Rationale and design of the prevention of paclitaxel-related neurological side effects with lithium trial - Protocol of a multicenter, randomized, double-blind, placebo- controlled proof-of-concept phase-2 clinical trial

Petra Huehnchen; Nikola Bangemann; Sandra Lischewski; Stefanie Märschenz; Friedemann Paul; Tanja Schmitz-Hübsch; Jens-Uwe Blohmer; Cornelia Eberhardt; Geraldine Rauch; Agnes Flöel; Sophie Adam; Philipp Schwenkenbecher; Ivo Meinhold-Heerlein; Oliver Hoffmann; Tjalf Ziemssen; Matthias Endres; Wolfgang Boehmerle

doi:10.3389/fmed.2022.967964

Rationale and design of the prevention of paclitaxel-related neurological side effects with lithium trial - Protocol of a multicenter, randomized, double-blind, placebo- controlled proof-of-concept phase-2 clinical trial

Front Med (Lausanne). 2022 Aug 11:9:967964. doi: 10.3389/fmed.2022.967964. eCollection 2022.

Authors

Petra Huehnchen^{1

2}, Nikola Bangemann³, Sandra Lischewski^{1

4}, Stefanie Märschenz^{1

4}, Friedemann Paul^{1

4

5

6

7}, Tanja Schmitz-Hübsch^{4

5

6

7}, Jens-Uwe Blohmer⁸, Cornelia Eberhardt⁹, Geraldine Rauch¹⁰, Agnes Flöel^{11

12}, Sophie Adam¹³, Philipp Schwenkenbecher¹⁴, Ivo Meinhold-Heerlein¹⁵, Oliver Hoffmann¹⁶, Tjalf Ziemssen¹⁷, Matthias Endres^{1

2

3

18

19

20}, Wolfgang Boehmerle^{1

2}

Affiliations

¹ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Klinik und Hochschulambulanz für Neurologie, Humboldt-Universität zu Berlin, Berlin, Germany.
² Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
³ Carl-Thiem-Klinikum Cottbus, Klinik für Senologie und Systemische Gynäkoonkologie mit Brustzentrum, Cottbus, Germany.
⁴ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, NeuroCure Clinical Research Center (NCRC), Berlin, Germany.
⁵ Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁶ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Experimental and Clinical Research Center, Berlin, Germany.
⁷ Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
⁸ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Klinik für Gynäkologie und Brustzentrum, Berlin, Germany.
⁹ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Pharmacy, Berlin, Germany.
¹⁰ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institut für Biometrie und Klinische Epidemiologie, Berlin, Germany.
¹¹ Universitätsmedizin Greifswald, Department of Neurology, Greifswald, Germany.
¹² German Center for Neurodegenerative Diseases (DZNE), Greifswald, Germany.
¹³ Mammazentrum Hamburg, Hamburg, Germany.
¹⁴ Medizinische Hochschule Hannover, Department of Neurology, Hanover, Germany.
¹⁵ Universitätsklinikum Giessen, Klinik für Gynäkologie und Geburtshilfe, Giessen, Germany.
¹⁶ Universitätsklinikum Essen, Klinik für Frauenheilkunde und Geburtshilfe, Essen, Germany.
¹⁷ Universitätsklinikum Carl Gustav Carus, Klinik und Poliklinik für Neurologie, Dresden, Germany.
¹⁸ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Center for Stroke Research Berlin (CSB), Berlin, Germany.
¹⁹ German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
²⁰ German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany.

Abstract

Introduction: Chemotherapy-induced polyneuropathy (CIPN) and post-chemotherapy cognitive impairment (PCCI) are frequent side effects of paclitaxel treatment. CIPN/PCCI are potentially irreversible, reduce quality of life and often lead to treatment limitations, which affect patients' outcome. We previously demonstrated that paclitaxel enhances an interaction of the Neuronal calcium sensor-1 protein (NCS-1) with the Inositol-1,4,5-trisphosphate receptor (InsP₃R), which disrupts calcium homeostasis and triggers neuronal cell death via the calcium-dependent protease calpain in dorsal root ganglia neurons and neuronal precursor cells. Prophylactic treatment of rodents with lithium inhibits the NCS1-InsP₃R interaction and ameliorates paclitaxel-induced polyneuropathy and cognitive impairment, which is in part supported by limited retrospective clinical data in patients treated with lithium carbonate at the time of chemotherapy. Currently no data are available from a prospective clinical trial to demonstrate its efficacy.

Methods and analysis: The PREPARE study will be conducted as a multicenter, randomized, double-blind, placebo-controlled phase-2 trial with parallel group design. N = 84 patients with breast cancer will be randomized 1:1 to either lithium carbonate treatment (targeted serum concentration 0.5-0.8 mmol/l) or placebo with sham dose adjustments as add-on to (nab-) paclitaxel. The primary endpoint is the validated Total Neuropathy Score reduced (TNSr) at 2 weeks after the last (nab-) paclitaxel infusion. The aim is to show that the lithium carbonate group is superior to the placebo group, meaning that the mean TNSr after (nab-) paclitaxel is lower in the lithium carbonate group than in the placebo group. Secondary endpoints include: (1) severity of CIPN, (2) amount and dose of pain medication, (3) cumulative dose of (nab-) paclitaxel, (4) patient-reported symptoms of CIPN, quality of life and symptoms of anxiety and depression, (5) severity of cognitive impairment, (6) hippocampal volume and changes in structural/functional connectivity and (7) serum Neurofilament light chain protein concentrations.

Ethics and dissemination: The study protocol was approved by the Berlin ethics committee (reference: 21/232 - IV E 10) and the respective federal agency (Bundesinstitut für Arzneimittel und Medizinprodukte, reference: 61-3910-4044771). The results of the study will be published in peer-reviewed medical journals as well as presented at relevant (inter)national conferences.

Clinical trial registration: [https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00027165], identifier [DRKS00027165].

Keywords: chemotherapy; cognitive impairment; lithium; neurotoxicity; paclitaxel; polyneuropathy; prevention.

Copyright © 2022 Huehnchen, Bangemann, Lischewski, Märschenz, Paul, Schmitz-Hübsch, Blohmer, Eberhardt, Rauch, Flöel, Adam, Schwenkenbecher, Meinhold-Heerlein, Hoffmann, Ziemssen, Endres and Boehmerle.