A Phase 2 interventional study of Reparixin in Breast Cancer, sponsored by Dompé Farmaceutici S.p.A. Terminated at 9 sites in United States. Open to female participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2021-05-14.
Sponsored by Dompé Farmaceutici S.p.A · Phase 2, Interventional, and Treatment
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.
The secondary objective was to define the pharmacokinetic (PK) profile of orally administered reparixin.
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.
12,544 studies on the registry are indexed under Breast Neoplasms; 2,892 are open to participants now.
This study's enrollment of 20 is below the median of 72 across 9,303 interventional studies indexed under Breast Neoplasms.
Browse Breast Neoplasms studies →Dompé Farmaceutici S.p.A is the lead sponsor of 51 studies on the registry; 4 are open to participants now.
Of its 18 completed or terminated interventional studies of FDA-regulated products, 18 (100%) have results posted.
Counted across the registry records on this site, refreshed daily.
Adequate organ function (defined by the following parameters):
Exclusion Criteria:
Hypersensitivity to:
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
Also known as: REP
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).
Time frame: 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)
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: At day 21
Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Cmax
Once absorbed, reparixin is highly protein bound. By comparing Cmax and AUC for unbound drug to that for total drug, only \< 0.1% to 0.2% of reparixin is available as unbound (free) drug. The intent of the PK outcomes was not to compare the results between the two cohorts; for this reason results for the PK outcomes are reported for the whole group of the treated patients. Cmax = Maximum plasma concentration obtained directly from the data without interpolation, expressed in concentration units
Time frame: 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
Once absorbed, reparixin is highly protein-bound. By comparing Cmax and AUC for unbound drug to that for total drug, only \< 0.1% to 0.2% of reparixin is available as unbound (free) drug. The intent of the PK outcomes was not to compare the results between the two cohorts; for this reason results for the PK outcomes are reported for the whole group of the treated patients. tmax = Time to reach the maximum plasma concentration obtained directly from the data without interpolation t1/2 = Terminal elimination half-life calculated as ln(2)/ lambda z; calculated only if the coefficient of determination R2 in lambda z estimation is at least 0.8.
Time frame: 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,
The intent of the PK outcomes was not to compare the results between the two cohorts; for this reason results for the PK outcomes are reported for the whole group of the treated patients. AUC0-8 = The area under the plasma concentration-time curve from time 0 to 8 hours post-dose; AUClast = The area under the concentration-time curve from time 0 to last quantifiable concentration AUCtau = The area under the plasma concentration-time curve for dosing interval (dosing interval \[tau\] = 8 hours); AUCinf = The total area under the plasma concentration-time curve from time zero to time infinity; AUC0-inf = AUClast + Clast/lambda zeta, where Clast is the last observed concentration ≥ lower limit of quantitation at time tlast. All these parameters were calculated by the linear trapezoidal rule.
Time frame: 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)
The intent of the PK outcomes was not to compare the results between the two cohorts; for this reason results for the PK outcomes are reported for the whole group of the treated patients. CL/F = Apparent oral clearance - for DF1681Y only, calculated as dose/AUCinf.; calculated only when the coefficient of determination R2 in lambda zeta estimation is at least 0.8 and percent AUC extrapolation is less than or equal to 20%. CLss/F = Steady state apparent oral clearance - for DF1681Y only calculated as dose/AUCtau.
Time frame: 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
The Leukocytes subsets analyzed are the following: Lymphocyte in WBC, Total T cell in lymphocytes, B cells in lymphocytes, T-helper cell in lymphocytes, CTL in lymphocytes, NKT cell in lymphocytes, ADCC NK subsets in lymphocytes, Regulatory NK subsets in lymphocytes, Exhausted NK subsets in lymphocytes, CD56-CD16+ NK subsets in lymphocytes, CD11b in PMNs - IL-8, CD18 in PMNs - IL-8, MFI of CD11b - IL-8, MFI of CD66b - IL-8, MFI of CD18 - IL-8, CD11b in PMNs - US, CD18 in PMNs - US, MFI of CD11b - US, MFI of CD66b - US, MFI of CD18 - US, Percent Monocytes expressing IL6 - IL-8,Percent Monocytes expressing IL1b - IL-8, Percent Monocytes expressing IL8 - IL-8, Percent Monocytes expressing TNFa - IL-8, Percent Neutrophils expressing IL6 - IL-8, Percent Neutrophils expressing IL1b - IL-8, Percent Neutrophils expressing IL8 - IL-8, Percent Neutrophils expressing TNFa - IL-8,Percent Monocytes expressing IL6 - US,Percent Monocytes expressing IL1b - US, etc.
