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

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by Dompé s.p.a.
Sponsor:
Information provided by (Responsible Party):
Dompé s.p.a.
ClinicalTrials.gov Identifier:
NCT01861054
First received: April 18, 2013
Last updated: October 28, 2014
Last verified: October 2014

April 18, 2013
October 28, 2014
February 2013
September 2015   (final data collection date for primary outcome measure)
  • Markers of Cancer Stem Cells (CSCs) in the primary tumor and the tumoral microenvironment [ Time Frame: Change in markers from baseline at day 21 ] [ Designated as safety issue: No ]
    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).
  • Serine-threonine protein kinase (AKT) [ Time Frame: Change in markers from baseline at day 21 ] [ Designated as safety issue: No ]
  • Focal adhesion kinase (FAK) [ Time Frame: Change in markers from baseline at day 21 ] [ Designated as safety issue: No ]
  • CXCR1 levels [ Time Frame: Change in markers from baseline at day 21 ] [ Designated as safety issue: No ]
  • interleukin-1beta [IL-1beta] [ Time Frame: Change in markers from baseline at day 21 ] [ Designated as safety issue: No ]
  • interleukin-6 [IL-6] [ Time Frame: Change in markers from baseline at day 21 ] [ Designated as safety issue: No ]
  • tumor necrosis factor-alpha [TNF-alfa] [ Time Frame: Change in markers from baseline at day 21 ] [ Designated as safety issue: No ]
  • granulocyte macrophage colony stimulating factor [GM-CSF] [ Time Frame: Change in markers from baseline at day 21 ] [ Designated as safety issue: No ]
  • IL-8 [ Time Frame: Evaluation at day 0 and day 21 ] [ Designated as safety issue: No ]
  • CD4, CD8, NK and Macrophages [ Time Frame: Change in markers from baseline at day 21 ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT01861054 on ClinicalTrials.gov Archive Site
  • PK profile of the treatment [ Time Frame: Day 1; Day 21 ] [ Designated as safety issue: No ]

    Day 1: Cmax, AUCinf (area under the concentration time curve from time 0 extrapolated to infinity calculated by adding Clast/LambdaZ to AUClast [area under the concentration time curve calculated by the linear trapezoidal rule - time 0 to last sample with a quantifiable concentration Clast at time tlast]), AUC0-8 (area under the concentration time curve from time 8 hours post dosing), tmax (time to maximum plasma concentration), LambdaZ (terminal rate constant), t1/2 (calculated as (ln 2)/LambdaZ) and CL/F (apparent oral clearance for DF 1681Y only).

    Day 21 (steady state): Cmax, AUCtau (AUC for a dosing interval), AUClast, tmax, and CL/F.

  • Vital signs (Blood Pressure, Heart rate, Body Temperature) [ Time Frame: Day 0 and within 28 days of last dose ] [ Designated as safety issue: Yes ]
  • Hematology parameters (hemoglobin, white blood cell (WBC) and differential count, platelets) [ Time Frame: Days 1, 7, 14 and 21 and at the off-treatment visit ] [ Designated as safety issue: Yes ]
  • Clinical chemistry parameters (sodium, potassium, calcium, serum creatinine, total protein, albumin, aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], urea, total bilirubin) [ Time Frame: Days 1, 7, 14 and 21 and at the off treatment visit ] [ Designated as safety issue: Yes ]
  • Urinalysis (pH, specific gravity and dipstick) [ Time Frame: up to 14 days prior to treatment; up to 28 days after treatment ] [ Designated as safety issue: Yes ]
Same as current
  • Markers of angiogenesis (CD31 staining) [ Time Frame: Change in markers from baseline at day 21 ] [ Designated as safety issue: No ]
  • Tumor infiltrating leukocytes (CD4, CD8, NK and macrophages) [ Time Frame: Change in markers from baseline at day 21 ] [ Designated as safety issue: No ]
  • Autophagy (P62 and LC3 by IHC) [ Time Frame: Change in markers from baseline at day 21 ] [ Designated as safety issue: No ]
Same as current
 
Pilot Study to Evaluate the Safety and Biological Effects of Orally Administered Reparixin in Early Breast Cancer Patients
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.

Interventional
Phase 2
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Breast Cancer
Drug: Reparixin
1000 mg Oral Reparixin t.i.d. for 21 consecutive days prior to surgery
Experimental: Treated patients
Patients eligible will be treated with Reparixin as add-in monotherapy
Intervention: Drug: Reparixin
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
40
December 2015
September 2015   (final data collection date for primary outcome measure)

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.
Female
18 Years and older
No
Contact: Pieradelchi Ruffini, MD +390258383500 pieradelchi.ruffini@dompe.com
United States
 
NCT01861054
REP0210
Yes
Dompé s.p.a.
Dompé s.p.a.
Not Provided
Not Provided
Dompé s.p.a.
October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP