To Assess Efficacy and Safety of Oral Reparixin in Patients With Fatigue and Locally Advanced / Metastatic Breast Cancer

Primary objective:

• 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, using FACITFatigue scale.

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 Patient Global Impression of Severity (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, or nab-paclitaxel or docetaxel) in adult patients with locally advanced or metastatic breast cancer.

This is a phase 2, multinational, multicenter, randomized, double-blind, placebo-controlled study. It will evenly randomize 68 evaluable men and women adult patients with CRF in locally advanced or metastatic breast cancer who are candidates to start single-agent taxane chemotherapy (paclitaxel, nab-paclitaxel or docetaxel). CRF will be assessed at baseline on a scale from 0 - 10 (with 10 being most severe), enrolling any patient who report a score of 1 - 6. Recruitment will be competitive among the study sites, until the planned number of patients is randomized. Patients will be assigned (1:1) to receive either oral reparixin treatment (1200 mg t.i.d. - treatment group) or masked placebo t.i.d. (control group). Randomization will be stratified by site and according to the type of chemotherapy (paclitaxel vs docetaxel vs nab-paclitaxel). Sparse blood samples will be collected in the whole population for reparixin (and metabolites), docetaxel, nab-paclitaxel, paclitaxel PK analysis. Reparixin or placebo will be administered for 16 weeks or until disease progression, withdrawal of consent or unacceptable toxicity, whichever occurs first. Following the completion of the treatment, or after premature discontinuation during the double-blind phase the patients will be followed up for safety assessments for an additional 30 days after last study therapy administration and will be followed for progressive disease and survival until twelve months after last enrolled subject off treatment, or until trial is terminated for other reasons, whatever occurs first.

Number of Patients Sixty-eight (68) evaluable adult patients with CRF with locally advanced or metastatic breast cancer who are candidates to receive single-agent taxane chemotherapy will be included in the study. Assuming that 10% of subjects will not be evaluable for primary analysis, a total of approximately 76 subjects is expected to be enrolled.

Eligibility Criteria:
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 HER2-negative breast cancer
* 4. Candidate to receive cycle 1 of treatment with single-agent taxane-based chemotherapy (paclitaxel, nab-paclitaxel, 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):

  1. Serum creatinine \< 140 μmol/L (\< 1.6 mg/dL) or creatinine clearance \> 60 mL/min
  2. Serum hemoglobin ≥ 11 g/dL; absolute neutrophil count ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L.
  3. Serum bilirubin ≤ upper limit of normal (ULN), except patients with Gilbert's syndrome.
  4. Serum Alanine aminotransferase (ALT), aspartate transaminase (AST) ≤ 1.5 x ULN
  5. Alkaline phosphatase ≤ 2.5 x ULN
  6. 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 of 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

Exclusion Criteria:

* 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 (SARSCoV- 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:

  1. untreated hypothyroidism
  2. pituitary disorder
  3. insomnia
  4. alcohol abuse
  5. uncontrolled pain as defined by pain intensity greater than 3 on a NRS (0-10)
  6. chronic \>G2 anemia
  7. uncontrolled cardiac disease or cardiovascular disorders
  8. acute infections
  9. major depressive disorder
  10. 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:

  1. intolerance or hypersensitivity to paclitaxel, nab-paclitaxel, docetaxel or any other concomitant drug used in the study
  2. intolerance or hypersensitivity to ibuprofen or to non-steroidal anti-inflammatory drug (NSAIDs)
  3. 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
  4. lactase deficiency, galactosaemia or glucose-galactose malabsorption
  5. 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 inability to pause these drugs during the study
* 17. Concurrent use of NSAIDs or inability to stop NSAIDs during the treatment period
* 18. Any contraindications to NSAIDs including but not limited to previous experience of asthma, urticaria, 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