Using pharmacokinetic simulation to guide dose escalation decisions for targeted IL2v immunocytokines
Hanna Silber Baumann(1), Christophe Boetsch(1), Volker Teichgräber(2), Benjamin Ribba(1), Valerie Cosson(1)
Roche Pharma Research & Early Development. (1) Clinical Pharmacology, Roche Innovation Center Basel, (2) Translational Medicine Oncology, Roche Innovation Center Zurich.
Objectives: To guide dose escalation of targeted IL2v compounds with a narrow safety window through pharmacokinetic (PK) simulation, when a continuous reassessment dose escalation method (with overdose control, EWOC) did not provide sufficient flexibility due to the presence of non-linear PK behaviour.
Methods: Two targeted immunocytokines, that contain a variant of IL-2 (IL2v), are currently being investigated in clinic. Their molecular design aims to avoid preferential activation of regulatory T-cells by removing CD25 binding, to increase the therapeutic index of IL-2 therapy and to improve PK properties over wild type IL2 (Proleukin). The PK properties of the IL2v’s are similar with the main elimination pathway likely mediated via interaction with the IL2 receptor (IL2R) expressed on circulating immune cells. The interaction with IL2R is also the cause of side effects which leads to a narrow safety window. A model describing the target mediated PK (TMDD) and expansion of the target pool has been presented previously [1,2]. Simulations were performed investigating different dosing intervals (e.g. QW, Q2W) and regimens for intra-patient dose escalation with the aim to find a regimen that would provide maintained peripheral exposure over several treatment cycles in order to optimize tumor uptake. We also aimed to understand the effects of dose and regimen on the expansion of the peripheral target pool.
Results: In general, the dose increase needed to maintain exposure was higher with a higher starting dose and a more frequent dosing, due to the effect on the target pool and TMDD. As an example, with a dose of 5 mg, no dose escalation was necessary to maintain exposure. By contrast, with a dose of 25 mg, a dose escalation of 60% was necessary when the regimen used was Q2W with an initial induction phase (2xQW). For the evaluated dose regimens, the median predicted exposure was in general maintained within 10% of that observed following the initial dose. With Q3W dosing, the target pool returned towards baseline in between doses and the required dose increase was lower compared to the QW/Q2W regimen. The simulations were used to guide dose escalation decisions in the clinic whilst managing safety.
Conclusions: Intra-patient dose escalation should benefit tumor uptake of the targeted IL2v’s, as it allows higher doses to be administered compared to when a fixed dose regimen is applied. Simulations were used to mitigate time dependent loss of exposure and to safely explore and optimize dose and schedule.
References:
[1] HP Grimm et al. PAGE 25 (2016) Abstr 5861 [www.page-meeting.org/?abstact=5861]
[2] Silber Baumann HE et al. When target expression drives drug exposure – an example with the antibody-cytokine fusion protein CEA-IL2v. PSI conference 2016.