Time frame: At Day 21
Patients recruitment: before initiating a study, the Investigator was required to have written and dated approval from the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) for the study protocol, written informed consent form (ICF), consent form updates, subject recruitment procedures (e.g., advertisements), and any other written information to be provided to subjects.
| Milestone | ER+ and/or PR+/ HER-2 - | ER-/PR-/HER-2- |
|---|---|---|
| Started | 18 | 2 |
| Safety population | 18 | 2 |
| Pk population | 4 | 2 |
| Completed | 18 | 2 |
| Not completed | 0 | 0 |
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).
| percentage of cells | ER+ and/or PR+/ HER-2 - | ER-/PR-/HER-2- |
|---|---|---|
| ALDH+ | 1.34 ± 2.737 | -0.40 ± 1.131 |
| CD44+/CD24- | -0.57 ± 5.617 | 0.20 ± 1.273 |
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)
| score on a scale | ER+ and/or PR+/ HER-2 - | ER-/PR-/HER-2- |
|---|---|---|
| Stain Phospho-AKT Extent | 0 (-1 to 2) | 0 (0 to 0) |
| Stain Phospho-AKT Intensity | 0 (-1 to 1) | 0 (0 to 0) |
| Stain AKT Extent | 0 (-4 to 1) | 1.0 (1 to 1) |
| Stain AKT Intensity | -0.5 (-3 to 2) | 0 (0 to 0) |
| Phospho-FAK Extent | 0 (-1 to 2) | 0 (0 to 0) |
| Phospho-FAK Intensity | 0 (-1 to 2) | -1.0 (-1 to -1) |
| Stain FAK Extent | 0 (-2 to 1) | 1.0 (1 to 1) |
| Stain FAK Intens | 0 (-2 to 2) | 0 (0 to 0) |
| Stain C-PTEN Extent | 0 (-4 to 2) | 0 (0 to 0) |
| Stain C-PTEN Intensity | 0 (-2 to 1) | 0 (0 to 0) |
| Stain D-PTEN Extent | 0 (-4 to 2) | 0 (0 to 0) |
| Stain D-PTEN Intensity | 0 (-2 to 1) | 0 (0 to 0) |
| Stain CXCR1 Extent | 0 (-4 to 1) | 1.0 (1 to 1) |
| Stain CXCR1 Intensity | -0.5 (-3 to 1) | 1.0 (1 to 1) |
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
| pg/ML | ER+ and/or PR+/ HER-2 - | ER-/PR-/HER-2- |
|---|---|---|
| Interleukin 1 Beta | 7.019 ± 30.3118 | 0 ± 0.000 |
| Interleukin 6 | 9.593 ± 39.2733 | 0 ± 0 |
| Interleukin 8 | -25.874 ± 134.3213 | 29.320 ± 41.6910 |
| TNFα | 2.669 ± 8.0313 | -0.890 ± 3.5780 |
| GM-CSF | -2.678 ± 8.2154 | 8.705 ± 12.3107 |
| VEGF | 253.584 ± 1120.6125 | 27.635 ± 39.0818 |
| b-FGF | 20.164 ± 93.4614 | -9.750 ± 13.7886 |
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.
| score on a scale | ER+ and/or PR+/ HER-2 - | ER-/PR-/HER-2- |
|---|---|---|
| Stain CD31 Extent | 0 (-2 to 1) | 1.0 (1 to 1) |
| Stain CD31 Intensity | 0 (-1 to 1) | 1.0 (1 to 1) |
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.
| score on a scale | ER+ and/or PR+/ HER-2 - | ER-/PR-/HER-2- |
|---|---|---|
| Stain P62 Extent | -1.0 (-3 to 1) | 0 (0 to 0) |
| Stain P62 Intensity | 0 (-2 to 0) | -1.0 (-1 to -1) |
Once absorbed, reparixin is highly protein bound. By comparing Cmax and AUC for unbound drug to that for total drug, only \< 0.1% to 0.2% of reparixin is available as unbound (free) drug. The intent of the PK outcomes was not to compare the results between the two cohorts; for this reason results for the PK outcomes are reported for the whole group of the treated patients. Cmax = Maximum plasma concentration obtained directly from the data without interpolation, expressed in concentration units
| micrograms/mL | Treated Patients - Total |
|---|---|
| Day1 - DF1681Y | 62.925 ± 31.5024 |
| Day21 - DF1681Y | 63.927 ± 15.7616 |
| Day1 - DF1681Y unbound | 145.167 ± 116.6114 |
| Day21 - DF1681Y unbound | 136.552 ± 104.8681 |
| Day 1 - DF2243Y | 15.788 ± 2.5240 |
| Day 21 - DF2243Y | 20.812 ± 9.9776 |
| Day 1 - DF2188Y | 7.302 ± 1.5129 |
| Day 21 - DF2188Y | 10.367 ± 4.3439 |
Once absorbed, reparixin is highly protein-bound. By comparing Cmax and AUC for unbound drug to that for total drug, only \< 0.1% to 0.2% of reparixin is available as unbound (free) drug. The intent of the PK outcomes was not to compare the results between the two cohorts; for this reason results for the PK outcomes are reported for the whole group of the treated patients. tmax = Time to reach the maximum plasma concentration obtained directly from the data without interpolation t1/2 = Terminal elimination half-life calculated as ln(2)/ lambda z; calculated only if the coefficient of determination R2 in lambda z estimation is at least 0.8.
| hours | Treated Patients - Total |
|---|---|
| Day1 - DF1681Y tmax | 2.667 ± 2.8752 |
| Day21 - DF1681Y tmax | 0.997 ± 0.5508 |
| Day1 - DF1681Y unbound tmax | 1.583 ± 1.2813 |
| Day21 - DF1681Y unbound tmax | 1.092 ± 0.4903 |
| Day 1 - DF2243Y tmax | 4.333 ± 2.3381 |
| Day 21 - DF2243Y tmax | 2.331 ± 0.8179 |
| Day 1 - DF2188Y tmax | 2.500 ± 1.2247 |
| Day 21 - DF2188Y tmax | 1.508 ± 0.5389 |
| Day1 - DF1681Y t1/2 | 2.090 ± 0.9847 |
| Day21 - DF1681Y t1/2 | 1.626 ± 0.4068 |
| Day1 - DF1681Y unbound t1/2 | 1.403 ± 0.4592 |
| Day21 - DF1681Y unbound t1/2 | 0.989 ± 0.1683 |
| Day 1 - DF2243Y t1/2 | 1.913 ± 0.3268 |
| Day 21 - DF2243Y t1/2 | 2.575 ± 0.6442 |
| Day 1 - DF2188Y t1/2 | 2.035 ± 1.0618 |
| Day 21 - DF2188Y t1/2 | 1.575 ± 0.1953 |
The intent of the PK outcomes was not to compare the results between the two cohorts; for this reason results for the PK outcomes are reported for the whole group of the treated patients. AUC0-8 = The area under the plasma concentration-time curve from time 0 to 8 hours post-dose; AUClast = The area under the concentration-time curve from time 0 to last quantifiable concentration AUCtau = The area under the plasma concentration-time curve for dosing interval (dosing interval \[tau\] = 8 hours); AUCinf = The total area under the plasma concentration-time curve from time zero to time infinity; AUC0-inf = AUClast + Clast/lambda zeta, where Clast is the last observed concentration ≥ lower limit of quantitation at time tlast. All these parameters were calculated by the linear trapezoidal rule.
| h*μg/mL | Treated Patients - Total |
|---|---|
| DF1681Y - AUC0-8 - Day 1 | 189.357 ± 60.2362 |
| DF1681Y - AUC0-8 - Day 21 | 174.303 ± 29.8012 |
| DF1681Y unbound- AUC0-8 - Day 1 | 222.602 ± 128.0328 |
| DF1681Y unbound- AUC0-8 - Day 21 | 233.382 ± 166.0402 |
| DF2243Y - AUC0-8 - Day 1 | 78.469 ± 18.8116 |
| DF2243Y - AUC0-8 - Day 21 | 105.001 ± 58.2634 |
| DF2188Y - AUC0-8 - Day 1 | 31.040 ± 7.9369 |
| DF2188Y - AUC0-8 - Day 21 | 33.395 ± 13.2129 |
| DF1681Y - AUCinf - Day 1 | 211.243 ± 71.4823 |
| DF1681Y - AUCinf - Day 21 | 182.479 ± 36.1551 |
| DF1681Y unbound - AUCinf - Day 1 | 235.152 ± 180.1547 |
| DF1681Y unbound - AUCinf - Day 21 | 234.547 ± 166.3017 |
| DF2243Y - AUCinf - Day 1 | 71.297 ± 25.6857 |
| DF2243Y - AUCinf - Day 21 | 129.275 ± 74.5406 |
| DF2188Y - AUCinf - Day 1 | 31.669 ± 11.2792 |
| DF2188Y - AUCinf - Day 21 | 35.092 ± 13.9473 |
| DF1681Y - AUClast - Day 1 | 189.319 ± 60.2817 |
| DF1681Y - AUClast - Day 21 | 172.296 ± 28.1847 |
| DF1681Y unbound - AUClast - Day 1 | 222.078 ± 128.1305 |
| DF1681Y unbound - AUClast - Day 21 | 231.235 ± 167.0377 |
| DF2243Y - AUClast - Day 1 | 76.821 ± 17.3033 |
| DF2243Y - AUClast - Day 21 | 97.360 ± 46.6809 |
| DF2188Y - AUClast - Day 1 | 31.028 ± 7.9336 |
| DF2188Y - AUClast - Day 21 | 35.433 ± 12.8434 |
| DF1681Y - AUCtau - Day 21 | 174.303 ± 29.8012 |
| DF1681Y unbound - AUCtau - Day 21 | 233.382 ± 166.0402 |
| DF2243Y - AUCtau - Day 21 | 105.001 ± 58.2634 |
| DF2188Y - AUCtau - Day 21 | 33.395 ± 13.2129 |
The intent of the PK outcomes was not to compare the results between the two cohorts; for this reason results for the PK outcomes are reported for the whole group of the treated patients. CL/F = Apparent oral clearance - for DF1681Y only, calculated as dose/AUCinf.; calculated only when the coefficient of determination R2 in lambda zeta estimation is at least 0.8 and percent AUC extrapolation is less than or equal to 20%. CLss/F = Steady state apparent oral clearance - for DF1681Y only calculated as dose/AUCtau.
| L/h | Treated Patients - Total |
|---|---|
| DF1681Y - CL/F - Day 1 | 5.173 ± 1.7466 |
| DF1681Y - CLSS/F - Day 21 | 5.866 ± 0.9086 |
| DF1681Y unbound - CL/F - Day 1 | 7156.189 ± 6334.8463 |
| DF1681Y unbound - CLSS/F - Day 21 | 5604.781 ± 2335.8016 |
The Leukocytes subsets analyzed are the following: Lymphocyte in WBC, Total T cell in lymphocytes, B cells in lymphocytes, T-helper cell in lymphocytes, CTL in lymphocytes, NKT cell in lymphocytes, ADCC NK subsets in lymphocytes, Regulatory NK subsets in lymphocytes, Exhausted NK subsets in lymphocytes, CD56-CD16+ NK subsets in lymphocytes, CD11b in PMNs - IL-8, CD18 in PMNs - IL-8, MFI of CD11b - IL-8, MFI of CD66b - IL-8, MFI of CD18 - IL-8, CD11b in PMNs - US, CD18 in PMNs - US, MFI of CD11b - US, MFI of CD66b - US, MFI of CD18 - US, Percent Monocytes expressing IL6 - IL-8,Percent Monocytes expressing IL1b - IL-8, Percent Monocytes expressing IL8 - IL-8, Percent Monocytes expressing TNFa - IL-8, Percent Neutrophils expressing IL6 - IL-8, Percent Neutrophils expressing IL1b - IL-8, Percent Neutrophils expressing IL8 - IL-8, Percent Neutrophils expressing TNFa - IL-8,Percent Monocytes expressing IL6 - US,Percent Monocytes expressing IL1b - US, etc.
