A Double-blind Study of Paclitaxel in Combination With Reparixin or Placebo for Metastatic Triple-Negative Breast Cancer

Study Overview
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Brief Summary
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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).

Detailed Description
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The study is a two arm, phase 2 study to evaluate the efficacy of the combination of paclitaxel and reparixin compared to paclitaxel and placebo in metastatic TNBC patients. In the study two groups There were two groups: Group 1: paclitaxel 80 mg/m2 intravenous (i.v.) (Days 1, 8, and 15 of 28-day cycle) + reparixin oral tablets 1200 mg three times a day (t.i.d.) continuing from Day 1 to Day 21. Group 2: paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15 of 28-day cycle) + placebo oral tablets 1200 mg t.i.d. continuing from Day 1 to Day 21. Study drug (reparixin/placebo) was administered with water prior to the start of the i.v. paclitaxel infusion on Cycle 1, Day 1 and then administered approximately every eight hours (six to ten hours) for 21 consecutive days during each cycle with seven days off-treatment between each cycle. It was preferable that reparixin was taken with food. However, if the patient was unable to eat, study drug was allowed to be administered. When in combination with paclitaxel (Day 1, 8 and 15 of each cycle), reparixin or placebo was administered every approximately eight hours with about 250 mL water and a light meal or snack. Paclitaxel was administered in combination with study drug (reparixin/placebo) as an i.v. infusion on Days 1, 8 and 15 of each 28-day cycle. On Cycle 1, Day 1, paclitaxel was administered at the clinic after the administration of study drug (reparixin/placebo). From that point forward, study drug (reparixin/placebo) was self-administered t.i.d. for 21 days. Combination treatment (three weeks on and one week off) continued until PD according to RECIST criteria version 1.1, withdrawal of consent or unacceptable toxicity, whichever occurred first. The next clinic visits were on Days 8 and 15 when a paclitaxel infusion was administered to the patient. The patients returned to the clinic again on Day 29/Day 1 of the next cycle. Tumor response and/or progression assessments were performed and documented every eight weeks according to RECIST criteria version 1.1. Metastatic tissue samples were analyzed for evaluation of CD24-CD44+ and aldehyde dehydrogenase positive (ALDH+) CSCs.

Official Title
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A Randomized, Double-blind, Placebo-controlled Phase 2 Study of Paclitaxel in Combination With Reparixin Compared to Paclitaxel Alone as Front-line Therapy for Metastatic Triple- Negative Breast Cancer (FRIDA)

