Pilot Study to Evaluate Safety & Biological Effects of Orally Administered Reparixin in Early Breast Cancer

NCT01861054 | Terminated Phase 2 Results DMC

• 1 other identifier: REP0210
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 9

Brief Summary

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. The primary objectives of this study were: 1- to evaluate the effects of orally administered reparixin on CSCs in the primary tumor and the tumoral microenvironment in an early breast cancer population: A. CSC were measured in tissue samples by techniques that could include: ALDEFLUOR assay and assessment of CD44/CD24 by flow cytometry, or examination of RNA transcripts by RT-PCR, aldehyde dehydrogenase-1, CD44/CD24 and epithelial mesenchymal transition markers (Snail, Twist, Notch) by immunohistochemistry (IHC). CSC were defined as ALDEFLUOR positive (ALDH-1+) and/or CD44 high/CD24 low by flow cytometry or RT-PCR and IHC and by the detection of ALDH-1+ cells with or without epithelial mesenchymal transition (EMT) transcription factor in IHC assays. B. Serine-threonine protein kinase (AKT), focal adhesion kinase (FAK), phosphatase and tensin homolog (PTEN) and chemokine receptor-1 (CXCR1) levels were measured in tissue samples by IHC. C. Measurement of markers of inflammation (interleukin-1beta \[IL-1β\], interleukin-6 \[IL-6\], interleukin-8 \[IL-8\], tumor necrosis factor-alpha \[TNF-α\], granulocyte macrophage colony stimulating factor \[GM-CSF\], vascular endothelial growth factor \[VEGF\], basic fibroblast growth factor \[b-FGF\] and high-sensitivity C-reactive protein \[hsCRP\]) in plasma, leukocyte subsets (enumerate T subsets, B, and natural killer/natural killer T \[NK/NKT\] cells) and study polymorphonuclear leukocyte \[PMN\] biology in peripheral blood samples. D. Measurement of markers of angiogenesis (CD31 staining), tumor-infiltrating leukocytes (CD4, CD8, NK and macrophages), autophagy (P62 and LC3 by IHC), EpCAM and EMT markers (CD326, CD45, Twist1, SNAIL1, SLUG, ZEB1, FOXC2, TG2, Akt2, P13k and CK19 by RT-PCR) and tissue cellularity (residual disease characterization in tumor bed) in tumor tissue samples. 2\. To evaluate the safety of oral reparixin administered three times daily (t.i.d.) for 21 consecutive days. The secondary objective was to define the pharmacokinetic (PK) profile of orally administered reparixin.

Conditions

Breast Cancer

Keywords

Cancer Stem Cells; Novel targeted therapy; CXCR1/2 Inhibitors

Outcome Measures

Primary Outcomes (5)

• Change From Baseline to Day 21 in Markers of Cancer Stem Cells (CSCs) in the Primary Tumor and the Tumoral Microenvironment (ALDH1,CD44/CD24)

  CSCs were measured in tissue samples by the following techniques: ALDH-1 by ALDEFLUOR and by immunohistochemistry (IHC); CD44/CD24 by flow cytometry or examination of RNA transcripts by RT-PCR and by immunohistochemistry (IHC); epithelial mesenchymal markers (Snail, Twist, Notch) by immunohistochemistry (IHC).

  At day 21

• Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC

  Pathway markers (AKT, FAK, PTEN and CXCR1) were measured in tissue samples at the pre-study (Day -14 to 0) and Day 21 (or within 24 hours of last dose). For the evaluation of the stain extent, the following semi-quantitative score method (0 to 4) was used: 0, no positive cells; 1, 1-25%; 2, 26-50%; 3, 51-75%; and 4, 76-100%. Hence for this scale, the higher the values, the worse is the outcome. For the evaluation of the stain intensity, the following score method (0 to 3) was used: 0, negative; 1, weak; 2, moderate, 3; strong. Also for this scale, the higher the score, the worse the outcome. Serine-threonine protein kinase (AKT, also known as protein kinase B, PKB) Focal adhesion kinase (FAK) Chemokine receptor-1 (CXCR1)

  Day 21 (or last day of treatment)

• Change From Baseline to Day 21 in Markers of Inflammation

  Markers of inflammation (IL-1β, IL-6, IL-8, TNF-α, GM-CSF, VEGF, and b-FGF) were measured in plasma from peripheral blood. IL = interleukins TNF-α = tumor necrosis factor-alpha GM-CSF = macrophage colony stimulating factor VEGF = vascular endothelial growth factor b-FGF = basic fibroblast growth factor

  At Day 21

• Change From Baseline-1 to Day 21-1 in Markers of Angiogenesis (CD31 Staining)

  CD31 staining by IHC. For the evaluation of the stain extent, the following semi-quantitative score method (0 to 4) was used: 0, no positive cells; 1, 1-25%; 2, 26-50%; 3, 51-75%; and 4, 76-100%. Hence for this scale, the higher the values, the worse is the outcome. For the evaluation of the stain intensity, the following score method (0 to 3) was used: 0, negative; 1, weak; 2, moderate, 3; strong. Also for this scale, the higher the score, the worse the outcome. CD31 is a transmembrane glycoprotein, 130-140 kDa, also know as platelet-endothelium cell adhesion molecule (PECAM-1). CD31 is ligand for CD38 and plays a role in thrombosis and angiogenesis. CD31 is strongly expressed in endothelial cells and weakly expressed in megakaryocytes, platelets, occasional plasma cells, lymphocytes (espc. marginal zone B-cells, peripheral T-cells) and neutrophils.

  At day 21

• Change From Baseline-1 to Day 21-1 in Markers of Autophagy (P62 and LC3B by IHC)

  Autophagy is a lysosomal degradation and recycling process implicated in cancer progression and therapy resistance. Labeling of p62 serves as a useful marker for the induction of autophagy, clearance of protein aggregates, and the inhibition of autophagy. Labeling of LC3B serves to track the binding of p62 and subsequent recruitment of autophagosomes. For the evaluation of the extent, the following semi-quantitative score method (0 to 4) was used: 0, no positive cells; 1, 1-25%; 2, 26-50%; 3, 51-75%; and 4, 76-100%. Hence for this scale, the higher the values, the worse is the outcome. For the evaluation of the intensity, the following score method (0 to 3) was used: 0, negative; 1, weak; 2, moderate, 3; strong. Also for this scale, the higher the score, the worse the outcome.

  At day 21

Secondary Outcomes (5)

• Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Cmax

  At Days 1 (pre-first dose and 0.25, 0.5, 1, 2, 4, 6, 8h post dose) and 21(pre-first dose and 0.25, 0.5, 1, 2, 4, 6, 8h post dose)

• Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2

  At Days 1 (pre-first dose and 0.25, 0.5, 1, 2, 4, 6, 8h post dose) and 21(pre-first dose and 0.25, 0.5, 1, 2, 4, 6, 8h post dose)

• Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21,

  At Days 1 (pre-first dose and 0.25, 0.5, 1, 2, 4, 6, 8h post dose) and 21(pre-first dose and 0.25, 0.5, 1, 2, 4, 6, 8h post dose)

• Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - CL/F (L/h) at Day 1, CLSS/F (L/h) Day 21)

  At Days 1 (pre-first dose and 0.25, 0.5, 1, 2, 4, 6, 8h post dose) and 21(pre-first dose and 0.25, 0.5, 1, 2, 4, 6, 8h post dose)

• Change From Baseline to Day 21 in Leukocytes Subsets

  At Day 21

Study Arms (1)

Treated patients - Total

EXPERIMENTAL

Patients eligible will be treated with Reparixin as add-in monotherapy

Drug: Reparixin

Interventions

Reparixin DRUG

1000 mg Oral Reparixin t.i.d. for 21 consecutive days prior to surgery

Also known as: REP

Treated patients - Total

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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):
• Serum creatinine \< 140 μmol/L or creatinine clearance \> 60 mL/min.
• Serum hemoglobin \> 9 g/dL; absolute neutrophil count \> 1.5 x 109/L; platelets \> 100 x 109/L.
• Serum bilirubin \< upper normal limit (UNL).
• 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.

You may not qualify if:

• 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:
• ibuprofen or to more than one non-steroidal anti-inflammatory drug;
• medications belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib.

Sponsors & Collaborators

• Dompé Farmaceutici S.p.A: lead

Study Sites (9)

Indiana University Simon Cancer Center

Indianapolis, Indiana, 46202-5289, United States

Location

University of Kansas Cancer Center, 4350 Shawnee Mission Pkwy, Suite 1500, Mailstop 6004

Fairway, Kansas, 66205, United States

Location

The Cancer Institute of New Jersey

New Brunswick, New Jersey, 08903, United States

Location

Weill Cornell Medical College

New York, New York, 10065, United States

Location

Montefiore Medical Center, MMC Medical Park at Eastchester

The Bronx, New York, 10461, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

Magee-Womens Hospital

Pittsburgh, Pennsylvania, 15213, United States

Location

Sara Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

The Methodist Hospital Research Institute

Houston, Texas, 77030, United States

Location

Related Publications (2)

• Goldstein LJ, Mansutti M, Levy C, Chang JC, Henry S, Fernandez-Perez I, Prausova J, Staroslawska E, Viale G, Butler B, McCanna S, Ruffini PA, Wicha MS, Schott AF; fRida Trial Investigators. A randomized, placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to paclitaxel alone as front-line therapy for metastatic triple-negative breast cancer (fRida). Breast Cancer Res Treat. 2021 Nov;190(2):265-275. doi: 10.1007/s10549-021-06367-5. Epub 2021 Sep 3.

  PMID: 34476645 DERIVED

• Goldstein LJ, Perez RP, Yardley D, Han LK, Reuben JM, Gao H, McCanna S, Butler B, Ruffini PA, Liu Y, Rosato RR, Chang JC. A window-of-opportunity trial of the CXCR1/2 inhibitor reparixin in operable HER-2-negative breast cancer. Breast Cancer Res. 2020 Jan 10;22(1):4. doi: 10.1186/s13058-019-1243-8.

  PMID: 31924241 DERIVED

Related Links

• Goldstein LJ Breast Cancer Research 22:4. doi: 10.1186/s13058-019-1243-8, 2020

MeSH Terms

Conditions

Breast Neoplasms

Interventions

reparixin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Pier Adelchi Ruffini, MD
• Organization: Dompé Farmaceutici

info@dompe.it

+39 (0)2 583831

Study Officials

• Lori J Goldstein, MD, PhD

  Fox Chase Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 18, 2013
• First Posted: May 23, 2013
• Study Start: February 1, 2013
• Primary Completion: March 1, 2015
• Study Completion: March 1, 2016
• Last Updated: May 14, 2021
• Results First Posted: March 25, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)