Breast Cancer
Conditions
Keywords
Cancer Stem Cells, Novel targeted therapy, CXCR1/2 Inhibitors
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.
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.
Interventions
DRUGReparixin
1000 mg Oral Reparixin t.i.d. for 21 consecutive days prior to surgery
Sponsors
Dompé Farmaceutici S.p.A
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline-1 to Day 21-1 in Markers of Autophagy (P62 and LC3B by IHC) | At day 21 | 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. |
| Change From Baseline to Day 21 in Markers of Cancer Stem Cells (CSCs) in the Primary Tumor and the Tumoral Microenvironment (ALDH1,CD44/CD24) | At day 21 | 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). |
| Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Day 21 (or last day of treatment) | 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) |
| Change From Baseline to Day 21 in Markers of Inflammation | At Day 21 | 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 |
| Change From Baseline-1 to Day 21-1 in Markers of Angiogenesis (CD31 Staining) | At day 21 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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 |
| 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) | 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. |
| 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) | 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. |
| 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) | 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. |
| Change From Baseline to Day 21 in Leukocytes Subsets | At Day 21 | 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. |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
It was planned to enroll 2 sub-groups of patients into the study, Group A: ER+ and/or PR+/HER-2- and Group B: ER-/PR-/HER-2-, and the sample size of 20 patients per group was chosen. Twenty patients in total were enrolled, 18 in Group A and 2 in Group B. The study was closed prematurely due to slow enrollment in group B. All 20 patients were included in the Safety Population and 6 (30%) were included in the PK population. All 20 patients completed the study.
Participants by arm
| Arm | Count |
|---|---|
| ER+ and/or PR+/ HER-2 - Patients of Group A (estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+)/human epidermal growth factor receptor-2 negative (HER-2-)) were given Reparixin 1000 mg (two 500 mg tablets) for 21 consecutive days. Reparixin was administered orally, every six to eight hours t.i.d. preferably with food. However, if the patient was unable to eat, reparixin could still be administered. Reparixin was administered with about 250 mL water and a light meal or snack | 18 |
| ER-/PR-/HER-2- Patients of Group B (estrogen receptor negative (ER-)/progesterone receptor negative (PR-)/HER-2-) were given Reparixin 1000 mg (two 500 mg tablets) for 21 consecutive days. Reparixin was administered orally, every six to eight hours t.i.d. preferably with food. However, if the patient was unable to eat, reparixin could still be administered. Reparixin was administered with about 250 mL water and a light meal or snack | 2 |
| Total | 20 |
Baseline characteristics
| Characteristic | ER+ and/or PR+/ HER-2 - | ER-/PR-/HER-2- | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 1 Participants | 17 Participants |
| Age, Continuous | 54.0 years STANDARD_DEVIATION 8.92 | 56.5 years STANDARD_DEVIATION 12.02 | 54.3 years STANDARD_DEVIATION 8.91 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 0 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 2 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 2 Participants | 17 Participants |
| Region of Enrollment United States | 18 participants | 2 participants | 20 participants |
| Sex: Female, Male Female | 18 Participants | 2 Participants | 20 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 20 |
| other Total, other adverse events | 15 / 20 |
| serious Total, serious adverse events | 1 / 20 |
Outcome results
Primary
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
Population: The Safety Population included all enrolled patients who took at least one dose of study drug reparixin. This population was used for primary endpoints and safety analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Markers of Angiogenesis (CD31 Staining) | Stain CD31 Extent | 0 score on a scale |
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Markers of Angiogenesis (CD31 Staining) | Stain CD31 Intensity | 0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Markers of Angiogenesis (CD31 Staining) | Stain CD31 Extent | 1.0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Markers of Angiogenesis (CD31 Staining) | Stain CD31 Intensity | 1.0 score on a scale |
