) HNI DeCL with IR AUC(0-∞) (P = 0.04). (2) Grade 3+ diarrhea (N = 4, 13%) predicted by SN38 AUC(0-∞) andMetabolic CL (P = 0.04), and gene variants for SCL22A2 and -28A3, ABCC2, UGT2B17, CYP2C18 and DPYD (P 

Conclusions

Hepatic functional imaging with extensive pharmacogenomics correlated with Irinotecan PK and PD enabling the future development of nomograms to individualize its dosing.

Clinical trial identification

Australian Clinical Trials Registry: ACTRN12610000898055

Legal entity responsible for the study

Peter MacCallum Cancer Centre

Funding

Australian Federal Government: National Health and Medical Research Council Project Grant

Disclosure

All authors have declared no conflicts of interest.