Pilot Study to Evaluate the Safety and Biological Effects of Orally Administered Reparixin in Early Breast Cancer Patients



Status:Terminated
Conditions:Breast Cancer, Cancer
Therapuetic Areas:Oncology
Healthy:No
Age Range:18 - Any
Updated:10/20/2017
Start Date:February 2013
End Date:March 1, 2016

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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

This is a pilot "window of opportunity" clinical study in patients with operable breast
cancer investigating use of reparixin as single agent in the time period between clinical
diagnosis and surgery. This study evaluates the effects of orally administered reparixin on
CSCs in the primary tumor and the tumoral microenvironment in an early breast cancer
population. The aim is to investigate if cancer stem cells (CSCs) and pathway markers
decrease in two early breast cancer subgroups (ER+ and/or progesterone receptor
positive/HER-2- and ER negative/progesterone receptor negative/HER‑2-) and to compare any
differences between the two subgroups to try to better identify a target population. 20
patients will be enrolled to each subgroup at ten sites in the US.

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.

Inclusion Criteria:

- Female aged > 18 years.

- Patients with operable breast cancer, with measurable tumors of more than 1 cm in
diameter, that are not candidates for neoadjuvant therapy.

- Zubrod (Eastern Co-operative Oncology Group [ECOG]) Performance Status (PS) of 0-1.

- No prior treatment by surgery, radiotherapy, hormone therapy e.g. TAMOXIFEN® or
RALOXIFEN® for prevention or chemotherapy.

- Scheduled to undergo definitive local surgery for breast cancer.

- Patients must be willing to undergo two mandatory tumor biopsies (pre and post
therapy) that are not required for standard care. A sample of tumor tissue removed
during surgery will also be collected for analysis.

- Patients must be able to swallow and retain oral medication (intact tablet).

- Able to undergo all screening assessments outlined in the protocol after giving
informed consent.

- Adequate organ function (defined by the following parameters):

1. Serum creatinine < 140 μmol/L or creatinine clearance > 60 mL/min.

2. Serum hemoglobin > 9 g/dL; absolute neutrophil count > 1.5 x 109/L; platelets >
100 x 109/L.

3. Serum bilirubin < upper normal limit (UNL).

4. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ UNL;
alkaline phosphatase (ALP) ≤ UNL; albumin within normal limits.

- Documented hormone receptor (ER and progesterone receptor) and HER-2- status.

- No known hepatitis B virus (unless due to immunization), hepatitis C virus, human
immune deficiency virus-I and II positive status.

Exclusion Criteria:

- Male.

- Pregnancy or lactation or unwillingness to use two adequate methods of birth control
throughout the study and for 30 days after study discontinuation.

- Any other breast cancer types including inflammatory form.

- Prior surgery to the breast area or primary axillary dissection.

- Prior treatment for breast cancer.

- Use of an investigational drug within 30 days preceding the first dose of study
medication.

- Any prior or current cancer, except in situ uterine carcinoma or basocellular
cutaneous cancer considered as definitively cured.

- Any associated medical condition considered incompatible with the study, e.g. cardiac,
renal, medullar, respiratory or hepatic insufficiency.

- Neurological or psychiatric disorders which may influence understanding of study and
informed consent procedures.

- Active or uncontrolled infection.

- Malabsorption syndrome, disease significantly affecting gastrointestinal function.

- Hypersensitivity to:

1. ibuprofen or to more than one non-steroidal anti-inflammatory drug;

2. medications belonging to the class of sulfonamides, such as sulfamethazine,
sulfamethoxazole, sulfasalazine, nimesulide or celecoxib.
We found this trial at
9
sites
New Brunswick, New Jersey 08901
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New Brunswick, NJ
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Fairway, KS
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Houston, TX
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Indianapolis, Indiana 46202
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Indianapolis, IN
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Nashville, Tennessee 37203
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from
Nashville, TN
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New York, New York 10021
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New York, NY
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Philadelphia, Pennsylvania 19111
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Philadelphia, PA
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Pittsburgh, Pennsylvania 15213
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Pittsburgh, PA
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1825 Eastchester Road
The Bronx, New York 10461
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The Bronx, NY
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