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: paclitaxel
* Drug: Reparixin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female aged ≥ 18 years. 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. 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 Patients with at least one baseline measurable lesion according to RECIST criteria version 1.1. Zubrod (Eastern Co-operative Oncology Group [ECOG]) Performance Status (PS) of 0-1. 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. Adequate organ function (defined by the following parameters): Serum creatinine < 140 μmol/L (< 1.6 mg/dL) or creatinine clearance > 60 mL/min. Serum hemoglobin ≥ 9 g/dL; absolute neutrophil count ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L. Serum bilirubin ≤ 1.5 x upper normal limit (UNL) except patients with Gilbert's syndrome 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. No history or evidence by CT scan or MRI, of brain metastases or leptomeningeal disease. No known hepatitis B virus (not due to immunization), hepatitis C virus, human immunodeficiency virus-I and -II positive status. Dated and signed IEC/IRB-approved informed consent. Exclusion Criteria: 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. Less than four weeks since last radiotherapy (excluding palliative radiotherapy). Pregnancy or lactation or unwillingness to use adequate method of birth control. 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. G>1 pre-existing peripheral neuropathy 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 Hypersensitivity to: paclitaxel ibuprofen or to more than one non-steroidal anti-inflammatory drug. medications belonging to the class of sulfonamides, with the exception of sulfanilamides (e.g., sulfamethoxazole).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: paclitaxel+reparixin<br>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 | Drug: paclitaxel<br>* paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15)<br>Drug: Reparixin<br>* reparixin oral tablets 1200 mg t.i.d. continuing from D 1 to Day 21 of 28-day cycle<br>* Other names: REP;|
| Active Comparator: paclitaxel+placebo<br>paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15) + placebo oral tablets 1200 mg t.i.d. continuing from D 1 to Day 21 of 28-day cycle | Drug: paclitaxel<br>* paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15)<br>Drug: placebo<br>* placebo oral tablets 1200 mg t.i.d. continuing from D 1 to Day 21 of 28-day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS was defined as the number of days between the date of randomization and the date of clinical disease progression, according to RECIST criteria version 1.1, as assessed by Independent Radiology Review, or to death due to any cause, whichever occurred first. Patients must have completed at least one course of treatment and performed at least one disease assessment to be considered evaluable for response. | Baseline up to every 8 weeks until disease progression or death, whichever occurs first, up to 721 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from randomization until death due to any cause. For patients who did not die, time of death was censored at the date of last contact. Patients must have completed at least one course of treatment and performed at least one disease assessment to be considered evaluable for response. | Baseline until death due to any cause, up to 985 days | 
| Objective Response Rate (ORR) | The ORR was defined as the percentage of patients achieving CR or PR in the Evaluable Population. The response rate was calculated from the independently reviewed assessment best response. In case of PR or CR, only confirmed cases were considered to be responses. Complete Response (CR) = Disappearance of all target lesions; Partial Response (PR) = >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Patients with unknown or missing response, including response of not all evaluated or unable to determine, were treated as non-responders; i.e., they were included in the denominator when calculating the percentages. Patients must have completed at least one course of treatment and performed at least one disease assessment to be considered evaluable for response. | Baseline up to every 8 weeks until documented disease progression, up to 56 months | 
| Median Progression-free Survival (mPFS) | PFS was defined as the time from randomization to first documentation of disease progression, according to RECIST criteria version 1.1, as assessed by Independent Radiology Review, or to death due to any cause, whichever occurred first. For each treatment group, the Kaplan-Meier estimates for the median PFS time, the first and third quartiles were presented, along with approximate 95% confidence intervals if there were a sufficient number of progressions or deaths. Patients must have completed at least one course of treatment and performed at least one disease assessment to be considered evaluable for response. | At screening and every 8 weeks, up to 721 days | 
| Duration of Overall Response (DOR) | Duration of overall response (DOR) in days for the investigator assessments is measured from the time response criteria are first met for CR or PR (whichever is first recorded on the Disease Response page on the CRF) until either death or the first date that recurrent or PD is objectively documented (on the Disease Response p. on the CRF or the Follow-Up Disease Evaluation page indicates disease progression and there is supporting information in the Disease Status pages) per RECIST version 1.1. Complete Response (CR) = Disappearance of all target lesions; Partial Response (PR) = >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. If a patient is lost to follow-up with no documentation of PD, DOR was censored at the last evaluable tumor assessment. DOR was calculated only for responding patients (PR or CR) as recorded on the CRF page Disease Response based upon the RECIST version 1.1. Duration of overall response wa | Baseline up to every 8 weeks until documented disease progression, up to 557 days | 
| Best Overall Response (BOR) | BOR is defined as the best response among all overall responses (in the order complete response [CR], partial response [PR], stable disease [SD], and progressive disease [PD]) recorded as an independent review response from the start of reparixin or placebo until disease progression/recurrence or end of treatment, or death, whichever comes first. The status of BOR of PR or CR needs to be confirmed by repeat tumor assessment within no less than 4 weeks according to RECIST version 1.1. Complete Response (CR) = Disappearance of all target lesions; Partial Response (PR) = >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. If the status of CR or PR cannot be confirmed by repeat tumor assessment, the best overall response of unconfirmed CR and PR will be PR and SD, respectively. Patients must have completed at least one course of treatment and performed at least one disease assessment to be considered evaluable for response. | From the start of treatment, every 8 weeks, up to 56 months | 
| Number of Treatment-Emergent Adverse Events (TEAEs), Overall and by Grade | Treatment-emergent adverse events (TEAEs) are those which first occur or increase in severity or relationship to study drug after the first dose of study drug and before 30 days after the last dose of study treatment, reparixin/placebo. In the case of missing or partial dates, any AE that could have started on or after first dose date was assumed to be treatment-emergent. In the case of missing or partial dates, imputed dates (see section 10.1 AE date imputation) were used. | Throughout the study, until off-treatment visit (performed 14 to 28 days following the last dose of study drug), up to 985 days | 
| Serious AEs and Fatal AEs | A serious adverse event (SAE) in human drug trials is defined as any untoward medical occurrence that at any dose - results in death, (fatal) - is life-threatening - requires inpatient hospitalization or causes prolongation of existing hospitalization - results in persistent or significant disability/incapacity, - may have caused a congenital anomaly/birth defect, or - requires intervention to prevent permanent impairment or damage. | Throughout the study, until off-treatment visit (performed 14 to 28 days following the last dose of study drug), up to 985 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Triple negative metastatic breast cancer, Cancer Stem Cells