Comparison: CD31 Extentp-value: 0.0951Wilcoxon (Mann-Whitney)
Comparison: CD31 Intensityp-value: 0.1643Wilcoxon (Mann-Whitney)
Primary
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
Population: The Safety Population included all enrolled patients who took at least one dose of study drug reparixin. This population was used for primary endpoints and safety analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Markers of Autophagy (P62 and LC3B by IHC) | Stain P62 Intensity | 0 score on a scale |
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Markers of Autophagy (P62 and LC3B by IHC) | Stain P62 Extent | -1.0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Markers of Autophagy (P62 and LC3B by IHC) | Stain P62 Extent | 0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Markers of Autophagy (P62 and LC3B by IHC) | Stain P62 Intensity | -1.0 score on a scale |
Comparison: P62 Extentp-value: 0.4183Wilcoxon (Mann-Whitney)
Comparison: P62 Intensityp-value: 0.3702Wilcoxon (Mann-Whitney)
Primary
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)
Population: The Safety Population included all enrolled patients who took at least one dose of study drug reparixin. This population was used for primary endpoints and safety analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain AKT Extent | 0 score on a scale |
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain FAK Intens | 0 score on a scale |
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain CXCR1 Extent | 0 score on a scale |
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain C-PTEN Extent | 0 score on a scale |
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain AKT Intensity | -0.5 score on a scale |
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain C-PTEN Intensity | 0 score on a scale |
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain Phospho-AKT Intensity | 0 score on a scale |
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain D-PTEN Extent | 0 score on a scale |
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Phospho-FAK Extent | 0 score on a scale |
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain D-PTEN Intensity | 0 score on a scale |
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain Phospho-AKT Extent | 0 score on a scale |
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Phospho-FAK Intensity | 0 score on a scale |
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain CXCR1 Intensity | -0.5 score on a scale |
| ER+ and/or PR+/ HER-2 - | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain FAK Extent | 0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain CXCR1 Intensity | 1.0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain Phospho-AKT Extent | 0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain Phospho-AKT Intensity | 0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain AKT Extent | 1.0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain AKT Intensity | 0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Phospho-FAK Extent | 0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain FAK Extent | 1.0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain FAK Intens | 0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain C-PTEN Extent | 0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain C-PTEN Intensity | 0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain D-PTEN Extent | 0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain D-PTEN Intensity | 0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Stain CXCR1 Extent | 1.0 score on a scale |
| ER-/PR-/HER-2- | Change From Baseline-1 to Day 21-1 in Pathway Markers by IHC | Phospho-FAK Intensity | -1.0 score on a scale |
Comparison: Phospho AKT Extentp-value: >0.9999Wilcoxon (Mann-Whitney)
Comparison: Phospho-AKT Intensityp-value: >0.9999Wilcoxon (Mann-Whitney)
Comparison: AKT Extentp-value: 0.2245Wilcoxon (Mann-Whitney)
Comparison: AKT Intensityp-value: 0.5785Wilcoxon (Mann-Whitney)
Comparison: Phospho-FAK Extentp-value: >0.9999Wilcoxon (Mann-Whitney)
Comparison: Phospho-FAK Intensityp-value: 0.3139Wilcoxon (Mann-Whitney)
Comparison: FAK Extentp-value: 0.212Wilcoxon (Mann-Whitney)
Comparison: FAK Intensityp-value: >0.9999Wilcoxon (Mann-Whitney)
Comparison: C-PTEN Extentp-value: >0.9999Wilcoxon (Mann-Whitney)
Comparison: C-PTEN Intensityp-value: 0.8728Wilcoxon (Mann-Whitney)
Comparison: D-PTEN Extentp-value: >0.9999Wilcoxon (Mann-Whitney)
Comparison: D-PTEN Intensityp-value: 0.8728Wilcoxon (Mann-Whitney)
Comparison: CXCR1 Extentp-value: 0.2265Wilcoxon (Mann-Whitney)
Comparison: CXCR1 Intensityp-value: 0.2403Wilcoxon (Mann-Whitney)
Primary
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
