Last updated on April 2018

A Double-blind Study of Paclitaxel in Combination With Reparixin or Placebo for Metastatic Triple-Negative Breast Cancer


Brief description of study

Reparixin oral tablets are being tested as a CSC targeting agent in patients with metastatic non- human epidermal growth factor receptor (HER2)-amplified BC. An open label Phase 1b clinical study (REP0111) is ongoing (enrollment completed) in five US sites, under IND # 112502, to test safety, tolerability, pharmacokinetics and detect early signs of antitumor activity of increasing doses of reparixin oral tablets in combination with a fixed dose of weekly paclitaxel. The study has demonstrated safety and tolerability of the combination across the three dose levels explored and recorded objective responses in the published range for single agent weekly paclitaxel in the target population. The highest dose level explored (i.e., 1200 mg t.i.d.) was identified as the recommended phase 2 dose. Durable responses have been recorded in patients with TNBC.

The current phase 2 study thus aims to evaluate the Progression Free Survival of patients with metastatic TNBC [newly diagnosed metastatic or relapsed following (neo)adjuvant chemotherapy] receiving reparixin in combination with paclitaxel versus paclitaxel alone.

Detailed Study Description

According to the cancer stem cell (CSC) model, tumors are initiated and maintained by a cellular subcomponent that displays stem cell properties. These properties include self-renewal, which drives tumorigenesis, and differentiation (albeit aberrant), which contributes to tumor cellular heterogeneity. The existence of CSCs has been described in a variety of haematologic and solid tumors including those of the breast, brain, colon, pancreas, lung, liver, and head and neck.

In addition to driving tumorigenesis, CSCs may contribute to tumor metastasis as well as to tumor recurrence after treatment. Although currently available drugs can shrink metastatic tumors, these effects are usually transient and often do not appreciably extend the life of patients. One reason for the failure of these treatments is the acquisition of drug resistance by the cancer cells as they evolve; another non-mutually exclusive possibility is that existing therapies fail to kill CSCs. The ability to shrink a tumor mass mainly reflects an ability to kill bulk, non CSC tumor cells. This is because CSCs represent only a tiny percentage of the total tumor cells in a neoplastic lesion and the majority of the bulk tumor cells have limited proliferative potential. It seems that normal stem cells from various tissues tend to be more resistant to chemotherapeutics than mature cell types from the same tissues. The reasons for this are not clear, but may relate to high levels of expression of anti- apoptotic proteins or ATP-binding cassette (ABC) transporters such as the multidrug resistance gene. If the same were true of CSCs, then one would predict that these cells would be more resistant to chemotherapeutics than bulk tumor cells with limited proliferative potential. Even therapies that cause complete regression of tumors might spare enough CSCs to allow regrowth of the tumors. Thus, therapies that are more specifically directed against CSCs might result in much more durable responses and even cures of metastatic tumors.

The CSC (Cancer stem cell) concept has important implications for understanding carcinogenesis as well as for the development of cancer therapeutics. According to this concept, tumors are initiated and maintained by a cellular subcomponent that displays stem cell properties. These properties include self-renewal, which drives tumorigenesis, and differentiation (albeit aberrant), which contributes to tumor cellular heterogeneity. The existence of CSCs has been described in a variety of hematologic and solid tumors including those of the breast, brain, colon, pancreas, lung, liver, and head and neck. In addition to driving tumorigenesis, CSCs may contribute to tumor metastasis as well as to tumor recurrence after treatment.

One of the therapeutic strategies being pursued to target CSCs involves inhibition of self renewal or survival pathways in these cells. These pathways include NOTCH (Notch signaling pathway), Hedgehog, and WNT (Wnt signaling pathway). Such strategies may be limited by the role of these pathways in normal stem cell function, which could result in systemic toxicities from pathway inhibition. In addition to intrinsic pathways regulating stem cell functions, normal and malignant stem cells are regulated by extrinsic signals generated in the microenvironment or CSC niche. In the breast, this niche is composed of immune cells, mesenchymal elements that include fibroblasts, endothelial cells, adipocytes, and extracellular matrix components. These components play an important role in normal breast development and carcinogenesis. If the cellular microenvironment plays an important role in the regulation of CSC growth and survival, then strategies aimed at interfering with these interactions represent a rational approach to target breast CSCs.

There are limited data on the impact of treatment tailoring based on CSCs detection. Gene profiling of CSCs could lead to identification of therapeutic targets on CSCs (e.g. hormone receptors, HER-2 [Human epidermal growth factor receptor-2] expression, EGFR [Epidermal growth factor receptor] expression), and could represent tumor biopsy in "real time". Several groups showed frequent discordance of HER-2 status between primary tumor and CSCs, and case reports showed clinical utility to use of trastuzumab-based therapy based on HER-2 CSCs status. Similarly, the hormonal status of CSCs could be different from that of the primary tumor, which could lead to increase the number of patients suitable for endocrine therapy, but also could explain why endocrine therapy fails in a subset of hormone receptor-positive patients. The study provided the in vivo demonstration that CXCR-1 (Chemokine receptor 1) targeting with specific blocking antibodies or reparixin is associated with reduced systemic metastases. The experimental data provides another therapeutic target in metastatic disease and warrants a pilot study investigation in humans to further explore effects of reparixin on breast CSCs and the tumoral microenvironment.

Reparixin seems to be a good candidate for use in breast cancer patients because of its very acceptable toxicity profile shown in the Phase I and II clinical trials conducted so far, along with its observed activity in vitro against breast cancer cell lines and in vivo in tumor xenografts in mice. It potentially addresses another therapeutic target in metastatic disease. The current phase 2 study thus aims to evaluate the Progression Free Survival of patients with metastatic TNBC [newly diagnosed metastatic or relapsed following (neo)adjuvant chemotherapy] receiving reparixin in combination with paclitaxel versus paclitaxel alone.

Clinical Study Identifier: NCT02370238

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Saverio Cinieri, MD

Ospedale "Di Summa-Perrino"
Brindisi, Italy
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