Chemotherapy is frequently accompanied by peripheral neuropathies so painful and debilitating that it may be necessary to reduce the dose of agent, delay one or more cycles of chemotherapy, or even cease treatment. Furthermore, the peripheral neuropathies can worsen after treatment has ended and may not resolve with time. Both the dose-limiting nature and the persistence of chemotherapy-induced peripheral neuropathies (CIPN) are significant health care problems. There are few - if any - evidence-based therapies for the relief of CIPN. The long term goal of this research team is to identify a new strategy to alleviated CIPN in cancer patients, resulting in a meaningful improvement in their quality of life and the ability to sustain better and longer treatment. Here we propose a phase II clinical trial of the efficacy of nicotinamide riboside (NR), a naturally occurring vitamin precursor of NAD+, as a therapeutic agent. This proposal is based on the hypothesis that paclitaxel injures primary afferent neurons by reducing NAD+ in these neurons and their fibers. Our preclinical data demonstrate that paclitaxel does indeed decrease levels of NAD+ in dorsal root ganglia and that NR protects neuronal NAD+ in the face of intense chemotherapy treatment. Moreover, pre- treatment with NR protects against, and post-treatment with NR reverses, the mechanical hypersensitivity and the aversive dimension of pain in a rodent model of CIPN induced by paclitaxel. The specific aim of this proposal is to evaluate if daily dosing of NR prevents progressive worsening of sensory neuropathy in patients undergoing adjuvant or neo-adjuvant therapy with paclitaxel or nab-paclitaxel for the treatment of stage 1-3 breast cancer. The primary outcome measure is the change in the grade of sensory neuropathy between the baseline assessment and the 8th day of NR treatment after the final (i.e.12th) taxane infusion as determined by the CTCAE questionnaire. Secondary outcome measures are incidence of dose reduction, actual vs planned cumulative dose of paclitaxel administered, percentage of patients with dose reduction, and patient-reported function. This trial will be an open-label study in which all patients receive NR. Comparisons will be made to historical data on severity and progression in this population. Additional analyses will confirm that NR increases levels of NAD+ or its metabolite NAAD in blood, and does not interfere with the pharmaco- kinetics of paclitaxel. This phase II clinical trial will provide preliminary data as to whether NR treatment prevents a progressive worsening of CIPN and enables patients to complete the chemotherapy treatment without a reduction in dose of paclitaxel. It will also generate preliminary data correlating efficacy to an increase in NAD+ levels. This work will drive large Phase III studies of NR in the treatment of CIPN, and the discovery of a new pharmacotherapy for a significant unmet need in oncology. The findings have great potential to transform the practice of oncology with a therapy that results in a meaningful improvement in the patient's quality of life and the ability to complete optimal chemotherapy treatment regimens.

HEALTH RELEVANCE Currently, there are no evidence-based therapies for the relief of chemotherapy-induced peripheral neuropathies (CIPN), which may be so debilitating that it becomes necessary to reduce the dose of agent, delay one or more cycles of cancer treatment, or even cease treatment. Demonstration that nicotinamide riboside, a naturally occurring precursor of NAD+, can reduce or prevent the progression of CIPN in patients will lead to Phase III clinical trials of efficacy. The introduction of new proven therapeutic agent for the relief of CIPN will be transformative for the patient, the oncologist, and cancer treatment.