| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cancer related fatigue in patients with locally advanced or metastatic breast cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Cancer related fatigue in patients with breast cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10082262 |
| E.1.2 | Term | Chemotherapy fatigue |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of the study is:
•To assess the efficacy of reparixin compared to placebo in limiting CRF in adult patients with locally advanced or metastatic breast cancer undergoing single-agent taxane chemotherapy (paclitaxel, nab-paclitaxel or docetaxel), using FACIT-Fatigue scale.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
•To evaluate change in Quality of Life in the two treatment arms.
•To assess the percentage of patients treated with reparixin compared to placebo delaying and discontinuing chemotherapy.
•To assess PGI-S score and Patient Global Impression of Change (PGI-C) score associated with reparixin compared to placebo.
•To assess the effect of reparixin compared to placebo on ECOG PS.
•To assess the effects of reparixin vs placebo on Objective Response Rate (ORR), Progression Free Survival (PFS), Overall Survival (OS).
The safety objective is:
•To assess the safety and tolerability of reparixin in adult patients undergoing taxane-containing chemotherapy
The pharmacokinetic (PK) objective is:
•To define the PK profile of orally administered reparixin, its metabolites (DF2243Y, DF2188Y, ibuprofen) and concomitant antineoplastic agents (paclitaxel, nab-paclitaxel or docetaxel) in adult patients with locally advanced or metastatic breast cancer.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be eligible for inclusion into this study, each patient must fulfil the following inclusion criteria:
1.Provide written informed consent before the initiation of any study-specific procedures
2.Male or female≥18 years of age
3.Pathologically documented locally advanced (not amenable to surgical resection) or metastatic HER-2 negative breast cancer
4.Candidate to receive cycle 1 of treatment with single-agent taxane chemotherapy (paclitaxel, nab-paclitaxel or docetaxel)
5.CRF score from 1 to 6 on a numeric rating scale (NRS) from 0 to 10, where 0 = no fatigue, 10 = worst possible fatigue, during the previous 24 hours and lasting for a minimum of 4 days
6.Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2
7.Life expectancy of at least 6 months as estimated by the investigator
8.Able to swallow and retain oral medication (intact tablet)
9.Adequate organ function (defined by the following parameters):
a) Serum creatinine < 140 µmol/L (< 1.6 mg/dL) or creatinine clearance > 60 mL/min
b) Serum hemoglobin ≥ 11 g/dL; absolute neutrophil count ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L
c) Serum bilirubin ≤ upper limit of normal (ULN), except patients with Gilbert’s syndrome
d) Serum Alanine aminotransferase (ALT), aspartate transaminase (AST) ≤ 1.5 x ULN
e) Alkaline phosphatase ≤ 2.5 x ULN
f) prothrombin time (PT) or activated partial thromboplastin time (aPTT, PTT) ≤ ULN
10.No known hepatitis B virus (not due to immunization), hepatitis C virus, human immunodeficiency virus-I and -II positive status
11.If a female with childbearing potential, have a negative serum β-human chorionic gonadotropin (β-hCG) serum pregnancy test and use a highly effective method to avoid pregnancy for the duration of the trial and for at least 6 months after completion of docetaxel, paclitaxel or nab-paclitaxel therapy. Males of reproductive potential should use effective contraception during treatment and for 6 months after the last dose of docetaxel, paclitaxel or nab-paclitaxel
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| E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria are NOT eligible for inclusion in the study:
1.More than 1 prior systemic chemotherapy for advanced disease. Patients may have received hormone therapy and biological therapy (e.g. CDK4/6 inhibitors) either alone or in combination
2.Malabsorption syndrome or disease significantly affecting gastrointestinal function including but not limited to gastrectomy or gastric outlet obstruction
3.History or evidence of neurological or psychiatric disorder or any other concurrent medical condition or disease that, in the opinion of the investigator or Medical Monitor may influence understanding of study and informed consent procedures, would pose a risk to subject safety or would interfere with the study evaluation, procedures or completion
4.Positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigenic test performed through nasal swab
5.Treatment with any investigational agent within at least 28 days or 5 half-lives (whatever is shorter) prior to Visit 1, recovered from previous treatment toxicity to Grade1 or better
6.Brain metastases that are untreated or symptomatic, or require any radiation, surgery, or continued steroid therapy to control symptoms from brain metastases
7.Treatment with oral morphine greater than 60 mg a day or equivalent
8.Other causes of fatigue, including but not restricted to:
a) untreated hypothyroidism
b) pituitary disorder
c) insomnia
d) alcohol abuse
e) uncontrolled pain as defined by pain intensity greater than 3 on a NRS (0-10)
f) chronic >G2 anemia
g) uncontrolled cardiac disease or cardiovascular disorders
h) acute infections
i) major depressive disorder
j) uncontrolled neurological disorders
9.Concomitant use of other medications/dietary supplements for fatigue
10.Concomitant use of cannabidiol (CBD) or Tetrahydrocannabinol (THC)
11.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
12.Patients who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
13.Patients who are employees of the sponsor or investigator or otherwise dependent on them
14.History of :
i. intolerance or hypersensitivity to Paclitaxel, nab-paclitaxel, docetaxel or any other concomitant drug used in the study
ii.intolerance or hypersensitivity to ibuprofen or to non-steroidal anti-inflammatory drug
iii.intolerance or hypersensitivity to more than one medication belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib; hypersensitivity to sulphanilamide antibiotics alone (e.g. sulfamethoxazole) does not qualify for exclusion
iv. lactase deficiency, galactosaemia or glucose-galactose malabsorption
v. documented allergic reaction or severe reaction of any kind to dairy products
15.Pregnancy or lactation or unwillingness to use adequate method of birth control. Effective contraceptive measures include intrauterine device (IUD), bilateral tubal occlusion, vasectomised partner, sexual abstinence
16.Concomitant use of ibuprofen or CYP2C9 inhibitors/inducers and unability to pause these drugs during the study
17.Concurrent use of NSAIDs or inability to stop NSAIDs during the treatment process
18.Any contraindications to NSAIDs including but not limites to previous experience of asthma, urticarial, or allergic-type reactions after taking aspirin or other NSAIDS
19.A history of gastrointestinal bleeding or perforation related to previous NSAIDs therapy or an active or history of recurrent peptic ulcer/haemorrhage, coagulation disturbances |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Assessment
Change from baseline in FACIT-F score [Time frame: week 16]
FACIT-F will be administered weekly. It consists of 13 items (that are responded to by affirming one of five Likert-type response categories (‘‘not at all,’’ ‘‘a little bit,’’ ‘‘somewhat,’’ ‘‘quite a bit,’’ and ‘‘very much’’). The instrument yields a summed total score ranging between 0 and 52 (52 = no fatigue at all).
