Clinical trial NCT02370238: A Double-blind Study of Paclitaxel in Combination With Reparixin or Placebo for Metastatic Triple-Negative Breast Cancer
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Breast Cancer
Keywords: Triple negative metastatic breast cancer
Cancer Stem Cells
Lead sponsor: Dompé Farmaceutici S.p.A
Sponsor class: INDUSTRY
Collaborators: name: PRA Health Sciences
First posted: 2015-02-24
Enrollment: 194
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Baseline up to every 8 weeks until disease progression or death, whichever occurs first, up to 721 days
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Baseline until death due to any cause, up to 985 days
measure: Objective Response Rate (ORR)
timeFrame: Baseline up to every 8 weeks until documented disease progression, up to 56 months
measure: Median Progression-free Survival (mPFS)
timeFrame: At screening and every 8 weeks, up to 721 days
measure: Duration of Overall Response (DOR)
timeFrame: Baseline up to every 8 weeks until documented disease progression, up to 557 days
measure: Best Overall Response (BOR)
timeFrame: From the start of treatment, every 8 weeks, up to 56 months
measure: Number of Treatment-Emergent Adverse Events (TEAEs), Overall and by Grade
timeFrame: Throughout the study, until off-treatment visit (performed 14 to 28 days following the last dose of study drug), up to 985 days
measure: Serious AEs and Fatal AEs
timeFrame: Throughout the study, until off-treatment visit (performed 14 to 28 days following the last dose of study drug), up to 985 days.
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Southern Cancer Center
state: Alabama
city: Bakersfield
country: United States
facility: CBCC Global Research a Comprehensive Blood and Cancer Center
state: California
city: Daytona Beach
country: United States
facility: Florida Cancer Specialists
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Alpharetta
country: United States
facility: Atlanta Cancer Care
state: Georgia
city: Athens
country: United States
facility: Northside Hospital, Inc.-Georgia Cancer Specialists
state: Georgia
city: Atlanta
country: United States
facility: Atlanta Cancer Care
state: Georgia
city: Atlanta
country: United States
facility: Northside Hospital, Inc.
state: Georgia
city: Canton
country: United States
facility: Northside Hospital, Inc.-Georgia Cancer Specialists
state: Georgia
city: Conyers
country: United States
facility: Atlanta Cancer Care
state: Georgia
city: Cumming
country: United States
facility: Atlanta Cancer Care
state: Georgia
city: Decatur
country: United States
facility: Atlanta Cancer Care
state: Georgia
city: Decatur
country: United States
facility: Northside Hospital, Inc.-Georgia Cancer Specialists
state: Georgia
city: Jonesboro
country: United States
facility: Atlanta Cancer Care
state: Georgia
city: Macon
country: United States
facility: Northside Hospital, Inc.-Georgia Cancer Specialists
state: Georgia
city: Marietta
country: United States
facility: Northside Hospital, Inc.-Georgia Cancer Specialists
state: Georgia
city: Newnan
country: United States
facility: Southeastern Regional Medical Center
state: Georgia
city: Sandy Springs
country: United States
facility: Northside Hospital, Inc.-Georgia Cancer Specialists
state: Georgia
city: Chicago
country: United States
facility: Swedish Covenant
state: Illinois
city: Normal
country: United States
facility: Mid Illinois Hematology & Oncology Associates, Ltd.
state: Illinois
city: Ann Arbor
country: United States
facility: University of Michigan Cancer Center
state: Michigan
city: Morristown
country: United States
facility: Summit Medical Group
state: New Jersey
city: Sparta
country: United States
facility: Regional Cancer Care Associates
state: New Jersey
city: Cary
country: United States
facility: Waverly Hematology Oncology
state: North Carolina
city: Dunmore
country: United States
facility: Hematology and Oncology Associates of Northeast PA
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Chattanooga
country: United States
facility: Tennessee Oncology PLLC
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: The Methodist Hospital
state: Texas
city: Bellevue
country: United States
facility: Overlake Medical Center
state: Washington
city: Appleton
country: United States
facility: Fox Valley Hematology and Oncology, SC
state: Wisconsin
city: Brasschaat
country: Belgium
facility: Algemeen Ziekenhuis Klina
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint- LUC UCL
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Mons
country: Belgium
facility: CHU Ambroise Paré
city: Namur
country: Belgium
facility: AZ St Elisabeth
city: Brno
country: Czechia
facility: Masaryk Memorial Cancer Institute
city: Horovice
country: Czechia
facility: Nemocnice Horovice a.s.
