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 May 2013 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 18, 2013
Last verified: May 2013
  Purpose

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.


Condition Intervention Phase
Breast Cancer
Drug: Reparixin
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Dompé s.p.a.:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Other Outcome Measures:
  • 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 ]

Estimated Enrollment: 40
Study Start Date: February 2013
Estimated Study Completion Date: September 2014
Estimated Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treated patients
Patients eligible will be treated with Reparixin as add-in monotherapy
Drug: Reparixin
1000 mg Oral Reparixin t.i.d. for 21 consecutive days prior to surgery

  Hide Detailed Description

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01861054

Contacts
Contact: Pieradelchi Ruffini, MD +390258383500 pieradelchi.ruffini@dompe.it

Locations
United States, Kansas
University of Kansas Cancer Center, 4350 Shawnee Mission Pkwy, Suite 1500, Mailstop 6004 Not yet recruiting
Fairway, Kansas, United States, 66205
Contact: Raymond Perez, MD       rperez3@kumc.edu   
Principal Investigator: Raymond Perez, MD         
United States, New York
Montefiore Medical Center, MMC Medical Park at Eastchester Not yet recruiting
Bronx, New York, United States, 10461
Contact: Joseph Sparano, MD       jsparano@montefiore.org   
Principal Investigator: Joseph Sparano, MD         
United States, Pennsylvania
Fox Chase Cancer Center Not yet recruiting
Philadelphia, Pennsylvania, United States, 19111
Contact: Lori J Goldstein MD, MD       Lori.Goldstein@fccc.edu   
Principal Investigator: Lori J Goldstein, MD         
United States, Texas
The Methodist Hospital Research Institute Recruiting
Houston, Texas, United States, 77030
Contact: Jenny C Chang, MD       jcchang@tmhs.org   
Principal Investigator: Jenny C Chang, MD         
Sponsors and Collaborators
Dompé s.p.a.
Investigators
Principal Investigator: Lori J Goldstein, MD Fox Chase Cancer Center
Principal Investigator: Jenny C Chang, MD The Methodist Hospital Research Institute
Principal Investigator: Joseph Sparano, MD Montefiore Medical Center
Principal Investigator: Raymond Perez, MD University of Kansas Cancer Center
  More Information

No publications provided

Responsible Party: Dompé s.p.a.
ClinicalTrials.gov Identifier: NCT01861054     History of Changes
Other Study ID Numbers: REP0210
Study First Received: April 18, 2013
Last Updated: October 18, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Dompé s.p.a.:
Cancer Stem Cells
Novel targeted therapy
CXCR1/2 Inhibitors

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases

ClinicalTrials.gov processed this record on October 23, 2014