Phase 1
Completed N=33
Pilot Study to Evaluate Reparixin With Weekly Paclitaxel in Patients With HER 2 Negative Metastatic Breast Cancer (MBC)
Source: ClinicalTrials.gov NCT02001974 ↗Enrolled (actual)
33
Serious AEs
23.3%
Results posted
Apr 2021
Primary outcomePrimary: Treatment-Emergent Adverse Events (TEAEs) — 106; 99; 506 adverse events
Summary
This is a phase I study to evaluate the safety and define the pharmacokinetic (PK) profile of orally administered reparixin in combination with paclitaxel in HER 2 (Human epidermal growth factor receptor-2) negative metastatic breast cancer patients.
The primary objective of this study was to evaluate the safety and define the pharmacokinetic (PK) profile of orally administered reparixin in combination with paclitaxel in HER-2 negative MBC patients.
The secondary objectives were to:
1. Evaluate the effects of orally administered reparixin on cancer stem cell (CSC) markers, the tumoral microenvironment and markers of cytokine inflammation;
2. Evaluate peripheral blood samples for enumeration of circulating tumor cells (CTCs), molecular characterization as CSCs and perform epithelial-mesenchymal transition (EMT) biomarker profiling;
3. Assess disease response for indication of efficacy.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Treatment-Emergent Adverse Events (TEAEs) |
106; 99; 506 | — |
| PRIMARY Plasma DF1681Y Concentrations by Time Point |
0.000; 0.000; 0.000; 20.648; 25.743; 34.689 | — |
| PRIMARY Plasma Unbound DF1681Y Concentrations by Time Point |
13.7; 22.4; 109.1; 13.1; 37.2; 74.5 | — |
| PRIMARY Plasma DF2243Y Concentrations by Time Point |
0.000; 0.000; 0.000; 0.188; 0.167; 0.813 | — |
| PRIMARY Plasma DF2188Y Concentrations by Time Point |
0.000; 0.000; 0.000; 0.547; 0.717; 1.781 | — |
| PRIMARY Plasma Ibuprofen Concentrations by Time Point |
0.040; 0.024; 0.030; 0.165; 0.260; 0.282 | — |
| PRIMARY Plasma Paclitaxel Concentrations by Time Point |
0.000; 0.000; 0.070; 1.483; 1.560; 2.275 | — |
| PRIMARY C0 and Cmax for DF1681Y |
0.00; 0.00; 0.00; 1.05; 4.24; 5.74 | 0.0341 sig |
| PRIMARY C0 and Cmax for DF2243Y |
0.00; 0.00; 0.00; 1.08; 4.68; 6.52 | 0.0015 sig |
| PRIMARY C0 and Cmax for DF2188Y |
0; 0; 0; 0.24; 1.36; 1.43 | 0.0097 sig |
| PRIMARY C0 and Cmax for Ibuprofen |
0.04; 0.02; 0.03; 0.41; 1.25; 1.08 | 0.1016 |
| PRIMARY Cmax for Paclitaxel |
2.35; 2.44; 3.10; 2.31; 2.55; 3.62 | 0.2375 |
| PRIMARY Tmax and t1/2 for DF1681Y |
0.90; 1.82; 1.41; 2.15; 1.01; 2.64 | — |
| PRIMARY Tmax and t1/2 for DF2243Y |
3.30; 4.32; 3.41; 3.51; 2.67; 4.00 | — |
| PRIMARY Tmax and t1/2 for DF2188Y |
2.05; 2.81; 2.44; 1.78; 1.33; 2.45 | — |
| PRIMARY Tmax and t1/2 for Ibuprofen |
3.50; 3.99; 2.86; 4.02; 2.66; 4.00 | — |
| PRIMARY Tmax and t1/2 for Paclitaxel |
1.14; 1.01; 1.22; 1.06; 1.06; 1.07 | — |
| PRIMARY AUC0-8 for DF1681Y |
86.7; 108; 194; 86.5; 124; 216 | 0.0134 sig |
| PRIMARY AUC0-8 for DF2243Y |
25.03; 40.4; 90.21; 25.8; 65.0; 108.7 | 0.0029 sig |
| PRIMARY AUC0-8 for DF2188Y |
9.79; 16.0; 36.3; 11.0; 24.6; 57.2 | 0.0081 sig |
| PRIMARY AUC0-8 for Ibuprofen |
4.35; 5.97; 14.8; 5.14; 10.93; 16.17 | 0.1335 |
| PRIMARY AUC0-8 for Paclitaxel |
4.05; 3.70; 5.82; 3.70; 5.17; 5.69 | 0.1449 |
| PRIMARY Rac0-8 for DF1681Y |
0.97; 1.3; 1.21; 0.63; 1.7; 1.01 | — |
| PRIMARY Rac0-8 for DF2243Y |
1.02; 1.82; 1.18; 0.78; 1.3; 1.08 | — |
| PRIMARY Rac0-8 for DF2188Y |
