Fit-for purpose use of mouse models to improve predictivity of cancer therapeutics evaluation.

UNLABELLED: Preclinical animal models are useful tools to better understand tumor initiation and progression and to predict the activity of an anticancer agent in the clinic. Ideally, these models should recapitulate the biological characteristics of the tumor and of the related tumor microenvironment (e.g. vasculature, immune cells) in patients. Even if several examples of translational success have been reported it is a matter of fact that clinical trials in oncology often fail to meet their primary endpoints despite encouraging preclinical data. For this reason, there is an increasing need of improved and more predictive models. This review aims to give an overview on existing mouse models for preclinical evaluation of cancer therapeutics and their applicability. Different types of mouse models commonly used for the evaluation of cancer therapeutics are described and considerations for a "fit-for purpose" application of these models for the evaluation of different cancer therapeutics dependent on their mode of action are outlined. Furthermore, considerations for study design and data interpretation to translatability of findings into the clinics are given. CONCLUSION: Detailed knowledge of the molecular/biological properties of the respective model, diligent experimental setup, and awareness of its limitations are indispensable prerequisites for the successful translational use of animal models.

Non-clinical pharmacokinetic/pharmacodynamic and early clinical studies supporting development of a novel subcutaneous formulation for the monoclonal antibody rituximab.

This overview article describes the non-clinical pharmacology, pharmacokinetic and clinical dose-finding programs supporting the development of a novel subcutaneous formulation for rituximab, a monoclonal antibody that selectively targets CD20-positive B-lymphocytes. The subcutaneous route of administration is expected to improve convenience for patients and to reduce healthcare professional resource use compared with conventional intravenous infusion. Various non-clinical and clinical studies were conducted to support the bridge from the approved intravenous formulation to the novel subcutaneous treatment. The underlying hypothesis for these studies was that achieving subcutaneous rituximab serum trough concentrations that are at least as high as those reached with the intravenous formulation would result in at least the same degree of receptor saturation. Preclinical mouse xenograft and cynomolgus monkey B-cell depletion studies were performed at intravenous and subcutaneous doses that were previously found to result in comparable serum concentrations in pharmacokinetic studies in the same species. Results from these non-clinical assessments guided dose selection for the subsequent phase 1b dose finding trials in patients with follicular lymphoma as part of maintenance treatment. A fixed dose of 1 400 mg was found to result in noninferior serum trough concentrations to the intravenous formulation. Clinical trials in the induction setting in patients with follicular lymphoma and chronic lymphocytic leukemia are currently ongoing.

Development of a subcutaneous formulation for trastuzumab - nonclinical and clinical bridging approach to the approved intravenous dosing regimen.

A subcutaneous (SC) formulation has been developed for the humanized monoclonal antibody (mAb) trastuzumab as an alternative to established intravenous (IV) infusion. The ready-to-use liquid SC formulation is injected as a fixed dose in approximately 5 min, which is expected to increase patient's convenience, reduce pharmacy preparation time, and administration costs overall.The trastuzumab dose as well as the dose of recombinant human hyaluronidase (rHuPH20), an enzyme that enables SC administration of volumes larger than 2 mL, was selected based on nonclinical xenograft, pharmacology, and pharmacokinetics mouse and minipig studies.The basic assumption for bridging from the IV to the SC regimen was that comparable trastuzumab serum trough concentrations would result in comparable efficacy. This hypothesis is confirmed by the results from the Phase 3 study in the neo-adjuvant/adjuvant setting. The safety profiles of the trastuzumab SC and IV formulations are comparable and consistent with the known safety profile of trastuzumab.