Population: The Safety Population included all enrolled patients who took at least one dose of study drug reparixin. This population was used for primary endpoints and safety analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Markers of Cancer Stem Cells (CSCs) in the Primary Tumor and the Tumoral Microenvironment (ALDH1,CD44/CD24) | ALDH+ | 1.34 percentage of cells | Standard Deviation 2.737 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Markers of Cancer Stem Cells (CSCs) in the Primary Tumor and the Tumoral Microenvironment (ALDH1,CD44/CD24) | CD44+/CD24- | -0.57 percentage of cells | Standard Deviation 5.617 |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Markers of Cancer Stem Cells (CSCs) in the Primary Tumor and the Tumoral Microenvironment (ALDH1,CD44/CD24) | ALDH+ | -0.40 percentage of cells | Standard Deviation 1.131 |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Markers of Cancer Stem Cells (CSCs) in the Primary Tumor and the Tumoral Microenvironment (ALDH1,CD44/CD24) | CD44+/CD24- | 0.20 percentage of cells | Standard Deviation 1.273 |
Comparison: Comparison on ALDH+ cells by ALDEFLUOR assayp-value: 0.3149Wilcoxon (Mann-Whitney)
Comparison: Comparison on CD44+/CD24- by flow citometryp-value: 0.8148Wilcoxon (Mann-Whitney)
Primary
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
Population: The Safety Population included all enrolled patients who took at least one dose of study drug reparixin. This population was used for primary endpoints and safety analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Markers of Inflammation | TNFα | 2.669 pg/ML | Standard Deviation 8.0313 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Markers of Inflammation | Interleukin 1 Beta | 7.019 pg/ML | Standard Deviation 30.3118 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Markers of Inflammation | GM-CSF | -2.678 pg/ML | Standard Deviation 8.2154 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Markers of Inflammation | Interleukin 8 | -25.874 pg/ML | Standard Deviation 134.3213 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Markers of Inflammation | VEGF | 253.584 pg/ML | Standard Deviation 1120.6125 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Markers of Inflammation | b-FGF | 20.164 pg/ML | Standard Deviation 93.4614 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Markers of Inflammation | Interleukin 6 | 9.593 pg/ML | Standard Deviation 39.2733 |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Markers of Inflammation | b-FGF | -9.750 pg/ML | Standard Deviation 13.7886 |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Markers of Inflammation | Interleukin 1 Beta | 0 pg/ML | Standard Deviation 0 |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Markers of Inflammation | Interleukin 6 | 0 pg/ML | Standard Deviation 0 |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Markers of Inflammation | Interleukin 8 | 29.320 pg/ML | Standard Deviation 41.691 |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Markers of Inflammation | TNFα | -0.890 pg/ML | Standard Deviation 3.578 |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Markers of Inflammation | GM-CSF | 8.705 pg/ML | Standard Deviation 12.3107 |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Markers of Inflammation | VEGF | 27.635 pg/ML | Standard Deviation 39.0818 |
Comparison: Interleukin 1 Betap-value: >0.9999Wilcoxon (Mann-Whitney)
Comparison: Interleukin 6p-value: 0.6945Wilcoxon (Mann-Whitney)
Comparison: Interleukin 8p-value: 0.9448Wilcoxon (Mann-Whitney)
Comparison: Tumor Necrosis Factor - alphap-value: 0.6292Wilcoxon (Mann-Whitney)
Comparison: Granulocyte Macrophage Colony Stm Factorp-value: 0.2354Wilcoxon (Mann-Whitney)
Comparison: Vascular Endothelial Growth Factorp-value: >0.9999Wilcoxon (Mann-Whitney)
Comparison: Basic Fibroblast Growth Factorp-value: 0.4719Wilcoxon (Mann-Whitney)
Secondary
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
Population: The Safety Population included all enrolled patients who took at least one dose of study drug reparixin. This population was used for primary endpoints and safety analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | B cell in lymphocytes | 2.678 percent of total | Standard Deviation 7.5565 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | CTL in lymphocytes | -0.639 percent of total | Standard Deviation 5.5106 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | CD56-CD16+ NK subsets in lymphocytes | 0.708 percent of total | Standard Deviation 1.6772 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL6 - IL-8 | 8.40590 percent of total | Standard Deviation 27.654326 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL1b - IL-8 | 8.27479 percent of total | Standard Deviation 24.364503 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL8 - IL-8 | -0.35947 percent of total | Standard Deviation 3.983235 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing TNFa - IL-8 | 0.40504 percent of total | Standard Deviation 1.906309 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL1b - IL-8 | 10.24530 percent of total | Standard Deviation 32.068081 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing TNFa - US | 0.46929 percent of total | Standard Deviation 2.8762 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL6 - LPS | -0.23 percent of total | Standard Deviation 8.015 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent FITC eColi Test | -1.056 percent of total | Standard Deviation 3.6456 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL8 - IL-8 | 0.04596 percent of total | Standard Deviation 1.667 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Lymphocyte in WBC | -2.51 percent of total | Standard Deviation 9.099 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Total T cell in lymphocytes | 1.28 percent of total | Standard Deviation 4.602 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing TNFa - IL-8 | 0.35635 percent of total | Standard Deviation 2.269023 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL6 - US | 9.77675 percent of total | Standard Deviation 29.705447 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL1b - US | 5.58031 percent of total | Standard Deviation 28.86294 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL8 - US | 0.14087 percent of total | Standard Deviation 2.716051 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing TNFa - US | -0.11532 percent of total | Standard Deviation 1.333406 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | T-helper cell in lymphocytes | -1.44 percent of total | Standard Deviation 5.158 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL6 - US | 5.50297 percent of total | Standard Deviation 21.932274 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL1b - US | 9.28329 percent of total | Standard Deviation 33.754437 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL8 - US | 0.45567 percent of total | Standard Deviation 2.05399 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | NKT cell in lymphocytes | 0.510 percent of total | Standard Deviation 1.5759 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL1b - LPS | -5.18 percent of total | Standard Deviation 18.237 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL8 - LPS | -4.2057 percent of total | Standard Deviation 21.72201 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing TNFa - LPS | -3.145 percent of total | Standard Deviation 8.8075 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL6 - LPS | -2.0310 percent of total | Standard Deviation 4.60857 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL1b - LPS | -1.68086 percent of total | Standard Deviation 5.470114 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | ADCC NK subsets in lymphocytes | 0.727 percent of total | Standard Deviation 4.1787 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL8 - LPS | 0.14986 percent of total | Standard Deviation 1.844687 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing TNFa - LPS | 0.1497 percent of total | Standard Deviation 1.97537 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Regulatory NK subsets in lymphocytes | -1.358 percent of total | Standard Deviation 3.2465 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL6 - LPS+IL-8 | -3.42 percent of total | Standard Deviation 6.783 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL1b - LPS+IL-8 | -4.79 percent of total | Standard Deviation 14.168 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL8 - LPS+IL-8 | -7.738 percent of total | Standard Deviation 12.9421 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Exhausted NK subsets in lymphocytes | -0.177 percent of total | Standard Deviation 1.7006 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing TNFa - LPS+IL-8 | -0.3018 percent of total | Standard Deviation 9.97119 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL6 - LPS+IL-8 | 1.2629 percent of total | Standard Deviation 20.77484 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | CD11b in PMNs - IL-8 | -1.48 percent of total | Standard Deviation 4.877 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL1b - LPS+IL-8 | 0.1980 percent of total | Standard Deviation 27.963 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL8 - LPS+IL-8 | 0.0348 percent of total | Standard Deviation 1.81583 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing TNFa - LPS+IL-8 | -0.0349 percent of total | Standard Deviation 1.75308 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent FITC eColi Control | 4.327 percent of total | Standard Deviation 7.7795 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent PMNs unstimulated | -5.025 percent of total | Standard Deviation 16.3554 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent PMNs fMLP | 9.152 percent of total | Standard Deviation 18.2092 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent L-selectin unstimulated | 4.341 percent of total | Standard Deviation 25.8071 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent L-selectin fMLP | -0.2845 percent of total | Standard Deviation 0.95877 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | CD18 in PMNs - IL-8 | -0.23 percent of total | Standard Deviation 4.104 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | MFI of CD11b - IL-8 | -1.63 percent of total | Standard Deviation 2.205 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | MFI of CD66b - IL-8 | -3.9 percent of total | Standard Deviation 507.79 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | MFI of CD18 - IL-8 | -13.0 percent of total | Standard Deviation 495.89 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | CD11b in PMNs - US | 1.56 percent of total | Standard Deviation 9.515 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | CD18 in PMNs - US | -5.758 percent of total | Standard Deviation 23.7696 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | MFI of CD11b - US | -0.84 percent of total | Standard Deviation 1.571 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | MFI of CD66b - US | 35.1 percent of total | Standard Deviation 536.54 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | MFI of CD18 - US | -105.64 percent of total | Standard Deviation 679.547 |
| ER+ and/or PR+/ HER-2 - | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL6 - IL-8 | 2.83019 percent of total | Standard Deviation 26.145843 |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | CD11b in PMNs - IL-8 | -11.60 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | MFI of CD66b - US | -757.0 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | NKT cell in lymphocytes | 0.140 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL6 - LPS+IL-8 | 1.20 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | CD56-CD16+ NK subsets in lymphocytes | 0.310 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | CD18 in PMNs - IL-8 | 2.10 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL1b - LPS+IL-8 | 25.90 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL6 - IL-8 | 0.36340 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Regulatory NK subsets in lymphocytes | 0.370 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | MFI of CD11b - IL-8 | 3.50 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Exhausted NK subsets in lymphocytes | -0.170 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL8 - LPS+IL-8 | -76.990 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | MFI of CD18 - US | -47.00 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing TNFa - LPS+IL-8 | -57.9100 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | MFI of CD66b - IL-8 | -929.0 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL8 - IL-8 | 0.05742 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Lymphocyte in WBC | -3.70 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL6 - LPS+IL-8 | 62.7900 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Total T cell in lymphocytes | -2.80 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL6 - IL-8 | 0.52600 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing TNFa - IL-8 | 0.03500 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | MFI of CD18 - IL-8 | 71.0 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL6 - US | 0.26500 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL1b - LPS+IL-8 | 81.6290 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL1b - US | 1.03400 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL1b - IL-8 | 0.32600 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL8 - US | -0.27600 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL8 - LPS+IL-8 | 1.0010 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | B cell in lymphocytes | 43.190 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing TNFa - US | 0.28200 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | CD11b in PMNs - US | -4.20 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing TNFa - LPS+IL-8 | 2.6490 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | T-helper cell in lymphocytes | -24.90 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL6 - US | 0.59260 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | CTL in lymphocytes | -24.100 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL8 - IL-8 | -0.04400 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL1b - US | 1.36450 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent FITC eColi Control | -8.500 