Pilot Study to Evaluate Reparixin With Weekly Paclitaxel in Patients With HER 2 Negative Metastatic Breast Cancer (MBC)
Condition: Metastatic Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Paclitaxel+Reparixin
Intervention description: Association of Paclitaxel at fixed dosage with three increasing dosage of Reparixin
Intervention MeSH terms: Paclitaxel
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 33.0
Sex: Female
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: HER 2 negative; metastatic breast cancer; Cancer Stem Cells

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Female aged ≥ 18 years.

          2. 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.

          3. Patients with at least one baseline measurable lesion according to RECIST version 1.1
             criteria.

          4. Zubrod (Eastern Co-operative Oncology Group [ECOG]) Performance Status (PS) of 0-1.

          5. An electrocardiogram (ECG) with no clinically significant abnormalities indicative of
             myocardial ischemia.

          6. Ongoing toxicity associated with prior anticancer therapy ≤ grade 1 Common Terminology
             Criteria for Adverse Events (CTCAE version 4.03) with the exception of alopecia.

          7. 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

          8. Life expectancy of at least three months.

          9. Patients must be able to swallow and retain oral medication (intact tablet).

         10. Able to undergo all screening assessments outlined in the protocol following written
             informed consent.

         11. 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 10**9/L; platelets ≥
                  100 x 10**9/L.

               3. Serum bilirubin ≤ 1.5 x upper normal limit (UNL).

               4. 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.

         12. No known hepatitis B virus (not due to immunization), hepatitis C virus, human
             immunodeficiency virus Ι and -ΙΙ positive status.

        Exclusion Criteria:

          1. Male.

          2. Pregnancy or lactation or unwillingness to use adequate method of birth control.

          3. HER-2 positive disease status.

          4. 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.

          5. Neurological or psychiatric disorders which may influence understanding of study and
             informed consent procedures.

          6. Active or uncontrolled infection.

          7. Malabsorption syndrome, disease significantly affecting gastrointestinal function.

          8. Hypersensitivity to:

               1. paclitaxel

               2. ibuprofen or to more than one non-steroidal anti-inflammatory drug.

               3. medications belonging to the class of sulfonamides, such as sulfamethazine,
                  sulfamethoxazole, sulfasalazine, nimesulide or celecoxib.

          9. Presence of brain metastases (this does not include primary brain tumors) or
             leptomeningeal disease.