1.12; 1.61; 1.52; 0.77; 1.32; 1.22 | — |
| PRIMARY Rac0-8 for Ibuprofen |
1.09; 1.99; 1.18; 0.65; 1.25; 1.23 | — |
| PRIMARY Rac0-24 for Paclitaxel |
0.90; 1.59; 1.04 | — |
| SECONDARY Count of Patients With Complete Response (CR), Partial Response (PR), Stable Disease (SD), Disease Progression (PD) at Each Assessment Visit |
1; 0; 0; 0; 1; 3 | — |
| SECONDARY Best Overall Response (BOR) |
1; 0; 1; 0; 0; 5 | — |
| SECONDARY Clinical Benefit Rate (CBR) |
25.0; 33.3; 56.5 | — |
| SECONDARY 6-month Progression-free Survival Rate |
25.0; 0.0; 17.4 | — |
| SECONDARY Median Time to Tumor Progression in Days (TTP) |
58; 67; 170 | — |
Eligibility Criteria
Inclusion Criteria
- Female aged ≥ 18 years.
- Patients with histologic or cytologic diagnosis of breast cancer with evidence of metastatic disease with documented HER-2 negative status and eligible for treatment with paclitaxel.
- Patients with at least one baseline measurable lesion according to RECIST version 1.1 criteria.
- Zubrod (Eastern Co-operative Oncology Group [ECOG]) Performance Status (PS) of 0-1.
- An electrocardiogram (ECG) with no clinically significant abnormalities indicative of myocardial ischemia.
- Ongoing toxicity associated with prior anticancer therapy ≤ grade 1 Common Terminology Criteria for Adverse Events (CTCAE version 4.03) with the exception of alopecia.
- Maximum of three prior chemotherapy lines for advanced breast cancer (not including neo/adjuvant chemotherapy). If prior treatment with paclitaxel, PD must have occurred > 12 months from the end of previous adjuvant treatment or for previous metastatic treatment no PD must have occurred during treatment or within 3 months of the end of treatment
- Life expectancy of at least three months.
- Patients must be able to swallow and retain oral medication (intact tablet).
- Able to undergo all screening assessments outlined in the protocol following written informed consent.
- Adequate organ function (defined by the following parameters):
- Serum creatinine 60 mL/min.
- Serum hemoglobin ≥ 9 g/dL; absolute neutrophil count ≥ 1.5 x 10**9/L; platelets ≥ 100 x 10**9/L.
- Serum bilirubin ≤ 1.5 x upper normal limit (UNL).
- Serum ALT, AST ≤ 2.5 x UNL but ≤ 5.0 x UNL in case of liver metastases; ALP ≤ UNL but ≤ 1.5 x ULN in case of liver metastases; albumin within normal limits. If ALP is greater than 1.5 x UNL (in the presence of liver metastases) the liver isoenzyme fraction will be measured. Liver isoenzyme fraction (absolute value) must be ≤ 1.5 x UNL.
- No known hepatitis B virus (not due to immunization), hepatitis C virus, human immunodeficiency virus Ι and -ΙΙ positive status.
Exclusion Criteria
- Male.
- Pregnancy or lactation or unwillingness to use adequate method of birth control.
- HER-2 positive disease status.
- Less than four weeks since last chemotherapy, radiotherapy or prior investigational therapy. Less than two weeks since last hormone or immunotherapy or signal transduction therapy.
- 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:
- paclitaxel
- ibuprofen or to more than one non-steroidal anti-inflammatory drug.
- medications belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib.
- Presence of brain metastases (this does not include primary brain tumors) or leptomeningeal disease.
Data sourced from ClinicalTrials.gov (NCT02001974). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.