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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

Phase 2
18 Years
Open (Enrolling)
Breast Cancer

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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.

Inclusion Criteria:

- Female aged > 18 years.

- Patients with histologically proven clinical stage II and IIa operable breast cancer,
with clinical tumor diameter of at least 2 cm.

- 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) (liver isoenzyme fraction) ≤ 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 adequate method of birth control.

- 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

- 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.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Markers of Cancer Stem Cells (CSCs) in the primary tumor and the tumoral microenvironment

Outcome Description:

CSCs will be measured in tissue samples by techniques that may include: ALDEFLUOR assay and assessment of CD44/CD24 by flow cytometry or examination of RNA transcripts by RT-PCR, aldehyde dehydrogenase 1 (ALDH1), CD44/CD24 and epithelial mesenchymal markers (Snail, Twist, Notch) by immunohistochemistry (IHC).

Outcome Time Frame:

Change in markers from baseline at day 21

Safety Issue:


Principal Investigator

Lori J Goldstein, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fox Chase Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

February 2013

Completion Date:

September 2014

Related Keywords:

  • Breast Cancer
  • Cancer Stem Cells
  • Novel targeted therapy
  • CXCR1/2 Inhibitors
  • Breast Neoplasms



Fox Chase Cancer Center Philadelphia, Pennsylvania  19111
The Methodist Hospital Research Institute Houston, Texas  77030
City of Hope Hospital, 1500 Duarte Road Duarte, California  91010
University of Kansas Cancer Center, 4350 Shawnee Mission Pkwy, Suite 1500, Mailstop 6004 Fairway, Kansas  66205
Montefiore Medical Center, MMC Medical Park at Eastchester Bronx, New York  10461