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)
Overview
- Phase
- Phase 2
- Intervention
- paclitaxel
- Conditions
- Metastatic Breast Cancer
- Sponsor
- Dompé Farmaceutici S.p.A
- Enrollment
- 194
- Locations
- 66
- Primary Endpoint
- Progression Free Survival (PFS)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief 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).
Detailed Description
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.
Investigators
Eligibility Criteria
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
- •Patients whose metastatic disease is TNBC are eligible even when their primary tumor expressed hormone receptors and/or HER
- •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.
- •Zubrod (Eastern Co-operative Oncology Group \[ECOG\]) Performance Status (PS) of 0-
- •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.
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:
- •ibuprofen or to more than one non-steroidal anti-inflammatory drug.
Arms & Interventions
paclitaxel+reparixin
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
Intervention: paclitaxel
paclitaxel+reparixin
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
Intervention: Reparixin
paclitaxel+placebo
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
Intervention: paclitaxel
paclitaxel+placebo
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
Intervention: placebo
Outcomes
Primary Outcomes
Progression Free Survival (PFS)
Time Frame: Baseline up to every 8 weeks until disease progression or death, whichever occurs first, up to 721 days
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.
Secondary Outcomes
- Best Overall Response (BOR)(From the start of treatment, every 8 weeks, up to 56 months)
- Number of Treatment-Emergent Adverse Events (TEAEs), Overall and by Grade(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(Throughout the study, until off-treatment visit (performed 14 to 28 days following the last dose of study drug), up to 985 days.)
- Overall Survival (OS)(Baseline until death due to any cause, up to 985 days)
- Objective Response Rate (ORR)(Baseline up to every 8 weeks until documented disease progression, up to 56 months)
- Median Progression-free Survival (mPFS)(At screening and every 8 weeks, up to 721 days)
- Duration of Overall Response (DOR)(Baseline up to every 8 weeks until documented disease progression, up to 557 days)