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent FITC eColi Test | -4.200 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL8 - US | 0.15020 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing TNFa - US | 0.54910 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL6 - LPS | -9.60 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | CD18 in PMNs - US | -0.400 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL1b - LPS | 27.80 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent PMNs unstimulated | 28.690 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing IL8 - LPS | -74.3700 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing TNFa - IL-8 | -0.39900 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Monocytes expressing TNFa - LPS | -56.400 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent PMNs fMLP | 23.300 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL6 - LPS | 72.3690 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | MFI of CD11b - US | -0.30 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL1b - LPS | 78.19200 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent L-selectin unstimulated | -25.000 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL1b - IL-8 | 0.33400 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing IL8 - LPS | 1.18700 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent L-selectin fMLP | -0.2460 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | Percent Neutrophils expressing TNFa - LPS | 1.7720 percent of total | — |
| ER-/PR-/HER-2- | Change From Baseline to Day 21 in Leukocytes Subsets | ADCC NK subsets in lymphocytes | 1.430 percent of total | — |
Comparison: Lymphocyte in WBCp-value: 0.6168t-test, 2 sided
Comparison: Total T cell in lymphocytesp-value: 0.6168t-test, 2 sided
Comparison: B cell in lymphocytesp-value: 0.1453t-test, 2 sided
Comparison: T-helper cell in lymphocytesp-value: 0.1453t-test, 2 sided
Comparison: CTL in lymphocytesp-value: 0.1453t-test, 2 sided
Comparison: NKT cell in lymphocytesp-value: >0.9999t-test, 2 sided
Comparison: ADCC NK subsets in lymphocytesp-value: 0.7634t-test, 2 sided
Comparison: Regulatory NK subsets in lymphocytesp-value: 0.5487t-test, 2 sided
Comparison: Exhausted NK subsets in lymphocytesp-value: >0.9999t-test, 2 sided
Comparison: CD56-CD16+ NK subsets in lymphocytesp-value: >0.9999t-test, 2 sided
Comparison: CD11b in PMNs - IL-8p-value: 0.1451t-test, 2 sided
Comparison: CD18 in PMNs - IL-8p-value: 0.2779t-test, 2 sided
Comparison: MFI of CD11b - IL-8p-value: 0.1444t-test, 2 sided
Comparison: MFI of CD66b - IL-8p-value: 0.1453t-test, 2 sided
Comparison: MFI of CD18 - IL-8p-value: 0.92t-test, 2 sided
Comparison: CD11b in PMNs - USp-value: 0.2779t-test, 2 sided
Comparison: CD18 in PMNs - USp-value: 0.6164t-test, 2 sided
Comparison: MFI of CD11b - USp-value: >0.9999t-test, 2 sided
Comparison: MFI of CD66b - USp-value: 0.2032t-test, 2 sided
Comparison: MFI of CD18 - USp-value: >0.9999t-test, 2 sided
Comparison: Percent Monocytes expressing IL6 - IL-8p-value: 0.525t-test, 2 sided
Comparison: Percent Monocytes expressing IL1b - IL-8p-value: 0.6706t-test, 2 sided
Comparison: Percent Monocytes expressing IL8 - IL-8p-value: 0.8312t-test, 2 sided
Comparison: Percent Monocytes expressing TNFa - IL-8p-value: 0.3992t-test, 2 sided
Comparison: Percent Neutrophils expressing IL6 - IL-8p-value: 0.2952t-test, 2 sided
Comparison: Percent Neutrophils expressing IL1b - IL-8p-value: 0.3992t-test, 2 sided
Comparison: Percent Neutrophils expressing IL8 - IL-8p-value: 0.2952t-test, 2 sided
Comparison: Percent Neutrophils expressing TNFa - IL-8p-value: 0.525t-test, 2 sided
Comparison: Percent Monocytes expressing IL6 - USp-value: 0.3992t-test, 2 sided
Comparison: Percent Monocytes expressing IL1b - USp-value: 0.2952t-test, 2 sided
Comparison: Percent Monocytes expressing IL8 - USp-value: >0.9999t-test, 2 sided
Comparison: Percent Monocytes expressing TNFa - USp-value: 0.3992t-test, 2 sided
Comparison: Percent Neutrophils expressing IL6 - USp-value: 0.3992t-test, 2 sided
Comparison: Percent Neutrophils expressing IL1b - USp-value: 0.2952t-test, 2 sided
Comparison: Percent Neutrophils expressing IL8 - USp-value: 0.3992t-test, 2 sided
Comparison: Percent Neutrophils expressing TNFa - USp-value: 0.2952t-test, 2 sided
Comparison: Percent Monocytes expressing IL6 - LPSp-value: 0.2238t-test, 2 sided
Comparison: Percent Monocytes expressing IL1b - LPSp-value: 0.2238t-test, 2 sided
Comparison: Percent Monocytes expressing IL8 - LPSp-value: 0.1543t-test, 2 sided
Comparison: Percent Monocytes expressing TNFa - LPSp-value: 0.1547t-test, 2 sided
Comparison: Percent Neutrophils expressing IL6 - LPSp-value: 0.1547t-test, 2 sided
Comparison: Percent Neutrophils expressing IL1b - LPSp-value: 0.1547t-test, 2 sided
Comparison: Percent Neutrophils expressing IL8 - LPSp-value: 0.4314t-test, 2 sided
Comparison: Percent Neutrophils expressing TNFa - LPSp-value: 0.3153t-test, 2 sided
Comparison: Percent Monocytes expressing IL6 - LPS+IL-8p-value: 0.47t-test, 2 sided
Comparison: Percent Monocytes expressing IL1b - LPS+IL-8p-value: 0.1605t-test, 2 sided
Comparison: Percent Monocytes expressing IL8 - LPS+IL-8p-value: 0.1605t-test, 2 sided
Comparison: Percent Monocytes expressing TNFa - LPS+IL-8p-value: 0.1605t-test, 2 sided
Comparison: Percent Neutrophils expressing IL6 - LPS+IL-8p-value: 0.1547t-test, 2 sided
Comparison: Percent Neutrophils expressing IL1b - LPS+IL-8p-value: 0.1547t-test, 2 sided
Comparison: Percent Neutrophils expressing IL8 - LPS+IL-8p-value: 0.3153t-test, 2 sided
Comparison: Percent Neutrophils expressing TNFa - LPS+IL-8p-value: 0.1543t-test, 2 sided
Comparison: Percent FITC eColi Controlp-value: 0.1601t-test, 2 sided
Comparison: Percent FITC eColi Testp-value: 0.2368t-test, 2 sided
Comparison: Percent PMNs unstimulatedp-value: 0.1605t-test, 2 sided
Comparison: Percent PMNs fMLPp-value: 0.47t-test, 2 sided
Comparison: Percent L-selectin unstimulatedp-value: 0.3392t-test, 2 sided
Comparison: Percent L-selectin fMLPp-value: 0.808t-test, 2 sided
Secondary
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)
Population: The PK Population consisted of patients who received at least one dose of reparixin and had at least one valid, quantifiable PK parameter. This population was used for PK analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF1681Y - AUCinf - Day 1 | 211.243 h*μg/mL | Standard Deviation 71.4823 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF1681Y unbound - AUCinf - Day 1 | 235.152 h*μg/mL | Standard Deviation 180.1547 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF2243Y - AUCinf - Day 1 | 71.297 h*μg/mL | Standard Deviation 25.6857 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF1681Y - AUClast - Day 21 | 172.296 h*μg/mL | Standard Deviation 28.1847 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF1681Y unbound - AUCtau - Day 21 | 233.382 h*μg/mL | Standard Deviation 166.0402 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF1681Y - AUC0-8 - Day 1 | 189.357 h*μg/mL | Standard Deviation 60.2362 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF1681Y - AUC0-8 - Day 21 | 174.303 h*μg/mL | Standard Deviation 29.8012 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF1681Y unbound- AUC0-8 - Day 1 | 222.602 h*μg/mL | Standard Deviation 128.0328 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF1681Y unbound- AUC0-8 - Day 21 | 233.382 h*μg/mL | Standard Deviation 166.0402 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF2243Y - AUC0-8 - Day 1 | 78.469 h*μg/mL | Standard Deviation 18.8116 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF2243Y - AUC0-8 - Day 21 | 105.001 h*μg/mL | Standard Deviation 58.2634 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF2188Y - AUC0-8 - Day 1 | 31.040 h*μg/mL | Standard Deviation 7.9369 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF2188Y - AUC0-8 - Day 21 | 33.395 h*μg/mL | Standard Deviation 13.2129 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF1681Y - AUCinf - Day 21 | 182.479 h*μg/mL | Standard Deviation 36.1551 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF1681Y unbound - AUCinf - Day 21 | 234.547 h*μg/mL | Standard Deviation 166.3017 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF2243Y - AUCinf - Day 21 | 129.275 h*μg/mL | Standard Deviation 74.5406 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF2188Y - AUCinf - Day 1 | 31.669 h*μg/mL | Standard Deviation 11.2792 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF2188Y - AUCinf - Day 21 | 35.092 h*μg/mL | Standard Deviation 13.9473 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF1681Y - AUClast - Day 1 | 189.319 h*μg/mL | Standard Deviation 60.2817 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF1681Y unbound - AUClast - Day 1 | 222.078 h*μg/mL | Standard Deviation 128.1305 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF1681Y unbound - AUClast - Day 21 | 231.235 h*μg/mL | Standard Deviation 167.0377 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF2243Y - AUClast - Day 1 | 76.821 h*μg/mL | Standard Deviation 17.3033 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF2243Y - AUClast - Day 21 | 97.360 h*μg/mL | Standard Deviation 46.6809 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF2188Y - AUClast - Day 1 | 31.028 h*μg/mL | Standard Deviation 7.9336 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF2188Y - AUClast - Day 21 | 35.433 h*μg/mL | Standard Deviation 12.8434 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF1681Y - AUCtau - Day 21 | 174.303 h*μg/mL | Standard Deviation 29.8012 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF2243Y - AUCtau - Day 21 | 105.001 h*μg/mL | Standard Deviation 58.2634 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - AUC0-8, AUCinf, AUClast, AUCtau at Day 21, | DF2188Y - AUCtau - Day 21 | 33.395 h*μg/mL | Standard Deviation 13.2129 |