city: Hradec Králové
country: Czechia
facility: Fakultni nemocnice Hradec Králové
city: Prague 2
country: Czechia
facility: Onkologická klinika VFN a 1.LF UK
city: Praha 10
country: Czechia
facility: Fakultní nemocnice Královské Vinohrady
city: Praha 5
country: Czechia
facility: Fakultní nemocnice v Motole, Onkologická klinika 2. LF UK a FN Motol
city: Zlin
country: Czechia
facility: Krajská nemocnice T.Bati, a. s.
city: Angers
country: France
facility: Centre Paul Papin
city: Caen
country: France
facility: Centre François Baclesse
city: La Roche sur Yon Cedex 9
country: France
facility: Centre hospitalier de Saint-Brieuc, Yves Le Foll
city: Limoges
country: France
facility: Centre Hospitalier Universitaire (CHU) De Limoges - Hopital Dupuytren
city: Marseille cedex 9
country: France
facility: Institut Paoli Calmettes
city: Nice Cedex 2
country: France
facility: Centre Antoine Lacassagne
city: Paris Cedex 15
country: France
facility: Hôpital Européen Georges Pompidou
city: Saint Herblain cedex
country: France
facility: Medicale Centre René Gauducheau
city: Brindisi
country: Italy
facility: Ospedale "Di Summa-Perrino"
city: Cagliari
country: Italy
facility: Azienda Ospedaliero-Universitaria
city: Catania
country: Italy
facility: Azienda Ospedaliero - Universitaria, Policlinico Vittorio Emanuele
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
city: Mestre
country: Italy
facility: Ospedale dell'Angelo
city: Milan
country: Italy
facility: Istituto Europeo di Oncologia
city: Milan
country: Italy
facility: Azienda Ospedaliera, Ospedale San Carlo Borromeo
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico S. Matteo
city: Pesaro
country: Italy
facility: Azienda Ospedaliera Ospedali Riuniti Marche Nord
city: Prato
country: Italy
facility: Nuovo Ospedale
city: Udine
country: Italy
facility: Azienda Opspedaliero Universitaria Santa Maria della Misericordia
city: Venezia
country: Italy
facility: Ospedale SS Giovanni e Paolo
city: Bialystok
country: Poland
facility: Bialostockie Centrum Onkologii im. Marii Sklodowskiej - Curie
city: Gdansk
country: Poland
facility: Wojewódzkie Centrum Onkologii
city: Lublin
country: Poland
facility: Centrum Onkologii Ziemi Lubelskiej im. sw. Jana z Dukli
city: Poznan
country: Poland
facility: Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu
city: Rzeszów
country: Poland
facility: Mrukmed. Lekarz Beata Madej Mruk i Partner. Spólka Partnerska Oddzial nr 1 w Rzeszowie
city: Warsaw
country: Poland
facility: Magodent Sp. z o. o.
city: La Coruña
country: Spain
facility: Centro Oncológico Regional de Galicia, Servicio de Oncologia Medica
state: Galizia
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: La Coruña
country: Spain
facility: Complejo Hospitalario Universitario La Coruña
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Centro Integral Oncológico Clara Campal, Hospital de Madrid Norte-San Chinarro
city: Vigo
country: Spain
facility: C. Hospital Xeral-Cies
Study officials:
affiliation: FASCOFox Chase Cancer Center
name: Lori J Goldstein, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schott AF, Goldstein LJ, Cristofanilli M, Ruffini PA, McCanna S, Reuben JM, Perez RP, Kato G, Wicha M. Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2-Negative Metastatic Breast Cancer. Clin Cancer Res. 2017 Sep 15;23(18):5358-5365. doi: 10.1158/1078-0432.CCR-16-2748. Epub 2017 May 24.