A Double-blind Study of Paclitaxel in Combination With Reparixin or Placebo for Metastatic Triple-Negative Breast Cancer
Condition: Metastatic Breast Cancer
MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms
Intervention: paclitaxel; Reparixin; placebo
Intervention description: paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15); reparixin oral tablets 1200 mg t.i.d. continuing from D 1 to Day 21 of 28-day cycle; placebo oral tablets 1200 mg t.i.d. continuing from D 1 to Day 21 of 28-day cycle
Intervention MeSH terms: Paclitaxel
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 194.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Triple negative metastatic breast cancer; Cancer Stem Cells

Summary:

      The Objectives of this study:

      The primary objective of the study was to evaluate progression-free survival (PFS) (defined
      as the number of days between the date of randomization and the date of clinical disease
      progression (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria
      version 1.1, as assessed by Independent Radiology Review, or death for any cause, whichever
      occured first) in patients with metastatic triple-negative breast cancer (TNBC) treated with
      the combination of paclitaxel and orally administered reparixin compared to paclitaxel alone.

      The secondary objectives were:

        -  To determine overall survival (OS).

        -  To evaluate objective response rates (ORR).

        -  To determine median PFS (mPFS).

        -  To assess the safety of the combination of paclitaxel and orally administered reparixin
           (referred to as combination treatment).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Female aged ≥ 18 years.

          2. Patients with pathologically documented metastatic triple negative breast cancer
             (TNBC), eligible for treatment with paclitaxel. Paraffin-embedded tissue must be
             available from metastatic sites, if reasonably accessible, or from the primary tumor,
             to confirm the diagnosis of TNBC and for correlative studies (only on metastatic
             tissue). Fifteen slides can be obtained if the full block is not available to be sent
             or released.

             TNBC will be defined as breast cancer with <1% ER+ and <1% PgR+ cells, and HER2
             immunohistochemistry score of 0 or 1+ and/or in situ hybridization (ISH) with HER2
             gene copy number <4 or a ratio of less than 2 between HER2 gene copy number and
             centromere of chromosome 17. Patients whose metastatic disease is TNBC are eligible
             even when their primary tumor expressed hormone receptors and/or HER2.

          3. Patients must be newly diagnosed metastatic or must have relapsed following a prior
             (neo)adjuvant chemotherapy regimen. If a taxane (i.e., paclitaxel or docetaxel) was
             administered as part of the (neo)adjuvant regimen, PD must have occurred > 12 months
             from the end of previous (neo)adjuvant treatment. For non-taxane (neo)adjuvant
             regimen, PD must have occurred > 6 months from the end of previous (neo)adjuvant
             treatment

          4. Patients with at least one baseline measurable lesion according to RECIST criteria
             version 1.1.

          5. Zubrod (Eastern Co-operative Oncology Group [ECOG]) Performance Status (PS) of 0-1.

          6. Life expectancy of at least three months.

          7. Patients must be able to swallow and retain oral medication (intact tablet).

          8. Able to undergo all screening assessments outlined in the protocol.

          9. Adequate organ function (defined by the following parameters):

               1. Serum creatinine < 140 μmol/L (< 1.6 mg/dL) 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 ≤ 1.5 x upper normal limit (UNL) except patients with Gilbert's
                  syndrome

               4. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x
                  UNL but ≤ 5.0 x UNL in case of liver metastases; alkaline phosphatase (ALP) ≤ UNL
                  but i) ≤ 2.5 x UNL in case of liver metastases and ii) ≤ 5 UNL in case of bone
                  metastases; albumin ≥ 2.5 g/dl.

         10. No history or evidence by CT scan or MRI, of brain metastases or leptomeningeal
             disease.

         11. No known hepatitis B virus (not due to immunization), hepatitis C virus, human
             immunodeficiency virus-I and -II positive status.

         12. Dated and signed IEC/IRB-approved informed consent.

        Exclusion Criteria:

          1. Prior therapy for metastatic TNBC (chemotherapy, hormone therapy or biological
             therapy), Patients may receive bisphosphonates and other therapies to treat bone
             metastases, however if used, bone lesions will not be considered as measurable
             disease.

          2. Less than four weeks since last radiotherapy (excluding palliative radiotherapy).

          3. Pregnancy or lactation or unwillingness to use adequate method of birth control.

          4. Neurological or psychiatric disorders which may influence understanding of study and
             informed consent procedures.

          5. Active or uncontrolled infection.

          6. Malabsorption syndrome, disease significantly affecting gastrointestinal function.

          7. G>1 pre-existing peripheral neuropathy

          8. Any other invasive malignancy from which the patient has been disease-free for less
             than 5 years with the exception of curatively treated basal or squamous cell skin
             cancer

          9. Hypersensitivity to:

               1. paclitaxel

               2. ibuprofen or to more than one non-steroidal anti-inflammatory drug.

               3. medications belonging to the class of sulfonamides, with the exception of
                  sulfanilamides (e.g., sulfamethoxazole).