Abstract A192: PK/PD modeling-based optimization of administration schedule for the histone deacetylase inhibitor (HDACi) S78454/PCI-24781 in phase I.
Authors: Robert Renata , Jacquet-Bescond Anne , Chenel Marylore , Fouliard Sylvain , du Rieu Quentin Chalret , Balasubramanian Sriram , Loury David , Loriot Yohann , Kloos Ioana , Soria Jean-Charles , Depil Stephane 
Published: June 2012

S78454 (also called PCI-24781) is a novel, orally bioavailable, hydroxamate-based pan-HDACi currently being tested in clinical trials in the US and EU. Two single agent Phase I studies have been completed in patients with advanced solid tumors. The first study (PCYC-0402) tested 4 different administration schedules with 4-week (wk) cycles: 1) TID and 2) BID 5 days/wk 3 wks/4; 3) BID on days 1–7 & 15–21; 4) BID on days 1–5 & 15–19. The planned dose levels were 30, 45, 60, 75 and 90 mg/m2.

The second study (CL1-002) tested an additional schedule: 5) BID 14 days on/7 days off in 3-week cycles. The maximum tolerated dose (MTD), defined by dose-limiting toxicity (DLT) occurring in at least 2/3 or 2/6 patients so that further dose-escalation is not undertaken, was established at 75 mg/m2 BID and the recommended dose at 60 mg/m2 BID.

The DLT, consistently observed across all these schedules, was reversible thrombocytopenia, common to all HDACi and directly related to their mechanism of action. To address this issue, a pharmacokinetic/pharmacodynamic (PK/PD) model was used to predict the optimal administration schedule that could allow higher doses with minimal thrombocytopenia.

Platelet-time profiles from the first study (PCYC-0402) were analyzed using a mixed effect model (Sheiner et al, 1980). This approach allowed the estimation of population mean parameters and their variability by the simultaneous fit of all data records, despite their heterogeneity. This PK/PD model consisted in a previously developed PK model of S78454 used as an input into a semi-physiological platelet time-course model (Friberg et al, 2002). This model was made up of a self-renewing progenitor compartment connected to transit compartments representing maturation process, and leading to a circulating compartment. A feedback mechanism mimicked the increase in proliferation rate when platelet count falls below baseline. The model was parameterized with baseline, feedback intensity, mean maturation time of platelets, and drug concentration/effect relationship. It adequately fitted observed platelet counts after different administration schedules and showed good prediction of adverse events related to haematological toxicity. Several administration schedules were simulated using this model. The results showed that a 4 days on/ 3 days off schedule was associated with the smallest platelet decrease. Accordingly, the protocol for study CL1–002 was amended. After reaching MTD in schedule 5, subsequent cohorts received S78454 on a revised schedule of 4 days on/ 3 days off, starting at one dose level below MTD (60 mg/m2 BID). The dose escalation followed the same design as the initial schedule with the same pre-defined dose levels. As expected, the dose escalation continued for two more dose levels beyond the MTD in schedule 5. At 105 mg/m2 BID, 2/3 patients included experienced DLTs of grade 4 thrombocytopenia, and therefore the MTD in the revised schedule was established at 105 mg/m2 BID.

In conclusion, early understanding of toxicities and PK determination allowed us to build a PK/PD model of thrombocytopenia, which predicted the optimal administration schedule. This optimized schedule is planned to be used in future trials with S78454/PCI-24781. This also provides a successful example of modeling early in development that can be applied to other therapeutics.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A192.