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

Abstract

IntroductionChemotherapy-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 analysisThe 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 disseminationThe 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].

Axonal degeneration in chemotherapy-induced peripheral neurotoxicity: clinical and experimental evidence

“…The majority of studies have assessed paclitaxel-treated patients (cumulative n=349) and all have demonstrated increased NfL following treatment. [91][92][93][94][95] In 31 paclitaxel-treated patients with breast or ovarian cancer, elevations in NfL were correlated with clinically graded and patient-reported CIPN, with greater NfL associated with more severe CIPN. 91 NfL remained elevated at 28 weeks post-treatment but returned to baseline after 40 weeks.…”

Seeing Neurodegeneration in a New Light Using Genetically Encoded Fluorescent Biosensors and iPSCs

“…A subsequent molecular analysis of cells exposed to antineoplastic agents at the threshold may identify biomarkers of CIPN or reveal pathways critical to preserving the neuron structure or function. With regard to the latter, preventative treatments that are currently undergoing trial or have demonstrated a reduced frequency and intensity of CIPN include oral cannabidiol, lithium, and zinc [ 142 , 143 , 144 ], which could be pre-administered as part of combinatorial therapy.…”

Mobile, alltagsnahe digitale Technologien für die Prävention der Alzheimer-Demenz: kognitive Gesundheit und kognitive Sicherheit

“…Chemotherapien können kognitive Störungen ("cancer-related cognitive impairment") induzieren, die durch leichte bis mittelschwere kognitive Defizite gekennzeichnet sind, darunter Beeinträchtigungen der Verarbeitungsgeschwindigkeit, des Gedächtnisses, der exekutiven Funktionen und der Aufmerksamkeit. Bis zu 75 % der Patienten, die mit Chemotherapie gegen Krebserkrankungen außerhalb des Nervensystems behandelt werden, sind von kognitiven Defiziten betroffen [21,37]. Ein wichtiger Schritt in der Prävention der Alzheimer-Demenz wäre, diese Aspekte der kognitiven Sicherheit in der Versorgung zu berücksichtigen.…”