Trial Information

A Single Arm, Preoperative, Pilot Study to Evaluate the Safety and Biological Effects of Orally Administered Reparixin in Early Breast Cancer Patients Who Are Candidates for Surgery

According to the cancer stem cell (CSC) model, tumors are organized in a cellular hierarchy
maintained by a subpopulation of cells displaying stem cell properties. These properties
include self-renewal (which drives tumorigenesis) and differentiation (which generates the
tumor bulk and contributes to cellular heterogeneity).

CSCs were first observed in hematological malignancies but have also been identified in
solid tumors of breast, prostate, brain, colon and pancreas. CSCs are thought to be
resistant to conventional chemotherapies and this may be why relapse occurs in many patients
and this might explain the failure to develop therapies that are consistently able to
eradicate solid tumors. 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 possibility is that existing
therapies fail to kill CSCs effectively. Existing therapies have been developed largely
against the bulk population of tumor cells because they are often identified by their
ability to shrink tumors. Because most cancer cells have limited proliferative potential, an
ability to shrink a tumor mainly reflects an ability to kill these cells. 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 adenosine triphosphate-binding
cassette 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
tumor cells with limited proliferative potential. Even therapies that cause complete
regression of tumors might spare enough CSCs to allow re-growth of the tumors. Therapies
that are more specifically directed against CSCs might result in much more durable responses
and even cures of metastatic tumors.

There are limited data on the impact of treatment tailoring based on CSC detection. Gene
profiling of CSCs could lead to identification of therapeutic targets on CSCs (e.g. hormone
receptors (HR), human epidermal growth factor receptor-2 [HER-2] expression, epidermal
growth factor receptor [EGFR] 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 for the 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 HR
positive (HR+) patients. More specifically, a recent observation from Ginestier et al.
demonstrated that over expression of chemokine receptor 1 (CXCR-1) is associated with the
aldehyde dehydrogenase positive (ALDH+) cells. In breast carcinomas, the ALDEFLUOR+
phenotype shows partial overlap with the CD44+CD24-Lin-CSC phenotype. Cellular hierarchies
have been identified in a series of molecularly characterized breast cancer cell lines and
it has been demonstrated that these lines contained ALDEFLUOR+ components that were both
tumorigenic and metastatic in NOD/SCID mice. Furthermore, previous observations demonstrated
that the addition of recombinant interleukin-8 (IL-8) increased the CSC population as well
as increasing its propensity for invasion. Moreover, tissue damage induced by
chemotherapeutic agents may induce IL-8 as part of the injury response. This suggests that
strategies aimed at interfering with the IL 8/CXCR-1 axis may be able to target CSCs,
increasing the efficacy of current therapies. This experimental data provides another
therapeutic target in breast cancer.

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. A phase 1 study is currently underway to study the effects of
reparixin in combination with paclitaxel in metastatic breast cancer.

This small pilot study aims at exploring the effects on breast CSC markers as well as the
safety and PK profile of orally administered single agent reparixin in HER-2 negative (HER
2-) early breast cancer patients in the 3 weeks prior to surgery.

The study will be performed in the interval between disease diagnosis and planned surgery
and may lead to a minimal delay in surgery. This is balanced by the potential benefits of
the study by evaluating CSCs and their prognostic importance as well as obtaining
information about the impact of reparixin therapy.