| percent of total | ER+ and/or PR+/ HER-2 - | ER-/PR-/HER-2- |
|---|---|---|
| Lymphocyte in WBC | -2.51 ± 9.099 | -3.70 ± NA |
| Total T cell in lymphocytes | 1.28 ± 4.602 | -2.80 ± NA |
| B cell in lymphocytes | 2.678 ± 7.5565 | 43.190 ± NA |
| T-helper cell in lymphocytes | -1.44 ± 5.158 | -24.90 ± NA |
| CTL in lymphocytes | -0.639 ± 5.5106 | -24.100 ± NA |
| NKT cell in lymphocytes | 0.510 ± 1.5759 | 0.140 ± NA |
| ADCC NK subsets in lymphocytes | 0.727 ± 4.1787 | 1.430 ± NA |
| Regulatory NK subsets in lymphocytes | -1.358 ± 3.2465 | 0.370 ± NA |
| Exhausted NK subsets in lymphocytes | -0.177 ± 1.7006 | -0.170 ± NA |
| CD56-CD16+ NK subsets in lymphocytes | 0.708 ± 1.6772 | 0.310 ± NA |
| CD11b in PMNs - IL-8 | -1.48 ± 4.877 | -11.60 ± NA |
| CD18 in PMNs - IL-8 | -0.23 ± 4.104 | 2.10 ± NA |
| MFI of CD11b - IL-8 | -1.63 ± 2.205 | 3.50 ± NA |
| MFI of CD66b - IL-8 | -3.9 ± 507.79 | -929.0 ± NA |
| MFI of CD18 - IL-8 | -13.0 ± 495.89 | 71.0 ± NA |
| CD11b in PMNs - US | 1.56 ± 9.515 | -4.20 ± NA |
| CD18 in PMNs - US | -5.758 ± 23.7696 | -0.400 ± NA |
| MFI of CD11b - US | -0.84 ± 1.571 | -0.30 ± NA |
| MFI of CD66b - US | 35.1 ± 536.54 | -757.0 ± NA |
| MFI of CD18 - US | -105.64 ± 679.547 | -47.00 ± NA |
| Percent Monocytes expressing IL6 - IL-8 | 8.40590 ± 27.654326 | 0.52600 ± NA |
| Percent Monocytes expressing IL1b - IL-8 | 8.27479 ± 24.364503 | 0.32600 ± NA |
| Percent Monocytes expressing IL8 - IL-8 | -0.35947 ± 3.983235 | -0.04400 ± NA |
| Percent Monocytes expressing TNFa - IL-8 | 0.40504 ± 1.906309 | -0.39900 ± NA |
| Percent Neutrophils expressing IL6 - IL-8 | 2.83019 ± 26.145843 | 0.36340 ± NA |
| Percent Neutrophils expressing IL1b - IL-8 | 10.24530 ± 32.068081 | 0.33400 ± NA |
| Percent Neutrophils expressing IL8 - IL-8 | 0.04596 ± 1.667000 | 0.05742 ± NA |
| Percent Neutrophils expressing TNFa - IL-8 | 0.35635 ± 2.269023 | 0.03500 ± NA |
| Percent Monocytes expressing IL6 - US | 9.77675 ± 29.705447 | 0.26500 ± NA |
| Percent Monocytes expressing IL1b - US | 5.58031 ± 28.862940 | 1.03400 ± NA |
| Percent Monocytes expressing IL8 - US | 0.14087 ± 2.716051 | -0.27600 ± NA |
| Percent Monocytes expressing TNFa - US | -0.11532 ± 1.333406 | 0.28200 ± NA |
| Percent Neutrophils expressing IL6 - US | 5.50297 ± 21.932274 | 0.59260 ± NA |
| Percent Neutrophils expressing IL1b - US | 9.28329 ± 33.754437 | 1.36450 ± NA |
| Percent Neutrophils expressing IL8 - US | 0.45567 ± 2.053990 | 0.15020 ± NA |
| Percent Neutrophils expressing TNFa - US | 0.46929 ± 2.876200 | 0.54910 ± NA |
| Percent Monocytes expressing IL6 - LPS | -0.23 ± 8.015 | -9.60 ± NA |
| Percent Monocytes expressing IL1b - LPS | -5.18 ± 18.237 | 27.80 ± NA |
| Percent Monocytes expressing IL8 - LPS | -4.2057 ± 21.72201 | -74.3700 ± NA |
| Percent Monocytes expressing TNFa - LPS | -3.145 ± 8.8075 | -56.400 ± NA |
| Percent Neutrophils expressing IL6 - LPS | -2.0310 ± 4.60857 | 72.3690 ± NA |
| Percent Neutrophils expressing IL1b - LPS | -1.68086 ± 5.470114 | 78.19200 ± NA |
| Percent Neutrophils expressing IL8 - LPS | 0.14986 ± 1.844687 | 1.18700 ± NA |
