Wide Spectrum Micronutrients Supplementation in Patients With Cancer Related Fatigue During Neoadjuvant and Adjuvant Chemotherapy

SAMPLE SIZE DETERMINATION Considering the average of the BFI 5 in the placebo group and the average 3 in the treated group, with standard deviation of 3, power at 80% and alpha 0.05, we obtain 37 patients per group, thus a total of 74 patients. If a drop-out rate of 20% is fixed, 92 patients in total are obtained. So, a sample of 92 subjects would be sufficient.

DATA SAFETY MONITORING BOARD / DATA MONITORING COMMITTEE No Data Safety Monitoring Board (DSMB) or Data Monitoring Committee (DMC) will be convened for the evaluation of safety data during the study. However, the Network Italiano Cure di Supporto in Oncologia (NICSO) society will be in charge of the evaluation of safety information. In fact, a Scientific Committee, composed by NICSO members, has been established to support the Sponsor in the continuous evaluation of safety data emerging from the study.

MONITORING AND QUALITY ASSURANCE The study will be monitored by adequately qualified and trained clinical monitors. Before the start of the study, the CRO (Contract Research Organization) responsible for the study site has the task to assess the adequacy of the study site and the staff involved. After start, the study will be monitored to ensure the proper conduct of the clinical study.

DATA COLLECTION An Electronic Case Report Form (e-CRF) will be used for recording patient's study data.

The Investigator will maintain a list of all persons authorized to make entries and/or corrections on the CRFs. Each authorized person will be provided with a user-specific ID (Identification) protected by a renewable password. Data entries and corrections will be made only by the authorized persons. The e-CRF system will record date and time of any entry and /or correction and the user ID of the person making the entry/correction. The system will keep track of all old and new values (audit trail).

Inclusion criteria

• Females aged 18 or higher.
• Patients diagnosed with histologically confirmed breast cancer.
• Patients having done at least one cycle of neoadjuvant or adjuvant chemotherapy (independently from type of chemotherapy) and who are on active chemotherapy treatment throughout the duration of the study (*).
• Patients with ECOG performance status ≤1 at screening.
• Patients with cancer related fatigue of moderate-severe intensity (Numerical Rating Scale NRS > 4).
• Patients able to follow the recommendations on the physical exercise to do.
• Patients who accept to use adequate contraceptive methods, if they are of child-bearing potential.
• Patients willing and able to give signed informed consent and, in the opinion of the Investigator, to comply with the protocol tests and procedures.

(*)Examples of chemotheraphy and standard therapeutic regimens in the neoadjuvant and adjuvant phase in breast cancer and on the basis of the biological characteristics of the neoplasm are as follows:

Neoadjuvant Chemotheraphy

• Epirubicin + Cyclophosphamide, 3 cycles -> Taxol* weekly for 12 weeks;
• Epirubicin + Cyclophosphamide -> Pertuzumab + Trastuzumab (or Phesgo) 3 cycles + Taxol weekly for 12 weeks;
• Carboplatin + Taxol* weekly for 12 weeks -> Epirubicin + Cyclophosphamide;

• Taxol could be replaced by Taxotere

Adjuvant Chemotheraphy

• Epirubicin + Cyclophosphamide, 4 cycles, every 21 days -> Taxol weekly for 12 weeks
• Epirubicin + Cyclophosphamide, 4 cycles, every 14 days -> Taxol, 4 cycles every 14 days
• Epirubicin + Cyclophosphamide, 4 cycles every 21 days -> Taxol weekly + Trastuzumab with or without Pertuzumab for 1 year
• Taxotere + Cyclophosphamide, 4 cycles, every 21 days.

These lists are not to be considered exclusive

Exclusion criteria

• Women who are pregnant or breast-feeding.
• Neoplastic disease other than primary breast cancer.
• Had major surgery other than breast cancer surgery (central venous access placement and tumor biopsies are not considered major surgery) within 4 weeks prior to randomization. Patients must be well recovered from acute effects of surgery prior to screening. Patients should not have plans to undergo major surgical procedures during the treatment period.
• Patients with known or symptomatic metastases.
• Patients unable to readily swallow. Patients with severe gastrointestinal disease (including esophagitis, gastritis, malabsorption, or obstructive symptoms) or intractable or frequent vomiting are excluded.
• Patients with known or suspected allergy or hypersensitivity to the study products or any of their excipients.
• Patients with an active, uncontrolled infection.
• Patients with uncontrolled diabetes mellitus.
• Patients with untreated clinically relevant hypothyroidism.
• Patients with concomitant not-correctable alterations, present before chemotherapy, possible determinants of fatigue (NRS ≥ 4), such as anemia, not well controlled pain (NRS > 4), insomnia, electrolyte imbalance, dehydration, anorexia/cachexia, hepatic, renal or heart failure, adrenocortical failure, neurological deficit.
• Other clinical diagnosis, serious chronic diseases (renal failure with creatinine clearance <30 ml / min; liver failure, heart failure with NYHA -New York Heart Association- class> 2), ongoing or intercurrent illness that in the Investigator's opinion would prevent the patient's participation.
• Patients receiving opioids or corticosteroids (except as replacement therapy at physiological dose, in subjects with adrenal insufficiency or to prevent emesis on the chemotherapy day).
• Patients receiving parenteral nutrition (either total or partial).
• Use of other investigational drug(s) within 30 days before study entry or during the study.
• Triple negative patients in neoadjuvant treatment with Pembrolizumab.