Journal Article

DZNE-2025-00506

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Results of the preclinical multicenter randomized controlled paclitaxel-induced neuropathy prevention replication study (PINPRICS).

Boehmerle, W. ; Hagenacker, T. ; Leo, M. ; Schmitt, L.-I. ; Lehmann, H. C. ; Klein, I. ; Stegherr, R. ; Konietschke, F. ; Endres, M. (Last author)DZNE* ; Huehnchen, P.

2025
[Verlag nicht ermittelbar] London

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Please use a persistent id in citations: doi:10.1186/s13104-025-07206-2

Abstract: Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and serious side effect of many cytotoxic drugs, including paclitaxel. Despite the identification of treatment options in animal models, clinical trials for the treatment or prevention of CIPN have been negative. Major challenges for successful clinical translation of preclinical data include a lack of reproducibility and randomization, small sample sizes and insufficient statistical tests. We therefore conducted a confirmatory, preclinical multicenter randomized controlled replication trial to test the safety and efficacy of three drugs for preventing paclitaxel-induced polyneuropathy: (1) nilotinib, (2) lithium carbonate and (3) interleukin-6-neutralizing antibodies. We preregistered the data analysis plan as well as the two-step study protocol: the optimal doses of the three compounds were assessed first and then tested in a mouse breast cancer xenograft model to compare safety and efficacy.Unfortunately, toxicity of intraperitoneally administered nilotinib in combination with paclitaxel was observed, and higher-than-expected tumor growth resulted in a lack of power when the trial was analyzed. Thus, although lithium carbonate and IL-6-neutralizing antibodies tended toward neuroprotection, the differences between these groups were not statistically significant. However, the PINPRICS study ultimately still provides important lessons with regard to the planning and conduction of multicenter preclinical trials.

Keyword(s): Paclitaxel: adverse effects (MeSH) ; Animals (MeSH) ; Mice (MeSH) ; Female (MeSH) ; Lithium Carbonate: pharmacology (MeSH) ; Lithium Carbonate: therapeutic use (MeSH) ; Lithium Carbonate: administration & dosage (MeSH) ; Pyrimidines: therapeutic use (MeSH) ; Pyrimidines: pharmacology (MeSH) ; Pyrimidines: administration & dosage (MeSH) ; Humans (MeSH) ; Peripheral Nervous System Diseases: chemically induced (MeSH) ; Peripheral Nervous System Diseases: prevention & control (MeSH) ; Antibodies, Neutralizing: pharmacology (MeSH) ; Antibodies, Neutralizing: therapeutic use (MeSH) ; Interleukin-6: immunology (MeSH) ; Interleukin-6: antagonists & inhibitors (MeSH) ; Antineoplastic Agents, Phytogenic: adverse effects (MeSH) ; Cell Line, Tumor (MeSH) ; Xenograft Model Antitumor Assays (MeSH) ; Breast Neoplasms: drug therapy (MeSH) ; Breast Neoplasms: pathology (MeSH) ; Chemotherapy-induced polyneuropathy ; Neuropathic pain ; Neuroprotection ; Preclinical replication study ; Paclitaxel ; Lithium Carbonate ; Pyrimidines ; nilotinib ; Antibodies, Neutralizing ; Interleukin-6 ; Antineoplastic Agents, Phytogenic

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Contributing Institute(s):

1. Interdisciplinary Dementia Research (AG Endres)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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