PREVENTION OF TOXICITIES INDUCED BY TAXANES

 

Taxanes Overview

Taxanes are chemotherapeutic agents used to treat various cancers. Taxanes are some of the most widely used chemotherapeutic agents and include paclitaxel, docetaxel, and cabazitaxel among others. Taxanes disrupt microtubule formation thereby preventing mitosis in rapidly growing cells. These actions create enormous oxidative stress and damage in both normal and cancerous cells.

Toxicities associated with taxanes, such as paclitaxel, include myelosuppression (low blood cell count), myalgia (muscle soreness), arthralgia (joint pain), peripheral neuropathy, mouth sores, hypersensitivity, nausea, vomiting, alopecia (hair loss), secondary malignancy (cancer), and many more. Furthermore, these side effects are often dose-limiting requiring a reduction in subsequent chemotherapy that may impact the overall success of the cancer treatment regimen.

Matrix Biomed, Inc.’s development program is directed to providing relief from toxicities associated with all taxanes. Specifically, Matrix Biomed, Inc. is  in the final development stages of clinical trials for the most widely used taxane, paclitaxel.

Preclinical Evidence Supporting TEMPOL’s Protection Against Paclitaxel Toxicities

In vivo TEMPOL has been shown to alleviate and prevent chemotherapy-induced neuropathic pain in rats by reducing the levels of inflammatory cytokines and free radicals in dorsal root ganglia (DRS). In a study conducted by the Department of Pain Medicine, Division of Anesthesiology and Critical Care, at The University of Texas MD Anderson Cancer Center, Dr. Hee Kee Kim found that TEMPOL ameliorates and prevents mechanical hyperalgesia in a rat model of chemotherapy-induced neuropathic pain. In conclusion, TEMPOL protected rats from paclitaxel induced neuropathic pain reducing pain behaviors by decreasing the levels of p-PKC, p-NF-κB, PDE4D, IL-1β, and MCP-1 (Kim 2016).

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kim-graph-b-paclitaxel

Analgesic effects of a single systemic injection (A) or systemic infusion (B) of TEMPOL on paclitaxel-induced neuropathic pain (PINP) in rats. Paclitaxel (PAC,2mg/kg) was injected intraperitoneally on four alternate days (days 0, 2, 4, and 6), and the mechanical threshold was measured. (A) On day 20 after the first paclitaxel injection, 24 rats were divided into four groups, which received an intraperitoneal injection of saline or 50, 100, or 200mg / kg of TEMPOL (5mL/kg). Note that the mechanical threshold returned to more than 10g of mechanical threshold (no pain condition in rats) at 0.5h after the injection of 200mg / kg of TEMPOL. (B) On day 20 after the first paclitaxel injection, 11 rats were divided into two groups. In the TEMPOL group (N D 6), the rats received an intraperitoneal infusion of TEMPOL (10mg/day) for 7 days (hatched box) in combination with intraperitoneal injections of TEMPOL (200mg/kg) on days 20 and 21 (arrowheads).In the saline group (N D 5), the rats received saline (vehicle) instead of TEMPOL. The systemic infusion of TEMPOL significantly increased the mechanical threshold on day 21, and the threshold remained significantly higher than the threshold in the control group for 8 days. The data are expressed as means with standard errors of the means. The asterisks indicate values that are significantly different (P < 0.05) from the corresponding values for the saline group as determined by a two-way repeated-measures analysis of variance with one repeated factor (time) followed by the Tukey post hoc test.

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TEMPOL decreased paclitaxel-induced mitochondrial superoxide levels in the primary DRG cell culture. (A) The DRG cells were cultured in a chambered cover glass in DMEM media for live cell imaging. Paclitaxel (1 mM) significantly increased the MitoSOX-detected red fluorescence intensity in the primary DRG cell cultures at 2h. TEMPOL (1 and 10 mM) decreased paclitaxel-induced red fluorescence intensity. The data are expressed as means  standard deviations for three independent experiments. The asterisks indicate values that are significantly different (P < 0.05) from the values before treatment with paclitaxel as determined by the unpaired t-test. (B) The MitoSOX-detected red fluorescence without paclitaxel at 2h. (C) The MitoSOX-detected red fluorescence at 2h after treatment with paclitaxel (1 mM). (D) The MitoSOX-detected red fluorescence of DRG cells at 2h after treatment with paclitaxel (1 mM) and TEMPOL (1mM). (E) The MitoSOX-detected red fluorescence of DRG cells at 2h after treatment with paclitaxel (1 mM) and TEMPOL (10mM). Scalebars: 20 mm.

Clinical Trial Design

Matrix Biomed, Inc. is in the final stages of protocol development directed to the prevention of taxane-induced toxicities such as neuropathy. This protocol follows the framework of the mucositis protocol and treatment regimen giving Matrix Biomed, Inc. high confidence that the FDA will approve this study. Additional endpoints will be directed to the prevention and reduction of neutropenia and myelosuppression. TEMPOL has been shown to ameliorate and prevent mechanical hyperalgesia in a model of chemotherapy-induced neuropathic pain.

  1. Objective: Prevention of Paclitaxel Induced Toxicities
  2. Stage: Phase IIb
  3. Study Population: Patients with stage 1-3 breast cancer receiving 12 week paclitaxel treatment
  4. Number of Patients: 120 patients (1:1 Randomization; Tempol capsule v Placebo)
    1. Primary Endpoint: Reduction in neuropathy severity as measured by the modified Total Neuropathy Score.
  1. Secondary Endpoints:
    1. Reduction in the incidence of premature chemotherapy discontinuation due to peripheral neuropathy by treatment group
    2. Reduction in the degree of peripheral sensory neuropathy in the two arms based on CTCAE v 5.0 grading
    3. Attenuation of the decrease in sensory nerve action potential on nerve conduction tests before and at the end of taxane-based chemotherapy
    4. Reduction in the incidence of grade 3 or 4 neutropenia as measured by the change in absolute neutrophil count
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