Katie Owens, Sylvain Fouliard, and Marylore Chenel
Department of Clinical Pharmacokinetics and Pharmacometrics, Institut de Recherches Internationales Servier, Suresnes, France
Introduction: The evaluation of the Objective Response Rate (ORR) in lymphoma patients is based on the assessment of various clinical measures [1-3]. One of the clinical measures assessed for response is lymph node size, recorded as the sum of the product of diameters (SPD). The analysis of multiple types of clinical measures in an integrated framework may improve the evaluation of the ORR in lymphoma patients.
Objectives: The objective was to develop a K-PD model to characterise the time course of SPD in lymphoma patients treated with abexinostat. The overall strategy is to integrate information on lymph node shrinkage data with other clinical measures of response to optimise the prediction of the ORR in lymphoma patients.
Methods: SPD data were available for 121 patients from two phase I and II clinical studies indicated for chronic lymphocytic leukaemia (CLL) (n=19), Hodgkin’s disease (HD) (n=11) and non Hodgkin lymphoma (NHL) (n=91). The patients were followed for a median time of two 3-week cycles of treatment receiving either fixed or BSA-adjusted oral doses of abexinostat under three dosing schedules. A population K-PD tumour growth inhibition (TGI) model was used to describe the SPD data, based on a longitudinal TGI model previously applied to tumour size (sum of longest diameters) and change in tumour glucose utilisation (maximal standardised uptake value) [4-5]. Dose and AUC were evaluated as predictors of change in SPD. Other clinical measures explored included PET scans, organomegaly, blood counts, circulating B lymphocyte counts, and serum monoclonal IgM concentration.
Results: The SPD data were well characterised by the TGI model. Individual fit analysis, goodness of fit plots, VPC and NPDE were used for model evaluation. 121 patients contributed to 389 SPD observations. Other categorical clinical measures investigated were PET scans, liver enlargement (n patients=114, n observations=657); spleen enlargement (n patients=113, n observations=656); continuous measures were leukocyte counts (n patients=121, n observations=2679); platelet counts (n patients=121, n observations=2660); haemaglobin concentration (n patients=121, n observations=2672); circulating B lymphocyte counts (n patients=15, n observations=67); and serum monoclonal IgM concentration (n patients=5, n observations=40).
Conclusions: The population K-PD TGI model was able to describe the time course of SPD in lymphoma patients and will be combined with other clinical measures in an integrated framework to optimise evaluation of the ORR.
References:
[1] Cheson BD, et al. Revised response criteria for malignant lymphoma. Journal of Clinical Oncology (2007) 25(5): 579-586
[2] Hallek M, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute – Working Group 1996 guidelines. Blood (2008). 111:5446-5456
[3] Kimby E, et al. Update on the recommendations for assessing response from the Third International Workshop on Waldenström’s Macroglobulinemia. Clinical Lymphoma and Myeloma (2006) 6(5): 380-383
[4] Claret L, et al. Model-based prediction of phase III overall survival in colorectal cancer on the basis of phase II tumour dynamics. Journal of Clinical Oncology (2009) 27(25): 4103-4108
[5] Schindler E, et al. PAGE 21 (2012) Abstr 2595 [www.page-meeting.org/?abstract=2595]
Reference: PAGE 23 () Abstr 3051 [www.page-meeting.org/?abstract=3051]
Poster: Drug/Disease modeling - Oncology