Secondary
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)
Population: The PK Population consisted of patients who received at least one dose of reparixin and had at least one valid, quantifiable PK parameter. This population was used for PK analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - CL/F (L/h) at Day 1, CLSS/F (L/h) Day 21) | DF1681Y - CL/F - Day 1 | 5.173 L/h | Standard Deviation 1.7466 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - CL/F (L/h) at Day 1, CLSS/F (L/h) Day 21) | DF1681Y - CLSS/F - Day 21 | 5.866 L/h | Standard Deviation 0.9086 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - CL/F (L/h) at Day 1, CLSS/F (L/h) Day 21) | DF1681Y unbound - CL/F - Day 1 | 7156.189 L/h | Standard Deviation 6334.8463 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - CL/F (L/h) at Day 1, CLSS/F (L/h) Day 21) | DF1681Y unbound - CLSS/F - Day 21 | 5604.781 L/h | Standard Deviation 2335.8016 |
Secondary
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)
Population: The PK Population consisted of patients who received at least one dose of reparixin and had at least one valid, quantifiable PK parameter. This population was used for PK analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Cmax | Day21 - DF1681Y | 63.927 micrograms/mL | Standard Deviation 15.7616 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Cmax | Day 1 - DF2188Y | 7.302 micrograms/mL | Standard Deviation 1.5129 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Cmax | Day1 - DF1681Y | 62.925 micrograms/mL | Standard Deviation 31.5024 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Cmax | Day1 - DF1681Y unbound | 145.167 micrograms/mL | Standard Deviation 116.6114 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Cmax | Day21 - DF1681Y unbound | 136.552 micrograms/mL | Standard Deviation 104.8681 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Cmax | Day 1 - DF2243Y | 15.788 micrograms/mL | Standard Deviation 2.524 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Cmax | Day 21 - DF2243Y | 20.812 micrograms/mL | Standard Deviation 9.9776 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Cmax | Day 21 - DF2188Y | 10.367 micrograms/mL | Standard Deviation 4.3439 |
Secondary
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)
Population: The PK Population consisted of patients who received at least one dose of reparixin and had at least one valid, quantifiable PK parameter. This population was used for PK analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2 | Day21 - DF1681Y tmax | 0.997 hours | Standard Deviation 0.5508 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2 | Day 1 - DF2243Y t1/2 | 1.913 hours | Standard Deviation 0.3268 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2 | Day1 - DF1681Y tmax | 2.667 hours | Standard Deviation 2.8752 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2 | Day1 - DF1681Y unbound tmax | 1.583 hours | Standard Deviation 1.2813 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2 | Day21 - DF1681Y unbound tmax | 1.092 hours | Standard Deviation 0.4903 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2 | Day 1 - DF2243Y tmax | 4.333 hours | Standard Deviation 2.3381 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2 | Day 21 - DF2243Y tmax | 2.331 hours | Standard Deviation 0.8179 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2 | Day 1 - DF2188Y tmax | 2.500 hours | Standard Deviation 1.2247 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2 | Day 21 - DF2188Y tmax | 1.508 hours | Standard Deviation 0.5389 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2 | Day1 - DF1681Y t1/2 | 2.090 hours | Standard Deviation 0.9847 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2 | Day21 - DF1681Y t1/2 | 1.626 hours | Standard Deviation 0.4068 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2 | Day1 - DF1681Y unbound t1/2 | 1.403 hours | Standard Deviation 0.4592 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2 | Day21 - DF1681Y unbound t1/2 | 0.989 hours | Standard Deviation 0.1683 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2 | Day 21 - DF2243Y t1/2 | 2.575 hours | Standard Deviation 0.6442 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2 | Day 1 - DF2188Y t1/2 | 2.035 hours | Standard Deviation 1.0618 |
| ER+ and/or PR+/ HER-2 - | Pharmacokinetics of Reparixin (DF1681Y, DF1681Y Unbound, DF2243Y, DF2188Y) - Tmax and T1/2 | Day 21 - DF2188Y t1/2 | 1.575 hours | Standard Deviation 0.1953 |