| Percent Neutrophils expressing TNFa - LPS | 0.1497 ± 1.97537 | 1.7720 ± NA |
| Percent Monocytes expressing IL6 - LPS+IL-8 | -3.42 ± 6.783 | 1.20 ± NA |
| Percent Monocytes expressing IL1b - LPS+IL-8 | -4.79 ± 14.168 | 25.90 ± NA |
| Percent Monocytes expressing IL8 - LPS+IL-8 | -7.738 ± 12.9421 | -76.990 ± NA |
| Percent Monocytes expressing TNFa - LPS+IL-8 | -0.3018 ± 9.97119 | -57.9100 ± NA |
| Percent Neutrophils expressing IL6 - LPS+IL-8 | 1.2629 ± 20.77484 | 62.7900 ± NA |
| Percent Neutrophils expressing IL1b - LPS+IL-8 | 0.1980 ± 27.96300 | 81.6290 ± NA |
| Percent Neutrophils expressing IL8 - LPS+IL-8 | 0.0348 ± 1.81583 | 1.0010 ± NA |
| Percent Neutrophils expressing TNFa - LPS+IL-8 | -0.0349 ± 1.75308 | 2.6490 ± NA |
| Percent FITC eColi Control | 4.327 ± 7.7795 | -8.500 ± NA |
| Percent FITC eColi Test | -1.056 ± 3.6456 | -4.200 ± NA |
| Percent PMNs unstimulated | -5.025 ± 16.3554 | 28.690 ± NA |
| Percent PMNs fMLP | 9.152 ± 18.2092 | 23.300 ± NA |
| Percent L-selectin unstimulated | 4.341 ± 25.8071 | -25.000 ± NA |
| Percent L-selectin fMLP | -0.2845 ± 0.95877 | -0.2460 ± NA |
Collected over throughout the study and at OTV (off treatment visit) up to the 30 days after the last dose of reparixin. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Total | 0/20 (0%) | 1/20 (5%) | 15/20 (75%) |
| Event | Total |
|---|---|
| POSTOPERATIVE WOUND INFECTIONInfections and infestations | 1/20 |
| Event | Total |
|---|---|
| FatigueGeneral disorders | 8/20 |
| NauseaGastrointestinal disorders | 5/20 |
| Procedural painInjury, poisoning and procedural complications | 5/20 |
| HeadacheNervous system disorders | 3/20 |
| InsomniaPsychiatric disorders | 3/20 |
| Abdominal painGastrointestinal disorders | 2/20 |
| ConstipationGastrointestinal disorders | 2/20 |
| FlatulenceGastrointestinal disorders | 2/20 |
| VomitingGastrointestinal disorders | 2/20 |
| PainGeneral disorders | 2/20 |
| Age, Categorical(Participants) | ER+ and/or PR+/ HER-2 - | ER-/PR-/HER-2- | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 16 | 1 | 17 |
| >=65 years | 2 | 1 | 3 |
| Age, Continuous(years) | ER+ and/or PR+/ HER-2 - | ER-/PR-/HER-2- | Total |
|---|---|---|---|
| Mean | 54.0 ± 8.92 | 56.5 ± 12.02 | 54.3 ± 8.91 |
| Sex: Female, Male(Participants) | ER+ and/or PR+/ HER-2 - | ER-/PR-/HER-2- | Total |
|---|---|---|---|
| Female | 18 | 2 | 20 |
| Male | 0 | 0 | 0 |
| Ethnicity (NIH/OMB)(Participants) | ER+ and/or PR+/ HER-2 - | ER-/PR-/HER-2- | Total |
|---|---|---|---|
| Hispanic or Latino | 6 | 0 | 6 |
| Not Hispanic or Latino | 12 | 2 | 14 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | ER+ and/or PR+/ HER-2 - | ER-/PR-/HER-2- | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 1 | 0 | 1 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 1 | 0 | 1 |
| White | 15 | 2 | 17 |
| More than one race | 1 | 0 | 1 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | ER+ and/or PR+/ HER-2 - | ER-/PR-/HER-2- | Total |
|---|---|---|---|
| United States | 18 | 2 | 20 |
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Dompé Farmaceutici S.p.A