Safety endpoints
•Physical examination (Body weight, height, body surface area and assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular system, abdomen, lymph nodes and extremities) [time frame: day 1 of each chemotherapy cycle, off treatment visit (or withdrawal)]
•Vital signs (blood pressure heart rate and Body Temperature) [time frame: day 1 of each chemotherapy cycle, off treatment visit (or withdrawal)]
•Safety Laboratory Tests (hematocrit, hemoglobin, red blood cells, platelets, white blood cells, differential white blood cells count, sodium, potassium, calcium, serum creatinine, urea, serum albumin, total bilirubin, fractionated bilirubin, ALT, AST, ALP) [time frame: day 1 of each chemotherapy cycle, off treatment visit (or withdrawal)]
•Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) [time frame: throughout the study]
PK endpoints
Plasma levels (data permitting) of reparixin, unbound reparixin and its metabolites (DF2243Y, DF2188Y, Ibuprofen), taxanes (paclitaxel,nab-paclitaxel or docetaxel) will be present for treatment cycles and doses and compared by cycles.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| According to the protocol |
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| E.5.2 | Secondary end point(s) |
2.Secondary Efficacy Assessment
•Change from baseline in FACIT-F score [Time frame: week 4, 8 and 12]
•EQ-5D-5L score [Time frame: day 1 of each 21- or 28-day cycle, off treatment visit (or withdrawal)]
The EQ-5D consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient’s health state. The EQ VAS records the patient’s self-rated health on a vertical visual analogue scale, where the endpoints are labelled ‘The best health you can imagine’ and ‘The worst health you can imagine’. The VAS can be used as a quantitative measure of health outcome that reflect the patient’s own judgement.
•Patient Global Impression of Severity (PGI-S) score [Time frame: day 1 of each 21- or 28-day cycle, off treatment visit (or withdrawal)]
The PGI-S is a single item designed to capture subject’s perception of overall symptom severity at the time of completion on a 5-point categorical response scale: “Please choose the response below that best describes the severity of your fatigue over the past week” and is scored from 1 to 5, with 1 indicating “None”, 2 “Mild”, 3 “Moderate”, 4 “Severe”, 5 “Very Severe”
•Patient Global Impression of Change (PGI-C) score [Time frame: day 1 of each 21- or 28-day cycle except for cycle 1 , off treatment visit (or withdrawal)]
The PGI-C is a single item designed to capture the subject’s perception of change in their overall symptom severity from baseline until the time of completion. Change in severity is captured using a 5-point scale: “Please choose the response below that best describes the overall change in your fatigue since you started receiving the taxane-based chemotherapy” and is scored from 1 to 5, with 1 indicating “Much better”, 2 “A little better”, 3 “No change”, 4 “A little worse”, 5 “Much worse”
•Proportion of patients delaying next administration of chemotherapy due to CRF [Time frame: throughout the study]
•Proportion of patients discontinuing chemotherapy due to CRF [Time frame: throughout the study]
•Change in ECOG PS [Time frame: baseline, day 1 of each 21- or 28-day chemotherapy cycle, off treatment visit (or withdrawal)]
•Overall Response Rate (ORR) [Time Frame: Through study treatment]
ORR is defined as the proportion of patients with best overall response of CR or PR) according to RECIST 1.1.
•Progression Free Survival (PFS) [Time Frame: Up to 12 months post-treatment]
PFS is defined as the time from the date of randomization until the date of the first documented progression or death due to any cause. PFS will be assessed based on local investigator assessment per RECIST 1.1.
•Overall Survival (OS) Time Frame: [Up to 12 months post-reparixin discontinuation]
OS is defined as the time from date of first administration of study treatment until date of death due to any cause
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| According to the protocol |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Germany |
| Italy |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The date of the last procedure of the last patient. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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